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+{"text": "Aim of this study was to biomechanically compare two different acetabular cup fixation constructs in terms of fracture fixation for displaced acetabular fractures involving the anterior column with hemitransverse fracture under partial and full weight-bearing conditions.n\u2009=\u20096) and primary THA with Burch\u2013Schneider reinforcement cage (BSRC) (n\u2009=\u20096).Two different reinforcement rings designed as cages for primary THA were biomechanically tested in terms of managing a complex acetabular fracture. Single-leg stance cyclic loading was performed to assess fracture gap movement and fragment rotation. Twelve hemi pelvis Sawbones were divided into two groups: primary THA with acetabulum roof reinforcement plate (ARRP) (p\u2009=\u20090.035) of the os ilium to os ischii gap compared to BSRC. Fracture gap movements between the os ilium and spina iliaca fragments were significantly reduced by 76% (p\u2009=\u20090.048) for ARRP in contrast to BSRC. The ARRP group also demonstrated significantly less movement in the fracture gaps os ischii to quadrilateral plate  and quadrilateral plate to spina iliaca . Significantly less rotational movement of the quadrilateral plate to the os ilium was exhibited by the ARRP group (p\u2009=\u20090.015).During loading under partial weight-bearing (250\u00a0N) fracture gap movement tended to be larger in the BSRC group as compared to the ARRP group. Under full weight-bearing conditions, the ARRP showed 60% significantly less motion (The presented acetabulum roof-reinforcement plate (ARRP) provides stable conditions at the acetabular component with adequate stabilization of a displaced acetabular fracture. The incidence of anterior column fractures combined with hemitransverse (ACPHT) fractures tremendously increases due to an aging society. Such fractures involve displacement of the quadrilateral plate (QLP) and are often associated with a higher degree of comminution and impaction in patients with osteoporotic bone quality , 25, 42.In the past, only a few biomechanical studies have analyzed the stability of acetabular fracture reconstruction methods underlining the necessity of stable osteosynthesis to prevent re-displacement of the QLP , 24. HowThis study compares two different reinforcement cages for displaced acetabular fractures providing fixation of the acetabular roof. Designed as a defect implant for revision surgery in hip bone defects, the Burch\u2013Schneider reinforcement cage (BSRC) aims to restore the anatomical rotational center of the hip . The fixThe study was conducted using synthetic hemi pelvises . A CT scan of one synthetic hemi pelvis bone was performed and DICOM data of the scan was segmented. After data segmentation, a negative of the prepared hemi pelvis model was used to create a virtual sawing template. This template was 3D printed with PolyJet technology. Using this template, an anterior column combined with posterior hemitransverse (ACPHT) fracture with additional break out of the quadrilateral plate Fig.\u00a0 was reprPrior to testing, specimens were attached to an artificial sacrum that consisted of a polyurethane cast  which was used to create an equal load distribution between the servohydraulic testing machine and synthetic bone, mimicking the sacroiliac joint. For correct placing of the sacrum substitute, anatomical correlations and geometric dimensions of a fourth generation Sawbones sacrum  corresponding to the hemi pelvis were used for manufacturing. The connection between sacrum and hemi pelvis was secured using three threaded rods (M8) with corresponding nuts. The artificial sacrum was reused for each test sample.The bones were randomly assigned to one of two methods of primary THA Fig.\u00a0: ARRP imBiomechanical testing was conducted using an Instron 8874 servohydraulic testing machine . A single-leg stance model Fig.\u00a0 was creaIn-vivo hip contact force angles resulting during single leg stance were obtained as according to Bergmann et al. . Loadingos ilium were determined and statistically analyzed . For statistical analysis, a Student\u2019s t test for independent samples was performed to identify differences between the two groups. Distribution for normality was checked with Shapiron\u2013Wilk test. Results are presented as mean value\u2009\u00b1\u2009standard deviation (SD).Fracture gap movements and quadrilateral plate fragment rotation with respect to the os ilium and os ischii , and the os ilium and spina iliaca . In addition, the ARRP group showed significantly less fracture gap movement between the quadrilateral plate the spina iliaca .Fracture gap movements were analyzed after 1000 cycles under partial weight-bearing 250\u00a0N) and after 31,000 cycles of loading under full weight-bearing  and the os ilium and spina iliaca fracture gap . ARRP also demonstrated significantly less movement in the fracture gaps os ischii to quadrilateral plate  and quadrilateral plate to spina iliaca . Although ARRP fixation showed less motion in the fracture gaps os ilium to quadrilateral plate (p\u2009=\u20090.318) and os ischii to os pubis (p\u2009=\u20090.065), these differences were not statistically significant.Under full weight-bearing conditions movements between fracture gaps were always larger for the BSRC fixation as compared to the ARRP fixation. The improvements in fixation stability due to the ARRP fixation were most relevant for the os ilium (Table p\u2009=\u20090.771) was similar for ARRP and BSRC. Nevertheless, the ARRP demonstrated less rotation around the horizontal (p\u2009=\u20090.199) and the longitudinal axis (p\u2009=\u20090.135). Under full weight-bearing conditions fragment rotation around the sagittal axis was approximately three times larger when a BSRC was used instead of an ARRP (p\u2009=\u20090.015). The rotations around the horizontal (p\u2009=\u20090.071) and longitudinal axis (p\u2009=\u20090.070) tended to be larger for BSRC as compared to ARRP.The rotation of the quadrilateral plate was assessed with respect to the um Table . After 1This biomechanical study compared two different reinforcement techniques for severely displaced acetabular fractures typically seen in geriatric patients. The acetabulum roof-reinforcement plate (ARRP) which employs a special cage fixation at the intact iliac bone in combination with fixed-angle screws demonstrated a consistently improved biomechanical stability compared to the Burch\u2013Schneider reinforcement cage (BSRC) technique. Even under unrestricted partial and full weight-bearing conditions, the ARRP resulted in interfragmentary fracture movements of typically less than 1\u00a0mm and can thus provide a biomechanically sound fracture healing environment.Displaced acetabular fractures with disruption of the quadrilateral plate frequently result in post-traumatic osteoarthrosis and long-term surgery outcome is directly related to accuracy of fracture reduction , 27. AnaThe indication for primary THA is often discussed and there is no need for primary THA in general cases . Howeveros ilium to os ischii, os ilium to spina iliaca, os ischii to quadrilateral plate and quadrilateral plate to spina iliaca. It was assumed that the cause for higher relative quadrilateral plate and fracture gap movement with BSRC is presumably due to a higher ARRP construct stiffness. The use of 13 angle stable screws fixed in the solid iliac bone seem to provide higher stability compared to the seven non-angle stable screws of the BSRC construct. Angular stability provided by the ARRP screws may be beneficial regarding the prevention of large fracture gap movements. Another reason for the higher stability of the ARRP might be caused by the fact that the monoaxial locking screws with different angles of the individual screws with respect to the implant might provide additional purchase in the iliac bone.In the postoperative simulation starting with partial and ending with full weight-bearing conducted in the present study, the comparison of construct stability among both groups revealed less quadrilateral plate movement for ARRP. Furthermore, the ARRP fixation stability was most significantly relevant under full weight-bearing conditions as compared to BSRC. Thus, protrusion of the femoral head  was sufficiently prevented by ARRP treated fractures. It is worth noting that testing showed that ARRP distinctly reduced the fracture gap movements in os ischii to os pubis was detected in both groups, although this may not be a disadvantage for both implants and could easily be addressed by methods such as additional plating. However, this would significantly increase operation time and be an unreliable method in geriatric patients favoring immediate postoperative full weight-bearing.A large movement in As the model studied represents loading under partial and full weight-bearing conditions, a single-leg stance model was chosen to evaluate fracture gap movement of both implants. In the presented test set-up fracture gap movements in both groups were analyzed at the beginning after 1000 cycles with 250\u00a0N and after 31,000 cycles, simulating long-term loading conditions. Egol et al.  indicateA cable was used to prevent the bones from collapsing and to achieve a hip joint load as according to Bergmann et al. . High loThis biomechanical study presents several strengths including (1) the use of a clinically relevant acetabular ACPHT fracture model; (2) utilization of fourth-generation Sawbones as a suitable biomechanical comparison for human bone , 37; (3)In conclusion, this biomechanical study compared two constructs in a clinically relevant scenario for cases of hip joint failure in the elderly with reduced bone quality. No clinically relevant implant failure or loss of reduction was noted in either construct. However, the acetabulum roof-reinforcement plate demonstrated increased fixation stability of the quadrilateral plate under partial and full weight-bearing conditions and provides a possible treatment option for anterior column with posterior hemitransverse acetabular fractures."}
+{"text": "We read with great interest the recent article by Keith et al. who concluded that their retrospective, observational study in adult patients with septic shock and multiple organ failure demonstrated improved 28-day survival with adjunct therapeutic plasma exchange (TPE) compared to standard care alone . The 28-"}
+{"text": "A 72-year-old man presented with excruciating epigastric pain. A chest computed tomography angiography revealed an aortic intramural hematoma. A filling defect within the distal ascending aorta was noted. Images of an intramular hematoma and surgical details of an ascending aortic replacement under deep hypothermic circulatory arrest are provided. A 72-year-old man presented with excruciating epigastric pain not associated with exercise or trauma. After excluding myocardial ischemia, a chest computed tomography angiography revealed an aortic intramural hematoma (IMH) of 5\u2009mm in thickness starting at the sinotubular junction (34\u2009mm) and extending circumferentially to the diaphragm 27\u2009mm;. A fillAn ascending aortic replacement was performed under deep hypothermic circulatory arrest. A thrombus covering a small intimal tear was found within the aortic lumen at the distal ascending aorta corresponding to the filling defect . No othDisruption of a vasa vasorum within the media or bleeding within the vicinity of a penetrating atherosclerotic ulcer are the mechanisms reported to cause IMH."}
+{"text": "Goblint is a static analysis framework for C programs specializing in data race analysis. It relies on thread-modular abstract interpretation where thread interferences are accounted for by means of flow-insensitive global invariants."}
+{"text": "With the recent increased use of lanthanum carbonate, several cases of lanthanum phosphate deposition to gastric mucosa in dialysis patients have been reported. However, the endoscopic appearance of the early-stage lesion and the over-time alterations of endoscopic findings due to the progression of lanthanum phosphate deposition remain unclear.An 80-year-old man receiving dialysis and taking lanthanum carbonate as a phosphate binder over a 4-year period underwent upper gastrointestinal endoscopy four times beginning 1\u2009year after initiation of treatment. The first endoscopic examination (after 1\u2009year of exposure to lanthanum carbonate) revealed rough mucosa with a few areas of white granular mucosa. Over the 3\u2009years of endoscopic follow-up, the white granular mucosa spread and multiple erosions appeared. Histopathological findings of biopsy specimens from an erosion showed extensive infiltration by histiocytes containing deposits. Scanning electron microscopy-energy dispersive X-ray spectroscopy (SEM-EDX) revealed that the presence of the deposits containing phosphorus and lanthanum in the gastric mucosa.On the basis of these results, the patient was diagnosed with gastropathy associated with lanthanum phosphate deposition.Over a 3-year period, endoscopic findings associated with lanthanum deposition gradually changed and expanded from the early stage. Lanthanum carbonate is commonly used in dialysis patients to improve the hyperphosphatemia associated with chronic kidney disease. Specific gastric mucosal findings associated with the deposition of lanthanum have been reported in recent years in patients taking lanthanum carbonate \u20134. VarioWe herein report the gradual changes in endoscopic findings resulting from lanthanum deposition over a 3-year period in a patient receiving ongoing oral administration of lanthanum carbonate.An 80-year-old Japanese man diagnosed with chronic renal failure secondary to type 2 diabetes received dialysis for 4\u2009years and took lanthanum carbonate at dose 750\u2009mg/day orally as a phosphate binder during this 4-year period. The patient underwent upper gastrointestinal endoscopy 1\u2009year after initiation of lanthanum carbonate because of epigastric discomfort.The endoscopic findings at this initial endoscopy included rough mucosa with a few white granular lesions in the lesser curvature of the gastric body with the atrophic change Fig.\u00a0a. After Histopathological findings on biopsy of erosion in greater curvature showed atrophic mucosa, intestinal metaplasia, and regenerative change. Many histiocytes containing granular or crystalline eosinophilic deposits were found extensively infiltrating the lamina propria, consistent with the presence of inflammation Fig.\u00a0.Fig. 2HScanning electron microscopy-energy dispersive X-ray spectroscopy (SEM-EDX) identified the deposition of phosphorus and lanthanum in gastric mucosa. Figure\u00a0We took biopsy specimens from erosion in greater curvature over time Fig.\u00a0. It was Because the patient has no abdominal symptoms, gastrointestinal endoscopy has been continued annually for follow-up observation. The patient signed the explanation and consent forms in the informed consent process for endoscopic examination.Lanthanum carbonate is a therapeutic agent for hyperphosphatemia and is widely used for the management of chronic renal failure in dialysis patients. Lanthanum carbonate has been available in the UK since 2007 and in Japan since 2009. Lanthanum carbonate strongly binds with phosphate ions in the intestinal tract to form minimally soluble lanthanum phosphate. Although the absorption rate of lanthanum from the gastrointestinal tract to the bloodstream is considered safe at less than 0.00127% , there hWe observed that the area of whitish granular mucosa and erosions expanded and the appearance of lesions became more apparent over time while being exposed to lanthanum carbonate over 3\u2009years. Interestingly, the lesion area spread on the atrophic area from near the pylorus toward the cardia. This spreading pattern seemed similar to the mucosal atrophy progress described by Takemoto et al. . This fiMeanwhile, the causality and the mechanism between lanthanum deposition and mucosal injury remains unestablished. Since the patient in this case report did not have an endoscopic examination before starting lanthanum carbonate, we could not assess the base-line gastric mucosa without the effect of the medication. Nonetheless, over-time endoscopic as well as histological observations clearly showed that the deposition of lanthanum and the number of histiocytes that infiltrated in the tissue were increasing and gastric inflammation became exacerbated during the treatment with lanthanum carbonate. Our findings imply the lanthanum deposition results in damaging the gastric mucosa. The studies to investigate the causal link and mechanisms of lanthanum deposition and mucosal injury are needed.One study found that 85.7% of dialysis patients treated with lanthanum carbonate had deposition in the gastrointestinal mucosa . Despite"}
+{"text": "Significance: Assessment of disease using optical coherence tomography is an actively investigated problem, owing to many unresolved challenges in early disease detection, diagnosis, and treatment response monitoring. The early manifestation of disease or precancer is typically associated with subtle alterations in the tissue dielectric and ultrastructural morphology. In addition, biological tissue is known to have ultrastructural multifractality.Aim: Detection and characterization of nanosensitive structural morphology and multifractality in the tissue submicron structure. Quantification of nanosensitive multifractality and its alteration in progression of tumor.Approach: We have developed a label free nanosensitive multifractal detrended fluctuation analysis(nsMFDFA) technique in combination with multifractal analysis and nanosensitive optical coherence tomography (nsOCT). The proposed method deployed for extraction and quantification of nanosensitive multifractal parameters in mammary fat pad (MFP).Results: Initially, the nsOCT approach is numerically validated on synthetic submicron axial structures. The nsOCT technique was applied to pathologically characterized MFP of murine breast tissue to extract depth-resolved nanosensitive submicron structures. Subsequently, two-dimensional MFDFA were deployed on submicron structural en face images to extract nanosensitive tissue multifractality. We found that nanosensitive multifractality increases in transition from healthy to tumor.Conclusions: This method for extraction of nanosensitive tissue multifractality promises to provide a noninvasive diagnostic tool for early disease detection and monitoring treatment response. The novel ability to delineate the dominant submicron scale nanosensitive multifractal properties may also prove useful for characterizing a wide variety of complex scattering media of non-biological origin. Subsequently, we have deployed two-dimensional multifractal detrended fluctuation analysis (2D-MFDFA)\u2013ex vivo study on murine tissue, we found interesting change in depth-resolved nanosensitive multifractality in submicron structures after tumor formation in breast tissue samples. This method for extraction of nanosensitive tissue multifractality promises to develop a noninvasive diagnosis tool for the detection of cancer development. This newly developed method offers exciting depth-resolved ultrastructural detection for better treatment and monitoring if there is a tumor response to treatment.Early disease progression in living tissues expected to exhibit nanosensitive structural alteration at the submicron scale. It is highly desirable to develop noninvasive, label-free techniques to detect nanoscale changes in biological tissue for early diagnosis and better treatment. Recently, many optical nanoscopic techniques were developed based on labeling22.1Flowchart of nsOCT is shown in 2.2,,\u00ae) has been used for implementation of simulation. The OCT signal was constructed as an interference spectrum of the reflected light from different layers of synthetic sample with the reflected light from a gold mirror. We have also added suitable noise in detector and source spectra to mimic experimental reality. The signal-to-noise ratio was 86\u00a0dB in this simulation. The inverse Fourier transform was performed to form A-lines nsOCT of a synthetic volume as each lateral position of en face images to compare.In our recent publications,2.3en face images to extract nanosensitive multifractal parameters namely, Hurst exponent [\u2013We have followed our established nsOCT methodology to construct depth-resolved dominant structures of synthetic and tissue volume. Flowchart of nsOCT processing displayed in Step 1:en face nsOCT image [size: The two-dimensional Step 2:Each square segment Step 3:en face nsOCT. The residual nanosensitive axial size variation or detrended subsurface is given by The local fit Step 4:The detrended fluctuation function en face image at each depth is en face image with size en face nsOCT map. Note that, in principle, we can calculate generalized Hurst exponents for The Step 5:The generalized Hurst exponents [en face nsOCT surface.From this above equation, the scaling exponent The classical multifractal scaling exponent en face nsOCT surface is related to en face image. The width of the singularity spectrum en face images. The higher value of en face indicates higher strength of multifractality. The Hurst scaling exponents: en face images at different depths. The The two-scaling exponent en face images.In this study, we have characterized (a)\u00a0Hurst exponent [2.4All animal procedures were performed in accordance with the Guidelines for Care and Use of Laboratory Animals of the \u201cAnimal Care Research Ethics Committee (ACREC), National University of Ireland Galway (NUIG)\u201d and approved by the \u201cHealth Product Regularity Authority (HPRA), Ireland\u201d.ex vivo analysis. Harvested samples were taken out from PBS and mounted on a glass slide to bring them under the objective of spectral domain OCT system  to record OCT images.Female BALB/c mice (Charles River Laboratories Ltd.) aged between 6 and 8 weeks were employed. A mouse received a mammary fat pad  injection of 33.1en face map of submicron structure at en face map of submicron structure. en face and in nsOCT detected en face, we have applied state of the art 2D-MFDFA on each en face images throughout the depth. en face in en face in en face has a multifractality (blue color plot) and can be detected with almost no error (red color plot). In addition, Hurst exponent [en face is almost equal in values confirms our capability to detect submicron scale structural correlation within a complex tissue sample. Similarly, en face in en face in en face image proved our capability to detect submicron scale structural multifractality within a complex tissue sample.We have recently demonstrated an experimental and numerical approach for nsOCT validation and detection of submicron structure with few nanometer accuracy.en face structures. The upper part of en face structures. Detected depth-dependent Hurst exponent [en face structure is very close to each other. These results validated our capability to detect submicron scale structural multifractality through the proposed nsMFDFA methodology from a tissue-like complex submicron scale multifractal structure with greater accuracy.The lower part of 3.2ex vivo tissue with healthy MFP and tumor portion. en face for healthy [blue plot extracted from volume in After successful validation of nsMFDFA approach, we have applied this technique on en face images to find nanosensitive multifractal parameters.In these regards, it is known that tissues have multifractality in submicron structure. Therefore, it is always interesting to have depth-resolved quantitative submicron scale multifractal parameters for better understanding. Quantitative submicron scale multifractal parameters can also help to develop computer-assisted automated differentiation of tumor tissue from healthy tissue. In this direction, we have performed 2D-MFDFA on depth-resolved nsOCT constructed en face images at en face and tumor (red color) en face image. en face, and tumor (red color) en face image. Variation of In en face images at different depths. Vertical lines at each depth represent standard deviation from mean trends over 10 samples. In en face images as tumor progress. In en face images as tumor progress.For further verification and confirmation, we have applied this extraction method of nanosensitive multifractality on 10 healthy MFP and 10 tumor volume images in different areas of a tissue sample. We found consistence differences of nanosensitive correlation and strength of multifractality over different depths of tissue. 4in vivo deployment. Exploiting the interference spectra recorded from tissue depths with the reference mirror, in vivo applications of this approach should be realized with a fiber optic-based handheld probe assisted with scanning lens and galvo mirror. Finally, the developed nsMFDFA method represents as a novel approach with much potential for in vivo detection of cancer initiation and other non-biological application remain to be rigorously evaluated.A novel approach to quantify submicron scale nanosensitive multifractality in combination with nsOCT and multifractal analysis has been demonstrated. We validated the nsOCT technique numerically on synthetic submicron scale axial structures. We developed a novel nanosensitive submicron scale multifractal analysis technique to characterize tissue depth-resolved ultrastructural morphology. Reduction of the Hurst exponent ["}
+{"text": "Peripheral arterial disease (PAD) is a major cause of diminished functional capacity and quality of life in a large portion of western populations. While 3D contrast-enhanced (CE) MRA is becoming a modality of choice for clinical PAD examinations, the potential for nephrogenic systemic fibrosis (NSF) in patients with renal insufficiency has triggered a renaissance of interest in non-contrast enhanced (NCE) MRA. Various NCE-MRA strategies employing 3D half-Fourier FSE  or balanThe FSD module was modified by using bipolar gradient rather than unipolar gradient before and after the center 180-RF pulse to address the artifactual issue resulted from imperfect frequency response  to selectively suppress arterial blood and to avoid otherwise venous contamination. The feasibility of this approach was demonstrated on healthy distal lower extremities. Further investigation on PAD patients, with CE-MRA or x-ray angiography correlation, is warranted. It is anticipated that this strategy could be applied to other vascular territories where appropriate choice of m1 (magnitude and direction) would vary with the specific flow patterns."}
+{"text": "Aortic coarctation is currently treated by both surgical and transcatheter methods. Patients can present with late complication of prior surgical repair including recoarctation and aneurysm formation. There are limited reports on safety and efficacy of thoracic endovascular aortic repair methods (TEVAR) in post-coarctation repair patients.We report an adult patient with aortic aneurysm formation following surgical coarctoplasty successfully treated with transcatheter TEVAR method obviating the need for open heart surgery.Endovascular repair of aneurysms in post-coarctoplasty patients is a promising method and should be considered in those with suitable anatomy based on prior imaging. Aortic coarctation refers to the congenitally stenotic aorta, more commonly found near the ligamentum arteriosum and adjacent to the left subclavian artery . CoarctaA 25-year-old female with history of surgical repair of coarctation in infancy and percutaneous device closure of a mid-muscular ventricular septal defect (VSD) at age eighteen presented to our adult congenital clinic for routine follow-up. She stated that she was asymptomatic and had normal functional capacity. Physical examination findings were within normal limits. Chest X-ray showed normal heart size and an abnormal bulging in the upper left heart border suggesting aneurysmal dilation of thoracic aorta Fig. . CardiacAortography was performed via femoral route, and injections were done using a radiopaque marker pigtail to get accurate measurements. Aortic angiography confirmed CMR findings Fig. .Fig. 3AInitially, the left subclavian artery ostium was occluded using a Occlutech\u00ae PDA occluder 8 \u00d7 10\u2009mm to eliminate the risk of endoleaks Fig. .Then a 2Follow-up CT angiography showed complete exclusion of the aneurysm with no complications Fig. . At 1-yeRepair of aortic coarctation has traditionally been based on surgical methods although catheter interventions are progressively improving . DiffereAlthough endovascular stent grafting has been approached cautiously in the treatment of such young patients, newer stent graft designs offer better conformability and durability, and endovascular stent grafting could be considered as a safe option for treatment of these patients. Advantages of stent grafts include the fact that they could cover the total length of the diseased aorta. However, long-term efficacy and freedom of reintervention remain to be investigated.Yazar et al. in their series of 13 patients with TEVAR for treatment of late complications after aortic coarctation reported cases suffering mortality and morbidity . Lala etThe present case highlights the importance of considering percutaneous methods of aneurysm repair in patients who are optimal candidates based on prior imaging, over the routine open surgical alternatives and thereby averting the risks associated with repeat surgical procedures. Large and multi-center trials with long-term follow-up focusing on postsurgical patients are needed to further clarify the role and potential shortcomings of the endovascular stent grafts in the management of these patients."}
+{"text": "Functional enrichment of genes and pathways based on Gene Ontology (GO) has been widely used to describe the results of various -omics analyses. GO terms statistically overrepresented within a set of a large number of genes are typically used to describe the main functional attributes of the gene set. However, these lists of overrepresented GO terms are often too large and contains redundant overlapping GO terms hindering informative functional interpretations.We developed GOMCL to reduce redundancy and summarize lists of GO terms effectively and informatively. This lightweight python toolkit efficiently identifies clusters within a list of GO terms using the Markov Clustering (MCL) algorithm, based on the overlap of gene members between GO terms. GOMCL facilitates biological interpretation of a large number of GO terms by condensing them into GO clusters representing non-overlapping functional themes. It enables visualizing GO clusters as a heatmap, networks based on either overlap of members or hierarchy among GO terms, and tables with depth and cluster information for each GO term. Each GO cluster generated by GOMCL can be evaluated and further divided into non-overlapping sub-clusters using the GOMCL-sub module. The outputs from both GOMCL and GOMCL-sub can be imported to Cytoscape for additional visualization effects.https://github.com/Guannan-Wang/GOMCL and www.lsugenomics.org.GOMCL is a convenient toolkit to cluster, evaluate, and extract non-redundant associations of Gene Ontology-based functions. GOMCL helps researchers to reduce time spent on manual curation of large lists of GO terms, minimize biases introduced by redundant GO terms in data interpretation, and batch processing of multiple GO enrichment datasets. A user guide, a test dataset, and the source code of GOMCL are available at  High-throughput \u201comics\u201d approaches are frequently employed to investigate expression changes and regulation of genes at a genome-wide level. Use of these genomic data often results in the identification of large lists of genes of interest. A standard approach to summarize the functions of these genes is to determine the enriched functions represented by Gene Ontology (GO) terms and other functional associations extracted from databases such as KEGG \u20133, ReactGO resources have become the most widely used knowledge base in terms of gene functions , 9, whicGOMCL is implemented in Python and allows grouping of lists of individual GO terms of interest into GO clusters using MCL Fig.\u00a0. GOMCL ehttp://geneontology.org/) as an input  or an Overlap Coefficient (OC) [Jaccard Coefficient (JC) is calculated as A\u2229B/A\u222aB, and preferred for clustering of similarly sized GO terms. The Overlap Coefficient (OC) is derived from A\u2229B/min , and works better to maximally reduce the redundancy between disproportionately sized GO terms. The construction of the GO term similarity network is initiated using only those interactions that pass a user-defined threshold for the Jaccard or Overlap coefficient of users\u2019 choice. MCL algorithm is subsequently applied to identify cluster structure in the initial network and assigns more similar GO terms into one cluster. The resulting GO clusters are ordered based on the number of genes in each cluster. GO terms with largest number of genes, or smallest enrichment p-value, or most other GO terms connected are selected and offered as potential representative GO terms for each cluster. GOMCL also reproduces the hierarchy of GO terms from the provided ontology structure for any user-selected clusters upon command to assist identification and interpretation of the functional themes of these clusters. A novel functionality enabled in GOMCL that is unavailable in previous tools for GO-network analysis, is the evaluation of clustering results by visualizing the distribution of similarity indexes between GO terms for each cluster. Taking this one step further, GOMCL includes a second module, called GOMCL-sub, which provides users customizable options to break down selected clusters produced by GOMCL into sub-groups with more specific functional themes. These functionalities combined, allows users to determine if there are distinct functional themes present in primary clusters and further identify these sub-structures in clusters of interest.GOMCL first trims the input GO lists by removing overly broad GO terms whose size is greater than a user-defined threshold. For example, a large GO term such as biological regulation (GO:0065007) has over 12,000 child GO terms, including 15,000 genes in Arabidopsis and is often uninformative as a term representing a meaningful biological function. GOMCL also enables users to separate input GO lists into biological process, molecular function, and cellular component categories or any combinations of these categories if clustering within different categories is preferred. Each term in the trimmed GO lists is then compared to each other, and similarity between any two GO terms is computed based on the overlaps between the members of these two GO terms as either a ent (OC) . Given aThe standard GOMCL output consists of a heatmap Fig.\u00a0a, a grapAs a proof of concept, we performed a GOMCL run on a list of over-represented GO terms identified from genes differentially expressed between two GFP tagged cell populations of Arabidopsis roots in a published study  to highlOverlap Coefficient of 0.5 and granularity of 1.5 were used for cluster identification. These cutoffs can be set by the user. Among the 244 GO terms, GOMCL identified five distinct clusters with minimal overlap between clusters and extensive overlaps among GO terms within each cluster  enriched in genes expressed higher in the cell population with high GFP intensity . GOMCL-sub further separated cluster C1 and C2 clusters in less than 2 mins with similar amount of memory used. Given the efficiency of the toolkit, this can be easily implemented to conduct batch processing of multiple datasets associated with large \u2013omics datasets.While the proof of concept analyses described above using GOMCL is used to highlight functional associations drawn from a typical RNAseq experiment, the use of GOMCL is not limited to summarizing functional processes from RNAseq data. For example, it has been recently successfully used in summarizing gene functions associated with multiple epigenetic marks in rice under phosphorus starved conditions . AdditioGOMCL is an open-source Python toolkit to identify clusters among GO term similarity networks using the MCL clustering algorithm. This toolkit allows grouping of GO terms into functional clusters to further simplify the interpretation of large datasets, reduce redundancy of functional interpretations, and especially when visual identification of cluster structure is not feasible due to a large number of enriched GO terms often found in -omics data (see Table\u00a0GOMCL can be used for batch processing of multiple enrichment test results defined by the user. It is applicable for any research project where lists of genes of interest are generated. It is compatible with a wide variety of GO enrichment analysis tools publicly available, which would reduce intermediate steps needed to convert different input formats to conform to GOMCL requirements.GOMCL currently uses the MCL algorithm for cluster identification and is compatible with commonly-used GO enrichment tools. For future versions, we consider implementing additional clustering methods, improving labeling of nodes, and supporting more GO enrichment analysis tools.Lists of overrepresented GO functions from GO enrichment analyses are often long and redundant. We present GOMCL as a convenient toolkit to identify functional clusters among GO term similarity networks and further separate the resulting clusters into more informative sub-groups. It enables the user to effectively summarize long lists of GO functions into biologically informative non-redundant clusters without hand-picked selections and look for major functional themes associated with the experiments. GOMCL assists with the unmet yet increasing need for interpreting large gene sets often produced from -omics studies.Additional file 1. GOMCL cluster information for each GO term.Additional file 2. Similarity connections of GOMCL clusters and hierarchical connections of GOMCL cluster C1.Additional file 3. GO hierarchical structure produced using GOMCL for cluster C2 described in Fig.\u00a0Additional file 4. Summary for GOMCL-sub clustering results of C1 described in Fig.\u00a0Additional file 5. GOMCL-sub sub-cluster information for each GO term in cluster C1 described in Fig."}
+{"text": "Epithelial ovarian cancer is one of the most lethal cancers in women and is typically diagnosed at an advanced-stage. Historically, primary tumor reductive surgery was attempted followed by postoperative chemotherapy in most patients diagnosed with advanced ovarian cancer. However, neoadjuvant chemotherapy followed by interval tumor reductive surgery is an alternative approach for patients with advanced-stage ovarian cancer where primary tumor reductive surgery is not feasible. Here, we review proposed models that can assist in selecting patients who would benefit most from neoadjuvant chemotherapy followed by surgery.Epithelial ovarian cancer remains a leading cause of death amongst all gynecologic cancers despite advances in surgical and medical therapy. Historically, patients with ovarian cancer underwent primary tumor reductive surgery followed by postoperative chemotherapy; however, neoadjuvant chemotherapy followed by interval tumor reductive surgery has gradually become an alternative approach for patients with advanced-stage ovarian cancer for whom primary tumor reductive surgery is not feasible. Decision-making about the use of these approaches has not been uniform. Hence, it is essential to identify patients who can benefit most from neoadjuvant chemotherapy followed by interval tumor reductive surgery. Several prospective and retrospective studies have proposed potential models to guide upfront decision-making for patients with advanced ovarian cancer. In this review, we summarize important decision-making models that can improve patient selection for personalized treatment. Models based on clinical factors  and molecular markers (circulating and tumor-based) are useful, but laparoscopic staging is among the most informative diagnostic methods for upfront decision-making in patients medically fit for surgery. Further research is needed to explore more reliable models to determine personalized treatment for advanced epithelial ovarian cancer. Epithelial ovarian cancer remains the fifth leading cause of death among women in the United States, with an incidence of 10.4/100,000 women/year and a death rate of 6.9/100,000 women/year in the 2017 statistics report . OvarianPlatinum-based drugs with paclitaxel are part of standard NACT regimen that have been used for newly diagnosed advanced ovarian cancers; however, limited information is available on use of bevacizumab (anti-angiogenesis drug), poly (ADP-ribose) polymerase (PARP) inhibitors and immunotherapy in NACT setting. Combination of bevacizumab with standard regimen in NACT setting demonstrated improved PFS among patients with advanced ovarian cancer ,14. Few The purpose of NACT is to decrease the tumor load and to increase the likelihood of achieving optimal cytoreduction  or RD \u2264 1 cm) at interval tumor reductive surgery (iTRS). Various diagnostic models have been developed to determine the ideal upfront treatment strategy for patients with advanced-stage ovarian cancer with no clear \u201cwinner.\u201d In this review, we provide a critical discussion of the available data and evolving models to aid in decision-making and guide future research.p = 0.586)  value = 0.846). Thus, the serum CA-125 to ascites leptin ratio could anticipate clinical response before primary treatment and could be helpful in selecting type of first-line treatment for patients with HGSOC [Serum CA-125 is the most common tumor marker used at diagnosis and subsequent surveillance visits. A retrospective study demonstrated that patients with a serum CA-125 of \u2264100 U/mL after NACT (before iTRS) had a higher likelihood of achieving optimal cytoreduction . Anotherth HGSOC .One retrospective study assessed the prognostic value of human epididymis 4 (HE4) protein marker preoperatively and at various time points during primary treatment for ovarian cancer . In thisADLH1-positive cancer stem cells have been shown to have an important role in platinum sensitivity. Increased expression of ALDH1 after NACT treatment indicated a 4.18 times higher risk of death and increased risk of poor outcome .Analyses of two publicly available microarray datasets revealed that higher levels of fatty acid\u2013binding protein 4 (FABP4) and alcohol dehydrogenase 1B (ADH1B) in primary tumors were associated with a higher incidence of RD after pTRS among patients with HGSOC . In The One study  analyzedExamination of samples from tumor tissues and ascites revealed that insulin-like growth factor (IGF)-I in ascitic fluid was an independent predictor of objective clinical response . The autOne study suggested that an increased level of serum calretinin (CRT), a calcium-binding protein, at the time of initial diagnosis was correlated with a higher amount of ascites and advanced FIGO staging. An increased level of serum CRT (sCRT level cutoff = 0.35 ng/mL) was associated with higher chances of suboptimal cytoreduction. Serum CRT levels were also found to be an independent predictor for PFS and OS .Results of a multicenter retrospective study  revealedIn another study , quantitThe heterogeneity and later stage of diagnosis make curative treatment difficult for patients with ovarian cancer. NACT followed by iTRS has been shown to be as effective as pTRS for advanced-stage ovarian cancers. NACT can be considered a primary treatment option for patients with FIGO stage IV and is preferred for patients with FIGO stage IIIc ovarian cancer for whom optimal cytoreduction is not achievable or for those with multiple comorbidities. Many models have been proposed based on clinical factors, radiology studies, laparoscopic triage, circulating molecular markers and tumor-based genetic markers to facilitate upfront decision-making. Among these, laparoscopic assessment is arguably the most informative surgical assessment tool available. Additional research is required to determine more reliable models and to direct decision-making in upfront clinical management for advanced epithelial ovarian cancer."}
+{"text": "There were cases of sudden death in some patients infected with COVID-19 including a few of young physicians, which had a huge impact on medical community and society . It is nIn addition to lung injury, cardiac injury has often been reported in patients with COVID-19 . Some exWe found that sinus bradycardia often occurred during sleep. So, deep sleep or sedation may be an important risk factor for sinus bradycardia. A few patients had mild to moderate decreased thyroid function, which was consistent with secondary pathological thyroid syndrome and may also be one of the causes of sinus bradycardia. When viral nucleic acid tests gradually turned negative, the heart rate returned to normal no matter whether the patient\u2019s condition improved or worsened and the uses of catecholamine were gradually discontinued. According to the results, we speculated that the inhibitory effect of virus on sinus node activity was the main cause of sinus bradycardia in these patients.https://www.genecards.org/). Biological processes (BP) for ACE2 gene showed that it not only promoted the contraction of cardiac muscle, but also regulated the cardiac conduction. Donoghue et al. demonstrated that cardiac ACE2 overexpression in transgenic mice caused sudden death in a gene dose-dependent fashion; they also found that increased ACE2 expression led to progressive conduction and rhythm disturbances with lethal ventricular arrhythmias via detailed electrophysiology [Previous study indicated that COVID-19 invaded host cells via the receptor angiotensin-converting enzyme 2 (ACE2) . Zou et ysiology . In lighTaken together, heart rate monitoring of severe COVID-19 pneumonia patients should be strengthened during treatment, and catecholamines should be appropriately applied when necessary. Moreover, a possible inhibitory influence of the virus on activity of cardiac nervous conduction system including sinus node via ACE2 should not be ignored when studying the pathogenic mechanisms among these patients."}
+{"text": "Intraocular medulloepithelioma is commonly treated with primary enucleation. Conservative treatment options include brachytherapy, local resection and/or cryotherapy in selected cases. We report for the first time the use of targeted chemotherapy to treat a ciliary body medulloepithelioma with aqueous and vitreous seeding.ab interno trabeculotomy followed by 360\u00b0 gonioscopy-assisted transluminal trabeculotomy 6\u2009months later was performed for uncontrolled intraocular pressure despite antihypertensive drugs combined to cyclophotocoagulation and 7 intravitreal anti-VEGF injections for recurrent iris neovascularization. Cataract was removed at the same operative time. The child has remained disease- and metastasis-free at a 5-year follow-up since the last melphalan injection (25-month follow-up after the combined lensectomy-trabeculotomy) with a controlled intraocular pressure under topical quadritherapy and a best corrected Snellen visual acuity of 0.08.A 17-month-old boy with a diagnosis of ciliary body medulloepithelioma with concomitant seeding and neovascular glaucoma in the right eye was seen for a second opinion after parental refusal of enucleation. Examination under anesthesia showed multiple free-floating cysts in the pupillary area associated with iris neovascularization and a subluxated and notched lens. Ultrasound biomicroscopy revealed a partially cystic mass adjacent to the ciliary body between the 5 and 9 o\u2019clock meridians as well as multiple nodules in the posterior chamber invading the anterior vitreous inferiorly. Fluorescein angiography demonstrated peripheral retinal ischemia. Left eye was unremarkable. Diagnosis of intraocular medulloepithelioma with no extraocular invasion was confirmed and conservative treatment initiated with combined intracameral and intravitreal melphalan injections given according to the previously described safety-enhanced technique. Ciliary tumor and seeding totally regressed after a total of 3 combined intracameral  and intravitreal  melphalan injections given every 7\u201310\u2009days. Ischemic retina was treated with cryoablation as necessary. Three years later, We report for the first time complete regression of a non-infiltrating ciliary body medulloepithelioma with seeding achieved with only a small number of intracameral and intravitreal melphalan injections. Concomitant secondary neovascular glaucoma and cataract needed appropriate management to allow long-term eye and vision preservation. DICER1 mutations has been found [Intraocular medulloepithelioma is a rare, nonhereditary, neuroepithelial tumor, usually arising from the nonpigmented ciliary epithelium of the ciliary body, more rarely the optic nerve, the retina or the iris . Its exaen found .Characteristic features of ciliary body medulloepithelioma include a grey-white to fleshy pink mass with a various quantity of cysts adjacent to the ciliary body, a lens notching with or without subluxation and a neoplastic cyclitic membrane , 4. The Here we report for the first time a case of intraocular medulloepithelioma with seeding at presentation successfully treated with intracameral and intravitreal melphalan chemotherapy.ab interno trabeculotomy followed by a 360\u00b0 gonioscopy-assisted transluminal trabeculotomy 6 months later to manage uncontrolled intraocular pressure despite antihypertensive drugs combined with cyclophotocoagulation and 7 intravitreal anti-VEGF injections for recurrent iris neovascularization. Cataract surgery with posterior capsulorhexis, anterior vitrectomy and sulcus implantation of a three-piece intraocular lens was performed during the first glaucoma surgery. Cytopathologic analysis of the vitrectomy fluid was negative for tumor cells. One year after the cataract was removed, YAG-laser capsulotomy was performed for posterior capsular lens opacification. The child has remained disease and metastasis-free at a 5-year follow-up since the last chemotherapy with a controlled intraocular pressure under topical quadritherapy and a best-corrected Snellen visual acuity of 0.08.A previously healthy 17-month-old boy was given topical antibiotics for a right eye redness appearing in the context of an ear, nose and throat infection. One week later, fixed mydriasis of the same eye was observed, and the child seen elsewhere for evaluation Fig.\u00a0a. IntraoIntraocular medulloepithelioma is a rare tumor of unknown incidence but still represents the most frequent pediatric primary malignant intraocular tumor after retinoblastoma . StandarIn this report, we describe for the first time the conservative management of a non-infiltrating ciliary body medulloepithelioma complicated with seeding at presentation using intraocular melphalan injections. Presence of seeding was so far considered as an indication for enucleation . MelphalIn conclusion, we report herein for the first time a case of non-invasive ciliary body medulloepithelioma with seeding at presentation successfully treated with only a small number of intraocular melphalan injections. To our knowledge, this is the first case of intraocular medulloepthelioma with seeding to be managed conservatively. Concomitant secondary neovascular glaucoma and cataract needed appropriate management to allow long-term eye and vision preservation. Further studies will help to better define the role of targeted chemotherapy for intraocular medulloepithelioma in the future."}
+{"text": "Osteoarthritis (OA) of the knee is one of the most common causes of pain in older adults. Recent evidence suggests that knee OA pain is characterized by alterations in central pain processing in the brain. Two nonpharmacological pain treatments, transcranial direct current stimulation (tDCS) and mindfulness-based meditation (MBM), have been shown to improve pain-related brain function in older adults with knee OA. Because tDCS promotes neuroplasticity, it may potentiate the effect of MBM that also stimulates adaptive changes in the brain. However, no studies have examined whether tDCS combined with MBM can reduce OA symptoms in older adults with knee OA. Thus, the purpose of this study was to examine the preliminary efficacy of tDCS combined with MBM in older adults with knee OA. Thirty participants with knee OA were randomly assigned to receive 10 daily sessions of home-based 2 mA tDCS combined with active MBM for 20 minutes (n=15) or sham tDCS combined with sham MBM (n=15). We measured OA-related clinical symptoms using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). Participants  had a mean age of 59 years. Active tDCS combined with active MBM significantly reduced scores on the WOAMC . Participants tolerated tDCS combined with MBM well without serious adverse effects. Our findings demonstrate promising clinical efficacy of home-based tDCS combined with MBM for older adults with knee OA. Future studies with larger-scale randomized controlled trials with follow-up assessments are needed to validate our findings."}
+{"text": "This letter describes the potential effect of B cell depletion on immune related adverse events associated with immune checkpoint inhibition. B cell depleting agents such as rituximab reduce B cell to plasma cell differentiation and antibody production. This treatment strategy is used in several immune mediated inflammatory diseases such as rheumatoid arthritis and small vessel vasculitis. The immune related adverse events associated with immune checkpoint inhibition resemble immune mediated inflammatory diseases. Here, we report a lower incidence of hypothyroidism in a trial of combined B cell depletion and immune checkpoint inhibitor treatment compared with studies of immune checkpoint inhibitor monotherapy. This letter aims to increase awareness of the immune related adverse events associated with immune checkpoint inhibition in future clinical trials of immune checkpoint inhibition together with B cell depletion . Hopefully, observations from these clinical trials can guide future treatment strategies to treat or prevent immune related adverse events associated with immune checkpoint inhibition. The next decade will bring fundamental knowledge about the immunology behind the immune related adverse events (irAEs) associated with immune checkpoint inhibition (ICI). This knowledge will come as a consequence of new clinical trials of ICI together with B cell depletion. These treatment regimens are designed to improve outcomes for patients with B cell hematologic malignancies. However, reports of the irAE profile will be a major add-on benefit from these clinical trials.During ICI 35% of cancer patients develop irAEs. This type of adverse events resembles immune mediated inflammatory diseases (IMIDs). When treating cancer, we try to induce immunological reactions against the tumor cells. When treating IMIDs, we try to dampen immunological reactions causing inflammation. Immune modulating therapy can therefore be a double-edged sword. However, the two processes might not be mutually exclusive.ICI refers to blocking antibodies targeting the programmed cell death protein 1 (PD1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA4) pathways. PD1 and CTLA4 are negative regulators of T cell activity and are upregulated in many malignancies. In this way, cancer cells evade immune surveillance. ICI results in increased activity of the immune system and increased recognition and elimination of cancer cells. Therefore, ICI is emerging as a potential treatment option for many malignancies including lymphoma. B cell depleting agents bind to B cell specific membrane proteins causing complement-dependent cytotoxicity and antibody-dependent cellular cytotoxicity. E.g. rituximab binds to CD20 found on mature B cells and is routinely used in the treatment of B cell lymphomas. This results in depletion of the cancerous B cells expressing the CD20 protein on their surface. However, depletion of all mature B cells will also reduce antigen presentation, B cell to plasma cell differentiation and antibody production. Therefore, rituximab is also used in the treatment of several IMIDs such as rheumatoid arthritis and small vessel vasculitis.Little is known about the immunological reactions causing irAEs. Some irAEs are associated with the presence of autoantibodies implying a role for B cells. The most frequent of these autoantibody-associated irAEs is thyroiditis.Until now, only one clinical trial combining ICI with B cell depletion has been completed. 2 To investigate whether rituximab alters the frequency of irAEs we compared the incidence of hypothyroidism in this phase II trial with the incidence of hypothyroidism in comparable studies of PD1 inhibitor monotherapy.2 intravenously 17\u00a0days after the first infusion of pidilizumab and weekly for 4\u00a0weeks. Of the 32 patients, two were ineligible and not treated. Thirty patients were available for toxicity analysis, but only 29 received the therapy. The incidence of hypothyroidism in the 29 patients that received combination therapy was 0% .The completed phase II clinical trial was a study of 32 patients with rituximab-sensitive follicular lymphoma treated with pidilizumab and rituximab . PidilizThis incidence contrasts with larger studies with PD1 inhibition monotherapy reporting between 6% and 10% of patients experiencing hypothyroidism  is a major limitation. Thyroiditis was chosen because it is one of the most frequent irAE. We did not compare any of the other irAEs. This letter primarily aims to increase awareness of the irAEs associated with ICI in future clinical trials of ICI together with B cell depletion. A list of these ongoing trials and their completion dates can be seen in Table"}
+{"text": "The conventional orthotopic heart transplantation (OHT)  results in atrial enlargement. The variability of atrial size and function in these patients has not been previously reported.1. Determine the variability in the post-OHT size and function of left and right atria; 2. Analyze the relationship of donor and native atria; 3. Compare cardiac MRI (CMR) with transthoracic echocardiogram (TTE).This is a retrospective observational study. Nine patients who had undergone OHT via biatrial anastomosis technique and had both CMR as well TTE within one month of each other were selected. Using the optimized apical 4-chamber views in both TTE and CMR cine images (SSFP), endocardial borders of the native and donor, right atrial (RA) and left atrial (LA) free wall and septum were traced from base to the valvular annulus and areas were determined in late systole when atrial volumes are maximal and late diastole when atrial volumes are minimal. RA and LA function was assessed quantitatively using percentage of change in cavity area or fractional area change (FAC). FAC was defined using the formula ([end-systolic area] - [end-diastolic area])/[end-systolic area] \u00d7 100). Native and donor areas were also combined to calculate the total area of the right and left atria. Comparison was made between the TTE and CMR values. Data for continuous variables are expressed as mean value +/- SD.See Tables Left atrial volumes consistently predict outcome in most patient groups studied. LA size is frequently severely distorted after OHT and is dependent upon extent of retained pulmonary vein cuffs or associated donor lung preparation, individual cardiac surgeon preferences, and cardiac recipient organ status. Knowing the variations in atrial sizes may provide a new avenue for clinical investigation Figure . A CMR aIt appears that the retained native atrium does not contribute to atrial contraction. This resulted in a negative total FAC% in 45% (4/9) of our patients. Given the large retained native atria, and its poor contribution to atrial contraction, this report suggests that minimizing this atrial reservoir may be valuable and warrants additional study. The underestimation of native atrial size reported by TTE is most likely due to apical fore-shortening of the true long-axis and the far field ultrasound imaging.This observational study suggests that despite a generally reasonable correlation between TTE and CMR measures of OHT atria, significant differences exist. Furthermore, because of suspected intra-atrial (donor versus native) mechanical dysynchrony, some patients surprisingly had a negative FAC% suggesting that the native atria is larger during donor atrial contraction \u2013 acting as a non-functioning reservoir. The association of this to the clinical outcome has yet to be determined."}
+{"text": "Embolic events are rare presentation of myxoma, which is one of the most prevalent benign cardiac tumors. Here we report the case of a 53-year-old man with presentation of acute anterior infarction and occlusion of the left anterior descending artery in association with left atrial myxoma. Intracoronary aspiration thrombectomy along with frequent balloon inflation was failed to recover distal coronary blood flow. Cardiac myxomas are the most common benign cardiac neoplasm. The exact etiology of the tumor has yet to be fully determined. Hemodynamic instability, intermittent syncope, congestive heart failure, pulmonary hypertension, sudden death and systemic embolization are some presentations of myxoma -3. CardiA 53-year-old man referred to emergency department with typical angina. Neither history of heart diseases in his past medical history nor any risk factors of cardiac diseases was seen in the patient. Electrocardiogram (ECG) showed hyper acute ST elevation in anterolateral and inferior leads. He was a candidate for Primary percutaneous coronary intervention (PCI). Coronary angiography revealed left anterior descending artery (LAD) occlusion at far mid portion. After wiring with some difficulties regarding to thrombotic manifestation of the lesion, thrombosuction (with Export\u00ae AP aspiration catheter medtronic) performed which was unsuccessful and despite several efforts of balloon inflation by the mini trek RX 2*15mm coronary dilation catheter, Abbott vascular, the thrombolysis in myocardial infarction flow grade (TIMI) was 0-1. TIMI grade 0 reveals no penetration of contrast beyond stenosis (100% stenosis) and TIMI grade 1 reveals penetration of contrast beyond stenosis without perfusion of distal vessel (99% stenosis).The procedure terminated unsuccessfully and the patient was admitted to cardiac care unit (CCU). His chest pain resolved 5 hours later and he was both hemodynamically and electrically stable. The day after admission echocardiography showed left ventricle ejection fraction (LVEF) 45% with some regional wall motion abnormalities in LAD territory and a large homogenous LA mass (3.5 \u00d7 3.5cm) attached to inter atrial septum that was protruded to mitral valve inflow . To prevThe present case was an acute anterior ST elevation myocardial infarction (STEMI) with unsuccessful PCI and diagnosis of left atrial myxoma. Non-sclerotic coronary artery diseases (NA-CAD) have several etiologies: coronary vasospasm, Kounis syndrome and coronary embolisms . CoronarData on this area is only based on case reports or case reviews . CoronarTransthoracic echocardiography (TTE) is helpful in diagnosis of myxoma. Initial treatment depends on etiology and amount of the blockage. In some cases, thrombus aspiration is alone sufficient to re-establish the blood flow. In other cases balloonangioplasty or stent insertion is essential to access a TIMI grade 3. Underlying conditions of embolism should be treated uniquely. Anticoagulant treatments in cases of atrial fibrilation, synthetic valve thrombosis and intracardiac thrombosis recommended. Surgery interventions suggested as the best option for some cases including tumors. Embolism caused by myxoma is rare and manifestations are often cerebral. Since in patients with acute myocardial infarction reperfusion time is very decisive, echocardiography may not be the first therapeutic priority. Exactly, like this case that PCI was preceding the echocardiography. To improve prognosis and prevent embolism, surgery is the only treatment of atrial myxoma. Complete resection is recommended to prevent tumor recurrence.The present case was an acute anterior ST elevation myocardial infarction (STEMI) with unsuccessful PCI and diagnosis of left atrial myxoma. Non-sclerotic coronary artery diseases (NA-CAD) should be taken into account in young people with no atherosclerotic risk factors who refer to emergency with acute myocardial infarction.The authors declare no competing interests."}
+{"text": "Hashimoto's thyroiditis can be present with a localized palpable nodule though presentation as a hyperfunction \"nodule\" is extremely rare. The first case of Hashimoto's thyroiditis and hot nodule was reported in 1971 by Warner.131scintigraphy. The nodule disappeared after eight months of sufficient thyroid hormone replacement therapy.We reported a 26-year-old hypothyroid woman in Hashimoto's thyroiditis background with a hyperactive thyroid nodule in both 99mTc and IToxic adenoma in hypothyroid patients can be resolved after levothyroxine (L-T4) replacement therapy. Hashimoto's thyroiditis (HT) is the most common cause of hypothyroidism in iodine-sufficient areas. Hypothyroidism is seen in up to 10 percent of the population, and its prevalence increases with age . This raA 26-year-old woman with family history of hypothyroidism on her mother side was referred to our endocrine clinic because of clinical hypothyroidism and a thyroid hot nodule . After hThe final cytological diagnosis was \u201csuggestive of thyroid neoplasm\u201d. The patient was referred to our clinic because of hot area in the thyroid gland isthmus (compatible with thyroid nodule) according to 99mTc pertechnetate thyroid scintigraphy report. Residual thyroid tissue had low uptake . We requested an I131 thyroid scintigraphy to rule out the false hot nodule report by 99mTc scintigraphy, which confirmed the hot condition of nodule . So we dL-T4 substitution therapy was started again with full dose (700 micg/week) and fine needle aspiration (FNAC) was repeated because of increase in nodule size. Cytology report revealed an adenomatous nodule in background of lymphocytic thyroiditis. The thyroid function tests were acceptable in follow-up .The nodule size diminished to 11*5 mm at the four months full dose levothyroxine replacement therapy and disappeared after 8 months follow-up according to sonography report .Hashimoto thyroiditis is the most common cause of primary hypothyroidism in rich iodine area. The diagnosis of Hashimoto thyroiditis can be confirmed when a patient with hypothyroidism had firm consistency thyroid on palpation and high level of thyroid peroxidase antibody .We reported a young hypothyroid female due to Hashimoto thyroiditis and a thyroid hot nodule in scintigraphy which disappeared with sufficient thyroid hormone therapy. Although there are numerous reports about thyroid nodule associated with Hashimoto's thyroiditis, but the association of hypothyroidism in Hashimoto thyroiditis background with thyroid hot nodule is rare. Scintigraphic findings in Hashimoto thyroiditis are very different such as multinodular goiter, diffuse hyperplasia and some of them mimic solitary nodule but the toxic adenoma is rare condition . To the The first US guided fine needle aspiration cytology (FNAC) report was suggestive of thyroid neoplasm whereas the second FNAC after 6 months reported an adenomatous nodule in a background of lymphocytic thyroiditis. Only available cytology report by Mousavi et al. in three cases showed normal follicular cells with lymphocytic infiltration in two of them . In some reports after six months follow-up, the nodule size decreased between 40-60 % on adequate thyroid hormone replacement therapy , 11 whicIn conclusion thyroid adequate replacement therapy has been advised for hypothyroid patients in Hashimoto thyroiditis background and toxic adenoma."}
+{"text": "Age-friendly environments aim to promote healthy and active aging by building and maintaining capacity across the life course and allow people who have a loss of capacity to continue engaging in activities that they value. Age-friendly community assessments are being conducted worldwide. This qualitative interpretive meta-synthesis (QIMS) aims to create a rich description of older adults\u2019 experiences with outdoor spaces and buildings as well as transportation as part of an age-friendly assessment. The themes that emerged regarding older adults\u2019 experiences with outdoor space and buildings included 1) accessibility and 2) appropriate infrastructure. Regarding transportation, the theme of accessibility included subthemes of 1) availability and 2) affordability. Further reduction indicated that age-friendliness can be conceptualized as environmental justice (EJ). The three areas of EJ including distributional justice, procedural justice, and recognition provide a helpful framework for social workers and their interdisciplinary partners to systematically document and evaluate their age-friendly community efforts."}
+{"text": "Coronary ostial stenosis is an uncommon but potentially lethal complication following aortic root replacement with or without aortic valve replacement . This manifests clinically as acute myocardial ischaemia in the early or late post-operative period. Traditionally, this might be managed with redo open-heart surgery.This case series describes two presentations where urgent percutaneous coronary intervention was used to manage myocardial infarction complicating aortic root surgery with coronary reimplantation. This series highlights the risk of acute myocardial infarction after cardiac surgery involving coronary reimplantation. Emergency percutaneous coronary intervention is feasible and illustrates the importance of shared post-operative care involving the cardiac surgeons and the cardiology team. Acute myocardial infarction is an unusual complication in the days to months following aortic root replacement with coronary reimplantation  and can be due to obstruction of the reimplanted artery. PCI can be considered as a salvage treatment for these patients.Cardiothoracic centres should perform complex aortic root surgery within the setting of an experienced multidisciplinary team involving cardiac surgeons, cardiologists with allied health professional input.Coronary ostial stenosis is an uncommon but recognized complication of aortic root surgery involving reimplantation of the coronaries to a graft and usually presents within the first 6\u2009months following aortic root surgery.This 38-year-old woman with background of Marfan\u2019s syndrome was admitted to hospital following an episode of syncope. Echocardiography (ECHO) showed severe dilation of the ascending aorta with mild mitral and aortic regurgitation (AR) and normal left ventricular systolic function. Computed tomography confirmed dilation at 57\u2009mm. Valve sparing aortic root replacement (David procedure) was carried out 2\u2009months later after which she made an unremarkable recovery, being discharged home 5\u2009days post -operatively. She was not on any regular medications prior to admission and refused any medications on discharge from hospital.Figure\u00a01]. Prior to this, she had experienced a short history of exertional chest pain. Angiography showed the right coronary artery (RCA) was occluded proximally with thrombus and appearance of mechanical disruption of the aorto-ostial anastomosis . Reperfusion was achieved after wiring and export of a large thrombus, followed by ventricular fibrillation (VF) cardiac arrest after which an intra-aortic balloon pump was inserted and the patient intubated. After discussion with the multidisciplinary team (MDT) in the catheterization lab, the decision was to proceed with intravascular ultrasound (IVUS)-guided percutaneous intervention. IVUS confirmed extrinsic mechanical compression at the right coronary neo-ostium with no atherosclerosis present. This was successfully treated with one drug-eluting stent (DES) . Emergency ECHO in the catheterization lab showed severe right and left ventricular systolic dysfunction (LVSD). She was extubated the next day. Echocardiography on the 8th day of admission showed a dilated left ventricle with moderate segmental function and notably dilated failing right ventricle. Her recovery was complicated by ventilator acquired pneumonia and atrial fibrillation (AF) and she was discharged home after 3-week hospital admission.She was readmitted 10\u2009days post -operatively directly from home to interventional cardiology via our regional optimal reperfusion service with an inferior ST-elevation myocardial infarction (STEMI) and cardiogenic shock .This 53-year-old gentleman with known bicuspid aortic valve and dilated aortic root developed decompensated heart failure related to severe AR in the setting of severely dilated aortic root (70\u2009mm). His left ventricular (LV) function was moderately impaired which improved with medical therapy prior to operation. Computed tomography coronary angiography (CTCA) showed trivial plaque without obstructive coronary artery disease. Three weeks later after optimizing his medical treatment, he underwent aortic valve repair with valve-sparing aortic root replacement (David procedure). Post-procedure ECHO showed no AR with good LV function. Aspirin was started in the post -operative period with plan to continue for 3\u2009months. After developing AF, he commenced on treatment dose low- molecular-weight heparin, amiodarone, and beta-blocker. His other medications included an angiotensin-converting enzyme inhibitor, statin, and omeprazole.Figure\u00a03). Therefore, a CTCA was performed which was suggestive of distortion of the proximal RCA . Urgent invasive angiography showed proximal RCA stenosis which was treated with one DES with good angiographic results. Echocardiography at Day 5 showed basal to mid-infero-lateral akinesia with overall moderate LVSD. The right ventricle size was normal with mildly impaired systolic function. Recovery was complicated by lower respiratory tract infection and ongoing AF but he was discharged home 12\u2009days later. At clinic review 2\u2009months post-operatively, he was well with no symptoms of angina or syncope and with mild shortness of breath only on moderate exertion. At follow-up, there was moderate segmental LVSD (consistent with the target vessel infarction), whilst RV function was normal.His inpatient recovery was complicated by recurrent chest pain on mobilizing. Levels of high-sensitivity troponin remained elevated at levels higher than expected in the post-operative period ( high-sensitivity troponin T peak 489\u2009ng/mL) raising clinical concern regarding ongoing ischaemia. ECG showed AF with an uncontrolled ventricular rate and new right bundle branch block  may be identified and corrected including possible refashioning of the coronary button. If this is not possible bypass may be an alternative, however, long-term outcome of a graft may be reduced given the potential for competitive flow through the coronary ostium which would vary through the cardiac cycle.PCI was felt to offer the best emergency salvage and the acute success of the procedure was supported by prompt improvement in haemodynamics with ST-segment resolution. In general, minimization of time to revascularization is the primary driver behind choice of revascularization in STE MI with cardiac bypass surgery being considered when the patient is not suitable for PCI.Cardiogenic shock in these cases may result from the target vessel myocardial infarction with contribution from potential suboptimal myocardial protection which is of vital importance in lengthy aortic root reconstructions (e.g. the lengthy David procedure).Of note, Patient 1 was not on antiplatelet or anticoagulation at time of discharge postoperatively having refused medications. Patient 2 was started on Aspirin post -operatively with a plan to continue for 3\u2009months. Often post -operative patients would be treated with either antiplatelet or anticoagulation for 3\u2009months to reduce the risk of thromboembolic complication and this may have contributed to the acute presentation of Patient 1 .Alongside early revascularization, both patients were treated with IV fluid to expand plasma volumes and treat RV infarction. In patients with RV infarction, hypotension and absence of pulmonary oedema should be treated with plasma expansion, ideally with invasive monitoring. Both these patients also had a degree of LV impairment which can make resuscitation more challenging as RV dilatation can increase diastolic LV pressures and contribute to low output state.These cases demonstrate the potential efficacy of PCI in management of both emergency STEMI and a high-risk non-STEMI. Prompt diagnosis and early multidisciplinary team discussion including with the operating surgeon allowed the patients to receive early and successful revascularization with PCI. Good communication was key to each of these decisions specifically collaboration between the surgical and cardiology teams.Acute myocardial infarction is an uncommon but important complication following aortic root replacement with coronary reimplantation. Extrinsic compression or distortion of the replanted coronary neo-ostium may result in vessel occlusion. Urgent PCI may facilitate emergency revascularization in these patients.Dr Carly Adamson graduated with MBChB from the University of Dundee in 2013. She has developed a keen interest in pursuing a career in cardiology during general medical training and is currently working as a Cardiology Clinical Fellow.European Heart Journal - Case Reports online.This study received grant funding from the British Heart Foundation (RE/13/5/30177).Slide sets: A fully edited slide set detailing this case and suitable for local presentation is available online as Consent: The author/s confirm that written consent for submission and publication of this case report including image(s) and associated text has been obtained from the patient in line with COPE guidance. Conflict of interest: none declared.ytz181_Supplementary_Slide_SetClick here for additional data file."}
+{"text": "The HOPE Project is an ongoing RCT testing whether Senior Corps volunteering for lonely older adults (age 60+) leads to reduced loneliness and improved quality of life\u2014outcomes associated with suicide in later life. We have randomly assigned 130 participants to 12-months of volunteering or active control. We will describe the trial as well as baseline characteristics of participants that may predict non-compliance with volunteering/control. We found no difference between conditions nor demographic characteristics  on non-compliance. Participants demonstrated wide variability in depression at baseline (PROMIS t-score range 38.9 to 71.4) and 18% reported suicide ideation; neither were associated with compliance (p>.20). These preliminary findings indicate that those with more severe mental health symptoms were equally willing/able to engage in volunteering as those without depression and suicide ideation. Volunteering is a highly scalable intervention (given nationwide Senior Corps infrastructure) that may function as upstream suicide prevention."}
+{"text": "Modern laser surgery uses Nd:YAG laser capsulotomy for posterior capsule opacification (PCO) and Nd:YAG laser vitreolysis for symptomatic vitreous floaters (VF). We report a case of acute retinal detachment seven days after Nd:YAG laser capsulotomy combined with Nd:YAG laser vitreolysis and analyze the cause of this complication.A 58-year-old myopic woman complained of decreased visual acuity and symptomatic floaters with her left eye for 3\u2009months. We found she had significant PCO and VF in the posterior vitreous. She underwent neodymium-doped yttrium aluminum (Nd:YAG) laser vitreolysis immediately after Nd:YAG capsulotomy. After 7\u2009days, she complained of rapid vision decline and dark shadows in her treated eye. We found she had a acute severe rhegmentogenous retinal detachment (RD) involving the macula. Then she underwent vitrectomy, retinal reattchment and silicone oil tamponade surgery immediately. Six months later, silicone oil was removed and the best corrected visual acuity (BCVA) of her left eye gradually improved to 10/20 and maintained during a 1-year follow-up period.As myopic patients are at risk of developing retinal detachment, Nd:YAG vitreolysis and capsulotomy should be performed with caution. The laser energy should be as low as possible and careful focus is necessary to reduce interference to the retina. Symptomatic floater is the common disease of the ophthalmological clinics. Because it may interfere with the patients\u2019 quality of vision, many patients are eager to remove their floaters. Webb  reportedA 58-year-old myopic woman visited our clinic, complaining of blurred vision and symptomatic floaters in her left eye for 3\u2009months. Ophthalmologic examination revealed significant Elsching pearl like PCO in her left eye and VF like a thick string in the posterior segment of the vitreous cavityFig.\u00a0a. The BCIn this case, the patient was treated with Nd:YAG laser capsulotomy and vireolysis therapy for PCO and VF in one procedure. Powell et al.  reported"}
+{"text": "Sleep studies examine how pain is associated with poor sleep. However, emergent research suggests poor sleep increases pain and may interfere with activities of daily living (ADL) among older adults. This study will examine how poor sleep may affect next-day pain interference and how this relationship may vary by cognitive function. Ten community-dwelling older adults with lower extremity chronic pain wore an Actigraph GT9X Link for 7 days to measure poor sleep and next-day pain interference . Multi-level mixed models accounted for intra-individual changes in sleep and pain interference and controlled for age, mild cognitive impairment (MCI) and depressive symptoms. Poor sleep among older adults with MCI  was also explored. Across 79 observations, increased number of awakenings  and movement index scores  were associated with increased next-day pain interference. In exploratory analyses, MCI intensified relationships between sleep efficiency , increased awakenings after sleep onset  and increased length of sleep awakenings  on next-day pain interference. This study\u2019s findings suggest poor sleep is associated with next-day pain interference and the ability to perform ADL. Older adults with MCI may be at an increased risk for poor sleep and pain-related interference in ADL. Interventions designed to moderate the association between poor sleep and pain in general and for adults with MCI in particular may be warranted."}
+{"text": "Platelet satellitism is a rare in vitro phenomenon that occurs when an immunoglobulinG antibody directed against the glycoprotein IIb/IIIa complex on the platelet membrane forms in ethylenediaminetetraacetic acid-treated peripheral blood at room temperature ,2. As thThe images presented here were obtained from a 5-year-old child with an upper respiratory tract infection accompanying asthma. Thrombocytopenia was not detected in complete blood count ."}
+{"text": "Combined hepatocellular-cholangiocarcinoma (CHC) is a primary hepatic malignancy with heterogeneously combined histological features of putative hepatic progenitor cells (HPC) origin. We describe a mouse model that exhibits the heterogenous histological and phenotypic finding similar to human CHC.\u2212/\u2212 C57BL/6 mice into syngeneic wild-type pre-conditioned C57BL/6 mice. We confirmed that p53\u2212/\u2212 murine hepatoblasts act as tumor-initiating cells (TICs) that generate CHC both in situ and within metastases. For comparative pathological study, 8 human cases of CHC with stem cell features were recruited by immunohistochemistry and multicolor fluorescence immunostaining.We injected hepatoblasts isolated from p53We identified corresponding areas in murine tumors matching each WHO criteria-described subtype of human CHC. In both murine and human tumors, HPC-like cells in tumor nests and associated stem cell features/traits are suggested histologically to be the progenitor origin of the cancerThe pathological characteristics of murine tumors recapitulate human CHC with stem cell features. These data provide additional comparative pathological evidence that CHC with stem cell features originate from HPCs and validate a model to study this cancer type in vivo. Combined hepatocellular-cholangiocarcinoma (CHC) represents fewer than 3% of human primary liver malignancies. CHC manifests combined histological features of both hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC) . AlthougAlthough the debate whether hepatocellular carcinoma (HCC) arises from stem cells that undergo malignant transformation or alternatively from de-differentiated, transformed mature hepatocytes continues , most evDuring the last 2 decades, there has been active research on tumorigenic role of liver parenchymal cells in experimental animals. A milestone study demonstrated that HPCs, hepatoblasts, and mature hepatocytes all can be transformed in vivo , suggestA minority of these studies have observed tumors with the marked heterogeneity typical of CHC \u201317. One \u2212/\u2212 C57BL/6 fetal hepatoblasts) trans-splenically into livers of inflammatory pre-conditioned syngeneic C57BL/6 mice ..6]. Chol+ tumor cells in murine tumors. Furthermore, the few AFP+ tumor cells are always found to be negative for EpCAM staining confirmed by double immunofluorescence  with hepatocyte regeneration . Specifically, every described subtype of human CHCs matched with corresponding areas in murine tumors. In both murine and human tumors, small, hyperchromatic, \u2018oval-like\u2019 cells in peripherally located tumor nests with stem-like features are suggested histologically to be the progenitor origin of the cancer, since the nests of cells appear to be at the head of a progressive maturation process from the undifferentiated small cells at the periphery to the mature cells at the center [Accumulating evidence from human tissues support the HPC origin of CHC, by identifying HPC-associated traits in tumor architecture; however, the observational nature of the pathological studies precludes drawing hard conclusions regarding cell origin of CHC since histological and biomarker profiles do not necessarily predict the cell of origin . Most exe center . These ae center \u201331.Genetic lineage tracing mediated by Cre recombinase has opened up the door for scientists to explore the cellular events in hepatocarcinogenesis. Numerous mouse models of hepatocarcinogenesis have demonstrated mature hepatocytes primarily generate HCC through malignant transformation under selective pressure induced by chronic inflammatory milieu , 32, 33.4, potentially limiting the genesis of CAFs in our model. It is also possible that the inflammatory milieu created by CCl4 administration cannot fully mimic human chronic liver disease, since liver tumor phenotype has been suggested defined by nature of chronic liver inflammation. Broad desmoplastic stroma found in our margin area of subcutaneous metastasis may support the idea. However, detailed mechanism will be interesting and should be investigated in the future.It is noteworthy that formation of fibrous stroma within murine orthotopic tumor was modest in our model. In human CC, the presence of a dense desmoplastic stroma is a prominent phenotype . The strThe pathological characteristics of murine hepatoblast-derived tumors recapitulate human CHC with stem cell features. The current study provides additional comparative pathological evidence that CHC with stem cell features originate from a progenitor cell. It is not surprising that causal relationship still cannot be demonstrated unless a convincing endogenous biomarker is innovated for in vivo tracking of HPC. Further study into the mechanisms by which HPC participate hepatocarcinogenesis, including epigenetic or somatic changes of tumor initiating cells during malignant transformation and interactions between microenvironment and tumor-initiating cells, will clarify the causal relationship between HPC and hepatocarcinogenesis.Additional file 1: Supporting Tables. List of antibodies and primers.Additional file 2. Supporting materials and methods."}
+{"text": "Vestibular symptoms such as vertigo and imbalance are known to occur in some cochlear implant patients during the immediate postoperative period; however, acute vertigo in implanted children occurring remotely from the postoperative period has not been previously well-described.A three-year-old girl with a history of bilateral sequential cochlear implantation presented with acute labyrinthitis associated with sudden onset of vertigo, balance impairment, and decline in right cochlear implant function 2 years after her most recent implant surgery. We describe her audiological and vestibular testing results during both the acute phase and following medical management and recovery.Acute labyrinthitis should be considered when sudden onset vertigo and/or imbalance presents in children with cochlear implants outside of the perioperative period. Such symptoms should prompt early assessment of cochlear implant function, so that the device can be reprogrammed accordingly. Vestibular loss is common in children with sensorineural hearing loss and with cochlear implants (CI) . FurtherA three-year-old girl with bilateral profound congenital sensorineural hearing loss of unknown etiology underwent right cochlear implantation (CI) at 12\u2009months old and left cochlear implantation at 16\u2009months old. Both implant surgeries were uneventful. Preoperative magnetic resonance imaging showed unremarkable cochlear and vestibular anatomy. Preoperative cervical vestibular evoked myogenic potential (VEMP) testing was normal.Two years post-implantation, the patient experienced the sudden onset of room-spinning vertigo and imbalance, accompanied by a parent-reported change in hearing performance. Cochlear implant programming 4 days after symptom onset demonstrated an increase in right-sided impedances, resulting in non-compliance across 4/22 channels Fig.\u00a0. Device All symptoms resolved entirely by 10\u2009days post-onset. At 29\u2009days post-onset, cochlear implant programming demonstrated that right impedance and stimulation levels returned to baseline. Audiological testing indicated baseline right CI soundfield puretone thresholds and word recognition scores. There were no residual balance deficits on clinical examination 4\u2009weeks after symptom onset. Vestibular retesting 1 year later showed a recovery of peripheral vestibular function, except for continued absence of ocular VEMP responses.Acute labyrinthitis in the setting of a cochlear implant has been described in a limited number of cases in adults, but this is the first pediatric case reported to our knowledge. Itayem and colleagues were the first to describe the clinical and electrophysiological constellation in adults, which they refer to as \u201ccochlear implant associated labyrinthitis.\u201d  They repEndocochlear inflammation has been implicated in other cases of suspected soft device failure. Benatti et al. reported a case of gradual performance decline plus acute onset facial nerve paralysis in an eight-year-old CI recipient, ultimately necessitating explantation . HistoloThis case highlights the utility of preoperative vestibular testing in the pediatric CI population, in which vestibular and balance impairment is common , 3, 7. TLabyrinthitis should be considered when acute onset vertigo occurs in children with cochlear implants remote from the perioperative period. Early device reprogramming and administration of systemic corticosteroids are interventions that may help to expedite recovery. Further research is needed to expand our knowledge of this presentation with regard to etiology and optimal management."}
+{"text": "A 74-year-old diabetic woman presented to the Emergency Department with a high fever and prostration. She had been recently admitted three times for acute urinary retention resulting from an infection with negative urine culture. Laboratory tests at admission showed high C-reactive protein level (16.7 mg/dL), impaired renal function (Cr 2.42 mg/dL), and pus cells (>70/ high-power field). A kidney ultrasound  revealedCandida glabrata. The patient was administered intravenous caspofungin and referred for bilateral nephrostomies with amphotericin instillations. Systemic amphotericin B was to be avoided to prevent further deterioration of her renal function. While under medical treatment, the patient refused surgical treatment and died. The blood cultures were negative and the urine culture yielded fluconazole-resistant Upper urinary tract fungal infections are uncommon and fungal bezoar formation is particularly rareAwareness of the various radiological findings of this rare clinical entity and an increased suspicion in high-risk individuals will help to overcome the challenges related to early diagnosis and proper treatment"}
+{"text": "As cancer management evolves into precision medicine national/international cancer meetings bring novel therapeutic approaches and potentially practice-changing results of clinical studies are presented. This year, the ASCO GI Symposium 2020 had also several updates from ongoing and finalized clinical trials. Although there were no groundbreaking results that impact the daily practice directly, several highly important data from ongoing studies were shared with the audience. In this report, the highlights of the ASCO GI Symposium 2020 are presented with a future perspective. The management of gastrointestinal cancers has substantially evolved into personalized medicine in the last decade, due to a better understanding of molecular underpinnings of each and unique gastrointestinal cancer . While tThe first day of the ASCO GI 2020 Symposium had mostly presentations and discussions on upper gastrointestinal\u00a0(GI) cancers. The FLOT4 trial . At thisHER2 amplification (KEYNOTE 811) . OThe targetability of the pancreatic cancer microenvironment has been investigated in multiple studies. Multiple agents that targeting dense stroma at multiple levels have failed to demonstrate any clinical activity including sonic hedgehog inhibitors and stroma modifying agents . One theBRCA1/2 and PALB2 mutations), which makes it an alternative to FOLFIRINOX in this subset of patients [The progress in homologous recombination deficient pancreatic cancer continues to evolve. The addition of veliparib to cisplatin and gemcitabine did not result in improvement in PFS or OS. However, cisplatin and gemcitabine combination arm achieved an objective response rate of 65.2% among pancreatic cancer patients with homologous recombination deficient (patients .IDH 1/2 mutations are currently actionable mutations with US FDA-approved drugs and are highly detected in biliary tract cancers with most notably among intrahepatic cholangiocarcinoma (approximately\u00a017% of patients) among all biliary cancers [IDH mutations [HER2 amplification, BRAF\u00a0V600\u00a0mutations and HRD pathway [The efficacy of immune checkpoint inhibitors in hepatocellular carcinoma (HCC) continues to evolve with different combinations. Recently, the IMPOWER 150 trial changed the standard of care of advanced-stage hepatocellular carcinoma to the combination of atezolizumab and bevacizumab as a first-line treatment . The com cancers . Current pathway , which wBRAF V600 mutations and specific types of MMR genes as a predictor of worse 12- and 24-month PFS rates [BRAF\u00a0V600\u00a0mutations in MMR-D colorectal cancer patients who are treated with immune checkpoint inhibitors. This novel finding may trigger novel therapeutic approaches for BRAF-mutant MMR-D colorectal cancer patients.The efficacy of immune checkpoint inhibitors in mismatch repair deficient (MMR-D) colorectal cancer has been well established as a subsequent line of therapy. Currently, clinical trials investigating these agents in the first-line setting with promising clinical outcomes . Most ofFS rates . Future BRAF V600 mutations are now among targetable genomic alterations in metastatic colorectal cancer patients. The combination of BRAF \u00b1\u00a0MEK inhibitors with anti-EGFR monoclonal antibodies has achieved promising responses in this highly aggressive subset of colorectal cancer patients leading to improvement in survival and quality of life outcomes [BRAF box is now open and outcomes . Locoregoutcomes . Proceedoutcomes . On the outcomes  suggestioutcomes . These aAnother growing scientific discussion in cancer research embraces the type of biopsy utilized for molecular profiling. Currently, the gold standard of molecular profiling is tissue biopsy. However, at the time of disease progression, performing liquid biopsy-based circulating tumor DNA analysis may provide further information perhaps particularly on disease heterogeneity, as well as novel mutations evolved through the progression of disease that may be actionable. Circulating tumor DNA can be also considered where tissue biopsy is not available or accessible in current clinical practice. Liquid biopsies are often being used in clinical trial protocols where specific molecular alterations are tested during the initial evaluation of patients for biomarker-driven trials. More research is indicated in that field to better characterize the use of liquid-based molecular profiling perhaps, more importantly, their sensitivity to specific molecular alterations such as HER2 amplification and microsatellite instability status.Collectively, the advances in the management of gastrointestinal cancers are highly promising for the future. The cancer management is evolving into personalized medicine than ever before as we better understand disease heterogeneity led by distinct molecular alterations for individual tumor type. Although this progress may bring some challenges such as financial toxicity and requirement more collaborative work to identify patients with specific molecular alterations to successfully conduct biomarker-driven clinical trials, precision medicine provides significant hope for cancer patients for improved quality and length of life."}
+{"text": "Primary cutaneous B-cell lymphomas (PCBCLs) are uncommon diseases with heterogeneous clinical pictures and prognoses. PCBCLs are classified into 3 main subtypes: cutaneous marginal zone lymphoma (PCMZL), cutaneous follicle center lymphoma (PCFCL), and cutaneous diffuse large B-cell lymphoma, leg-type (DLBCL-LT). Each subtype has a distinct clinical presentation and histopathological, molecular and immunologic profiles. They also differ considerably in prognosis and treatment . We repoA 32-year-old woman presented with multiple tender erythematous papules of 1 month\u2019s duration on her right forearm on top of an AV fistula that was made for renal dialysis. She was a known renal failure patient since her early twenties and had been on renal dialysis since then. She reported that lesions on her forearm were increasing in number and size and becoming more painful. Physical examination revealed multiple erythematous papules and nodules on the forearm. They were firm in consistency and tender on palpation. One of the nodules showed superficial ulceration . Given tHistopathological examination revealed grenz zone and diffuse infiltration of large pleomorphic cells occupying the whole dermis . Some miPCBCL-LT is considered an aggressive type of cutaneous B-cell lymphoma. It presents clinically as nodules of violaceous color with frequent ulceration. It is predominant in elderly females. Secondary involvement of other organs can occur shortly after diagnosis that leads to a poor prognosis. Distinction for systemic lymphoma can be difficult . TypicalPrimary cutaneous B-cell lymphomas are rare tumors and often represent a diagnostic challenge. Extensive immunohistochemical studies are crucial to determining the type in addition to laboratory and radiological workups to exclude extracutaneous involvement."}
+{"text": "The management of cardiac arrest during video assisted thoracic surgery is challenging. Checklist use improve the management of operating-room crises.Case presentation: Cardiac arrest (asystole) occurred during anatomical pulmonary resection by minimally invasive surgery. Conversion to thoracotomy was decided (thoracic surgeon and anesthesiologist conjointly) to check for absence of cardiac bleeding and to start cardiac massage (4\u2009min no-flow). After few minutes, ventricular fibrillation occurred and persisted despite shocks. Extracorporeal life support with veno-arterial extracorporeal membrane oxygenation allowed a return of spontaneous circulation (45\u2009min low-flow).The patient survived without central neurologic deficit due to perfect team work process using a crisis check-list (strengthened by a comprehensive simulation program with crisis resource management). A multicenter series showed a prevalence of 1.5% of major intraoperative complications after video assisted thoracic surgery (VATS) anatomical lung resections . The aimA 56-year-old man had smoking history at 40 packs / year, no other history. A suspicious pulmonary nodule was detected in the left lower lobe. FEV1 and DLCO values were respectively 93 and 55%. A basal segmentectomy was planned for this increasingly central nodule according to multidisciplinary meeting.VATS segmentectomy was started according to the World Health Organisation surgical safety checklist. Cardiac arrest (asystole) occurred immediately after placement of the first port . After communication between the thoracic surgeon and anesthesiologist, it was decided to apply the Code Red procedure Fig.\u00a0, to convIn post-operative, coronarography showed coronary disease, without stenting. Then, redo for pericardial hemostasis was done by thoracotomy during the night. Therapeutic hypothermia (36 degrees Celsius) was done over a period of 24\u2009h. The patient was weaned off the pump at Day 2 because of cardiac recovery, then extubated at Day 4 without central neurologic deficit. He was discharged from intensive care unit at Day 7. The left ventricular ejection fraction was 45%. The patient was discharged from hospital at Day 18. Another coronarography with interventricular artery stenting was done at 2\u2009months.In prolonged cardiac arrest with failing conventional measures, rescue by extracorporeal support provides an ultimate therapeutic option . VA ECMOAn in situ intraoperative crisis simulation model for thoracic surgical emergencies was created, implemented, and demonstrated to be effective as a proof of concept at identifying latent threats to patient safety and differentiating the nontechnical skills of trainees and consultant surgeons . We haveOur perfect team work process was strengthened by a comprehensive simulation program focussing on human factors and surgical crisis resource management. Our intraoperative crisis simulation program allowed us to apply perfectly our Code Red for the management of cardiac arrest during minimally invasive thoracic surgery."}
+{"text": "Haemophilus influenzae (NTHi) is an important cause of human illness, including pneumonia and acute exacerbations of chronic obstructive pulmonary disease (COPD). We report here the draft genome of an isolate of NTHi collected from the sputum of a patient presenting with COPD in Tasmania, Australia.Nontypeable  Haemophilus influenzae (NTHi) is an important cause of human illness, including pneumonia and acute exacerbations of chronic obstructive pulmonary disease (COPD). We report here the draft genome of an isolate of NTHi collected from the sputum of a patient presenting with COPD in Tasmania, Australia.Nontypeable  Haemophilus influenzae (NTHi) is a key pathogen that colonizes damaged airways in COPD patients and causes acute exacerbations that contribute to morbidity and mortality (\u2013Chronic obstructive pulmonary disease (COPD) is a serious, progressive condition characterized by a persistent reduction in lung airflow . It has ortality \u20137. Here,2 atmosphere followed by storage at 2 to 8\u00b0C. Bacterial identification was performed using a Bruker matrix-assisted laser desorption ionization\u2013time of flight (MALDI-TOF) mass spectrometer. A single colony of Haemophilus influenzae was suspended in 200 \u03bcl phosphate-buffered saline (PBS), and then genomic DNA was extracted using the DNeasy blood and tissue kit . The genomic DNA preparation was further purified using the High Pure PCR template preparation kit . DNA library preparation was carried out using a Nextera XT DNA library preparation kit  as described previously  website (https://pubmlst.org/hinfluenzae/) (\u2013uenzae/) , assigneuenzae/) \u201317, whicIn conclusion, this study presents the published genome sequence assembly of an NTHi isolate from a case of COPD in Tasmania. The application of genome sequencing has the potential to provide insights into recurrent exacerbations of COPD due to NTHi and the ability to distinguish between relapse and reinfection.This work was conducted in accordance with ethics approval number H0016214 from the Tasmanian Health and Medical Human Research Ethics Committee.JAAECN000000000. The version described in this paper is version JAAECN010000000. The associated BioProject and BioSample accession numbers are PRJNA603840 and SAMN13942196, respectively.This whole-genome shotgun project has been deposited at DDBJ/EMBL/GenBank under the accession number"}
+{"text": "A 69-year-old woman with hyperlipidemia and ocular cicatricial pemphigoid presented with frequent (burden: 47%) symptomatic  premature ventricular complexes (PVCs) with an outflow tract morphology and associated cardiomyopathy [left ventricular (LV) ejection fraction: 40%]. She underwent a negative ischemic workup and was started on guidelines-directed medical therapy without improvement in her LV function.She underwent an initial PVC ablation using activation mapping with an ablation catheter and radiofrequency (RF) energy was delivered from the right ventricular outflow tract (RVOT), LV outflow tract (LVOT), and right\u2013left coronary commissure. Unfortunately, the PVC recurred three months later and her cardiomyopathy continued.. Activation mapping was then performed in the coronary sinus at the level of the anterior interventricular vein with an ablation catheter. Early far-field timing was also noted in this location.She presented for a redo ablation with the Advisor\u2122 HD Grid Mapping Catheter, Sensor Enabled\u2122. Initial activation mapping in the RVOT revealed late timing as was the case in the coronary cusps. Meanwhile, activation mapping with the Advisor\u2122 HD Grid catheter in the LVOT revealed an early fractionated signal just below the left coronary cusp .A coronary angiogram revealed the ablation catheter to be at a safe distance from the left anterior descending coronary artery. Ablation was performed in this region at 20 W with suppression of the PVC achieved after 15 seconds, but it returned after 30 seconds. Attention was then turned to the early signal in the LVOT identified with the Advisor\u2122 HD Grid catheter. Ablation at this site with 35 W eliminated the PVC within five seconds At five months postablation, the patient remained without any further PVCs and with normalization of her LV function. Guidelines-directed medical therapy is gradually being weaned. This case demonstrates the greater value of high-resolution signal detection with the Advisor\u2122 HD Grid catheter in the case of intramural PVCs relative to traditional ablator-based mapping."}
+{"text": "As the novel coronavirus 2019 (COVID-19) has rapidly become a global pandemic, emergency physicians worldwide play essential roles in the frontline management of critically ill patients with COVID-19. In emergency airway management, video laryngoscopes (VL) are recommended over direct laryngoscopy to minimize healthcare worker exposure to aerosolized particles.2Emphasis should be on proper training with the DIY VL, as intubation with VL requires different skills when compared with DL and commercial VL.In conclusion, we believe DIY VL is an acceptable option in clinical settings with limited resources in response to emergency endotracheal intubation in the COVID-19 pandemic.VideoThe video shows a view from the low-cost videolaryngoscope during simulated intubation. Please see Supplementary File."}
+{"text": "Anastomotic leak remains a common complication after esophagectomy. It is associated with perioperative mortality and prolonged hospital stay. Some have suggested that it may also contribute towards poorer long-term survival, although the mechanism is unclear. A French multicenter study defined severe esophageal leak (SEAL) as that which equated to a grade III/IV Clavien\u2013Dindo complication. This study demonstrated a poorer long-term prognosis in patients who developed SEAL following esophagectomy;The present study evaluates outcomes from a single center over a 20-year period.These data may help allay fears that anastomotic leak may potentially contribute towards poorer overall prognosis. The importance of managing leaks appropriately is vital for short-term outcomes. High-volume centers, by definition, have increased experience in managing such complications, and a judicious and aggressive strategy has been shown to lead to minimal risk of perioperative mortality from such leaks."}
+{"text": "Calorie restriction (CR) is a promising strategy to attenuate age-related disease risk. Higher protein diets enhance satiety but may also impair metabolic health and accelerate aging. The effect of higher protein intake on adherence to CR and cardiometabolic markers of healthspan remains unknown. We used the Geometric Framework for Nutrition to examine the association between diet composition and 1) CR adherence; and 2) cardiometabolic risk factors during a 2-year intervention. The CR group consumed higher percentage energy from protein and lower fat at 12 months compared to baseline . Higher protein intake over the 2-year intervention was associated with higher adherence to CR. No effect of diet composition on cardiometabolic risk factors was observed. These findings suggest that dietary protein plays a critical role in adherence to CR with no adverse effects on cardiometabolic markers of healthspan. Part of a symposium sponsored by the Nutrition Interest Group."}
+{"text": "A 69-year-old lady diagnosed with congestive cardiac failure three years prior presented with worsening shortness of breath and bilateral leg swelling. She does not have a history of acute coronary syndrome, however an angiogram performed two years ago revealed a two-vessel disease. She also has hypothyroidism secondary to thyroidectomy. A cardiovascular examination revealed a raised jugular venous pulsation, displaced apex beat, muffled heart sounds, a pan systolic murmur heard loudest at the mitral region with radiation to the axilla and mid inspiratory crepitations over the lung bases with pitting oedema till the level of the mid-shin. These features are suggestive of an acute decompensation of congestive cardiac failure with mitral regurgitation. Her previous echocardiogram revealed an ejection fraction of 28% with global hypokinesia, dilated left ventricle and severe mitral regurgitation. A chest radiograph was done and revealed a very massive symmetrical cardio pericardial silhouette. This heart has a globular appearance, a flask or water bottle configuration with relatively smooth left and right cardiac contours. This is characteristic of pericardial effusion. The patient was treated with intravenous diuretics and supplemental oxygen along with the necessary supportive treatment of cardiac failure."}
+{"text": "The concentration determination of such xenon binding sites in samples of unknown dilution remains, however, challenging. Contrary to 1H CEST agents, an internal reference of a certain host  at micromolar concentration is already sufficient to resolve the entire exchange kinetics information, including an unknown host concentration and the xenon spin exchange rate. Fast echo planar imaging (EPI)-based Hyper-CEST MRI in combination with Bloch\u2013McConnell analysis thus allows quantitative insights to compare the performance of different emerging ultra-sensitive MRI reporters.Xenon magnetic resonance imaging (MRI) provides excellent sensitivity through the combination of spin hyperpolarization and chemical exchange saturation transfer (CEST). To this end, molecular hosts such as cryptophane-A or cucurbit[ It lacks a \u201cbulk pool\u201d that is in chemical exchange with a dilute agent pool that can indirectly provide enhanced sensitivity by accumulating a signal loss from the CEST agent. The hyperpolarizable noble gas 129Xe, however, has been used with CEST detection in an approach coined Hyper-CEST because it only engages in transient, non-covalent binding . We demonstrate in this study that a careful analysis of saturation transfer spectra acquired with a set of different RF saturation pulse settings allows determination of all these parameters by using the full Hyper-CEST (FHC) solution ) = tot]/[Xe]) as given in    are conso 150 \u03bcM . This isgiven in . We can [Xe] see . This yi \u00b1 2) \u03bcM . This wafB in this case thus requires at least [CrA-ma]min \u2248 1 129Xe NMR spectroscopy. The important prerequisite for the absolute quantification method proposed in this present work is that both the Xe host occupancy When multiple samples with different host concentrations are under investigation, the saturation pulse strengths should be chosen accordingly. This ensures that the CEST effect responses remain within a reasonable dynamic range of the Xe depolarization rate . Furtherz-spectra is the experimental confirmation that a reproducible steady-state magnetization has been reached after each gas delivery for the individual acquisitions. Another aspect to consider is a variable protonation at the host portals that might impact the Xe affinity in different pH. While the concept of pH is irrelevant in the DMSO conditions used here, such pH-depending protonation might be a relevant aspect in aqueous solutions and should be adjusted with appropriate buffer systems for comparison studies.This condition can be easily fulfilled in in vitro experiments where the repetitive bubbling with the Xe gas mix ensures that the solution is always chemically saturated with the gas according to the Ostwald coefficient. The fraction of bound Xe is determined by the binding constant and remains unchanged during the experiment. A stable baseline in the Overall, this exchange parameter mapping technique is (for now) only reliable and attractive for in vitro applications where different hosts for reversible binding of Xe shall be compared side by side with two clearly defined spin pools. Chemical engineering that aims to tune the exchange rate is a prime example of this. Translation to biological systems requires more detailed separation of the individual components as a live cell assay would clearly increase the number of involved spin pools (Xe and host can both be present in different micro-environments). In vivo applications would also be limited until there is further knowledge available regarding the complete exchange network of all participating pools, the occupancy of hosts, and the solubility of Xe and how this can be compared in different tissues and if any correction methods can be applied to obtain absolute quantitative numbers.It is noteworthy that a quantification based on this approach requires a spectrally resolved CEST-response because the math framework otherwise fails to derive the exchange kinetics. Therefore, hosts providing exchange kinetics that appear fast on the NMR timescale and only cause a broad MT effect  cannot 129Xe in CEST studies has certain advantages over exchanging 1H nuclei: First, it allows combination with spin hyperpolarization  = 50 129Xe  was obtained with a continuous-flow (0.35 SLM) custom-designed polarizer  = 2340 Circa 25 % Xe spin hyperpolarization of a 2% Xe gas mix {2, 10, 88}-vol.% of {Xe, Nolarizer  via spinT = 295 K). For excitation and detection, a 10 mm inner diameter double-resonant probe (129Xe and 1H) was used. The 129Xe Hyper-CEST images were obtained with a 129Xe Hyper-CEST echo-planar imaging [k-space sampling where only 32/1.68 = 19 lines of the full k-space have been acquired [NMR experiments were done at shown in , such in imaging  pulse seacquired ); doubleacquired ); echo tz-spectra from different saturation parameters (see figure captions). A mask was applied to exclude pixels outside the phantom area. All calculations and fitting routines were implemented and performed in Matlab 7  on a standard desktop PC  as described in [qHyper-CEST analysis was performed based on the imaging series that yielded pixel-wise ribed in . Pixel-wBy extending the qHyper-CEST concept to imaging with pixel-wise analysis, we mapped the unique fingerprint of a specific Xe-host system within a particular chemical environment. We could demonstrate the determination of absolute host concentrations as an extended analysis of the previously introduced FHC approach. Our results provide faster insights into the Xe-host binding kinetics since multiple Xe-host systems can be screened at once.This quantitative MRI approach demonstrates the potential of the FHC approach for data sets with increased spatial resolution compared to initial qHyper-CEST analysis. It will be of particular interest for in vitro tests of newly developed Xe biosensors but also for quantitative physical chemistry studies of Xe-binding host structures where the simultaneous detection of multiple samples overcomes the challenges of introducing hyperpolarized spin reporters."}
+{"text": "Psychotropics use to manage behavioral and psychological symptoms of dementia (BPSD) in nursing homes (NHs) has been the focus of policy attention due to their adverse effects. We hypothesized that NHs with lower nursing staffing would have greater reliance on psychotropics use to control BPSD. A NH deficiency of care can be cited for inappropriate psychotropics use (F-tag 758). The association between the occurrence of F-758 tags and nurse staffing in residents with dementia was examined using the 2017-18 Certification and Survey Provider Enhanced Reporting data . Staffing measures included nursing hours per resident day (HPRD) and registered nurse (RN) skill-mix. Generalized linear mixed models that included covariates  estimated the magnitude of the associations. There were 1,872 NHs with F-758 tags indicating inappropriate psychotropics use for NH residents with dementia. NHs with greater RN and certified nurse assistant (CNA) HPRD had significantly lower odds of F-758 tags  and similar findings were found in NHs with greater RN skill-mix . There were no significant associations between the occurrence of F-758 tags and licensed practice nurse and unlicensed nurse aide HPRD. This study found that RN and CNA staffing had inverse associations with inappropriate psychotropic use citations among residents with dementia. NHs with higher RN staffing ratios may be better able to implement alternatives to pharmacological approaches for BPSD. It is suggested that NHs be equipped with adequate nurse staffing levels to reduce unnecessary psychotropics use."}
+{"text": "The treatment strategy for aortic valve and lung cancer patients includes concomitant or two-stage procedures. Conventional simultaneous operations are usually performed under the median sternotomy.A 72-year-old man was admitted to our hospital after experiencing chest tightness after activity for two months. Aortic valve regurgitation had been confirmed when squamous cell carcinoma of the lung was discovered. The therapeutic strategy for these patients is controversial. Considering the potential risk of tumour metastasis and the risk of cardiopulmonary bypass (CPB), we recommended concomitant\u00a0transcatheter aortic valve implantation (TAVI) and a lobectomy. A trans-apical TAVI with left-sided intercostal thoracotomy was successfully performed, followed by an immediate video-assisted thoracoscopic surgery (VATS) lobectomy and selective lymph node dissection.We suggest that a one-stage surgery of pulmonary resection following TAVI is an acceptable and safe choice after careful evaluation and should be performed as soon as possible in response to lung cancer in elderly patients with aortic valve disease. Lung cancer can be incidentally discovered during preoperative evaluation of aortic valve regurgitation. The treatment strategy includes concomitant or two-stage surgery. The conventional simultaneous operation for valve replacement and lung resection is usually performed under the median sternotomy. Here, we describe a way to treat both diseases through concomitant trans-apical TAVI and VATS lobectomy and selective lymph node dissection, avoiding the adverse effects of CPB, repeated anaesthesia and pain without delaying lung cancer treatment.A 72-year-old male patient was admitted to our hospital. He had been experiencing chest tightness and blood in his sputum for two months. A transoesophageal ultrasound revealed moderate to severe aortic valve regurgitation Fig.\u00a0a, a resuLung cancer and severe valvular heart disease occasionally coexist. The therapeutic strategy for these patients is controversial. The incidental finding rate of lung nodules on CT scans for TAVI is about 18% , and a fThe number of elderly patients with simultaneous aortic valve disease and lung tumours is increasing. We suggest that a one-stage surgery of pulmonary resection following TAVI is an acceptable and safe choice after careful evaluation and should be performed as soon as possible for elderly patients with lung cancer and aortic valve disease."}
+{"text": "Ablation at this region terminated the AFL within a few seconds and the AFL was no longer inducible postablation. This case demonstrates the use of the high-resolution Advisor\u2122 HD Grid catheter using high-density wave technology to analyze orthogonal electrograms at a single location, thereby facilitating rapid identification and treatment of AFL.A 75-year-old woman with hypertension and symptomatic drug-refractory paroxysmal atrial fibrillation (AF) elected to undergo AF ablation. Pulmonary vein isolation was performed with a wide antral circumferential ablation. As her esophagus was bordering the left-sided ostia and our left-sided ablation lesion set was more antral, we were also able to isolate her posterior wall. Rapid atrial pacing postablation induced an eccentric atrial flutter (AFL) with a cycle length of 260 ms. Activation mapping with the EnSite Precision\u2122 mapping system with the Advisor\u2122 HD Grid Mapping Catheter, Sensor Enabled\u2122 catheter revealed localized reentry at the left atrial appendage/left superior pulmonary vein ridge. At the critical location, significant compression was seen on the activation color map with a fractionated signal with a duration of 190 ms, essentially encompassing two-thirds of the tachycardia cycle length"}
+{"text": "An 18 yr old caucasian man presented with neurological symptoms and breathlessness. Echocardiography demonstrated a left ventricular abnormality of unclear aetiology. The patient was referred onwards to our unit for further assessment by cardiac magnetic resonance. Imaging was performed on a 1.5 T Philips Intera Acheiva, using a five element phased-array surface coil.On steady state free precession (SSFP) cine images the appearances were of marked left ventricular hypertrophy with partial cavity obliteration. Left ventricular cavity volumes were reduced and ejection fraction was 54%. Early post contrast inversion recovery gradient echo (IRGE) images showed an area of low signal within the LV cavity distinct from the myocardium. The mass was markedly hypointense to both myocardium and the blood pool. Delayed IRGE sequences 10 minutes following the administration of contrast demonstrated widespread subendocardial hyperenhancement in all myocardial segments sparing only the basal septum. CMR was able to confidently establish the diagnosis of endomyocardial fibrosis with a large left ventricular thrombus burden.The patient had no history of foreign travel or malnutrition, making a vasculitis the most likely aetiology.Baseline blood testing demonstrated a mild eosinophilia of 17%, a C reactive protein of 27 mg/L  and an erythrocyte sedimentation rate of 27 mm/h . Further imaging demonstrated normal renal arteries on MR angiogram. However CT thorax demonstrated pulmonary haemorrhage and MRI brain demonstrated white matter abnormalities in the cerebral cortex. These findings were in keeping with the clinical diagnosis of vasculitis, Although autoantibodies were all normal, the most likely process is a variant of Churg Strauss.Cardiac MR was able to establish the diagnosis of endomyocardial fibrosis which was pivotal in identifying the underlying vasculitic disease process."}
+{"text": "Our type system addresses this difficulty with a novel combination of refinement types and fractional ownership types. Fractional ownership types provide flow-sensitive and precise aliasing information for reference variables. ConSORT interprets this ownership information to soundly handle strong updates of potentially aliased references. We have proved ConSORT sound and implemented a prototype, fully automated inference tool. We evaluated our tool and found it verifies non-trivial programs including data structure implementations.We present ConSORT, a type system for safety verification in the presence of mutability and aliasing. Mutability requires"}
+{"text": "The shotgun injury may cause large-scale bone and soft tissue destruction especially when people get shot from a very close range. Here we present a case of Gustilo type IIIC open fractures of the proximal tibia with vascular injury, large bone and soft tissue defect treated with Masquelet technique in combination with cross-leg pedicle flap.A 34-year-old man presented with open proximal tibial fracture of Gustilo type IIIC, AO/OTA (Arbeitsgemeinschaft f\u00fcr Osteosynthesefragen/Orthopaedic Trauma Association) classification 41-C2.3, caused by a shotgun injury from very close range (2 m). The wound was complicated with anterior tibial artery injury and segmental bone loss. After radical debridement, the fracture was temporarily stabilized with external fixator, followed by double plate fixation with cement spacer filled into the bone defect in accordance with the Masquelet technique. The soft tissue defect was covered with a cross-leg pedicle flap. At 3 months after trauma, the cement spacer was replaced by mixed autologous and synthetic bone graft. The fracture had successfully healed by 12 months after trauma.When the integrity of lower leg vessels is doubtful, the Masquelet technique in combination with cross-leg pedicle flap is an effective and safe alternative treatment for this condition.We recommend to manage Gustilo type IIIC open fractures of the proximal tibia with bone defect with Masquelet technique in combination with cross-leg pedicle flap especially when the free flap technique is relatively contraindicated or trauma surgeon is not a highly-skilled microsurgeon. TradiVery few studies have reported clinical and radiographic outcomes of Gustilo type IIIC open fractures caused by shotgun injury . Here we2The case report has been written according to the SCARE 2018 guidelines .2 open wound. Radiographs indicated comminuted fracture with bone loss about 7 cm and multiple shotgun pellets . We filled the bone defect with vancomycin and gentamicin loaded cement spacer . The skiWe replaced the cement spacer with mixed autogenous and synthetic bone graft at 12 weeks after trauma ,6. At 123The treatment of open fracture involves segmental bone loss and large soft tissue defect along with major vessel injury caused by shotgun injury is challenging. Free vascularized osteocutaneous flap such as fibula and iliac crest flap have been reported as reliable flap with satisfactory results . HoweverBone transport is also an effective technique for long bone defects. However, the prolonged external fixator use may cause stiffness of ankle and knee, low quality of life and potential pin tract infection are also the drawbacks.Generally, nonvascularized bone graft is not advocated for reconstruction in bone defects over 5 cm. Masquelet et al. introduced a technique to treat bone defects of more than 5 cm with non-vascularised bone graft in 2000 . The incMasquelet introduced a technique to treat segmental bone loss . ProponeThe cross-leg pedicle flap is a historical flap for treating lower extremity trauma . When fr4This case report highlights the value of treating segmental bone loss, large soft tissue defect and vascular injury caused by shotgun injury using the Masquelet technique in combination with cross-leg pedicle flap coverage. We recommend this effective and safe method to restore bone and soft tissue defect simultaneously without the need for microsurgery while ensuring an excellent outcome.All the three authors disclose any financial and personal relationships with other people or organisations that could inappropriately influence of our work.We have no source of funding for our research.We have the IRB approve letter attached as supplement data.We have consents from the patient and authors.Chun-Yen Chen\u2019s work was Data collection, and original draft.Yung- Cheng Chiu\u2019s work was study design and methodology providing.Cheng-En Hsu\u2019s work was data analysis or interpretation and writing the paper.Out was not a human study.Yung- Cheng Chiu AND Cheng-En Hsu.Not commissioned, externally peer-reviewed."}
+{"text": "We study two models: a pessimistic model where flows interfere in a worst-case manner along equal-cost shortest paths, and an optimistic model where flows are routed in a best-case manner, and we present a complete picture of the algorithmic complexities. We further propose a strategic search algorithm that checks only the critical failure scenarios while still providing correctness guarantees. Our experimental evaluation on a benchmark of Internet and datacenter topologies confirms an improved performance of our strategic search by several orders of magnitude.To ensure a high availability, communication networks provide resilient routing mechanisms that quickly change routes upon failures. However, a fundamental algorithmic question underlying such mechanisms is hardly understood: how to verify whether a given network reroutes flows along"}
+{"text": "Kidney stones (KS) versus Nephrocalcinosis (NC) all arrows pointed upwards to indicate an increase.The original publication of this article  containeKidney stones (KS) versus Nephrocalcinosis should point downwards to indicate a decrease. The exception is Urinary proteins, this remains an increase.However, as shown in the data from the tables: all arrows in The incorrect Fig.\u00a0 and corr"}
+{"text": "After carotid artery stenting, retrieval of the embolic protection device can sometimes be difficult due to incomplete stent expansion, stent fracture, vasospasm, and vessel tortuosity. In this technical report, we describe a novel rescue technique used in a patient with diffuse calcific atherosclerosis of the left common and proximal left internal carotid arteries who underwent left internal carotid artery stenting with cerebral protection and in whom, due to an under-expanded proximal carotid stent strut in relation to a densely calcified plaque, we were initially unable to advance the retrieval device. Carotid artery stenting is the preferred treatment for patients with symptomatic carotid stenosis and who are considered \u201chigh risk\u201d for carotid endarterectomy . The useA middle-aged patient presented to our clinic with a past medical history of multiple prior strokes, hypertension, hyperlipidemia, chronic kidney disease, and chronic obstructive pulmonary disease (COPD). The patient developed stroke symptoms while in rehabilitation for a fractured hip after a fall. On work-up, the patient was found to have extensive atherosclerotic changes throughout the cervical vasculature, including bilateral severe to critical internal carotid artery (ICA) stenoses, right vertebral artery occlusion and moderate stenosis of the left vertebral artery origin Figure  and 1B.\u00a0The patient underwent right carotid endarterectomy but unfortunately developed hoarseness postoperatively due to vocal cord palsy. The patient also had a preexisting type two aortic dissection. For the treatment of her high-grade left internal carotid artery (ICA) stenosis, she opted for minimally invasive endovascular stenting. The procedure was performed under monitored anesthesia care (MAC) using dexmedetomidine (Precedex\u2122) with continuous cardiovascular monitoring. A 65 cm long 6 French Super Arrow-Flex\u00ae sheath  was placed in the proximal descending aorta and a 6 French Envoy\u00ae guiding catheter  was used to select the origin of the left common carotid artery (CCA). There was a severe diffuse atherosclerotic disease of the left CCA and ICA with extensive irregular atherosclerotic plaque formation and multiple plaque ulcers Figure . Two areAn 8 x 36 mm Carotid Wallstent\u00ae (Boston Scientific) was then deployed in the left cervical ICA, spanning from the C3 to C7 level and extending into the left CCA Figure . Due to Despite successful angioplasty, the capture device for the EPD would not advance over the wire. We then advanced a 125 cm soft-tipped 5 French Sofia\u00ae intermediate/distal access catheter (MicroVention\u00ae Terumo) Figure , arrow aTwo 8 x 29 mm overlapping Carotid Wallstents (Boston Scientific) were then placed across the severely diseased left CCA Figure -C up to There have been descriptions of rescue strategies to retrieve trapped embolic protection filters including external carotid compression, rotation of the head to the contralateral side to change carotid angulation, use of different catheters like the vertebral and JR-four catheters and carotid endarterectomy (CEA) -8. CEA fHaving a \"plan B\" can make all the difference between a successful and unsuccessful procedural outcome. The navigability of a distal access catheter makes it a useful tool not only for intracranial interventions but also as a rescue tool to recapture a trapped EPD. Our rescue technique has not been described in the literature and could prove very useful in difficult situations during carotid artery stenting. Other helpful considerations include the use of docking wires which provide extra length to EPD wires and the \"buddy-wire\" technique which can help provide stability and guidance for a catheter."}
+{"text": "We report a 62-year-old woman who was scheduled for an elective Tirone David valve sparing aortic root replacement under cardiopulmonary bypass. Within the next few hours, the patient developed bilateral acute ischemia of both lower limbs. A thoracic and abdominopelvic computed tomography scan showed acute Type A aortic dissection with a perforation at the brachiocephalic arterial trunk and a complete malperfusion of the inferior mesenteric and iliac arteries. Iatrogenic acute Type A aortic dissection (AAAD) following cardiopulmonary bypass may occur intraoperatively (with recognition during the primary cardiac surgery), within the first 2 weeks, classified as early postoperative AAAD or late (>30 days after primary heart surgery).We report the case of a 62-year-old woman without previous medical history. After discovery of an aortic murmur, echocardiography demonstrated 3+ aortic insufficiency and an aneurysm of the ascending aorta. Computed tomography (CT) scan revealed an ascending aortic diameter of 70\u2009mm.The patient underwent an elective David valve sparing aortic root replacement.Within the next few hours, the patient developed bilateral acute ischemia of both lower limbs and asymmetric blood pressure in the upper limbs. Transthoracic and transesophageal echocardiography revealed a flap in the distal ascending aorta, the aortic arch, and the descending thoracic aorta, suggestive of acute aortic dissection. A thoracic and abdominopelvic CT scan with three-dimensional volume rendering was performed. It showed an acute Type A aortic dissection with fenestration at the brachiocephalic arterial trunk and complete malperfusion of the inferior mesenteric and iliac arteries 23.Despite maximal management with revascularization of the lower extremities by axillofemoral bypass, total colectomy, and stenting of the abdominal aorta, evolution was unfavorable with multiorgan failure leading to the death of the patient 72\u2009hours later. Iatrogenic AAAD is a rare complication that must be recognized early to deliver the appropriate therapy. Intraoperative diagnosis may be difficult."}
+{"text": "Multifocal choroiditis (MFC) is a relatively uncommon bilateral inflammatory chorioretinopathy affecting Caucasian young women with myopia. We present images from a case of completely unilateral multifocal choroiditis following EBV-positive mononucleosis that demonstrated a dramatic clinical response to immunosuppression.A 20-year-old woman with bilateral high myopia (\u22126D) and a documented normal prior retinal examination presented with visual loss in the right eye 2 months following confirmed Epstein-Barr virus (EBV) positive mononucleosis. Ophthalmoscopic examination showed completely unilateral placoid lesions of variable age. The left eye was unaffected. Fluorescein angiography revealed active leakage, especially in the parafovea. Spectral domain optical coherence tomography (SD-OCT) demonstrated sub-retinal pigment epithelial nodular deposits, some of which were confluent with overlying intra-retinal fluid and indistinct margins. Upon treatment with the immunosuppressant azathioprine there was significant resolution of the lesions in her right eye along with improvement in vision.This is a rare case of completely unilateral MFC following an episode of EBV positive mononucleosis that showed a dramatic response to immunosuppression. MFC is a relatively uncommon, chronic, bilateral inflammatory chorioretinopathy that predominantly affects young healthy myopic white women between the second and sixth decades of life with no known associated systemic disease or other recognized ocular syndromes . It is cA 20-year-old woman presented with visual loss in the right eye. She had high myopia bilaterally (\u22126D). A normal prior retinal examination was documented 5 years prior to presentation. A routine contact lens exam 1 year prior to presentation recorded 20/20 vision. Review of systems was notable for confirmed EBV positive mononucleosis 2 months prior to the development of ocular symptoms. At that time, she had headaches, fatigue, sore throat and lymphadenopathy. No eye pain, redness or light sensitivity was noted. EBV mononucleosis was confirmed using the heterophile antibody (Monospot) test. The patient reported trouble with distance vision 2 months after the mononucleosis was diagnosed.At presentation 6 months after her symptoms began ophthalmic examination of the right eye revealed quiet anterior chambers with scant anterior vitreous cells only in the right eye. Retinal examination showed punched out nummular chorioretinal lesions admixed with patchy areas of coarse pigmentation overlying subretinal fibrosis. The completely unilateral placoid lesions of variable age were associated with an overlying fibrinous band in the macula and a peripheral Schlaegel line Fig.\u00a0a-arrow. Extensive systemic workup was performed. Given the history of EBV and the presence of sub-RPE deposits, lymphoma was ruled out with a chest CT scan. It only revealed reactive cervical lymph nodes. No hepatosplenomegaly was noted. Complete blood count with differential demonstrated a slight increase in lymphocytes (59.9% reference range 10\u201350%). The rest of the differential was within normal limits. RPR was non-reactive and the FT-ABS was negative. Interferon-Gamma release assay (QuantiFERON-TB gold) was negative. West Nile antibodies were negative, Brain MRI was negative for any CNS lesions or cerebral vasculitis. Liver enzymes were mildly raised: ALT 94\u2009IU/L (reference range 7\u201352\u2009IU/L) and AST 62\u2009IU/L (reference range 15\u201340\u2009IU/L). The pattern of elevated aminotransferases and lymphocytosis in the setting of EBV positivity was considered to be consistent with infectious mononucleosis [Given the activity of the MFC, the patient was started on an initial empiric high dose trial of prednisone. As the prednisone was tapered, she was switched to the immunosuppressant, azathioprine. There was significant interval resolution of the inflammatory nature of the lesions in the right eye. Over the following 8 months dramatic improvement was demonstrated resulting in consolidation of the subretinal lesions and decreased inflammation Fig.\u00a0. Vision During the patient\u2019s course, she self-discontinued the azathioprine. During that three-month interval, there was an increase in the activity of the multifocal lesions evident on her exam and new areas of inflammation Fig.\u00a0 and a coOur patient\u2019s prior history of EBV- positive mononucleosis was established with the heterophile antibody test which is an agglutination assay that detects anti-red blood cell antibodies produced as part of a polyclonal antibody response occurring during EBV infection. Heterophile antibody tests are rapid, cheap and specific tests with a result that is interpreted as positive or negative (for agglutination) and can be performed from the onset of symptoms of infectious mononucleosis , 7. A poThe development of multifocal choroiditis may be one of the delayed sequelae of EBV infection. Chronic EBV infection has been conjectured to predispose to molecular mimicry and affect various major organ systems including the eye . InteresAzathioprine is a steroid sparing immunosuppressant, mainly used in rheumatologic diseases. The patient had continuous improvement of her inflammatory lesions in the right eye after initiating azathioprine. The visual improvement was somewhat surprising, given the extent of associated fibrosis. The patient showed dramatic improvement in her retinal lesions over 8 months. It seems unlikely that this dramatic visual improvement over 8 months was unrelated to immunosuppression with azathioprine. She had 20/200 vision for a year with persistent active lesions before initiating azathioprine that completely subsided with vision improvement from 20/200 to 20/40 with immunosuppression. This course does not appear to follow the natural history of the disease , rather There is considerable value of titrating immunosuppression to the disease activity as evidenced by the reduced number of lesions along with improvement in vision with azathioprine immunosuppression. In fact, our patient demonstrated test-retest reliability when she self-discontinued the medicine Figs.\u00a0 and 9 ThIn summary, we present a completely unilateral case of MFC temporally correlated with EBV infection that demonstrated a dramatic improvement in vision and lack of involvement of the fellow eye with aggressive immunosuppression."}
+{"text": "We report a case of a 45-year-old male suffering from arterial hypertension who was found to have an aortic coarctation with marked hypertrophic compensatory collateral arterial circulation. Although coarctation is relatively rare, this must be included in the differential diagnosis in patients with arterial hypertension with a positive gradient between upper and lower limbs. A 45-year-old male was evaluated for arterial hypertension. A pressure gradient (18\u2009mm Hg) between upper and lower limbs was noted. Among the various diagnostic examinations, the patient underwent multidetector computed tomography (MD-CT) angiography. This showed an aortic coarctation at the level of isthmus proximal third of thoracic aorta with significant hypertrophic compensatory collateral arterial circulation . At theAortic coarctation in adults is generally recognized via systemic arterial hypertension associated with a pressure gradient between the upper and lower extremities."}
+{"text": "There is a known link between myocardial fibrosis as defined by late gadolinium enhancement (LGE), severity of left ventricular remodeling and ventricular arrhythmias in hypertrophic cardiomyopathy (HCM). Noninvasive quantification of fibrosis may offer the possibility for risk stratification. Due to their often diffuse and blurred character these lesions remain difficult to differentiate from healthy myocardium in several cases.Recent studies showed the superiority of Gadobenate dimeglumine (Gd-BOPTA) compared with Gadopentetate dimeglumine (Gd-DTPA) in distinguishing infarcted from viable myocardium which can be explained by the higher relaxivity of Gd-BOPTA. Therefore we hypothesized that Gd-BOPTA may have advantages over Gd-DTPA for depiction of non-ischemic fibrosis.We prospectively enrolled eight Patients with clinically established HCM and positive LGE during clinical routine scan with 0.2 mmol/kg Gd-DTPA (0.5 molar). They underwent a second scan at least 72 hours apart from the first CMR exam with 0.2 mmol/kg Gd-BOPTA (0.5 molar) using the same CMR protocol and sequence parameters. None of the patients had renal failure, coronary artery disease or general contraindications for CMR.LGE was assessed in a short axis stack acquired 15 minutes after contrast administration by using state of the art inversion recovery gradient echo sequence  with a TI adjusted to null signal from normal myocardium. Positive LGE was judged positive if signal intensity was above mean + 2 standard deviations of remote myocardium.Signal intensities of injured myocardium, healthy myocardium, LV cavity and air were measured in identical locations by using anatomical landmarks in dedicated software . Signal to noise ratio (SNR) and contrast to noise ratio (CNR) were calculated.We observed no complications relating to contrast administration. Both the SNR of injured myocardium  and the CNR between healthy and injured myocardium  were significantly higher with Gd-BOPTA. SNR of LV cavity was significantly higher  with Gd-BOPTA resulting in a poorer contrast between injured myocardium and blood which did not affect the diagnosis since LGE was exclusively non-subendocardial.Gd-BOPTA improves the visualization of non-ischemic fibrosis in HCM. This may offer the potential for a more accurate quantification of focal myocardial fibrosis in this setting."}
+{"text": "In vivo1H magnetic resonance spectroscopy studies have found elevated brain glutamate or glutamate + glutamine levels in bipolar disorder with surprisingly high reproducibility. We propose that the elevated glutamate levels in bipolar disorder can be explained by increased pyruvate carboxylase-mediated anaplerosis in brain. Multiple independent lines of evidence supporting increased pyruvate carboxylase-mediated anaplerosis as a common mechanism underlying glutamatergic hyperactivity in bipolar disorder and the positive association between bipolar disorder and obesity are also described. The biotin-dependent pyruvate carboxylase employs pyruvate and the polar molecule bicarbonate instead of COde novo glutamate synthesis via pyruvate carboxylase-mediated anaplerosis in astrocytes  in vivo1H MRS studies of bipolar disorder have found elevated glutamate or glutamate + glutamine with surprisingly high consistency  for the pooled studies that reported glutamate + glutamine in all area of the brain . Analyses of medicated and non-medicated bipolar disorder patients found that the effect size for glutamate level increase in non-medicated patients was much higher  than in medicated patients , consistent with that medications decreased brain glutamate. Increased serum \u03b1-ketoglutarate and glutamate and increased glutamate in post-mortem brain tissue samples obtained from bipolar disorder individuals have also been reported (n = 20) were significantly higher in both mania phase  and remission  than matched controls  (n = 15) was found to be significantly higher than in the normal control samples   . In contde novo glutamate synthesis (in vivo1H MRS, serum and post-mortem studies can be readily explained by increased pyruvate carboxylase-mediated anaplerosis in brain of patients with bipolar disorders. This explanation is also supported by the significant comorbidity between bipolar disorder and obesity as described in section Glutamate, Bipolar Disorder, and Comorbid Obesity.It is well-known in the neurochemical literature that brain relies on pyruvate carboxylase-mediated anaplerosis for ynthesis \u201321. Beca1H MRS studies have reported transient elevation of glutamate or glutamate + glutamine levels in activated brain tissue in response to stimuli or tasks (de novo synthesis of glutamate from glucose (in vivo13C MRS studies of anesthetized rodents found that acute stimulation did not increase pyruvate carboxylase-mediated anaplerotic flux rate in brain (A large body of evidence has consistently demonstrated that there is a significant mismatch or uncoupling between glucose utilization and oxidative metabolism in stimulated brain accompanying increased glutamatergic activities . Similaror tasks . In precor tasks . These r glucose . It shou glucose . Recent in brain , 54.2. As lactate accumulation can only account for a portion of the large decrease in oxygen-to-carbohydrate index accompanying the mismatch between stimulation of glucose utilization and oxidative metabolism, it has been proposed that increased de novo glutamate synthesis via pyruvate carboxylase-mediated anaplerosis contributes to the large decrease in oxygen-to-carbohydrate index when glucose utilization outpaces oxidative metabolism during stimulation of brain activity (The molar ratio of the arterio-venous difference of oxygen to glucose + \u00bd lactate is commonly referred to as the oxygen-to-carbohydrate index. The oxygen-to-carbohydrate index is reduced when more glucose and lactate are taken up into the brain than are oxidized to COactivity , 51.31P and 1H MRS studies have found reduced oxidative phosphorylation and elevated lactate and glutamate + glutamine levels in brain in bipolar disorder, indicating impaired oxidative metabolism (18F]fluorodeoxyglucose have reported small or no differences between healthy controls and bipolar disorder patients in glucose utilization rate in the prefrontal cortex or brain as a whole (31P and 1H MRS and PET results, taken together, indicate that there is a considerable mismatch between oxidative metabolism and glucose utilization in brain in bipolar disorder. Therefore, the elevated glutamate + glutamine levels are consistent with mitochondrial dysfunction and a chronic mismatch between glucose utilization and oxidative metabolism in bipolar disorder accompanied by incomplete carbohydrate oxidation and increased pyruvate carboxylase-mediated anaplerosis.tabolism , 42, 43. a whole \u201358. Ther a whole \u201358. Cons1H MRS was found to be more pronounced with higher body mass index (Bipolar disorder and obesity are positively associated \u201362 with ss index . In compss index .de novo fatty acid synthesis [(in vivo1H and 13C MRS study of a mouse model of high-fat diet consumption has also found significantly elevated glutamate and glutamate + glutamine levels as well as increased pyruvate carboxylase-mediated anaplerotic flux rate in the hypothalamus of treated animals (Pyruvate carboxylase plays a crucial role in lipogenesis and gluconeogenesis in mammals. It converts pyruvate and bicarbonate into oxaloacetate for further conversion into citrate which is then exported from mitochondria and cleaved in cytosol to supply precursors for nthesis [; Figure nthesis [. Of the nthesis [. The pyrnthesis [. Animal nthesis [. Furthernthesis [. A recen animals . Taken t2 for a variety of biological processes. In the central nervous system carbonic anhydrase inhibition enhances inhibitory neurotransmission. Many anticonvulsants are strong carbonic anhydrase inhibitors. Adjunctive acetazolamide, a sulfonamide carbonic anhydrase inhibitor, improved prophylactic efficacy in 44% of the treatment-resistant bipolar disorder patients (Catalysis by carbonic anhydrase is necessary to speed up the reversible hydration of COpatients . One of patients \u201379. Of tpatients . Topirampatients .2-fixing enzymes pyruvate carboxylase and acetyl-CoA carboxylase to bicarbonate and decreases pyruvate carboxylase-mediated anaplerosis in peripheral tissues (de novo synthesis of both fatty acids and non-saponifiable lipids (de novo lipogenesis and gluconeogenesis in liver (Inhibition of carbonic anhydrase limits the access of CO tissues . It has e lipids . Carboniin liver , 82. In in liver .2, which is generated by the highly active neuronal oxidative metabolism, from neurons by free diffusion. This distinct distribution of intracellular carbonic anhydrase in brain leads to the conversion of CO2 into bicarbonate primarily in astrocytes, rendering astrocytes as sinks of CO2 (2 fixation by limiting the supply of bicarbonate to pyruvate carboxylase, resulting in reduced TCA cycle intermediate levels and reduced glutamate production (2 hydration catalyzed by carbonic anhydrase and pyruvate carboxylation catalyzed by pyruvate carboxylase (de novo synthesis of glutamate by carbonic anhydrase inhibition may play a significant role in the antiepileptic properties and mood stabilization effects of anticonvulsants that are also carbonic anhydrase inhibitors. Therefore, both mechanistic and clinical studies of carbonic anhydrase inhibition support the proposed connections among bipolar disorder, obesity and pyruvate carboxylase-mediated anaplerosis.Carbonic anhydrase in brain is predominantly expressed in glial and choroid cells \u201388. The s of CO2 . In cultoduction . Since iboxylase , limitatA single pyruvate carboxylase isoform is expressed in humans and found in mitochondria only . PyruvatPrevious studies have shown that pharmacological inhibition of pyruvate carboxylase by phenylacetic acid markedly reduced hepatic gluconeogenesis in rats . The effin vivo1H MRS. Multiple independent lines of evidence suggest that increased pyruvate carboxylase-mediated anaplerosis is a common mechanism underlying glutamatergic hyperactivity and the significant positive association between bipolar disorder and obesity. As the increased prevalence of obesity in bipolar disorder is associated with illness severity and poor treatment outcomes development of preventive and treatment strategies targeting pyruvate carboxylase-mediated anaplerosis may be warranted.Increased pyruvate carboxylase-mediated anaplerosis can readily explain the elevated glutamate or glutamate + glutamine levels in brain in bipolar disorder observed by JS performed literature analysis and proposed the hypothesis. JT performed literature search. JS and JT wrote the paper. Both authors reviewed the manuscript and agreed on its final version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "We employed electrophysiological and fluorescence imaging techniques to describe the characteristics of a novel type of neuron discovered in the mouse dorsal striatum. Transgenic mice that express YFP-tagged channelrhodopsin-2 (ChR2) in neurons driven by the promoter for tyrosine hydroxylase (TH) were used and the intrinsic electrical properties of YFP-positive neurons in the dorsal striatum of these mice were characterized using whole-cell patch clamping in acute brain slices. Passive membrane properties - such as membrane capacitance, resting membrane potential and input resistance -and action potential properties- such as amplitude, kinetics and adaptation - were extracted from raw data files. Filling these neurons with neurobiotin enabled visualization of neuronal morphology via immunohistochemical labeling with streptavidin-conjugated fluorophore. Subsequent two-photon imaging allowed analyses of morphological properties such as somaticsize, dendritic branching  and density of dendritic spines. Unbiased analyses and hierarchical clustering of both morphological and functional data allowed us to identify a previously undescribed type of striatal neuron with unique properties. To facilitate identification of this new cell type, an end-to-end automated electrophysiology pipeline was developed that extracts relevant parameters and determines striatal neuron identity using neural-network based classifiers. These data and the software tool will permit other investigators to identify this novel type of neuron in their studiesand thereby better understand theroles thatthese neuronsplay in dorsal striatum circuitry. Specifications Table1\u2022These data present in detail the basis for identifying a novel type of neuron in the dorsal striatum that has unique intrinsic electrical properties and morphological properties; future studies can use these data as a reference.The software tool that we provide can help researchers identify the novel neuron in their future studies.\u2022Researchers who study striatal circuitry can benefit from these data; in particular, the distinct properties of the novel neuron type lend its unique computational properties that can be examined in modeling studies that utilize our dataset.2\u2022+cells in the dorsal striatum; stimulating currents ranged from \u2212200 to +200 pA, in 50 pA increments. Each current pulse lasted one second.These recordings were used to extract and analyze input resistance, sag amplitude andAP properties .All .abf files are electrophysiology data recorded using pClamp 10.4 (Molecular Devices). They are current clamp recordings from YFP\u2022https://bit.ly/3etT5tZ. These data can also be converted into the open source format Neurodata Without Borders (NWB) and analysed using software provided by the Allen Institute for Brain Science here: https://bit.ly/2Yr906KDespite being a proprietary format, files in the .abf format can be analysed using the free software Clampfit provided by Molecular devices available here: \u2022In addition to data, we have created a freely available tool that allows users to extract electrophysiology data from .abf files in an automated and reproducible manner. A classifier is then used to determine cell identity from the extracted data. All tif. files are two-photon imaging data acquired using an Olympus FV-1000 microscope with a 25x objective (NA=1.05).All imaging dataare Z-stack images.\u2022Analysed data can be found in the figures in Mao et\u00a0al., 2019 (doi: 10.3389/fncir.2019.00032).3As the data collection process has already been described in the table above, here we will focus on the data analyses.3.1A total of 12 intrinsic electrical properties were used to classify ChR2-YFP expressing neurons of the dorsal striatum; these properties were clustered using unsupervised hierarchical clustering  To cluster the data, we used PCA with singular value decomposition to reduce the dimensionality of our electrophysiology dataset. This was implemented using the pcaMethods package in R. For unsupervised hierarchical clustering, we used the three principle components that accounted for 69% of the total variance in our dataset. We identified the optimal cluster number using silhouette analysis implemented in R and visualized clusters using a dendrogram using the R package Clustvis.3.2l-Measure to obtain parameters such as surface area against path distance and spine density. Dendritic branching was analyzedby Sholl analysis utilizing the Simple Neurite Tracer plugin in ImageJ.For morphological analysis of neurobiotin-labeled neurons, cells were digitally reconstructed using a software suite for reconstruction of neuronal morphology (AdReconstructor). Firstly, pre-processing algorithms were applied to remove common sources of noise, such as non-specific background staining and neurobiotin leakage. Reconstruction of cell morphology was performed using the All Path Pruning algorithms developed by Xiao and Peng (2013) and post-processing measures were applied to ensure reconstructionaccuracy To examine the relationship between electrophysiological and morphological properties, we also performed unsupervised hierarchical clustering of morphological features extracted from 15 digitally reconstructed neurons filled with neurobiotin. The morphological properties extracted were based on definitions used in Scorcioni et\u00a0al. (2008) 3.3To allow users to interact with the data presented in this paper, we have created a freely available tool that performs automated extraction of electrophysiological parameters used to distinguish striatal TH-interneuron identity  The program is written in the R programming language The authors declare that they have no known competing financial interests or personal relationships which have, or could be perceived to have influenced the work reported in this article."}
+{"text": "Arabidopsis thaliana catalyze RNA dependent DNA Methylation pathway along with small interfering RNA. Several developmental functions have also been attributed to DNA methylation. This review will highlight aspects of RdDM pathway dynamics, evolution and functions in seed plants with focus on recent findings on conserved and non-conserved attributes between angiosperms and gymnosperms to potentially explain how methylation has impacted variations in evolutionary and developmental complexity among them and advance current understanding of this crucial epigenetic pathway.RNA Directed DNA Methylation (RdDM) is a pathway that mediates de novo DNA methylation, an evolutionary conserved chemical modification of cytosine bases, which exists in living organisms and utilizes small interfering RNA. Plants utilize DNA methylation for transposable element (TE) repression, regulation of gene expression and developmental regulation. TE activity strongly influences genome size and evolution, therefore making DNA methylation a key component in understanding divergence in genome evolution among seed plants. Multiple proteins that have extensively been studied in model plant  These findings dispute the generalization of similarities among large gymnosperm genomes and point to conifer potentially being unique. However, an anticorrelation is theorized to exist between recombination based elimination of TEs and heterochromatization driven by epigenetic mechanisms as observed in P. abies and fritillaria.  and asymmetrical CHH  which comprises of DEFECTIVE IN RNA DIRECTED DNA METHYLATION 1(DRD1), DEFECTIVE IN MERISTEM SILENCING 3 (DMS3) and RNA DIRECTED DNA METHYLATION 1 (RDM1) . This hypothesis is likely to be supported by the occurrence of NRPE1 the largest subunit of Pol V in conifer P. abies, Ginkgo biloba and Welwitschia mirabilis predominantly display 21 nt siRNA , maintenance of CHG methylation involves crosstalk between CHROMOMETHYLASE 3 (CMT3) and H3K9 histone methyltransferase for demethylation  in CG context and much less in non-CG context apart from gymnosperm Non-CG methylation is also complex and its functions not well characterized. It requires CHROMOMETHYLASES (CMT2&3) which are plant specific methyltransferases that evolved prior to the diversification of land plants. However, CMT2 is hypothesized to have evolved with the angiosperm specific duplication (\u2265\u2009236 MYA)  setting and maintenance overlap and incorporate histone modifications  which binds methylated DNA and acetylates histone 3 (H3) lacking H3Kme2 and H3Kme3  compared to wild types  respectively while CHH methylation displayed a correlation coefficient (r\u2009=\u20090.00003) consistent with similar findings that global and gene body mCG and mCHG positively correlate with genome size  and P. abies (70%) are densely methylated as proportion of TEs correlates positively to levels of methylation.We conducted a Pearson R correlation test between repeat element and methylation percentage in different contexts using seven previously studied sample seed plant species Fig.\u00a0, includiZ. mays with larger genomes than A. thaliana and higher TE content undergo spreading of silencing to genes adjacent to TEs, in particular promoter regions of genes . Methylation in these species therefore plays a role in regulating gene expression and mutations may result in lethal abnormalities.Comparably, DNA methylation regulates gene expression in a genome size dependent manner. Angiosperms such as Gene regulation occurs through repression of transcription by preventing the binding of transcription factors or promoting repressive histone modifications such as H3K9me  demethylation, occurring in the central cell of the female gamete and the vegetative cell of the male gamete  are upregulated leading to gradual demethylation at loci of ripening genes such as CNR   transcription accompanied by hypomethylation in the host plant  and demethylases (ROS1) are recruited to their target loci. Likewise, mechanisms of non-CG methylation maintenance and establishment warrant further comment.Research so far has managed to illuminate majority of the key genes involved in the RdDM pathway and their roles in various stages in model plant Further, the functions of gene body methylation and non-CG methylation remain largely unknown despite them displaying different levels in various tissue types and species (Hisataka et al. 2012; Kawakatsu et al. More studies need to focus on expanding to sequencing methylomes of less studied seed plant species with larger, more complex genomes as well as plants from more clades of land plants for comparison with currently available information. Such research could reveal crucial details about variations in genome evolution dynamics and more DNA methylation functions particularly in relation to seed plants Fig.\u00a0.Fig. 7SuWMR wrote the initial draft and collected the references. TW restructured the manuscript and increased the scope. QFW contributed to subsequent revisions. All authors read and approved the manuscript."}
+{"text": "South African rabies viruses originating from dogs and jackals (canid viruses) are closely related and highlight cross-species transmission events between the two canine species. Rabies due to the canid lyssavirus variant is a significant public health matter in this country. The complete coding sequences of 23 canid lyssaviruses from South Africa are reported here. South African rabies viruses originating from dogs and jackals (canid viruses) are closely related and highlight cross-species transmission events between the two canine species. Rabies due to the canid lyssavirus variant is a significant public health matter in this country. The complete coding sequences of 23 canid lyssaviruses from South Africa are reported here. Lyssavirus genus  (Rabies virus (RABV) is the prototype species of the virales)  and causvirales) . The domvirales) , resultivirales) .de novo assembling of all the reads and mapping of the same reads to existing rabies genomes (GenBank accession numbers KT336433 to KT336436) using default settings in CLC Genomics Workbench v.9 (Qiagen). A single consensus sequence was produced for each sample from an assembly of all the contigs previously generated. The newly obtained consensus sequence was used as a template to map all the original reads in order to estimate the average coverage and possible variants  showing typical signs of central nervous system infection, preserved in glycerol-saline, and transported to the laboratory see . Total v5\u2013ants see . The gents see 5\u2013. The seqts see 5\u2013, 7\u20139.MT454631 through MT454654 (PRJNA638742.The complete coding sequences were submitted to GenBank and are available under accession numbers MT454654  and BioP"}
+{"text": "Influenza viruses have perplexed scientists for over a hundred years. Yearly vaccines limit their spread, but they do not prevent all infections. Therapeutic treatments for those experiencing severe infection are limited; further advances are held back by insufficient understanding of the fundamental immune mechanisms responsible for immunopathology. NK cells and T cells are essential in host responses to influenza infection. They produce immunomodulatory cytokines and mediate the cytotoxic response to infection. An imbalance in NK and T cell responses can lead to two outcomes: excessive inflammation and tissue damage or insufficient anti-viral functions and uncontrolled infection. The main cause of death in influenza patients is the former, mediated by hyperinflammatory responses termed \u201ccytokine storm.\u201d NK cells and T cells contribute to cytokine storm, but they are also required for viral clearance. Many studies have attempted to distinguish protective and pathogenic components of the NK cell and T cell influenza response, but it has become clear that they are dynamic and integrated processes. This review will analyze how NK cell and T cell effector functions during influenza infection affect the host response and correlate with morbidity and mortality outcomes. Influenza is a rapidly mutating RNA virus which causes yearly global epidemics characterized by about 1 billion infections and 290,000\u2013650,000 deaths  and subsequent development of acute respiratory distress syndrome (ARDS) leads to death  in the bone marrow . Natural cytotoxicity refers to NK cell killing of target cells in the absence of inhibitory signals from self MHCI molecules K\u00e4rre, . ADCC isNK cell inhibitory receptors of the killer cell immunoglobulin-like receptor (KIR) (human) and Ly49 receptor (mouse) families bind self MHC I molecules and inhibit cytotoxicity toward healthy self cells; malignant or infected cells which downregulate MHC I are susceptible to NK cell killing  . Binding to Fas by FasL induces apoptosis in the target cell through a caspase-dependent pathway . Na\u00efve T cells also circulate through the lymphatics and are activated by APCs in the lymph nodes  and humoral (Th2) immunity in response to foreign pathogens. After initial activation, differentiation is driven by cytokine-dependent transcription factor expression  cells. TRM cells are generally identified by the expression of CD69 and CD103, but this method is not entirely accurate as CD69 can be transiently expressed on activated circulating cells and there are some TRM cells which do not express one or both of these markers  NCR1 (mouse), NKp44 and NKp46 (human) encoded by the NK cell costimulatory receptors 2B4 and NTB-A bind to HA and enhance NK cell cytotoxicity, but cannot activate NK cells on their own  binds to the Fc portion of influenza-specific antibodies and initiates ADCC. Studies in humans and macaques demonstrate seasonal influenza infections elicit cross-reactive antibodies to HA and NA epitopes of multiple influenza strains; these antibodies promote NK cell ADCC against infected target cells  and intracellular nucleoprotein (NP) are important for T cell-mediated heterosubtypic immunity to influenza. Significant research in the 1970s and 80s identified T cell immunity to NP and M1 were responsible for cross-reactivity between strains whereas T cell clones specific for HA or NA only mediated strain-specific protection  stimulates NK and Th1 IFN-\u03b3 production during influenza infection  following lethal dose influenza infection and found lower IL-17 levels and higher IL-10 levels correlated with increased protection without compromising viral clearance. Interestingly, they only saw these effects when they treated with rIL-27 at peak viral titer or later, compared with worse outcomes if they treated at early stages of infection. Likely, the early inflammatory response is necessary for favorable outcomes, but as adaptive immune cells accumulate in the lung increased inflammation mediates harmful tissue damage  are an alternative model which address some challenges associated with mouse and human studies. They have been successfully infected with numerous influenza strains including 1918 and 2009 pandemic H1N1  and acute respiratory distress syndrome (ARDS) during influenza infection. Developing these drugs is challenging as preventing the inflammatory response entirely would lead to uncontrolled viral replication. It is difficult to identify individual components of inflammatory responses which are directly responsible for immunopathology vs. those which are essential host responses or are simply byproducts of the inflammatory environment.Current anti-viral therapeutics are limited to two approaches: neuraminidase and M2 ion channel inhibitors. Both aim to limit replication and spread of the virus: NA inhibitors target its enzymatic activity and M2 ion channel blockers prevent its proton channel function. These therapies have limited potential, however, because of side effects and the emergence of resistant strains  antibody constructs can activate T cells to kill target cells independent of antigen-specificity. BiTE\u00ae antibody constructs are fusions of 2 single chain fragment variable (scFv) molecules: one binds to the antigen of interest and the other binds to CD3\u03b5 on cytotoxic T cells. These have been implemented in the cancer immunotherapy field, and M2e-specific BiTE\u00ae constructs show protective effects in mice infected with influenza , autologous or allogenic T and NK cells\u2014are promising cancer treatments. CAR T and NK cells can be targeted to a specific antigen by combining an antigen-specific Fv to an intracellular signaling domain which promotes cytotoxicity upon antigen binding (Gross et al., Current therapies targeting NK cell and T cell responses are limited. Anti-inflammatory approaches are more commonly studied because hyperinflammatory responses leading to cytokine storm are a common cause of morbidity and mortality in severe influenza infections. These efforts are hindered by incomplete understanding of the mechanisms behind protective and pathogenic inflammatory responses. Furthermore, the contributions of cytotoxic NK and T cells to the inflammatory response and the effects of anti-inflammatory therapeutics on their functions are poorly understood. Some studies have moved away from efforts to target a single anti-viral mechanism; cell-based immunotherapy approaches could supplement anti-inflammatory therapeutics and promote more efficient viral clearance by cytotoxic NK and T cells. Preliminary data shows that NK cells and T cells can be activated to potently kill influenza-infected cells without contributing to damaging inflammatory responses, but their potential in humans has not yet been evaluated.Despite 2018 marking 100 years since the deadliest influenza pandemic in history, our understanding of influenza virus infections is far from complete. Countless host protection mechanisms have been characterized in mice with much focus on a hallmark of severe disease: hyperinflammatory responses and subsequent cytokine storm. Numerous other studies have attempted to correlate human disease outcomes with these immune mechanisms. NK and T cells are at the forefront of these responses: cytotoxic killing of infected cells is essential for host survival, but NK cell and T cell pro-inflammatory functions may contribute to immunopathology. Through years of research, the field is still unable to clearly distinguish protective responses from harmful ones; Studies addressing this issue will be fundamental to develop effective treatments for severe infections.Some therapeutic approaches attempt to limit inflammation, but until we can distinguish harmful inflammatory mechanisms from necessary anti-viral responses this will be difficult. Others are turning to cell-based therapies to activate NK cell and T cell cytotoxicity against infected cells, but support for these approaches is backed by limited data. Developing effective treatments for severe influenza infections will likely involve a combination of these strategies. Regardless, understanding NK and T cell responses\u2014both cytotoxicity and cytokine production\u2014will undoubtedly be vital to develop effective therapeutics which can improve disease outcomes for patients experiencing severe influenza infections.KF and SP conceptualized the content of and wrote the article. KF generated the figure. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Orthopedic procedures involving the hip have remained challenging for regional anesthesia given the complex innervation, painful nature contributing to difficulty positioning, and a desire to maintain mobility to hasten postoperative recovery. The revision total hip arthroplasty (THA) poses a greater challenge for an effective regional analgesia due to complex surgical approach, scarring from previous surgery and limited patient mobility. The quadratus lumborum (QL) block has demonstrated to provide effective analgesia for primary hip surgery in recent studies. The pericapsular nerve group (PENG) block has also shown to provide analgesia in patients with hip fractures. There is no standard of care regional anesthesia technique for hip surgeries, and the regional practice varies widely among anesthesia providers. This retrospective case series studied the effect of combining the QL with PENG block on the revision THA analgesia. Given the prevalence of osteoarthritis amongst the increasingly aging population and subsequent need for total hip arthroplasty, the frequency of revision hip surgeries is expected to rise. It is estimated that more than 2.5 million patients in the United States alone have had a total hip arthroplasty (THA) . RevisioThe hip has both an anterior and posterior capsule, but the anterior capsule contains predominantly nociceptive fibers while the posterior predominantly has mechanoreceptors. Favoring analgesia without limiting mobility, the anterior capsule is an ideal target for regional anesthesia techniques. In addition, the hip joint is innervated by both the lumbar (L1-4) and sacral (L4-S4) plexus . The perQuadratus lumborum (QL) block has proven effective analgesia for total hip arthroplasty and decreasing opioid requirements for up to 48 hours postoperatively, due potentially to its spread to the paravertebral space . The proWe hypothesized that the combination of PENG with QL block would provide adequate analgesia for the revision THAs, while also limiting motor weakness and thus improving postoperative outcomes. We examined whether addition of pericapsular nerve group (PENG) block with the quadratus lumborum block would provide superior analgesia and would prove to decrease opioid requirements and pain scores.This retrospective case series included patients undergoing revision total hip arthroplasty (THA) at a tertiary academic medical center. Sixteen patients undergoing revision THA provided written consent for the nerve block(s).\u00a0Eight patients had a QL and PENG block performed and eight patients had only a QL block performed. The nerve block(s) were performed preoperatively with the patient in a supine position for the PENG block and in lateral decubitus position for the QL block.\u00a0Seven out of eight revision THA patients in the PENG and QL group were done under general endotracheal tube anesthesia (GETA) with a lone patient done under spinal anesthesia. All eight revision THA patients in the QL only group were performed under GETA.\u00a0The visual analog scores of pain in the post-anesthesia care unit (PACU) and at 6, 12, and 24 hours after surgery were obtained.\u00a0In addition, cumulative oral morphine equivalent (OME) usage was obtained for PACU, for the first 6 hours, 6-12 hours, and 12-24 hours postoperatively.Ultrasound-guided technique for PENG blockA low-frequency curvilinear transducer was placed in the transverse plane over the anterior inferior iliac spine (AIIS) and moved over inferiorly to visualize the pubic ramus. The femoral artery and iliopubic eminence (IPE) were then visualized Figure . Using iUltrasound-guided technique for transmuscular (anterior) QL blockA low-frequency curvilinear transducer was placed in the axial plane over the spinous process at the level of L4. The probe was moved laterally until the transverse process of L4 was visualized. The \u201cshamrock sign\u201d was then visualized which consists of the following: QL muscle laterally, erector spinae muscle posteriorly, psoas major muscle anteriorly, and transverse process of L4 medially (stem of leaf). Using in-plane technique either a 10 cm echogenic 21g short bevel needle (seven out of 16 patients) or 9 cm 18g Tuohy needle (nine out of 16 patients) was advanced from a posterior  to anterior  direction and 25 ml of local anesthetic 0.25% Bupivacaine was deposited in the fascial plane between the QL and psoas major muscles  and analgesic efficacy . The disIn a recent case series utilizing PENG block for THA, postoperative pain scores and OME use were lower in the group undergoing primary hip surgery compared to revisions . This reTo the best of our knowledge, this is the first retrospective case series study to combine the PENG block with the QL block for revision THA analgesia. The main findings of this study are superior analgesia with the combination blocks as compared to only QL block for revision THAs. Also opioid requirements in the combination group were lower up to at least the first 24 hours.\u00a0Findings of the opioid sparing analgesic effect in the era of opioid epidemic and preservation of lower limb muscle strength in the era of accelerated physical therapy after THA are therefore encouraging.The anterior lumbar QL block technique deposits local anesthetic deep to the anterior thoracolumbar fascia between the QL and psoas major muscles, in close proximity to the lumbar plexus with potential local anesthetic spread to the paravertebral (PVB) region. The anterior QL block aims to block the lumbar plexus branches, including the lateral femoral cutaneous nerve, which innervates the surgical incision site commonly used in THA approach. A recent cadaveric study and case series concluded that the supra-iliac approach to the anterior QL block involved T10-L3 dermatomal coverage and provided effective analgesia for total hip surgery .Post-operative pain management after THA has always been a challenging goal to achieve. Multiple regional techniques have been used in the past, but there is not a \u201cbest proven intervention\u201d for THA analgesia . The maiPostoperative opioid requirements after THA vary depending on the type of regional anesthesia technique used. One study of continuous femoral nerve blocks for THA showed opioid requirement of approximately 160 mg of OMEs and another study of continuous lumbar plexus block showed approximately 114 mg OMEs in first 48 hours [There are some limitations to this case series such as small sample size, retrospective design, and publication bias . Also weAt the same time, this case series explores a new combination approach for THA patients which can be utilized to provide effective analgesia for revision or complex hip arthroplasty. Large sample size studies are warranted to further understand this new technique and also to compare its efficacy with traditional blocks for hip analgesia. Also cadaveric and magnetic resonance imaging studies are required for better understanding of anatomical spread of local anesthetic and nerves covered with PENG block.The PENG plus anterior QL block provided adequate post-operative analgesia for patients undergoing revision THA. This combination block for revision THA reduced pain scores and had opioid sparing effects post operatively. The PENG block is an easy ultrasound-guided regional technique which can be performed in supine position for patient comfort. Further prospective randomized studies are warranted to determine the efficacy of PENG block for analgesia and quality of recovery after hip surgery. Also safety of PENG block alone or in combination with other blocks needs further investigation."}
+{"text": "Biosci Rep (2020) 40(8), https://doi.org/10.1042/BSR20201313) would like to correct their Ethics Approval statement. The correct Ethics Approval should be as follows:The study was approved by the ethics committee of the Fourth Hospital of Hebei Medical University. The patients or their relatives gave written informed consent prior to entering the study.The authors of the original article \u201cCirc_0000144 functions as a miR-623 sponge to enhance gastric cancer progression via up-regulating GPRC5A\u201d (The authors apologise for any inconvenience or misunderstanding that this error may have caused."}
+{"text": "Schmorls node (SN) are mostly asymptomatic and incidental findings on MRI. However, sometimes they present like acute onset low back pain or acute exacerbation of chronic back pain after minor trauma.We present rare case of symptomatic infected SN in 67\u2009years female patient presented with complains of low back pain radiating to right buttock. After initial conservative treatment failed subsequent imaging showed significant increase in size of lesion with focal signal changes in disc space gave suspicion of underlying secondary pathology. Patient operated for complete excision of lesion. Histopathological report was suggestive of pyogenic vertebral osteomyelitis. Patient improved well postoperatively.Most of the time acute SN responds well to conservative treatment; however rapid deterioration of symptoms or persistent severe pain should give suspicion of underlying secondary pathology. Schmorl\u2019s node (SN) is herniation of intervertebral disc into vertebral body through end plate defect. They first described by Christian Schmorl in 1927. SN are mostly asymptomatic and incidental findings on MRI; however sometimes they present like acute onset low back pain or acute exacerbation of chronic back pain after minor trauma , degenerWe present atypical presentation of acute symptomatic SN with infective pathology. There are no reports in the literature regarding the occurrence, imaging follow-up, treatment and outcome of symptomatic acute infective SN till date.Sixty-seven\u2009years female patient presented to our hospital with complains of low back pain radiating to right buttock since 1\u2009month with visual analogue scale (VAS) score 7. There was no associated fever or significant trauma in recent past. She had no other medical or surgical history in the past. Clinically, there was no tenderness over lumbar spine. Patient was neurologically intact.A plain radiograph of lumbar spine was showing L4\u20135 narrowing of disc space with mild degenerative scoliosis. Dynamic plain radiograph does not show any features of instability. Computed tomography (CT) scan showed osteolytic bone lesion at inferior end plate of L3 vertebral body Fig.\u00a0. InitialWe performed partial corpectomy L3 and expandable cage insertion through lateral retroperitoneal approach with posterior bone cement augmented percutaneous pedicle screw fixation L2-L4. Sample sent for histopathological examination and microbiology culture. Post operative MRI showed complete excision of lesion with persistent marrow signal changes at anterio-superior part of L4 vertebral body (Fig. Most of the SNs are asymptomatic and incidental finding . It is rVarious theories have been proposed to explain the pathogenesis of SN in which widely accepted theory is axial load model proposed by Dar et al.  They proConventional radiograph has very limited value for diagnosing SNs. It is useful only in late stage of SN where sclerosis appear around lesion. These findings can be seen early and in more details on CT scan. Alternatively, Presence of bone oedema on Dual energy CT can suspect the infective/inflammatory pathology . MRI is Conservative line of management always will be first line of management in symptomatic SN. Symptoms usually resolves within 2 to 6\u2009months; however marrow edema on MRI gradually subsides over period of 3 to 12\u2009months . We alsoPeng et al.  did segmTypical Histopathological examination of pyogenic vertebral osteomyelitis shows inflammatory cell infiltration, vascular proliferations with granulation tissue, fibrosis, thrombosed blood vessels and bony necrosis depending upon stage of disease; as seen in current case report Fig.\u00a0. It was In this study, we present the first report of infectious SN, which is very similar to acute non-infected Symptomatic SN at the beginning. Therefore, if infected SN is suspected based on laboratory studies Careful follow-up observation is essential. However, the clinical course along with MRI and CT findings and histological images are more suggestive of infective pathology instead of degeneration hence managed aggressively with excision of infective focus.SN is always considered as one of the differential diagnosis of acute low back pain. Most of the time patient responds well to conservative treatment with analgesics and bed rest. Rapid deterioration of symptoms or persistent severe pain despite of conservative treatment should give suspicion of underlying another secondary pathology. It should be aggressively investigated and treated without further delay. MRI is investigation of choice for early diagnosis as well as to differentiate between symptomatic and asymptomatic SN. Currently there is no established treatment modality. Future investigations should address interventions for treating symptomatic SNs."}
+{"text": "Jia and colleagues have concluded that plasma endostatin shows a useful value for predicting failure to recover from acute kidney injury (AKI) . They stEndostatin is a useful biomarker to predict recovering failure from acute kidney injuryHui-Miao Jia, Wen-Xiong LiWe appreciate the comments of Honore et al. on our article.In this study, endostatin plasma concentration was detected immediately after acute kidney injury (AKI) diagnosis and before the renal replacement therapy (RRT) started and showed a useful value to predict the recovering from AKI failure. Early prediction aims to enable individual treatments and effective interventions that may improve clinical outcomes. Endostatin is a 28-kDa molecule that can be removed by a high flux membrane . Differe"}
+{"text": "Flow diverting stents have been used safely and effectively for the treatment of intracranial aneurysms, particularly for large and wide necked aneurysms that are not amenable to conventional endovascular treatment with coiling. The Surpass Streamline device  is a relatively new and unique flow diverting stent which maintains constant device mesh density over varying vessel diameters. This may potentially provide advantages compared to other flow diverting stents in achieving aneurysmal occlusion.Two patients with VRAA were treated using the Surpass Streamline device. The first patient was a 65-year-old male with an incidental 2.4\u2009cm aneurysm originating from the hepatic artery near the gastroduodenal artery (GDA). The second patient was a 56-year-old male with an incidental 1.9\u2009cm renal aneurysm arising from an anterior inferior segmental branch of the left renal artery. A Surpass flow diverting stent was used to successfully exclude the aneurysm neck in both cases.Reduced flow was achieved in one patient . Preserved flow and stagnation  was achieved in the other. There was preserved distal flow in the parent arteries. No immediate complications were encountered in either case. Complete occlusion of both aneurysms was seen on follow up CT angiographic imaging within 8-weeks.The Surpass flow diverting stent can be used safely and effectively to treat VRAA. It should be considered in unruptured large and giant wide necked VRAAs aneurysms. Additional large prospective studies are required for further validation. Flow diversion is a well-established technique for the treatment of intracranial aneurysms with high technical success and low recurrence rates  are more frequently being detected with the increasing use of cross sectional imaging. They are rare with an estimated prevalence of 2\u20133% . The size (>\u20092\u2009cm) and lobulatedmorphology suggested high risk of rupture and so the patient was referred for endovascular treatment. The presence of a wide neck made conventional coil embolization less desirable  was placed into the right common femoral artery. Initial angiogram of the celiac artery using a 6-French Cobra-2 catheter  demonstrated a wide-necked aneurysm arising from the terminiation of common hepatic artery involving the origin of the GDA  was placed into the right common femoral artery. Angiography via a 6-French Cobra-2 catheter  demonstrated a 1.9\u2009cm wide-necked renal artery aneurysm arising from an anterior inferior segmental branch of the left renal artery Fig.\u00a0a. SystemBoth procedures were uncomplicated and technically successful with no immediate or short-term complication. At 8 and 3\u2009weeks follow up CTA imaging respectively both aneurysms were completely occluded Figs.\u00a0 and 5. DThe use of endovascular procedures as first line treatment for the management of VRAA is becoming increasingly popular , liquid embolic agents such as n-butyl cyanoacrylate or ethylene vinyl copolymer (Onyx) and precipitating hydrophobic injectable liquid (PHIL) , Silk , Flow Reduction Endoluminal Device , p64  and LEO Baby . The unique braided design of these devices produces low radial opening forces to facilitate navigation while greater metal coverage and reduced porosity encourages aneurysm occlusion. Rapid flow reduction promotes thrombosis within hours to days, and sometimes months, and provides a scaffold for neointimal proliferation over the aneurysm neck  with no reported mortalities  and the presence of important arterial branches precluded the use of conventional coil embolization, standard self-expanding or balloon-expandable covered stents. The Surpass flow diverter was ideally suited obviating the risk of distal end organ ischaemic complications. Recent publications demonstrate successful treatment of visceral aneurysms with stents with flow diverting properties, where similarly, parent and side branch patency is deemed important. The double-layer micromesh Roadsaver, similar to the Surpass, has increased mesh density and reduced poor size resulting in improved aneurysm occlusion  indicating successful treatment. Importantly, in patient 2 no change in flow was observed. However, there was stagnation of contrast within the aneurysm (OKM Grade A3). The reduction in flow and stagnation highlights the advantage of the Surpass flow diverter which allows for preservation of side branch and perforator vessels. It is important for operators using this device to be aware that it can take hours to days to achieve complete aneurysm occlusion. At 8\u2009week and 3\u2009weeks respectively both aneurysms were completely occluded on follow up imaging. Systemic anticoagulation and antiplatelet agents may interfere with this; however, a short course of dual antiplatelet therapy is required to maintain stent patency until endothelialization occurs.We advocate for the use of dual antiplatelet therapy to prevent in-stent thrombosis when using flow diverting stents for peripheral aneurysms. Both patients were administered dual antiplatelet therapy for 1\u2009week prior to the procedure (100\u2009mg Aspirin and 75\u2009mg clopidogrel) with the plan to continue this for 6\u2009months postprocedure, at which point clopidogrel is ceased. Most studies evaluating flow diverting stents have used similar regimes and premature cessation of clopidogrel has been linked with a higher risk stent thrombosis, even at 3\u2009months  immediately following stent deployment. Importantly, the Surpass flow diverter is limited to use in smaller vessels with a maximum vessel diameter of 5.3\u2009mm with the 5\u2009mm device. Consideration should also be given to material costs compared to conventional endovascular methods.The Surpass flow diverting stent demonstrates early safety and efficacy in the treatment of VRAA. This novel report of its use in the peripheral vasculature highlights its expanding role extra-cranially. It should be considered in those aneurysms with wide necks or arising from difficult parent vessel anatomy with the constant mesh density potentially providing improved flow reduction over a range of vessel diameters when compared to other commercially available flow diverting stents. Its use should be further validated in larger case series or prospective studies. There is scope for future work to evaluate the long-term clinical outcomes with this device."}
+{"text": "Background: Wave speed is needed to separate net wave intensity into forward and backward traveling components. However, wave speed in diseased coronary arteries cannot be assessed from hemodynamic measurements obtained distal to a stenosis. Wave speed inherently depends on arterial wall properties which should be similar proximal and distal to a stenosis. Our hypothesis is that proximal wave speed can be used to separate net wave intensity obtained distal to a stenosis.Methods: We assessed coronary wave speed using the sum-of-squares single-point technique (SPc) based on simultaneous intracoronary pressure and flow velocity measurements in human coronary arteries. SPc at resting flow was determined in diseased coronary vessels of 12 patients both proximal and distal to the stenosis. In seven of these vessels, distal measurements were additionally obtained after revascularization by stent placement. SPc was also assessed at two axial locations in 14 reference vessels without a stenosis.Results: (p < 0.02), despite the lower distending pressure downstream of the stenosis. The corresponding separated wave energy tended to be underestimated when derived from SPc at the distal compared with the proximal location. (p = 0.48). Accordingly, no significant difference in separated wave energy was observed for forward or backward waves.Results:  No diffeResults:  In diseaocation.  After suConclusion: In diseased coronary vessels, SPc assessed from distal hemodynamic signals is erroneously elevated. Our findings suggest that proximal wave speed can be used to separate wave intensity profiles obtained downstream of a stenosis. This approach may extend the application of wave intensity analysis to diseased coronary vessels. Wave intensity analysis has emerged as a powerful time-domain method to investigate the dynamic interactions between the contracting myocardium and coronary blood flow. Coronary wave intensity distinguishes between concurrently generated upstream and downstream contributions on coronary hemodynamic waveforms and is characterized by forward (aortic) and backward-traveling (microcirculatory) waves \u20133. ComprWave speed is fundamental to split net wave intensity into separate forward and backward traveling components . Local cIn patients, wave intensity analysis has been applied to study changes in coronary-cardiac interaction through interventions ranging from pacing and exercise to alterations in left ventricular mechanics by Valsalva maneuver, aortic valve replacement, or left ventricular stunning \u201314. In aAccording to the Moens-Korteweg equation, arterial pulse wave velocity intrinsically depends on the elastic properties of the vessel wall. It can reasonably be expected that the elastic wall properties are similar in angiographically normal vessel sections proximal and distal to a focal stenosis. We therefore hypothesized that proximal wave speed may be suitable to separate the net wave intensity profile obtained distal to a stenosis. To test this hypothesis, we analyzed hemodynamic signals obtained at different axial locations in diseased and unobstructed coronary arteries in patients.The dataset for this study was extracted from existing hemodynamic recordings obtained in patients with stable angina pectoris and a single stenosis in a coronary artery, who were scheduled for elective percutaneous coronary intervention (PCI). Exclusion criteria were age below 18 or over 80 years, left main stenosis, subtotal or serial lesions, severe aortic valve disease or heart failure, hypertrophic cardiomyopathy, prior myocardial infarction <6 weeks before PCI or prior cardiac surgery.Cardiac catheterization was carried out by standard femoral approach. All anti-anginal medication was continued. Intracoronary nitroglycerin (0.1 mg) was administered in order to relax epicardial vessel tone, and coronary angiograms were recorded for quantification of stenosis severity. Aortic pressure (Pa) was measured via the guiding catheter at the coronary ostium. A dual-sensor equipped guide wire  was advanced into the study vessel to simultaneously acquire intracoronary pressure (Pd) and flow velocity (U) signals . HemodynStudyManager software  to derive cycle-averaged values for all relevant variables.Vessel dimensions and stenosis diameter reduction were determined by quantitative angiogram analysis . Pressure and flow velocity signals were extracted from the digital recordings and processed using the in-house developed Wave intensity analysis was carried out using custom software written in Delphi . The single-point estimate of coronary wave speed (SPc) was assessed according to the sum-of-squares method  as repor3 was used for blood density. Summations were taken over an integer number of three to eight consecutive cardiac periods during resting flow .\u22122 s\u22122). Four dominant peaks during the cardiac cycle characterize coronary wave intensity waveform: the forward-traveling compression wave (FCW) in early systole and early diastolic backward-traveling expansion wave (BEW), leading to flow acceleration, and the backward compression wave (BCW) and forward expansion wave (FEW), that cause flow deceleration  and backward traveling (negative WI) waves, the area under the respective curve was integrated to yield the corresponding wave energy . Unpaired Student's t-test assuming equal variance was used to compare data in reference vessels with those in diseased vessels after PCI. Agreements were assessed with Bland-Altman analysis. A two-sided probability value of p < 0.05 was considered significant.All values are expressed as mean \u00b1 SEM unless otherwise noted. Comparison between results obtained at proximal and distal locations in the same vessel were performed by paired Student's Simultaneous pressure and flow velocity signals of sufficient quality at rest conditions were collected in 12 patients both upstream and downstream of the stenosis. The patient characteristics are shown in p < 0.0002) and the pressure difference to aortic pressure was less than downstream of the stenosis (p < 0.005).Hemodynamic variables (mean \u00b1 SEM) are summarized in p < 0.02). Despite the lower distending pressure downstream of the lesion, SPc at that location was on average 10.1 \u00b1 3.4 m/s higher than upstream. The corresponding separated wave energy tended to be underestimated when calculated using SPc derived at the distal compared with the proximal location . As shown in p = 0.48). After PCI, no significant difference in wave energy was observed for either forward or backward separated waves  oscillations during the cardiac cycle . All subjects gave written informed consent conform the Declaration of Helsinki.MS conceived the study. LC and MS designed the methodology. JB and JP conducted the experiments to collect the intracoronary hemodynamic data. LC performed wave intensity analysis. LC and MS carried out the statistical analysis and wrote the first draft of the manuscript. All authors contributed to the article and approved the submitted version.JP serves as a consultant for Philips-Volcano, manufacturer of sensor-equipped guide wires. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "A significant need exists to improve enrollment of people-of-color (POC) in randomized clinical trials as the gold standard for evaluating new therapies so that health disparities can be reduced. Improving representation in clinical trials is expected to improve the applicability of clinical findings more broadly, especially for minority subgroups. This cross-sectional study assessed the perception of organizational climate (OC) among staff in five cancer research groups (CRGs) of a mid-Atlantic NCI-designated comprehensive cancer center. The Organizational Climate Measure (OCM), a measure of four OC models of the Competing Values Framework, was used. Enrollment data were obtained from the 2016 Cancer Research Management System data and 2017 enrollment rates. A statistically significant difference in mean scores was found in the Pressure to Produce Scale . One CRG\u2019s staff reported lower pressure to meet targets than three other CRGs (p < .05) and trending towards significance for the fourth CRG (p < .08). This suggests that organizational priorities considering all patients as potential clinical trial participants increases accrual. A statistically significant negative relationship between the Outward Focus sub-scale and POC enrollment  was also found, suggesting that an external organizational focus, alone, is insufficient to increase POC accrual. Implications for future research include 1) does the organizational priority of decreasing the pressure to produce influence accrual of POC? and 2) does an OC that is flexible and externally focused lead to a more effective means of accruing POC as clinical trial participants?"}
+{"text": "Individuals exposed to elder mistreatment are affected in dissimilar ways. Most existing studies are cross-sectional and fail to capture the change in mental health of older adults with exposure to elder mistreatment. This study aims to examine depression trajectories of elder mistreatment victims and identify protective factors. Data were drawn from the two-wave Population Study of Chinese Elderly in Chicago (PINE) with 725 participants who reported elder mistreatment at the baseline. Depression was measured by Patient Health Questionnaire-9. Self-mastery was assessed by the Pearlin Mastery Scale. Conscientiousness was evaluated by the NEO Five-Factor Inventory. Multinomial logistic regression was used while controlling demographic factors and recurrence of elder mistreatment. We identified four depression trajectories among elder mistreatment victims: chronic (9.61%), delayed (6.27%), recovery resilience (21.17%), and resistance resilience (62.95%). The chronic group was showing severe depression in both waves. The delayed group experienced a delayed reaction with increasing depression over time. The depression level of the recovery resilience group bounced back from elder mistreatment. The resistance resilience group exhibited low depression over time. Elder mistreatment victims with increasing self-mastery were more likely to be in recovery resilience group than in chronic group . In addition, elder mistreatment victims with increasing conscientiousness were less likely to be in delayed group than in resistance resilience group . Healthcare providers and social service agents could focus on elder mistreatment victims with chronic and delayed depression trajectories. Interventions could promote mental health of elder mistreatment victims through improving self-mastery and conscientiousness."}
+{"text": "Avascular necrosis and non-union are two most dreaded complications of femoral neck fracture fixations. Hip replacement seems to be a simple solution for this complex problem. However, the long-term efficacy of prosthetic replacement in the young population with higher functional demand is still questionable. Femoral head preserving valgus subtrochanteric osteotomies in properly selected cases have strong support from literature. The conventional technique of valgus subtrochanteric osteotomy involves lateral based wedge resection. Alternatively, a simpler sliding oblique subtrochanteric osteotomy without any wedge removal can also be performed. We hereby describe a successful case of sliding subtrochanteric osteotomy with 135\u00b0 dynamic hip screw (DHS) plate fixation in treating non-union neck of femur fracture in a young gentleman. In non-union, surgical options are mainly divided into head salvage or sacrificing procedures, depending on the viability of the femoral head. Preservation of the femoral head can be achieved via biological or biomechanical methods. Bone grafts  improve the microenvironment biology. Valgus hip angulation osteotomy improvises the biomechanical load of the hip joint. It will reorient a vertical fracture into a horizontal fracture, thus converting shearing force into compressive force across the fracture site. However, surgeons nowadays tend to favour the easier option of femoral head sacrificing hip arthroplasty. This provides immediate pain relief and early mobilisation, which is the goal of treatment in elderly patients. However, one must remember the goal of treatment in young adults should be focusing on preserving the femoral head due to the mismatch between their high functional demand and prosthetic implants longevity in the long term. Thus, an alternative, less radical approach like valgus hip angulation osteotomy is worth considering in younger people. We report a case of femoral neck non-union in a young adult treated with valgus sliding subtrochanteric osteotomy and the rationale behind it.Femoral neck fracture fixation can be complicated with non-union, especially in Pauwels type-3 fracture owing to high shearing force across the fracture site, with reported average incidence of 12% in literatureA 33-year-old gentleman suffered a left hip neck of femur fracture from a fall. A pelvic radiograph demonstrated a displaced neck of left femur basicervical fracture, Pauwels type-3. He underwent immediate fracture reduction and fixation with two cannulated screws . No immeHowever, six months post-operation, he complained of persistent left groin pain upon moving his left hip, and he was unable to bear weight on the affected limb. Pelvic radiograph  showed n1. Thus, obtaining anatomic reduction and stable fixation remains the key to successful treatment of femoral neck fractures. Failure is often a result of not achieving these principles. Initial operation with two cannulated cancellous screws fixation was a suboptimal management for this patient, who had typical Pauwels type-3 basicervical femoral neck fracture. A primary DHS fixation would have provided a more stable fixation. Cannulated cancellous screw fixation is still possible provided three cannulated screws with triangular configuration are used. Three screws offer better stability and can withstand higher load before failure compared to two vertical screws2.A non-union femoral neck fracture is common because of the absence of periosteal cambium layer and the continuous synovial bathing. These prevent hematoma formation, which in turn leads to decreased healing potential1. Pauwels type-3 fracture describes femoral neck fracture which is more vertically orientated (more than 50\u00b0), resulting in high shearing force across the fracture site that predispose to fixation failure and fracture non-union. Pauwels\u2019 valgus intertrochanteric osteotomy realigns the neck shaft angle; reorient vertical fracture into horizontal fracture pattern. Thus, it converts shearing force to compressive force across the fracture site, creating an optimal healing environment as illustrated in the schematic diagram  is used to pack the fracture site to further enhance fracture healing.We do not recommend this technique as a primary fixation in Pauwels III acute femoral neck fracture because of the potential morbidity associated with the creation of an additional osteotomy. It should only be reserved for management of revision of non-unions and implant failures. Acute fracture fixation still adheres to the principle of anatomic reduction with rigid fixation. Muscle pedicle bone grafting using quadratus femoris muscle or gluteus minimus muscle should be employed if the biological cause of non-union like coexistence avascular necrosis or late presenter is suspectedTreatment of femoral neck non-union in young adults can be challenging with many methods of fixation available. The principle of a revision surgery is to first establish the cause of non-union. The biomechanical problem seems to be the primary cause of non-union detected early. Thus, femoral head preserving surgery should be the mainstay of treatment and valgus sliding subtrochanteric osteotomy provides a viable option."}
+{"text": "Accumulating evidence suggests that sedentary behavior (SB), or time spent sitting, is regulated by both conscious  and non-conscious  motivational processes. Much of the work investigating these processes has employed summary-based measures of typical motivation and behavior. This study employed ecological momentary assessment (EMA) methods and accelerometry to determine the extent to which conscious and non-conscious processes regulate minority older adults\u2019 momentary decisions to engage in SB. Over the course of the 8-day study, minority older adults  answered 6 EMA questionnaires/day on a mobile phone and wore an ActivPAL activity monitor to measure SB. EMA questionnaires assessed momentary intentions to limit SB over the next two hours. SB habit strength was self-reported at an introductory session. Results from a multilevel linear regression model indicated that on occasions when individuals had stronger intentions than usual to limit SB, they subsequently engaged in less SB . Individuals who had stronger SB habits, tended to engage in more SB . An additional multilevel model revealed that habits did not significantly moderate the association between momentary intentions and subsequent SB . In conclusion, minority older adults\u2019 momentary SB appears to be directly influenced by both conscious and non-conscious motivational processes, though the interactive effects are unclear. Interventions to reduce minority older adults\u2019 SB should include content to increase intentions to limit SB  and disrupt habitual SB ."}
+{"text": "Orthodromic tachycardia using a left lateral accessory pathway was repeatedly induced.A 49-year-old woman with multiple documented episodes of narrow QRS complex tachycardia underwent electrophysiology study at our hospital. Baseline ventricular pacing demonstrated eccentric retrograde coronary sinus activation consistent with a left lateral accessory pathway 1 was used by collecting the absolute dV/dt bipolar electrogram from the high-density grid to help distinguish the mitral valve anulus, collecting both atrial and ventricular electrograms to delineate functional block located at the valve plane . At the location of the accessory pathway, bipolar fusion and pathway potentials recognized and annotated on the high-density grid were able to showcase the atrial insertion point of the accessory pathway (1C). Additionally, during ventricular pacing and, similarly, during orthodromic supraventricular tachycardia, EnSite Precision\u2122 open-window propagation and, in particular, the SparkleMap\u2122 display feature  and 2B allowed for more precise localization of the atrial insertion of the bypass tract by dynamically displaying wavefront propagation superimposed on top of the local activation timing and voltage maps  and 2.Transseptal puncture allowed access to the left atrium and left ventricle, where high-density mapping was performed across the mitral valve anulus during ventricular pacing using the Advisor\u2122 HD Grid Mapping Catheter, Sensor Enabled\u2122 and the EnSite Precision\u2122 electroanatomic mapping system to localize the concealed left lateral accessory pathway. The open-window mapping technique. A thorough waiting period and electrophysiology study showed no evidence of accessory pathway conduction and the patient has remained symptom-free during follow-up.Ablation was performed with the TactiCath\u2122 Contact Force Ablation Catheter, Sensor Enabled\u2122 at a power of 30 W and a minimal contact force of 10 g while the patient was in orthodromic supraventricular tachycardia. The tachycardia was terminated with a single lesion delivered to the mitral valve annulus at the atrial insertion site, subsequently eliminating the accessory pathway"}
+{"text": "Rosai-Dorfman disease is a histiocytic lesion that affects lung rarely.We present a 52-year-old female diagnosed with right intrabronchial mass invading the bronchial wall and the extrabronchial tissues with lymphadenopathy. Multiple bronchoscopic biopsies were not diagnostic. Pneumonectomy was performed and postoperative histology revealed marked mucin impaction and bronchial dilatation. The pulmonary tissue showed areas of hemorrhage and chronic inflammation. The mass exhibited an excessive number of lymphocytes, plasma cells, and numerous histiocytes engulfing them (lymphocytophagocytosis). These histiocytes were S100 protein and CD68 positive. These features are consistent with Rosai-Dorfman disease.Rosai-Dorfman Disease with pulmonary affection can be misdiagnosed as malignancy. Careful histological examination of the specimen for emperipolesis or lymphocytophagocytosis together with S100 protein and CD68 positivity are the clue for proper diagnosis. Rosai-Dorfman disease (RDD) is a histiocytic lesion that commonly occurs in young males . TypicalA 52-year-old female with a history of hypothyroidism presented with continuous cough and shortness of breath. General examination was normal and local chest examination revealed absent breathing sounds on the right side. Pulmonary function test showed a mixed obstructive and restrictive lung pathology. Chest x-ray revealed complete opacity on the right side and contralateral mediastinal shift. Computed tomography (CT) scan of the chest showed infiltrative right hilar soft tissue lesion measures 4\u2009\u00d7\u20095\u2009cm with an endobronchial extension of the lesion obliterating the right main and upper lobe bronchus Fig.\u00a0a and b. Rosai-Dorfman disease is an uncommon nonmalignant histiocytic proliferative disorder that was originally described as a discrete pathological disorder in 1969 by Rosai and Dorfman . MoreoveRosai-Dorfman disease involving the tracheobronchial tree is rarely reported in the literature . The disThe prognosis of RDD is generally benign. Many cases of RDD undergo spontaneous complete resolution, especially in cases with nodal involvement only ; while oIn conclusion, Rosai-Dorfman disease with pulmonary affection can be misdiagnosed as malignancy. Careful histological examination of the specimen for emperipolesis or lymphocytophagocytosis together with S100 protein and CD68 positivity are the clue for proper diagnosis."}
+{"text": "On December 1, 2020, this report was posted online as an MMWR Early Release.Acinetobacter baumannii (CRAB), an opportunistic pathogen primarily associated with hospital-acquired infections, is an urgent public health threat (Carbapenem-resistant A. baumannii with meropenem minimum inhibitory concentration testing of \u22658 \u03bcg/mL) isolates from weekly ICU point prevalence surveys (colonization screening) and from clinical infections. Hospital A retrospectively reviewed microbiology records for CRAB isolated from inpatient specimens since November 2019 and instituted prospective surveillance of laboratory results to identify all CRAB isolates. Inpatients with hospital-acquired CRAB infection were defined as those for whom CRAB was isolated from clinical or colonization screening specimens collected on or after hospital day 3 and who had no earlier CRAB isolated from specimens during the same hospitalization; incident CRAB was a patient\u2018s first CRAB infection or colonization. Patients\u2019 demographic characteristics, diagnoses, treatments, disposition, and COVID-19 status were collected from medical records. Diagnoses of CRAB infection or colonization were determined by infectious disease specialists. NJDOH began an investigation to assess IPC practices at hospital A and gather additional data. This activity was reviewed by CDC and was conducted consistent with applicable federal law and CDC policy.*Hospital A is an urban, acute-care hospital in New Jersey with approximately 500 beds. In May 2020, hospital A notified NJDOH of an increase in CRAB  whose incident CRAB infection or colonization occurred during the facility\u2019s surge in COVID-19 cases (March\u2013June 2020) , and 17 A. baumannii with documented resistance to three or more classes of antibiotics) was applied to hospital clinical laboratory antimicrobial susceptibility data for incident cases  or these were different introductions remains unclear.The COVID-19 pandemic has required hospitals to take unprecedented measures to maintain continuity of patient care and protect health care personnel from infection. This outbreak highlights that MDROs can spread rapidly in hospitals experiencing surges in COVID-19 cases and cause serious infections in this setting. To reduce spread of MDROs and the risk of infection for patients, hospitals should remain vigilant to prevent and detect clusters of unusual infections and respond promptly when they are detected. Facilities should prioritize continuity of core IPC practices  to the greatest extent possible during surges in hospitalizations and make every effort to return to normal operating procedures as soon as capacity allows.Acinetobacter baumannii (CRAB) causes health care\u2013associated infections that are challenging to contain and often linked to infection prevention and control (IPC) breaches.Carbapenem-resistant A New Jersey hospital reported a cluster of 34 CRAB cases that peaked during a surge in COVID-19 hospitalizations. Strategies to preserve continuity of care led to deviations in IPC practices; CRAB cases decreased when normal operations resumed.Hospitals managing surges of patients with COVID-19 might be vulnerable to outbreaks of multidrug-resistant organism (MDRO) infections. Maintaining IPC best practices  to the extent possible could mitigate spread."}
+{"text": "Cerebral hyperperfusion syndrome (CHS) and reversible cerebral vasoconstriction syndrome (RCVS) are two syndromes characterized by disordered vascular autoregulatory mechanisms of brain. These may be seen after carotid endarterectomy (CEA). We present a patient who developed both syndromes after CEA which is a rare occurrence. Cerebral hyperperfusion syndrome (CHS) is a rare but well-known complication after major cerebral revascularization procedures including carotid endarterectomy (CEA) and carotid artery angioplasty/stenting (CAS) -2. CliniOn the other hand, the reversible cerebral vasoconstriction syndrome (RCVS) is another known complication after CEA or CAS among many other causes recognized for RCVS . This syA 59-year-old female with a history of hypertension presented to an outside hospital with symptoms concerning for transient ischemic attacks affecting the right middle cerebral artery (MCA) territory causing brief (<15 min) episodes of left hemiparesis. Imaging showed previous infarcts in the right frontal cortex Figure\u00a0, as wellThe patient improved clinically on post-craniectomy day 1 having purposeful extremity movements and following commands occasionally. However, she started to have seizure-like activity  lasting for hours, although her electroencephalogram (EEG) was negative. Levetiracetam and lacosamide were started. Due to the occurrence of post-CEA ICH and questionable head CT angiography concerning for vasculitis, cerebral catheter angiography was performed on post-craniectomy day 7. The angiogram demonstrated a patent right ICA Figure\u00a0 and diffWe report a patient with post-CEA CHS presenting with ICH whose clinical course was complicated with RCVS. Fitas et al. reported a 55-year-old-female with post-CEA imaging signs such as cortical edema and focal cortical SAH (compatible with early post-operative CHS) which was later complicated by increasing Lindegaard ratios in serial transcranial Doppler studies (over the course of 10 days) compatible with RCVS\u00a0.\u00a0Also, ACHS after CEACerebral hyperperfusion syndrome is a well-known complication after carotid artery revascularization procedures including CEA and CAS\u00a0, 9. ThisAngiographic findings reported for CHS include: (1) extravasating contrast material in distal vascular bed of the brain, and (2) arteriovenous shunting signs with early draining vein(s) and capillary blush during the CHS phase which fade after resolution of CHS\u00a0.Management of CHS is generally towards aggressive control of blood pressure keeping it within normal limits if not lower, in addition to symptomatic treatment for seizures and brain edema\u00a0. Beta-blRCVS after CEAReversible cerebral vasoconstriction syndrome is a relatively newly described entity after CEA. Although episodic vasoconstriction has been reported before, Call and Fleming were the first to systematically describe this syndrome in 1988\u00a0. It is cAngiographically, the cerebral vessels show segmental spasm which is diffuse and bilateral and affects both anterior and posterior circulations\u00a0. TypicalReversible cerebral vasoconstriction syndrome may be associated with ischemic or hemorrhagic stroke. Hemorrhagic sequelae include different forms of ICH, namely, SDH, SAH, and intraparenchymal hemorrhage\u00a0. The mosTreatment of RCVS is usually supportive. If present, any existing vasoactive medications should be discontinued. Calcium channel blockers have been suggested to relieve the vasoconstriction, although they may not necessarily prevent cerebral vasoconstriction or ICH\u00a0. Intra-aThe Management Dilemma of Co-existing CHS and RCVSReversible cerebral vasoconstriction syndrome and CHS represent two opposite ends of the pathophysiological spectrum of post-CEA/CAS cerebral dysautoregulation. On one end of the spectrum, the paralyzed arterioles of the brain cannot resist the suddenly increased CBF via proper reciprocal vasoconstriction (CHS). On the other end, diseased autoregulation of the brain leads to exaggerated vasoconstriction after CEA or CAS that may result in RCVS. These phenomena were both seen in the presented case. This constellation of pathophysiological phenomena creates a management challenge. Treatment of CHS requires lowering blood pressure control and avoiding vasodilator medications, whereas treatment of RCVS requires vasodilator therapy, and possibly controlled hypertensive therapy to treat strokes (if present).\u00a0There is no standard therapy for co-existing CHS and RCVS. We suggest meticulous work up of candidates for CEA/CAS to identify patients at increased risk for disordered cerebral autoregulation . These patients should be carefully followed after revascularization and be treated in a timely fashion to prevent the devastating complications of stroke and/or ICH. When evidence exists to support the coexistence of both syndromes, we suggest cautiously treating the prevailing syndrome (CHS versus RCVS) which is creating the symptoms while avoiding overtreatment (that may cause the other syndrome to become symptomatic) and staying vigilant for the symptoms of the other syndrome. These patients may be followed with daily transcranial Doppler\u00a0or other studies to detect signs of dysfunctional autoregulation\u00a0.Reversible cerebral vasoconstriction syndrome and CHS represent the two ends of the dysautoregulation spectrum in post-CEA patients. We report a rare case of concomitant CHS and RCVS after CAE. Proper identification of high-risk patient may warrant more diagnostic tests to detect the signs of dysautoregulation in post-CEA patients to prevent poor outcomes from these syndromes."}
+{"text": "Preoperative localization of non-palpable lung nodules plays an important role in video assisted thoracic surgery (VATS). Although percutaneous computed tomography (CT)-guided hook wire marking has become widely accepted, it is accompanied by rare but fatal complications such as air embolisms. We herein report a case of a submillimeter pulmonary nodule successfully localized by a mobile CT scan with a navigation system.A 40-year-old-man presented with the two right pulmonary nodules 4 years after a radical left nephrectomy for a renal clear cell carcinoma. One of the nodules was too small to palpate and preoperative marking was applied using a mobile CT scan with a navigation system. We successfully performed VATS wedge resection for both nodules and confirmed a pathological diagnosis of a metastasis from the renal cell carcinoma. The maximum pathological size of the smaller nodule was 500 \u03bcm.Preoperative marking of the lower lobe lesion in the present case was essential for VATS. Our novel technique was helpful for the precise marking without any morbidity.Preoperative marking using a mobile CT scan with a navigation system is safe and easily applicable. It might be a useful option for VATS of non-palpable lung nodules. Although percutaneous CT-guided hook wire marking has become widely accepted , it requ2A 40-year-old-man presented with right pulmonary nodules 4 years after a radical left nephrectomy for a renal clear cell carcinoma  without any drug use nor allergic history. He had no significant familial history. Chest CT revealed two circumscribed nodules in the right upper and lower lobes respectively, suggesting metastatic lung tumors . WithoutThe details of the procedure have been described elsewhere . BrieflyThe nodule in the upper lobe was resected in the usual manner. The operative time was 118 min without any procedure-related morbidity.The histopathological examination of both specimens revealed that the cytoplasm was filled with glycogen and phospholipids, consistent with a metastasis from the renal clear cell carcinoma . The max3The lungs are one of the most frequent metastatic sites from a renal cell carcinoma and a pulmonary metastasectomy is a feasible option in selected patients . Two favVarious methods have been proposed for the localization of non-palpable small pulmonary nodules. A CT-guided hook wire marking is one of the most common procedures and is often accompanied by procedure-related complications such as a pneumothorax and pulmonary hemorrhage . Air embThe O-arm\u2122 is a mobile preoperative CT imaging system. The obtained images are transferred to the Stealth Station\u2122S7 navigation system and allow virtual fluoroscopy to identify the preferred skin marking site . The sec4We herein report a case of a submillimeter metastatic lung tumor successfully resected using a mobile CT with a navigation system for the preoperative marking. This method is safe and easily applicable and might be a useful option for VATS of non-palpable lung nodules even in submillimeter cases.\u3000The authors declare that they have no competing interests.Not applicable.Not applicable.Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.Asuka Uebayashi wrote this paper. All authors read and approved the final manuscript.Not applicable.Toru Nakamura.Not commissioned, externally peer-reviewed."}
+{"text": "A 93-year-old woman presented with confluent yellow plaques with an intense golden glow symmetrically on the neck and lateral face  mimickinThe location of plane xanthomas can serve as a clue to a particular underlying disease. Plane xanthomas in a normolipemic patient with favored distribution on the neck, upper trunk, and flexural folds should prompt a search of underlying hematological disorders such as monoclonal gammopathy or lymphoproliferative disease ,2. Plane"}
+{"text": "We describe a 38-year-old male who underwent percutaneous coronary intervention (PCI) using a third-generation drug-eluting stent (DES) with a thin stent for an anomalous left main coronary artery (LMCA) originating from the right coronary sinus with a retro-aortic course. Six months later, in-stent restenosis (ISR) occurred due to stent implantation in angled lesions with significant hinge motion. An intravascular ultrasound (IVUS) revealed significant neointimal hyperplasia. The vessel wall of an angled coronary artery lesion is exposed to mechanical stress from the deployed stent. It has been reported before in the major coronary arteries but not in an anomalous LMCA. An angled coronary lesion, which is often accompanied by hinge motion, is reportedly a risk factor for in-stent restenosis (ISR) with all generations of coronary stents . SeveralA 38-year-old male patient with a 15-pack\u00a0per year smoking history presented to another hospital with acute\u00a0anterolateral ST-elevation myocardial infarction. He was thrombolyzed with t-PA with the complete resolution of his electrocardiography (ECG) changes. Echocardiogram\u00a0revealed mild left ventricular (LV) dysfunction with a left ventricular ejection fraction (LVEF) of 40%-45% and anterior/lateral wall hypokinesis. He was then transferred to our center where he was taken to the catheterization laboratory and a diagnostic coronary angiogram was done after obtaining\u00a0informed consent. The angiogram revealed a normal right coronary artery and an anomalous origin of the left main coronary artery from the right coronary cusp\u00a0Figure . Normal Six months later, he was admitted again due to the recurrence of chest pain with a normal ECG and mild troponin rise. The echocardiogram revealed an LVEF of 50%. Of note, the patient quit smoking since discharge. The coronary angiogram\u00a0revealed significant proliferative type three ISR (10 mm extending beyond the stent margins) Figure . The finThe clinical incidence of ISR after BMS implantation is approximately 20%-35%. The use of DES has led to a further decrease in the occurrence of ISR to 5%-10% . These iThe clinical significance of the high incidence of vessel wall injuries and ISA in angled lesions is still unclear. A recent clinical study of second-generation DES reported that lesion angle had no impact on one-year clinical outcomes, inconsistent with a past report in the bare metal stent era . This miISR is not uncommon and several risk factors have been reported as predisposing factors for such unwanted outcomes. Stenting of an angled lesion is associated with a higher incidence of ISR as compared to a non-angled lesion. It has been reported previously in the major coronary arteries. To our knowledge, our case is the first to report such an effect on an anomalous left main coronary artery."}
+{"text": "Limited mitochondria outer membrane permeability (MOMP) is a novel biological process where mammalian cells initiate the intrinsic apoptosis pathway with increased mitochondrial permeability but survive. One of the major consequences of limited MOMP is apoptotic endonuclease-induced DNA double strand breaks. Recent studies indicate that these DNA double stand breaks and ensuing activation of DNA damage response factors such as ATM play important but previously underappreciated roles in carcinogenesis and tumor growth. Furthermore, novel non-canonical roles of DNA repair factors such as ATM in tumor growth and treatment are also emerging. In this review, we try to summarize recent findings on this newly revealed link between DNA double strand break repair and cell death pathways. Mitochondria outer membrane permeability (MOMP) is a biological process initially described for cells undergoing programmed cell death or apoptosis. MOMP has been considered an essential process in the intrinsic pathway of apoptosis , 2. In tIn a separate study, we showed that myc-induced transformation of mammary epithelial cells depended on limited MOMP, i.e., sublethal Caspase 3 and endoG activation . In factATM) quinoline-2-one core. It showed excellent pharmacokinetics, a low predicted clinical dose, and a high maximum absorbable dose when orally administered at the preclinical level . AZD0156 animals . AZD0156 animals . It was  animals . When co animals . A cliniIn summary, because of availability of clinical trial-ready small molecule compounds, it is very feasible to combine cytotoxic cancer therapy such as radiotherapy with ICB therapy and ATM inhibition. Such a \u201ctriple\u201d threat approach may hold great promise in treating some forms of malignancies that are currently not responsive to ICB treatment alone.MOMP/apoptosis and DNA damage response are two fundamental biological processes previously thought to be well understood. However, it is evident from the literature that we covered in this review that each has numerous non-canonical and often times counter-intuitive functions. Recent studies on those non-canonical functions provided important new insights into the roles of those two processes in carcinogenesis and tumor response to treatment. Some of the insights may lead to the development of effective treatment/prevention strategies for cancer."}
+{"text": "Mesenchymal stem cells (MSCs) from several tissue sources have been investigated in clinical trials for multiple disorders, and mixed results from these trials have been documented , indicat2 strain) heart failure model to study cardiac repair mechanisms mediated by MSCs [2 hamster heart is known to exhibit an early aging phenotype due to progressive loss of cardiomyocytes and functional decline, it is important to determine whether the aging heart of older TO2 hamster may be able to achieve functional improvement in response to MSC therapy. Echocardiography performed 1 month after MSC injection shows that both the saline (HBSS) - and MSC-treated old TO2 hamsters exhibited a similar decline in function as indicated by indistinguishable fractional shortening (FS) and left ventricular end-diastolic dimension (LVDd) between the two groups (This host tissue deficit remains a major challenge in regenerative medicine because the aging population usually require the therapy. We previously used a hamster (TO by MSCs . However2 hamsters, it is ineffective in treating the older cardiomyopathic hamsters. Advanced age typically exhibits more prevalent adverse events in humans. Although the human heart has been known to harbor a significant number of resident stem cells possessing limited regeneration capacity, age-related ECM remodeling and stem cell senescence can lead to declining cardiomyocyte populations and myocardial dysfunction [2 heart may profoundly interfere with the growth factor signaling cascade mediated by the administered MSCs. The finding highlights the progressive nature of the fibrogenic process in the cardiomyopathic heart, which can interfere with the regenerative therapy. Thus, host tissue aging/fibrosis represents a major consideration in the design of MSC therapy.Thus, although MSC therapy is effective in treating younger TOfunction ,8. Similfunction ,10. Sinc"}
+{"text": "Strain and crack are critical indicators of structural safety. As a novel sensing device, a patch antenna sensor can be utilized to wirelessly estimate structural strain and surface crack growth through resonance frequency shift. The main challenges for the sensor are other effects such as temperature fluctuation that can generate unwanted resonance frequency shift and result in large noise in the measurement. Another challenge for existing designs of patch antenna sensor is the limited interrogation distance. In this research, thermally stable patch antenna sensors are investigated for more reliable measurement. Fabricated on a substrate material with a steady dielectric constant, a new passive (battery-free) patch antenna sensor is designed to improve reliability under temperature fluctuations. In addition, another newly designed dual-mode patch antenna sensor is proposed to achieve a longer interrogation distance. Extensive experiments are conducted to characterize the patch antenna sensor performance, including thermal stability, tensile strain sensing, and emulated crack sensing. The two new patch antenna sensors are demonstrated to be effective in wireless strain and crack measurements and have potential applications in structural health monitoring (SHM). Civil structures, such as buildings and bridges, can suffer from damage caused by various types of loads during the life span. Without proper maintenance, the damage can adversely affect the performance of a structure and may even result in structural failure . StructuThe development of wireless communication technology has facilitated a more convenient application of SHM systems on large structures. A typical wireless sensing system consists of a server and multiple sensor nodes. The server coordinates the wireless sensing network and receives measurement data from all the sensor nodes. Each sensor node usually has at least an embedded processor and a wireless transceiver. The advantageous features of onboard computing and wireless communication enable the dense and rapid deployment of sensor nodes. During past decades, various wireless sensing systems have been developed for SHM. For example, a low-cost wireless modular monitoring system was first proposed by Straser and Kiremidjian . Among oTo address the challenge of power source, passive (battery-free) wireless sensors have been proposed and studied. With the integration of technologies such as near field communication (NFC) and radiofrequency identification (RFID), passive wireless sensors harvest energy from the interrogation signal and do not require an onboard power supply. Among various passive wireless sensors for strain measurement, antenna sensors stand out for its simple configuration and low cost . The senAlthough extensive simulations and experiments have validated the strain and crack sensing performance of passive antenna sensors, thermal stability and limited interrogation range remain as major challenges for reliable measurement. Besides structural strain, other environmental disturbances, such as temperature fluctuation, can also result in the resonance frequency shift of the antenna by changing the dielectric constant of antenna substrate. A large frequency shift due to temperature fluctuation brings difficulty in distinguishing strain and crack effects from the temperature effect. To improve the strain and crack sensing performance during temperature fluctuation, this research proposes RFID antenna sensors with a thermally stable substrate material. Another limitation of the passive antenna sensor is the relatively short interrogation distance, due to lack of onboard power source. Some researchers have investigated techniques to increase the interrogation distance of RFID-based strain sensors ,24. NeveThe rest of the paper is organized as follows. \u00ae 5880  substrate [\u00ae 5880 substrate undergoes large resonance frequency change, due to its large dielectric constant variation (approximately 125 ppm/\u00b0C) [\u00ae 6202  is chosen as the new antenna substrate material. As the substrate provides more stable dielectric constant under temperature fluctuation, the patch antenna sensor is expected to have more consistent resonance frequency when temperature fluctuates. In addition, integrated with energy harvesting technology, a dual-mode patch antenna sensor is designed to achieve longer interrogation distance. Among several types of antennas that can be used as strain and crack sensor, patch antenna and its variations are simple and low-profile. Previous research work has proposed the patch antenna sensor with RT/duroidubstrate . Althoug\u00ae 6202 as substrate material which has a more stable dielectric constant under temperature fluctuation. The material RT/duroid\u00ae 6202 is a poly-tetra-fluoro-ethylene (PTFE) composite with limited woven glass reinforcement. The low dielectric constant (This section describes the passive patch antenna sensor design. The sensor adopts RT/duroid2) of the RFID chip further reduces the total size of the antenna sensor. The broad operation frequency range (from 840 MHz to 960 MHz) of the RFID chip facilitates international usage. The chip\u2019s high sensitivity and low power design provide a long interrogation range of the passive patch antenna sensor. In addition, the compatibility with external power enables the design of a dual-mode patch antenna sensor, which achieves a longer interrogation range and is described in The SL3S1013 RFID chip  is chosen for wireless communication. The RFID chip contains a 96-bit tag identifier including a 48-bit factory locked unique serial number. Equipped with an advanced anti-collision mechanism, the RFID chip enables the reader to simultaneously access multiple antenna sensors nearby. The small footprint (0.0394 \u00d7 0.0571 inches2. The sensor adopts a quarter-wave rectangular patch (folded-patch) antenna topology [j199.7 topology . The topive mode ) and the2. Both the drawing and picture show that a patch antenna sensor and a power management circuitry are fabricated on the same piece of substrate. Equipped with the power management circuitry, this sensor can harvest solar energy, storing energy in a rechargeable coin battery, and operating in active mode. When the battery runs out, this dual-mode RFID patch antenna sensor can automatically fall back to passive mode.This section describes the dual-mode patch antenna sensor design. Despite the advantages of operating without an onboard power supply, the passive patch antenna sensor can only support limited interrogation range. To increase the interrogation distance, a dual-mode RFID antenna sensor is designed. j205.5 The patch antenna sensor is designed similarly as described in j205.5 \u03a9 . The desThe power management circuitry derives energy from solar radiation and supplies regulated voltage to the RFID chip. The energy harvesting IC (integrated circuit) chip MAX17710  is adopted for this application. This IC chip both charges a cell battery with over-charge protection and powers the RFID chip with over-discharge protection. The harvested solar energy is stored in a high-capacity Lithium-Ion rechargeable coin cell battery RJD2032C1T1 , which improves the reliability of the patch antenna sensor.The strain/crack induced resonance frequency shift of the antenna sensor can be wireless detected and utilized to estimate the structural strain and surface crack propagation. This section describes the sensing mechanism of patch antenna sensors. A patch antenna sensor can wirelessly measure strain and/or crack on a structural surface through the shift of its electromagnetic resonance frequency. According to electromagnetic theory, the resonance frequency \u22125 (10 micro-strains) to 10\u22123 (1000 micro-strains). If the effective dielectric constant of the substrate remains as constant, the change of resonance frequency When strain Here This section describes the wireless measurement mechanism of the RFID based patch antenna sensor. To wirelessly obtain the resonance frequency, an RFID reader Tagformance Lite  is used to interrogate the patch antenna sensor. Thermal stability of the patch antenna sensor is investigated through an outdoor temperature test  and a te\u00ae 5880 substrate and the other with RT/duroid\u00ae 6202 substrate, are installed on the web surface of a steel I-section column. Metal foil strain gages are installed to measure the temperature-induced strain on the steel column surface. To keep track of temperature fluctuations in the field, two thermocouples are installed near the sensors. A reader antenna is placed 12 inches away from patch antenna sensors for wireless interrogation.An outdoor temperature test is conducted to study the influence of the temperature fluctuation on the resonance frequency of the patch antenna sensors. \u00ae 5880 substrate during the test. Meanwhile, the patch antenna senor with RT/duroid\u00ae 6202 substrate shows a total of ~0.1 MHz resonance frequency change, which is much less than that of the previous design with RT/duroid\u00ae 5880 substrate.The outdoor test starts at noon with ambient temperature at around 76 \u00b0F. The temperature is measured every 20 min. until 17:00. The temperature fluctuation is plotted in \u00ae 6202. A temperature chamber test is conducted to further investigate the thermal effects on the resonance frequency change of the patch antenna sensor with substrate material RT/duroid\u00ae 6202. For comparison, the resonance frequencies of a patch antenna sensor with substrate material RT/duroid\u00ae 5880 during temperature fluctuation are plotted in the same figure [\u00ae 6202 substrate when the chamber temperature reduces from 101 \u00b0F down to 37 \u00b0F. On the other hand, the patch antenna senor with RT/duroid\u00ae 5880 substrate experiences ~5 MHz resonance frequency change when the temperature changed from 103 \u00b0F to 33 \u00b0F. The comparison between two different types of substrate materials indicates that the antenna sensor with RT/duroid\u00ae 6202 substrate provides much better thermal stability.The chamber is heated to 101 \u00b0F at the beginning of the test and gradually cooled down to 37 \u00b0F. A total of 9 temperature levels are tested. After the temperature becomes stable at each level, five frequency sweeps are conducted to measure the interrogation power threshold of the patch antenna sensor. The resonance frequency of the antenna sensor at each temperature level is extracted from the averaged interrogation power threshold curve. e figure . A totalLaboratory tensile tests are conducted to evaluate the strain sensing performance of the dual-mode patch antenna sensor. This section describes the tensile strain sensing performance of the dual-mode patch antenna sensor working in passive mode. The load applied by the tensile machine is configured so that approximately each loading step generates a 50 The resonance frequency of the patch antenna sensor at each strain level is determined by peak picking of each average interrogation power threshold curve. As expected, the resonance frequency decreases as the tensile strain increases. This section describes the tensile strain sensing performance of the dual-mode patch antenna sensor working in active mode. The interrogation distance is increased to 60 inches, about 1.67 times longer than that of the passive mode test. All the other experimental setup and data analysis methods are the same as before. The average interrogation power threshold curves at different loading steps/strain levels are plotted in The resonance frequency of the patch antenna sensor at each strain level is determined by peak picking of each average interrogation power threshold curve. As expected, the resonance frequency decreases as the tensile strain increases. To investigate the crack sensing performance of the patch antenna sensor, an emulated crack test is carried out. For crack sensing, the antenna sensor is bonded on the rotating and fixed plates, above the gap and at the center of the crack opening line, as shown in In total, eleven gap opening sizes are wirelessly measured during the experiment. The resonance frequencies extracted from interrogation power curves are plotted in In this paper, thermally stable patch antenna sensors have been designed and validated for monitoring strain and crack growth of civil structures. Extensive experiments lead to the following conclusions. The temperature-induced dielectric constant change can result in unwanted resonance frequency change in patch antenna sensors. The thermally stable substrate material can improve the strain and crack sensing performance of patch antenna sensors by preserving the dielectric constant at different temperature levels. The tensile test results demonstrate that the developed patch antenna sensors can measure small structural strain by wireless identifying the resonance frequency shift. In addition, working in active mode, the dual-mode patch antenna sensor can achieve longer interrogation distance with the assistance of solar-charged battery power. The emulated crack sensing test results show that the designed patch antenna sensor is capable of tracking surface crack propagation. As the crack grows, the resonance frequency of the patch antenna sensor decreases as expected.Future research can investigate calibration according to temperature effects to further eliminate the unwanted uncertainties in the strain and crack measurements. Sensor performance may also be fine-tuned through more detailed multiphysics modeling and simulation."}
+{"text": "Toxicity of misfolded proteins and mitochondrial dysfunction are pivotal factors that promote age-associated functional neuronal decline and neurodegenerative disease across species. Although these neurotoxic challenges have long been considered to be cell-intrinsic, considerable evidence now supports that misfolded human disease proteins originating in one neuron can appear in neighboring cells, a phenomenon proposed to promote pathology spread in human neurodegenerative disease. We have found that C. elegans adult neurons that express aggregating proteins can extrude large (~5\u00b5M) membrane-surrounded vesicles that can include the aggregated proteins and damaged mitochondria. We speculate that throwing out the trash may correspond to a conserved mechanism that constitutes a fundamental, but formerly unrecognized, branch of neuronal proteostasis and mitochondrial quality control. I will discuss our current understanding of the mechanisms of neuronal trash elimination."}
+{"text": "Inflammatory pseudotumors (IPTs) are benign masses arising from nonspecific inflammatory conditions including surgical invasion. We herein report the rare case of an IPT mimicking port-site metastasis in a 69-year-old patient who underwent retroperitoneal robotic partial nephrectomy for stage T1a renal cell carcinoma. Radiological examination performed six months after the surgery revealed the presence of a mass underneath the abdominal wall which coincided with a port site. The tumor was resected by laparoscopic transperitoneal approach, and histological examination led to the diagnosis of an IPT that consists of xanthogranulomatous inflammation. We also discuss the etiology of IPT formation and features distinguishing IPTs from port-site metastasis. Inflammatory pseudotumors (IPTs) which are caused by nonspecific inflammatory conditions can develop at nearly every body site . Albeit A 69-year-old Japanese male with diabetes mellitus underwent right-sided retroperitoneal RPN for an incidental renal tumor . Five po18F]fluorodeoxyglucose- (FDG-) positron emission tomography- (PET-) CT, the mass had a mild FDG uptake with a maximum standardized uptake value of 3.2 (Follow-up computed tomography (CT) scan performed six months after the surgery revealed an emerging small mass below the right side of the abdominal wall coinciding with a 12\u2009mm AirSeal\u2122 assistant port site . By [18Fe of 3.2 . FurtherTumor resection was subsequently performed by laparoscopic transperitoneal approach . AlthougIPTs are benign tumors which mimic malignant neoplasms and comprise cells associated with both acute and chronic inflammation. The pathogenesis and etiology of IPTs are unspecific; therefore, IPTs have been described under various names such as xanthogranuloma, inflammatory myofibroblastic tumor , and lipSchloffer's tumor might be considered the diagnosis in the present case based on the potential etiology because it is possible that Vicryl\u2122 suture or Surgicel\u2122 used in RPN might have provoked a foreign body reaction. Asano et al.  reportedIn the present case, the Surgicel\u2122 bolster placed on the renal parenchymal defects was nearly invisible at the IPT site. This image finding shows that the Surgicel\u2122 bolster was normally diminished with time after surgery . It is uWhile the exact cause of IPT in the present case remains unknown, we speculate that the following two processes were more likely etiologies. The first one is chronic inflammation by microabscess formation underneath the abdominal wall, which might be partially due to diabetes mellitus. The second is the involvement of FN. Fat fragments produced in RPN might migrate to a port site and subsequently develop FN provoking chronic inflammation. Amblee and Ganesh  reportedThe preoperative differentiation between IPT and PSM of RCC is difficult because of the rarity of both conditions, which were reported in very few case reports \u20134, 9\u201311.Song et al. , who rep"}
+{"text": "Hypoplastic right heart syndrome with pulmonary atresia is a rare cyanotic heart disease with poor prognosis requiring urgent intervention to establish the pulmonary blood flow. Pulmonary blood flow is achieved by BT shunt or percutaneous techniques like PDA stenting or pulmonary valve perforation. Various series have shown that early surgical intervention causes high mortality in these patients. Pulmonary valve perforation is a suitable, physiological alternative to surgical techniques in selected patients.We report a case of hypoplastic right heart syndrome with pulmonary atresia and restrictive VSD presenting with cyanosis from birth and underwent pulmonary valve perforation successfully.Duct-dependent pulmonary circulation is a pediatric emergency, palliative procedure for establishing adequate pulmonary blood flow is essential early in the life. In the management of duct-dependent pulmonary circulation, RVOT perforation is an effective and safe option in suitable high-risk subgroups. The induced pulmonary regurgitation along with established physiological antegrade flow would be beneficial in the remodeling of tripartite/hypertrophied small RV. Hypoplastic right heart syndrome with pulmonary atresia is a rare form of cyanotic congenital heart disease with poor prognosis, high morbidity, and mortality. Early palliation for establishing adequate pulmonary flow is necessary for the relief of cyanosis and duct dependence. These patients are usually treated by aorto pulmonary shunt (BT shunt) followed by univentricular or 1.5 ventricular repair or biventricular repair at a later stage depending on the right ventricular growth if at all it grows. With the advent of use of radio frequency or laser-assisted perforation of pulmonary valve and balloon dilatation percutaneous techniques has garnered importance in achieving pulmonary flow. A series percutaneous techniques offered better outcome compared to surgical repair [z score of annulus \u2212 1.94. There was a severe TR, with measured RVSP of 110 mmHg (+mean RAP). There was a restrictive muscular ventricular septal defect, hypertrophied, hypoplastic tripartite RV, and valvular pulmonary atresia. The branch pulmonary arteries were confluent measuring 2.7/2.5 mm each. The duct arising from the under surface of the left aortic arch, supplying pulmonary circulation  wire was used to perforate the atretic pulmonary valve with serial dilatation using coronary balloons  to obtain the desired diameter (as assessed preoperatively by echocardiogram). The final injection showed unobstructed contrast filling both branch pulmonary arteries with good bilateral arborization  and arterial lines (5 Fr) were established by digital palpation. A JR guiding catheter was crossed across the tricuspid valve and placed at the dimple of atretic pulmonary valve. The position was confirmed in orthogonal views with a hand injection in a diagnostic JR catheter placed in aortic arch. The course of the PDA showed the retrograde filling of MPA up to the atretic part reassuring the position of the guide. A GAIA (ASAHIHypoplastic right heart syndrome (HRHS) is a rare cyanotic heart disease due to the underdevelopment of right heart structures . The spectrum of disorders varies from simple hypoplastic RV with or without pulmonary stenosis to grossly underdeveloped RV with pulmonary and/or tricuspid atresia , 2. VentDuct-dependent pulmonary circulation is a pediatric emergency, palliative procedure for establishing adequate pulmonary blood flow is essential early in the life. In the management of duct-dependent pulmonary circulation, RVOT perforation is an effective and safe option in suitable high-risk subgroups. The induced pulmonary regurgitation along with established physiological antegrade flow would be beneficial in the remodelling of tripartite/hypertrophied small RV.Additional file 1:.Additional file 2:.Additional file 3:.Additional file 4:.Additional file 5:.Additional file 6:.Additional file 7:."}
+{"text": "Case Presentation. Three patients with recurrent retinal detachment were treated between January and March 2018. In all cases, the intraoperative internal search did not demonstrate any obvious break or hole. MembraneBlue-Dual (Trypan Blue 0.15% + Brilliant Blue G 0.025%\u2009+\u20094% PEG) was then injected into the subretinal space using a 41-gauge cannula. The eye was rotated such that the dye was pushed through a tiny break which was causing the retinal detachment. 180-degree laser retinopexy was performed on a single eye. After silicon oil removal and absorption of the gas tamponade, retinas remained attached at three-months follow-up.  The purpose of this case series is to demonstrate that subretinal blue dye injection, with and without 180-degree endolaser retinopexy, can be considered a useful tool in finding occult rhegmatogenous retinal breaks in eyes with recurrent retinal detachment.  Chromophore-assisted occult retinal break detection can be considered a useful but not risk-free surgical technique in managing some unexpected and challenging intraoperative situations. Finding retinal holes or breaks is a key point for a successful retinal detachment repair. In redo surgery, this goal is sometimes difficult to achieve because of the modifications of the retina and vitreous and sclera consequences of the previous surgery. Trypan Blue dye-assisted occult retinal break detection represents a relatively novel technique which can simplify identification of previously unseen retinal breaks  helping Three patients with recurrent retinal detachment were treated at the Casa Sollievo della Sofferenza Hospital between January and March 2018. All of them underwent a standard three-port pars plana vitrectomy as well as intraoperative indentation using a binocular indirect RESIGHT (Zeiss) fundus viewing system. The first patient attended vitrectomy having had previously a failed pneumoretinopexy retinal detachment repair; no holes or breaks were detected by intraoperative careful search so MembraneBlue-Dual was injected into the subretinal space using a 41-gauge cannula designed for macular translocation. Perfluorocarbon heavy liquid was then injected into the vitreous cavity displacing the subretinal fluid toward the retina periphery. The eye was rotated such that the dye was vented out of a very tiny break located just anteriorly to the preexisting corioretinal scar. A second patient with a clinical history of multiple surgeries for retinal detachment  presented with a new onset macula off retinal detachment eight months after a successful silicon oil removal. On the superior temporal quadrant was still visible an apparently well buckled and partially treated tear with no other obvious hole or break. Again, MembraneBlue-Dual was injected into the subretinal space and perfluorocarbon heavy liquid injected into the vitreous cavity displacing the subretinal fluid. The dye started leaking out of the superior temporal already buckled tear which was initially considered safe (Video Missing retinal breaks during retinal detachment surgery is a well-recognized cause of failure in primary repairs . In some"}
+{"text": "A 33-year-old gravid female was brought to the emergency department after she collapsed in the street. Point-of-care ultrasound showed free fluid in the abdomen and confirmed an intrauterine pregnancy. Surgical teams were consulted, and cross-sectional imaging revealed a spontaneously ruptured splenic artery aneurysm (SAA). The patient was taken expeditiously to the operating room for splenic artery ligation and subsequent splenectomy.Ruptured SAA in pregnant patients is associated with significant mortality for both mother and fetus. Maintaining a high index of suspicion in the correct population is crucial to avoid diagnostic errors and provide definitive care with operative repair. A 33-year-old gravida 1 para 0 at 18 weeks gestational age presented to the emergency department for syncope. The patient had passed out while crossing the street and emergency medical services were activated. She reported severe abdominal pain after arrival and vitals showed a heart rate of 120 beats per minute and a blood pressure of 88/52 millimeters of mercury. Point-of-care ultrasound showed free fluid in the left upper quadrant and confirmed an intrauterine pregnancy with good cardiac activity. Obstetrics and general surgery teams were consulted. Following improvement of the patient\u2019s vital signs with a crystalloid bolus, a computed tomography was performed, which revealed a spontaneously ruptured and previously undiagnosed 2.6-centimeter splenic artery aneurysm (SAA)  and 2.The patient was taken emergently to the operating room where surgeons evacuated six liters of blood that originated from her splenic artery rupture. Splenectomy was successful in stabilization; however, post-operatively no fetal heart rate was found and a dilation and evacuation was subsequently performed. The patient was discharged home on day 14.The true incidence of SAA is unknown; however, estimates range from 0.02\u201310.4%.5What do we already know about this clinical entity?Splenic artery aneurysms are usually asymptomatic until ruptured at which point they are associated with high mortality. Pregnant women are at increased risk.What is the major impact of the image(s)?Images show ruptured aneurysm in conjunction with the developing fetus. These images are uncommon as such patients are often too unstable for advanced imaging.How might this improve emergency medicine practice?Understanding this deadly disease can improve emergency physicians\u2019 ability to quickly make the diagnosis and initiate effective treatment."}
+{"text": "Teaching point: CT may help distinguishing benign from life-threatening pneumatosis intestinalis. A 78-year old woman presented with epigastric pain and non-bloody diarrhea 6 days after a second cure of adjuvant chemotherapy for gastric adenocarcinoma  and Irinotecan).Massive Pneumatosis Intestinalis (PI) could be seen Figure  to E on Pneumatosis intestinalis which is defined as the presence of gas within the digestive tract wall is a radiographic finding resulting of a large spectrum of underlying diseases. The nature and severity of the disease determines the clinical significance of PI, not the amount of air. Initially considered indicative of advanced intestinal infarction, PI may be found in benign conditions such as immunosuppressive states.Pathogenesis of PI is multifactorial but two main theories emerge. The \u2018bacterial theory\u2019 hypothesizes the action of gas-forming bacilli entering the submucosa through mucosal breaks or increased mucosal permeability. The \u2018mechanical theory\u2019 hypothesizes that increasing of intraluminal bowel pressure with loss of intestinal mucosal integrity allows normal bowel gas to dissect the bowel wall.Regarding this, patients with cancer have a greater propensity to develop PI - often benign - because they cumulate multiple risk factors . Thrombogenic and vasospastic effects of 5-FU on the intestinal epithelium may have played a role in our patient.Independently from the clinical status, CT may help differentiate benign from worrisome PI and guide proper clinical treatment . Alarm s"}
+{"text": "To study variation in, and clinical impact of high Therapy Intensity Level (TIL) treatments for elevated intracranial pressure (ICP) in patients with traumatic brain injury (TBI) across European Intensive Care Units (ICUs).2\u2009<\u20094\u00a0kPa), and secondary decompressive craniectomy) in patients receiving ICP monitoring in the ICU stratum of the CENTER-TBI study. A random effect logistic regression model was used to determine between-centre variation in their use. A propensity score-matched model was used to study the impact on outcome (6-months Glasgow Outcome Score-extended\u00a0(GOSE)), whilst adjusting for case-mix severity, signs of brain herniation on imaging, and ICP.We studied high TIL treatments , intensive hyperventilation (PaCO313 of 758 patients from 52 European centres (41%) received at least one high TIL treatment with significant variation between centres (median odds ratio\u2009=\u20092.26). Patients often transiently received high TIL therapies without escalation from lower tier treatments. 38% of patients with high TIL treatment had favourable outcomes (GOSE\u2009\u2265\u20095). The use of high TIL treatment was not significantly associated with worse outcome . However, a sensitivity analysis excluding high TIL treatments at day 1 or use of metabolic suppression at any day did reveal a statistically significant association with worse outcome.Substantial between-centre variation in use of high TIL treatments for TBI was found and treatment escalation to higher TIL treatments were often not preceded by more conventional lower TIL treatments. The significant association between high TIL treatments after day 1 and worse outcomes may reflect aggressive use or unmeasured confounders or inappropriate escalation strategies.Substantial variation was found in the use of highly intensive ICP-lowering treatments across European ICUs and a stepwise escalation strategy from lower to higher intensity level therapy is often lacking. Further research is necessary to study the impact of high therapy intensity treatments.https://clinicaltrials.gov/ct2/show/NCT02210221?id=NCT02210221&draw=1&rank=1 and with Resource Identification Portal (RRID: SCR_015582).The core study was registered with ClinicalTrials.gov, number NCT02210221, registered 08/06/2014,  Limiting the impact of secondary insults by controlling harmful levels of intracranial pressure (ICP) is an essential part of Traumatic Brain Injury (TBI) care in the intensive care unit (ICU). Interventions used to reduce ICP are typically titrated to balance their clinical effect against their side effects, which may be significant or even life-threatening. The intensity of such interventions can be quantified by the therapy intensity level (TIL) score. The TIL score was first introduced in 1987  which waDespite this proposed framework for rational use of ICP therapies, past studies have found wide variations between centres in their deployment , 5. SomeTherefore, the aim of this study is to investigate the variation in the use of high TIL therapies in clinical practice and explore the impact on clinical outcome in patients with TBI in European ICUs.Data from the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) study were used for this analysis . CENTER-TBI recruited patients with TBI, presenting between December 19, 2014 and December 17, 2017  p\u2009=\u20090.004).  patients were well matched in terms of their baseline characteristics .An important finding is that a large proportion of patients receiving high TIL treatments nevertheless recovered to good functional outcome (moderate disability to good recovery) at 6\u00a0months. High TIL treatment might be an appropriate final resource for patients with refractory high ICP values and may be beneficial in this group. Nevertheless, since there could be risks of such treatments, this emphasises the need for their rational use. More work is required to understand if outcome benefits could result from a more consistently gradated and progressive application of treatment intensity and/or a shift from institutional policies towards individualized medicine.. explored various definitions for aggressive treatment, such as the definitions \u2018use of ICP monitoring in more than 50% in patients meeting the BTF guidelines criteria\u2019 and \u2018aggressiveness based on a TIL score \u2019 . High TIL therapies are shown in bold.Additional file 2. Missing data. Description: This figure shows the proportion of missing data in the original data (before imputation). In the left panel the proportion of missingness per variable is shown. In the combination plot (grid) all patterns of missing (red) and observed data (blue) are shown. For example, the bottom row shows all patients with complete data, above that the patients with the combination missing data for Hb and gluc, ect. The bars on the right of the combination plot show the frequency of occurrence of the combinations.Additional file 3. Treatments on the TIL scale .Description: This table shows the number and percentages of ICP-monitored patients receiving ICP-lowering treatments on the TIL scale. Each row shows the number of patients (frequency) that receive that treatment (a patient could receive multiple treatments per topic).Additional file 4. Daily TIL scores. Description: This figure shows the daily high TIL scores (cumulative score of the high TIL treatments) plotted against the daily low TIL scores (cumulative score for low TIL treatments). It shows that at the same high TIL scores a variety of low TIL treatment (scores) is applied (in some cases even no low TIL treatment). Also, the figure shows mainly at day 3 (dark green) higher TIL treatments are applied including higher low TIL scores.Additional file 5. Treatments on the TIL scale (high TIL patients). Description: This table shows the number and percentages of high TIL patients receiving ICP-lowering treatments on the TIL scale. Each row shows the number of patients (frequency) that receive that treatment (a patient could receive multiple treatments per topic) Bolt treatment are regarded as high TIL treatment.Additional file 6. Higher tier ICP-lowering treatments in patients receiving high TIL treatment. Description: This figure shows the proportion of patients that receive first and second tier treatments of the high TIL patients across 7 days at the Intensive Care Unit.Additional file 7. Variation in high TIL treatment percentages across centres (centre-level). Description: This table describes the between-centre variation for high TIL treatments across the days. The number of centres are the centres that actually apply the individual treatments. The mean percentage represents the mean percentage of patients across centres that receive the therapy, while the IQR and min-max represents the variation in treatment use between centres.Additional file 8. Baseline characteristics matched dataset. Description: This table describes the baseline characteristics of the matched cases with complete data . Significant group differences were determined by using the chi-square or Fisher\u2019s exact test  for categorical variables and an ANOVA or Kruskal Wallis test  for continuous variables.Additional file 9. Maximum ICP values prior to start high TIL use per treatment group. Description: This figure shows the differences in maximum ICP values prior to high TIL treatment between patients with a high TIL (1) versus a low TIL treatment (0). The median ICP for low TIL is 22 [16-28] and for high TIL 22 [16-27]. This difference is not statistically significant."}
+{"text": "Teaching Point: Retropharyngeal hematoma appearing under rivaroxaban is uncommon but should be suspected in cases of dysphagia, dysphonia or breathing difficulties. A 74-year-old man was admitted to the emergency department for progressive dysphagia and mild dysphonia in the context of minor bicycle trauma that had occurred four days earlier. He had no significant swelling nor any cervical spine pain and no limitation of neck movement. He had no signs of airways being compromised. Previous medical history included anticoagulation with rivaroxaban for atrial fibrillation and aortic valve replacement four months before the bicycle trauma. Examination of the oropharynx was unremarkable. He was afebrile, with normal blood pressure.Figure 1, double arrow). Contrast-enhanced computed tomography (CECT) with oral gastrografin administration revealed hematoma extending from the retropharyngeal to the superior mediastinal space without active bleeding or vertebral fracture . Axial US image showed a slightly echoic and heterogeneous liquid collection pushing forward trachea and thyroid .Lateral cervical X-ray showed increased soft tissue thickness of 30 mm in front of C5  and axial sequence with fat saturation  confirmed methemoglobin hyperintensity. A control MRI carried out three months later showed the disappearance of the hematoma.The hematoma was not drained due to its good tolerance. The patient was monitored closely. On magnetic resonance imaging (MRI) performed seven days later, T1-weighted sagittal  can be done at the patient\u2019s bedside. MRI offers the advantage of anatomical precision and is recommended for follow-up.Non-compressive hematoma can be treated conservatively by cervical spine immobilization and close clinical monitoring. For a retropharyngeal hematoma producing significant airway obstruction, a tracheostomy may be necessary. Surgical evacuation is generally reserved for hematomas that develop quickly, obstruct mechanical ventilation, or do not resolve themselves traditionally."}
+{"text": "Polycarpa aurata were identified with activity against Mycobacterium tuberculosis H37Rv. Native magnetic resonance mass spectrometry (MRMS) against a panel of 37 proteins from Mycobacterium proteomes showed that a fraction from a 95% ethanol re-extraction specifically formed a protein-ligand complex with Rv1466, a putative uncharacterized Mycobacterium tuberculosis protein. The natural product responsible was isolated and characterized to be polycarpine. The molecular weight of the ligand bound to Rv1466, 233 Da, was half the molecular weight of polycarpine less one proton, indicating that polycarpine formed a covalent bond with Rv1466.In recent years, there has been a revival of interest in phenotypic-based drug discovery (PDD) due to target-based drug discovery (TDD) falling below expectations. Both PDD and TDD have their unique advantages and should be used as complementary methods in drug discovery. The PhenoTarget approach combines the strengths of the PDD and TDD approaches. Phenotypic screening is conducted initially to detect cellular active components and the hits are then screened against a panel of putative targets. This PhenoTarget protocol can be equally applied to pure compound libraries as well as natural product fractions. Here we described the use of the PhenoTarget approach to identify an anti-tuberculosis lead compound. Fractions from  Drug discovery research and development has experienced two periods with different centric strategies, namely phenotypic-based drug discovery (PDD) and target-based drug discovery (TDD) . CommonlPenicillium species in 1928  KD of polycarpine with Rv1466 was determined using the following equations [The relative abundances of protein-ligand complex to total protein in the mass spectra correlated to the relative equilibrium concentrations of ligand to total protein in solution. The pseudo quations :(1)\u03a3\u00a0I(PKD could be obtained as a parameter of a nonlinear least-squares curve fitting.Experimental relative ratios of protein-ligand complex and total protein ion abundances were plotted against the total concentration of ligand. The pseudo"}
+{"text": "During visual fixation, the eyes make small and fast movements known as microsaccades (MSs). The effects of MSs on neural activity in the visual cortex are not well understood. Utilizing voltage-sensitive dye imaging, we imaged the spatiotemporal patterns of neuronal responses induced by MSs in early visual cortices of behaving monkeys.Our results reveal a continuous \u201cvisual instability\u201d during fixation: while the visual stimulus moves over the retina with each MS, the neuronal activity in V1 \u2018hops\u2019 within the retinotopic map, as dictated by the MS parameters. Neuronal modulations induced by MSs are characterized by neural suppression followed by neural enhancement and increased synchronization. The suppressed activity may underlie the suppressed perception during MSs whereas the late enhancement may facilitate the processing of new incoming image information. Moreover, the instability induced by MSs applies also to neural correlates of visual perception processes such as figure-ground (FG) segregation, which appear to develop faster after fixational saccades.Video stream:https://vimeo.com/362367119"}
+{"text": "Scientific Reports 10.1038/s41598-020-58917-4, published online 06 February 2020Correction to: The Article does not include a reference to a recent relevant paper, which is now cited as Reference 1 below, and should be included in the text as follows.In the Discussion,\u201cLarge nerve specimens with large axonal loads often have fixation artefacts, hence absolute axonal loads may not be able to be determined as accurately.Other recent studies on the microanatomy of the facial nerve with large research collectives have used semi-automated or automated methods for axon quantification.\u201dshould read:\u201cLarge nerve specimens with large axonal loads often have fixation artefacts, hence absolute axonal loads may not be able to be determined as accurately.The ultimate goal of microanatomic nerve research is optimizing intraoperative decision making. Other studies have attempted intraoperative axon quantification successfully in animal nerve cross sections using a rapid automated quantification method, however being dependent on commercial software .Other recent studies on the microanatomy of the facial nerve with large research collectives have used semi-automated or automated methods for axon quantification.\u201d"}
+{"text": "We examined daily affective vulnerability to short sleep  as a risk factor for developing chronic conditions 10 years later. Participants  from the National Study of Daily Experiences reported sleep duration and affect in daily diary telephone interviews. Chronic conditions were assessed with a 39-item checklist . Multilevel structural equation models revealed that individuals with heightened negative affect following short sleep had an increased number of chronic conditions after 10 years . Positive affective vulnerability  was marginally associated with 10-year chronic conditions . Adding to the well-established connections between sleep duration and well-being across adulthood, these findings suggest that affective vulnerability to short sleep represents a unique risk factor for long-term health as people age."}
+{"text": "Neuroendocrine differentiation (NED) of prostate cancer represents an acknowledged predictor of resistant and more aggressive disease. NED can be functionally exploited in vivo using PET/CT imaging with somatostatin analogs radiolabeled with 68Ga. Many previous reports have shown that 18F-FDG PET/CT should also be used in cases such as guiding management, as NED is systematically associated with increased glycolysis. We hereby discuss the case of a metastatic prostate cancer patient in which 68Ga-Dotatoc PET/CT revealed the occurrence of NED with low FDG-avidity."}
+{"text": "In this case we discuss the management of a pediculated floating thrombus in the aortic arch which led to peripheral embolization and acute ischemia oft he left leg.A healthy 46\u2009year old female patient presented with pain in her left leg and progressive numbness. Computed Tomography Angiography (CTA) showed an acute ischemia of the left leg (Rutherford 2 B) with a 2\u2009cm thrombus distal of the aortic bifurcation. Emergency operation with embolectomy, selective thrombembolectomy and patch plasty on the tibioperoneal trunk and local lysis was performed. As part of a further diagnostic examination a thoracic CT scan has been performed revealing a pediculated-floating 2\u2009cm thrombus in the aortic arch. Four days after the initial operation thrombus excision via a minimally invasive access way has been performed. After initiation of the extracorporeal circulation, selective unilateral antegrade cerebral perfusion has been established in mild (30\u201332\u2009\u00b0C) systemic hypothermia. Patients postoperative course was uneventful. Histological evaluation of the mass demonstrated thrombotic material without evidence of infection or malignacy.A pediculated spontaneous thrombus may develop in aortic arch in patients without traditional risk factors or family history of embolic events. Two stage operation was feasible and safe. Peripheral embolization of a thrombus fragment located in the aortic arch is a rare finding in clinical practice. In non-aneurysmal vessels but especially in young patients with no history of atherosclerosis this condition becomes rare. In the current manuscript we aimed to report and discuss the surgical management of a pediculated-floating 2\u2009cm thrombus in the aortic arch which already lead to an acute ischemia of the left leg (Rutherford 2 B). Procedural steps were initiated after interdisciplinary decision making in the Cardio-Vascular-Surgery Team.A 46\u2009year old female patient presented with pain in her left leg and progressive numbness. She has no history of valvular heart disease, atrial fibrillation, hypercoagulable disorder, peripheral vascular disease or claudication. Due to absent pedal pulse an emergency Computed Tomography Angiography (CTA) was initiated with diagnosis of an acute ischemia of the left leg (Rutherford 2 B) with a 2\u2009cm thrombus distal of the aortic bifurcation Fig.\u00a0. EmergenFour days after the initial operation thrombus excision via a minimally invasive access way  was performed. Basic operative steps were as follows: Limited skin incision (8\u2009cm) followed by left sided L-shaped partial upper sternotomy beginning from jugulum diverted to 4th intercostal space. Direct arterial cannulation via right axillary artery and venous cannulation through the right atrium. After initiation of the extracorporeal circulation, selective unilateral antegrade cerebral perfusion was established in mild 30\u201332\u2009\u00b0C) systemic hypothermia under control of brain tissue oxygen saturation with near-infrared spectroscopy (INVOS). Longitudinal incision of the distal ascending aorta, direct visualization and excision of the 2\u2009cm thrombus  scan was negative. Long-term electrocardiogram (ECG) monitoring showed no atrial fibrillation or any other pathologic finding. The patient was referred for hematology consultation with negative results for congenital or acquired thrombophilia. Paraproteins were excluded, there were no Janus-Kinase-2 (JAK-2) mutations. Antithrombin and functional Protein C were normal. During therapy with phenprocoumon, Protein S was lower so that hereditary Protein S deficiency cannot be fully excluded. Oral anticoagulants are continued while Aspirin was stopped due to a resistance. In the clinical follow up the patient presented in a good clinical condition. CT scan 1 year postoperative showed no further embolic events or remaining embolic material in the aorta.Spontaneous Aortic Arch thrombus is a rare but previously in literature described origin for peripheral embolization . Common Thrombus in the ascending aortic or aortic arch can be associated with embolic events with a subsequent cerebral, visceral and peripheral ischemia. The latter is decisive for the clinical appearance of the patient, which can vary. Once peripheral emboli is retrieved and the peripheral circulation is restored patients without an obvious etiology for the embolic event warrant urgent hypercoagulable screening and diagnostic imaging, including CT-Scan of the thoracic and abdominal aorta as well as echocardiography, to rule out pathology of the thoracic aorta as well as intracardiac thrombus.Medical treatment including heparinization, endovascular stenting, or surgery have been proposed according to the International Guidelines for the treatment of mobile aortic thrombosis  but no cGiven the concern for potential cerebral and recurrent peripheral embolization, we decided against conservative management with anticoagulant agents alone and pursued urgent surgical exploration via a minimally invasive access way. Since the thrombus was pediculated catheterbased thrombectomy was not discussed in this case.Our standard surgical approach for aortic arch surgery has been described previously in detail . Main stAligned with actuarial literature initiation of systemic anticoagulation with phenprocoumon or antiplatelet therapy with aspirin should be considered as secondary prophylaxis for recurrent emboli . AspirinA pediculated spontaneous thrombus may develop in aortic arch in patients without traditional risk factors or family history of embolic events.Two-step surgical treatment of the peripheral acute ischemia followed by minimally invasive thrombectomy in the aortic arch performing through a partial upper sternotomy can be performed safely in a setting of mild systemic hypothermia during selective unilateral antegrade cerebral perfusion."}
+{"text": "Antimicrobial surface coatings function as a contact biocide and are extensively used to prevent the growth and transmission of pathogens on environmental surfaces. Currently, scientists and researchers are intensively working to develop antimicrobial, antiviral coating solutions that would efficiently impede/stop the contagion of COVID-19 via surface contamination. Herein we present a flavonoid-based antimicrobial surface coating fabricated by laser processing that has the potential to eradicate COVID-19 contact transmission. Quercetin-containing coatings showed better resistance to microbial colonization than antibiotic\u2013containing ones."}
+{"text": "Corneal refractive surgeries cause epithelial damage and induce wound healing processes. To promote wound healing after photorefractive keratectomy, the effectiveness of an autologous platelet tissue graft was assessed.A 45-year-old Asian male with low myopia and/or myopic astigmatism received photorefractive keratectomy in both eyes. The right eye was postoperatively treated with an autologous platelet tissue graft using the GPS III Platelet Concentration System to prepare platelet-rich plasma, while the left eye was not treated. Both eyes achieved the expected uncorrected distance visual acuity, but the platelet-rich-plasma-treated right eye obtained improved visual acuity more than 1 week before the untreated left eye. Perceived pain after photorefractive keratectomy was much lower and of shorter duration in the treated right eye than it was for the left eye. Pericorneal injection on the bulbar conjunctiva with superficial keratitis resolved earlier in the right eye than the left eye.Autologous platelet tissue grafting using a GPS III to obtain platelet-rich plasma was effective in promoting corneal wound healing after photorefractive keratectomy. Thus, platelet-rich plasma may be beneficial for patients undergoing corneal refractive surgeries. Laser litation \u20133. LASIKlitation , which cPhotorefractive keratectomy (PRK) emerged before LASIK, and this refractive surgery has been equally beneficial compared with LASIK for patients with low myopia and/or myopic astigmatism. PRK entails removing the cornea from the epithelial layers to the Bowman\u2019s layer or the anterior stroma to the degree required for myopia correction \u20133. The mThe present study was thus conducted to determine if an autologous platelet tissue graft could promote wound healing after PRK, since autologous platelet tissue grafts have shown promise in the promotion of wound healing in many other surgical settings \u20139.A 45-year-old male received PRK using a MEL 90 excimer laser  under the control of the triple-A algorithm[To determine if an autologous platelet tissue graft may be beneficial for the promotion of wound healing after PRK, we used Gravitational Platelet Separation System with disposable separation tubes (GPSIII: BioMet Biologics) for preparation of PRP . The PRPSodium fluorescein was used to evaluate corneal abrasion  in both Myopic correction occurred as expected. Uncorrected distance visual acuity (UDVA) was postoperatively monitored starting at day 3 for 25 days Fig. After 2PRK and LASIK are widely accepted and performed as corneal refractive surgeries to improve vision. Owing to the differences in surgical procedures, both approaches have merits and demerits \u20135. PRK dHere, we used the GPS III system  to obtaiThe corneal epithelium is a self-renewing tissue containing ample stem cells residing in the corneoscleral junction and limbus , 3. FollWhile there is little information on the effects of PRP for epithelial regeneration after corneal refractive surgery, it can be hypothesized that PRP is beneficial, as it contains significant amounts of PDGF, TGF-\u03b2, and EGF . In thisThis study has a few limitations that should be noted. Since we presented results from only one patient, a greater number of patients should be treated to fully evaluate the effects of PRP on the wound healing process. Moreover, it is possible that other preoperative heath conditions might affect the outcomes of PRP treatment.PRP treatment was effective for promoting corneal wound healing after PRK, and PRP may be beneficial for patients undergoing corneal refractive surgeries."}
+{"text": "Suppressing fat in late gadolinium enhancement (LGE) images is a challenging task in a variety of clinical settings. Both fat and LGE appear bright in these images making it difficult to quantify the exact extent of LGE or even in some cases e.g. in myocarditis to establish the presence of late enhancement, which because of its subepicardial location may be easily confused with pericardial fat. We tested the clinical utility of a novel in/opposed phase LGE sequence in this setting.We implemented a cardiac gated two-dimensional inversion recovery prepared pulse sequence to acquire gradient echo images (in and opp.-LGE) with two echo times (2.4 and 5.0 ms) 10 minutes after the IV injection of gadolinium DTPA (0.2 mmol/Kg BW) in a single breath hold. This was achieved at the cost of an increase in bandwidth (140 vs. 400 Hz/Px) in comparison to the standard LGE sequence. All other sequence parameters including the inversion time were kept constant  Images were acquired twice once using the conventional non-fat sat LGE (con-LGE) sequence and then using the proposed in/opposed phase approach in 28 patients with positive LGE secondary to ischemic and non-ischemic conditions. Images were evaluated both quantitatively and qualitatively. Contrast to noise (CNR) ratios between fat, normal and enhanced myocardium were measured. One independent observer visually evaluated the diagnostic quality of all images.Fat was homogenously suppressed over the entire FOV in all cases. The CNR between fat and normal myocardium decreased significantly in opp-LGE compared to con-LGE  indicating effective fat suppression. Furthermore, the CNR between LGE areas and the pericardial fat increased significantly in opp-LGE compared to con-LGE  implying better LGE-fat differentiation. The qualitative assessment proved the sequence robustness over a wide range of indications and that this approach could provide additional diagnostic information over that obtained from con-LGE in 2/28 patients. Figure We provide a first clinical utilization of a novel fat suppression late enhancement imaging combining in/opposed phase imaging with conventional inversion recovery gradient echo sequences. This approach enables effective differentiation between fat and enhanced myocardium, which should result in accurate LGE quantification."}
+{"text": "Within the last decade significant progress has been accomplished in the field of allogeneic hematopoietic cell transplantation (HCT). The articles in this special topics series present progress in improving clinical outcomes using some of the most vibrant current research and translational approaches, including novel reduced-intensity conditioning regimens, donor graft engineering, quantification of the microbiome, and tailored immunosuppressive therapies. Much of the progress described is due to improvements in immune reconstitution that results in durable allograft tolerance. Consequently, there is reduced graft-vs.-host disease (GVHD) and improvement in controlling infectious disease complications. In addition, improved immune reconstitution also appears to facilitate much-needed graft-vs.-leukemia effects, as relapse remains the major challenge of our field. Many of the articles in this special topics series are organized around our increasing understanding of GVHD and a suite of new tools and approaches to prevent and treat this dreaded immune complication.Thangavelu and Blazar from the University of Minnesota provide an overview of our current understanding of GVHD pathophysiology and thoroughly review novel therapeutic strategies to induce immune tolerance focusing on biologicals, epigenetic modulation, and adoptive cell therapy. In particular, light is shed on the role of the intestinal microbiome for GVHD induction by K\u00f6hler and Zeiser: within the last years it became evident in various preclinical and clinical studies that changes of the bacterial composition affects the risk of intestinal GVHD which also constitutes a potential target to prevent deleterious damage of the gut. For patients with steroid-refractory acute and chronic GVHD, extracorporeal photopheresis (ECP) is an established procedure to induce immune tolerance and a significant impact of apoptotic bodies to modulate dendritic-cell function has been established. Ni et al. now suggest that also NK-cell subsets are influenced by ECP in such a way that CD56highCD16\u2212 NK cells were decreased and cytotoxicity shifted toward a regulatory phenotype while maintaining antileukemic activity.Soares et al. who performed a prospective comparative analysis that suggests that thymic damage results in dysfunctional thymic output with increased CD8+ terminally differentiated effector memory T cells and decreased T-cell receptor diversity. This study emphasizes the thymus as critical organ for central immune tolerance during immune reconstitution and sustained immune tolerance after allogeneic HCT. Simonetta et al. performed a comprehensive analysis of PD-1 expression on T cells following allogeneic HCT noticing an increase early after transplantation without impaired production of cytotoxic effector molecules. This study provides insight into dynamic T-cell regulation also suggesting that timing should be considered when check point inhibitors are applied.Efforts to define normal and healthy from abnormal and immune reconstitution that puts recipients at increased risk of GVHD continues to develop with the application of immune monitoring, as illustrated by Bertaina and Roncarolo from Stanford University review such approaches focusing on T- and B-cell depletion strategies as well as regulatory T cells. In particular, three papers included in this Research Topic explore double-negative T cells, myeloid-derived suppressor cells (MDSCs) and invariant natural killer T (iNKT) cells for GVHD prevention. Haug et al. found that TCR\u03b1\u03b2+CD4\u2212CD8\u2212 T cells inhibit mammalian target of rapamycin (mTOR) signaling and prevent metabolic adaption of conventional T helper cells resulting in decreased homing receptor expression and production of proinflammatory cytokines. The expansion of MDSCs from hematopoietic stem cells has been studied by Park et al. showing that these cells retain a suppressive phenotype and ameliorate GVHD in a xenogeneic GVHD model also resulting in improved survival. Jahnke et al. demonstrate that human iNKT cells that have been shown to promote immune tolerance after allogeneic HCT can also be expanded from cryopreserved donor lymphocytes efficiently lysing patient AML blasts.Efforts to engineer donor grafts have shown evidence in pre-clinical and clinical studies of improved immune reconstitution. Stahl et al. summarize preclinical and clinical data about the CD4 antibody MAX.16H5 that has been investigated in auto- and alloimmunity. Wajant and Beilhack from W\u00fcrzburg highlight the impact of tumor necrosis factor signaling on the regulation of FoxP3 regulatory T cells being known as central players for sustained immune tolerance after allogeneic HCT.Finally, two review articles provide detailed insights into innovative approaches of immune tolerance induction. This Research Topic bundles cutting-edge, innovative, and translational original research articles as well as excellent reviews from renowned scientists highlighting recent progress in the field of transplant immunology and immune tolerance.DS and EM wrote the editorial.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "The routine use of sentinel lymph node biopsy (SLNB) to accurately stage melanoma patients has been incorporated into most international melanoma guidelines. On average, over 80% of patients are sentinel node negative.The melanoma follow-up (MelFO) study is an international phase III randomized controlled trial where participants are randomized into two groups\u2014one following the conventional schedule recommended in the UK National Institutes for Health and Care Excellence (NICE) melanoma guidelines,These reflections were written at a time when most modern healthcare services have been disrupted beyond recognition during the COVID-19 pandemic. It is likely that many services will be rationalized in the future, once the pandemic subsides. Accordingly, evidenced-based follow-up regimens will be needed to ensure that the appropriate balance is struck between diagnosing early the few recurrences in low-risk groups such as these and not overburdening both patients and society alike.The UK MelFO study has shown that 3\u00a0years after staging with a negative SLNB, AJCC stage IB\u2013IIC cutaneous melanoma patients assigned to the prescribed reduced stage-adjusted follow-up schedule reported no difference in levels of anxiety, cancer worry, and mental health-related QoL when compared with those of patients assigned to the follow-up schedule as currently advised in the UK NICE melanoma guideline. These results mirror the findings of the Dutch group who recently reported very similar results using the same protocol in 2019."}
+{"text": "A combination of left ventricular aneurysm (LVA) and ventricular septal rupture (VSR) in an acute myocardial infarction (AMI) patient presenting as heart failure is extremely rare. Here, we report a rare case of concurrent true inferoposterior LVA and VSR secondary to inferior wall myocardial infarction (IWMI) presenting as chronic heart failure (CHF). To the best of our knowledge, this is the third reported case in the literature.A 61-year-old man, who had an IWMI about one month prior, presented with CHF. Echocardiography revealed true inferoposterior LVA and VSR. Coronary angiography revealed double vessel disease involving the right coronary artery\u00a0(RCA) and left circumflex artery (LCX). Left ventricular angiography confirmed a large posterobasal aneurysm and VSR. The patient underwent successful coronary artery bypass grafting (CABG) and ventriculoplasty along with VSR patch repair. Mechanical complications after acute myocardial infarction (AMI) are rare and account\u00a0for <1% of the total cases. Left ventricular aneurysm (LVA) is the most common mechanical complication of ST-elevation myocardial infarction (STEMI). However, the incidence of LVA has decreased dramatically to 0.2%\u00a0due to early revascularization therapy. The most common site of LVA is the anterior wall and true LVA involving the inferoposterior wall is rare, comprising only 9% of total cases Mortality with an IWMI, when complicated with VSR, is substantially high. But our case is exceptional, as the patient was hemodynamically stable with the symptoms of gradually progressive heart failure for almost one month. It might be because a giant aneurysm may act as a buffer area to shunting flow thereby preventing the surge of pulmonary artery pressure.There are only a few case reports in the literature for concurrent true vertical reduction aortoplasty and VSR after MI -14. WhilMechanical complications after AMI are rare but still prevalent. Concurrent true inferoposterior LVA and VSR secondary to IWMI can present as symptoms of CHF. High clinical suspicion and thorough physical examination at first medical contact can lead to the early identification of these cases. Echocardiography and LV angiography are valuable in diagnosing these types of rare cases. Combined CABG and ventriculoplasty with VSR patch repair are effective in treating this often fatal complication of inferior STEMI."}
+{"text": "The XENON1T collaboration recently reported the excess of events from recoil electrons, possibly giving an insight into new area beyond the Standard Model (SM) of particle physics. We try to explain this excess by considering effective interactions between the sterile neutrinos and the SM particles. In this paper, we present an effective model based on one-particle-irreducible interaction vertices at low energies that are induced from the SM gauge symmetric four-fermion operators at high energies. The effective interaction strength is constrained by the SM precision measurements, astrophysical and cosmological observations. We introduce a novel effective electromagnetic interaction between sterile neutrinos and SM neutrinos, which can successfully explain the XENON1T event rate through inelastic scattering of the sterile neutrino dark matter from Xenon electrons. We find that sterile neutrinos with masses around 90 keV and specific effective coupling can fit well with the XENON1T data where the best fit points preserving DM constraints and possibly describe the anomalies in other experiments."}
+{"text": "Seven fish vertebrae were chosen for analysis from the 49-KEN-147 archaeological site in the Kenai Peninsula, Alaska. Mitochondrial DNA analysis of the ancient fish bones revealed that they were from sockeye and coho salmon. Here, we report the ancient mitochondrial genomes for three sockeye salmon and one coho salmon fish bone. Seven fish vertebrae were chosen for analysis from the 49-KEN-147 archaeological site . A single fish bone had CYTB and D-loop sequences that matched coho salmon (Oncorhynchus kisutch). All but one of the corresponding GenBank sequences were exact matches (100% identity) for the entire fish bone sequence (100% coverage). One D-loop sequence that matched sockeye salmon had a 99% identity for 100% coverage due to a single indel.DNA extractions were carried out in a dedicated clean room at the ancient DNA laboratory in the Carl R. Woese Institute for Genomic Biology of the University of Illinois at Urbana-Champaign (UIUC) following a protocol optimized for ancient DNA extraction  using bowtie2 . Variants were called in SNVer  phylogeny was inferred using RaXML v. 8 (Stamatakis The species identifications are consistent with interpretations of a salmon-intensive subsistence strategy of the Riverine Kachemak tradition targeting sockeye salmon and including other species such as coho salmon Reger ."}
+{"text": "SCs were demonstrated to express more genes of neurotrophic factors in alginate shell. Enhanced proliferation and differentiation tendency of NSCs was observed when they were co-cultured with SCs. This model has strong potential for application in SCI repair.Cellular therapies play a critical role in the treatment of spinal cord injury (SCI). Compared with cell-seeded conduits, fully cellular grafts have more similarities with autografts, and thus might result in better regeneration effects. In this study, we fabricated Schwann cell (SC)-neural stem cell (NSC) core\u2013shell alginate hydrogel fibers in a coaxial extrusion manner. The rat SC line RSC96 and mouse NSC line NE-4C were used in this experiment. Fully cellular components were achieved in the core portion and the relative spatial positions of these two cells partially mimic the construction of nerve fibers  G2017002].Conflict of interest statement. None declared."}
+{"text": "A 70-year-old male with prior aorta endovascular aneurysm repair presented with progressive lower extremity weakness over the course of several hours. There was noted loss of palpable bilateral femoral pulses in the emergency department. Computed tomography angiography revealed a kinked and occluded aortic endograft. He subsequently underwent successful axillobifemoral bypass revascularization.Kinking of endograft limbs and occlusion has been reported in a small percentage of patients. Bilateral leg ischemia due to aortic endograft occlusion is rare. A 70-year-old male with a history of abdominal aorta endovascular aneurysm repair (EVAR) presented to the emergency department (ED) as a trauma activation after a fall and subsequent lower extremity weakness. The patient reported a near-syncopal episode the night preceding the fall and progressive lower extremity weakness over the course of the morning. On arrival to the ED, he complained of lower extremity weakness with noted initial 2+ palpable, bilateral femoral and dorsalis pedis pulses. Shortly thereafter, he lost palpable femoral pulses bilaterally and had noted cool lower extremities. Computed tomography angiography (CTA) was remarkable for kinking and occlusion of the abdominal aorta endograft below the renal vessels \u20133. The pThe patient had undergone EVAR approximately three years prior and had been taking aspirin and clopidogrel but, per the patient, clopidogrel was recently discontinued by his primary care physician to decrease endoleak at aneurysm repair. CTA demonstrated a kinked endograft and thrombus within the graft into the iliac arteries. Kinking of endograft limbs and occlusion has been reported in 2\u20134% of patients, which can result in acute limb ischemia.3What do we already know about this clinical entity?Kinking and occlusion has been reported as a complication in 2\u20134% of patients who underwent endovascular aneurysm repair (EVAR) of the abdominal aorta.What is the major impact of the image(s)?These images demonstrate kinking and occlusion of the abdominal aorta EVAR endograft with resulting bilateral leg ischemia, which is very rare.How might this improve emergency medicine practice?Emergency physicians should consider endograft complications in patients with a history of EVAR presenting with lower extremity neurovascular complaints."}
+{"text": "Objectives: This study aimed to investigate the effects of transitioning into spousal caregiving, changes in social participation, and their interactions on depressive symptoms among community dwelling old adults over time. Methods: The samples included old adults who were non-caregivers at 2011 baseline of China Health and Retirement Longitudinal Study (CHARLS) and joined the follow-up surveys in 2013 and 2015. Generalized estimating equations (GEE) was used to analyze the effects of caregiving transitions (transitioning into low-intensity or high-intensity caregivers versus the non-caregivers) and changes in social engagement on the depressive symptoms over time. Results: The results showed that old adults who transitioned into spousal caregiving over a 4-year period reported more depressive symptoms than those remained non-caregivers. Old adults who continued or increased social participation reported fewer depressive symptoms than those without social participation. Individuals who continued social participation during the transitions into high-intensity caregiving showed less severe elevated depressive symptoms than their counterparts who did not engage in social participation. Conclusion: The results highlighted that continuous social participation might be a protective factor for old adults against negative psychological outcomes during the transition to high-intensive caregiving."}
+{"text": "Drought stress limits growth and yield of crops, particularly under smallholder production systems with minimal use of inputs and edaphic limitations such as nitrogen (N) deficiency. The development of genotypes adapted to these conditions through genetic improvement is an important strategy to address this limitation. The identification of morpho-physiological traits associated with drought resistance contributes to increasing the efficiency of breeding programs. A set of 36 bean genotypes belonging to the Middle American gene pool was evaluated. A greenhouse study using soil cylinders was conducted to determine root vigor traits  under drought stress. Two field trials were conducted to determinate grain yield, symbiotic nitrogen fixation (SNF) ability and other shoot traits under drought stress. Field data on grain yield and other shoot traits measured under drought were related with the greenhouse data on root traits under drought conditions to test the relationships between shoot traits and root traits. Response of root vigor to drought stress appeared to be related with ideotypes of water use (water savers and water spenders). The water spender ideotypes presented deeper root system, while the water saver ideotypes showed a relatively shallower root system. Increase in SNF ability under drought stress was associated with greater values of mean root diameter while greater acquisition of N from soil was associated with finer root system. We identified seven common bean lines  that showed greater root vigor under drought stress in the greenhouse and higher values of grain yield under drought stress in the field. These lines could serve as parents for improving drought resistance in common bean. Drought stress is one of the major abiotic constraints limiting agricultural productivity, particularly for smallholder systems. Drought affects different plant processes resulting in reduced gas exchange, crop growth and productivity  production, affecting around 60% of bean producing regions and generating losses in production from 10 to 100% . Several shoot and root traits improve resistance to drought . Better remobilization of photosynthates to the grains is essential for the success of high yielding genotypes under drought stress  determine genotypic differences in root vigor under drought stress and test the relationships between root vigor and grain yield and SNF ability; and (ii) identify a few promising genotypes that combine root vigor with greater values of SNF ability and grain yield under drought stress which could serve as parents in breeding programs aimed to improve drought resistance in common bean.Phaseolus coccineus ; one landrace of tepary bean (Phaseolus acutifolius) G 40001 from Veracruz-Mexico, and two interspecific lines between tepary bean and common bean (INB 841 and INB 827) developed from five cycles of congruity backcrossing of tepary with ICA Pijao ; five interspecific lines between elite line SER 16 and BFS  lines have been developed to improve adaptation to low soil fertility and drought. SER, SCR and RCB , SEN  and NCB  lines have been developed for improved adaptation to drought, disease resistance and commercial grain. ALB  lines were developed for improved adaptation to drought and aluminum toxicity in acidic soil.\u20133. The seeds were germinated in paper towels and uniform seedlings were selected for transplanting to transparent plastic cylinders, each of which was inserted into PVC sleeve-tubes. Plants were grown for 45 days in these plastic cylinders/PVC sleeve-tubes with an average maximum and minimum temperature of 34 and 21 \u00b0C. A randomized complete block design (RCB) with three replications was used. One level of water supply treatment was applied: progressive soil drying with no watering after 10 days of growth in order to simulate terminal drought stress conditions. The initial soil moisture was at 80% of field capacity. Plants received no water application and each cylinder was weighed at 2 day intervals to determine the decrease in soil moisture content until the time of plant harvest.A greenhouse study was conducted at the main experiment station of the International Center for Tropical Agriculture (CIAT) in Palmira, Colombia, using transparent plastic cylinders  filled with a Mollisol from Palmira, Colombia  and proportion of fine roots or proportion of roots (%) with diameter less than 0.5 mm, were estimated through image analysis using WinRHIZO software . Total root and shoot dry weight per plant were determined after the roots and shoots were dried in an oven at 60 \u00b0C for 48 h.Plants were harvested at 45 days after transplanting (35 days of withholding of water application to induce water-stress treatment) when the plants are at early pod development. The root traits were evaluated at this time since the greatest phenotypic differences between the genotypes were observed  were recorded for each plot. Leaf area was measured using a leaf area meter  and the leaf area index (LAI) was calculated as leaf area per unit land area. The stomatal conductance was measured with a portable leaf porometer (Decagon SC-1) on a fully expanded young leaf of one plant within each replication. The following attributes were determined according to Beebe et al. (Grain yield and other shoot traits such as: days to flowering (DF), days to physiological maturity (DPM), canopy biomass (CB), leaf area index (LAI), stomatal conductance (SC), seed number per area (SNA), pod number per area (PNA), harvest index (HI), pod harvest index (PHI), pod partitioning index (PPI), grain carbon isotope discrimination (CID-G), percentage of N derived from the atmosphere using grain tissue (%Ndfa-G), percentage of N derived from soil using grain tissue (%Ndfs-G) and total shoot and seed N content per unit area  PROC MIXED and PROC CORR (SAS Institute Inc. P < 0.05) between genotypes were observed in visual root growth rate under drought conditions. Water spender lines were superior in their visual root growth rate under drought conditions and these were considered as genotypes with high root vigor (Based on genotypic differences in grain carbon isotope discrimination (CID-G), leaf stomatal conductance, canopy biomass, and grain yield under drought stress, the lines resistant to drought conditions were classified into two groups, water savers  and water spenders   in total root length were observed under drought conditions  combined higher values of total root biomass with superior grain yield under drought stress . Five geP < 0.05) were observed in fine root proportion under drought stress conditions. Ten genotypes  developed fine roots under drought stress (acutifolius (G 40001) and its inter-specific progeny INB 841 presented a fine root system but with relatively low values of total root length and total root biomass under drought stress , total root length (r = 0.22*) and total root volume (r = 0.22*). Also a significant and positive correlation (r = 0.58***) was observed between total root length and fine root proportion (r = -0.27**) (A positive and significant correlation was observed between different root traits and grain yield under drought conditions . Grain yoportion . A negat-0.27**) . No corr-0.27**) .r = 0.43***); fine root proportion and %Ndfs (r = 0.46***); fine root proportion and shoot N uptake in kg ha\u20131 (r = 0.37***); and total root length and shoot N uptake in kg ha\u20131 (r = 0.39***). Seven lines  combined fine root system development  probably resulting from a deeper root system, higher canopy biomass production and improved partitioning of photosynthates to grain. A few lines of the water saver type combined higher water use efficiency (WUE) with a relatively shallower root system and better photosynthate partitioning under drought stress. Superior SNF ability under drought stress was related with superior presence of roots with greater values of mean root diameter. Superior N uptake from the soil was associated with a larger root system with more presence of fine roots. Seven lines  combined the shoot and root traits of water spending ideotype characterized by superior grain production and a vigorous and deeper root system under drought stress. Four genotypes  that were superior in their SNF ability under drought stress were also identified and these could serve as parents for further improvement of SNF ability and drought resistance of common bean.Click here for additional data file."}
+{"text": "MindfulGarden (MG) is a digital device resembling a flat screen TV, with touchless sensors that react to voice and motion. In this study 13 long-term care home residents aged 74-100 exhibiting Behavioural and Psychological Symptoms of Dementia (BPSD) were randomized to treatment and control groups. On days 1-3 the treatment group received usual care plus exposure to MG during morning and evening care - events well documented to be problematic for residents and care staff; controls received usual care only. On day 4 both groups were exposed to MG with verbal cueing. A 26-item checklist was used to record frequency and types of disruptive BPSD exhibited; care duration was recorded in minutes. There was a trend toward reduction of BPSD and duration of care during morning care. Findings suggest that verbal cueing may be important for successful implementation of MG in calming residents with dementia during routine care."}
+{"text": "Schizotypy refers to a continuum of symptoms from subclinical manifestations in the general population to severe symptoms in schizophrenia spectrum disorders. Neuroimaging studies revealed significant relationships between schizotypy and cortical anatomy in the general population. However, it remains unclear whether these structural associations has a gender specificity.The present study used structural MRI data to investigate the relationship between subclinical schizotypy symptoms and cortical and subcortical morphometric measures in male and female samples of healthy individuals.et al. Schizophr Bull. 2004; 30 335-350) were calculated. Partial correlation analysis  was used to assess the associations between ROIs cortical thickness and total schizotypy or 4 factors scores including age and sex as covariates. The same analysis was performed for subcortical volumes including intracranial volume as additional covariate.164 right-handed healthy unmedicated individuals  underwent structural MRI at 3T Philips scanner. T1-weighted images were processed via FreeSurfer 6.0 to quantify cortical thickness for 34 regions-of-interest (ROIs) according to Desikan atlas and volumes for 7 subcortical structures at each hemisphere. Schizotypy levels were assessed using self-report Schizotypal Personality Questionnaire, total schizotypy score and 4 factors scores  and negative factor of schizotypy  (Image). No correlations survived correction for multiple comparisons in female sample. There were no differences in age, caudal middle frontal gyrus thickness, total schizotypy or negative factor of schizotypy scores between male and female subgroups.In male group we revealed a positive correlation between greater thickness of the left caudal middle frontal gyrus and higher total schizotypy  and levels of schizotypy is gender specific. We showed that total and negative schizotypy positively correlated with thicker DLPFC in male but not in female sample. The present data are inverse to findings of prefrontal cortical thinning observed in schizophrenia. Such correlations suggest that thicker cortex could be a potential compensatory mechanism or could reflect alterations in trajectory of cortical thickness reductions across the lifespan.The work was supported by RFBR grant 20-013-00748None Declared"}
+{"text": "It has also been associated with a variety of reproductive disorders and adverse pregnancy outcomes. Recent studies highlight the VitD role in regulating male and female reproductive health , 2. Matireatment . Supplemreatment .Liu et\u00a0al. investigated the influence of thyroid autoimmunity (TAI) and VitD levels on early pregnancy outcomes in women of normal thyroid function who undergo in vitro fertilization (IVF). The study found low serum VitD in subjects with TAI with fewer good-quality embryos. Additionally, aging also reduced the chances of pregnancy. The paper provides clinical practice guidelines for managing infertility in patients with normal thyroid function. Future studies should explore the effectiveness of VitD interventions in patients with TAI-assisted reproductive techniques (ART).A perspective study authored by Liu et\u00a0al. emphasizes the influence of TAI on serum and follicular fluid (FF) VitD levels and VitD receptor expression in granulosa cells (GCs) on laboratory results in infertile patients undergoing IVF or intracytoplasmic sperm injection (ICSI) treatment. The study found that TAI has a more detrimental effect on the maturation of good-quality embryos as compared to low VitD levels.Another prospective study by Wei-Jiun Li et\u00a0al.: The original article describes that low VitD levels are a risk factor for Post partum heamorrhage (PPH), and low levels of VitD are associated with an increased likelihood of experiencing low haemoglobin levels before delivery. Therefore, the study recommends that VitD should be corrected during antenatal care to avoid PPH and its complications.A study conducted by Shan et\u00a0al.: The original article declared that lower serum 25(OH)D levels were associated with higher risks of hyperandrogenemia (HA) in females with polycystic ovary syndrome (PCOS). The study identified increased BMI and age greater than 26 years as risk factors for PCOS women with VitD deficiency which should be considered for HA assessment and correction of VitD.Zhou et\u00a0al.: This meta-analysis concludes that VitD supplementation improves the chemical pregnancy rate in infertile women with VitD deficiency; however, VitD supplementation does not improve the clinical pregnancy rate and all secondary outcomes. Further studies are needed to explore the role of VitD on other IVF outcomes, like fertilization rate and ongoing pregnancy rates.Li et\u00a0al. reviews \u201cnine randomized controlled trials (RCTs) for PCOS undergoing therapy with magnesium supplementation alone or in combination with other agents\u201d. The study outcome indicated that magnesium supplementation in combination with other supplements may be a potential therapeutic option for improving metabolic disorders in PCOS patients.Another systematic review authored by Recent studies have found promising results in using VitD supplementation to improve oxidative stress, reproductive endocrine and metabolic parameters. VitD may positively affect fertility and metabolic health by influencing hormone levels and metabolic markers . HoweverFA initiated the write-up of the editorial. MB, AK, and RR completed the write-up. All authors revised the manuscript before final submission. All authors contributed to the article and approved the submitted version."}
+{"text": "Current methods of storing explanted donor livers at 4\u00b0C in University of Wisconsin (UW) solution result in loss of graft function and ultimately leads to less-than-ideal outcomes post transplantation. Our lab has previously shown that supplementing UW solution with 35-kilodalton polyethylene glycol (PEG) has membrane stabilizing effects for cold stored primary rat hepatocytes in suspension. Expanding on past studies, we here investigate if PEG has the same beneficial effects in an adherent primary rat hepatocyte cold storage model. In addition, we investigated the extent of cold-induced apoptosis through treating cold-stored hepatocytes with pan caspase inhibitor emricasan. In parallel to storage at the current cold storage standard of 4\u00b0C, we investigated the effects of lowering the storage temperature to \u20134\u00b0C, at which the storage solution remains ice-free due to the supercooling phenomenon. We show the addition of 5% PEG to the storage medium significantly reduced the release of lactate dehydrogenase (LDH) in plated rat hepatocytes and a combinatorial treatment with emricasan maintains hepatocyte viability and morphology following recovery from cold storage. These results show that cold-stored hepatocytes undergo multiple mechanisms of cold-induced injury and that PEG and emricasan treatment in combination with supercooling may improve cell and organ preservation."}
+{"text": "Teaching Point: An edematous ileocecal valve may mimic a residual intussusception after reduction. Differential diagnosis is important for therapeutic implications. A two-year-old boy was transferred to the emergency department from a regional hospital with intermittent episodes of intense abdominal pain. An intussusception was diagnosed by ultrasound whereafter hydrostatic reduction with single-contrast enema was attempted. The reduction was diagnosed incomplete , and theAbdominal ultrasound showed a small target sign in the transverse plane without presence of mesenterial fat, vessels or lymph nodes between the layers of the target sign . The widIleocolic intussusception is one of the most common pediatric abdominal emergencies. Fluoroscopic enema reduction (air- or water-soluble contrast) is the initial treatment of choice with a success rate of 80\u201395%, sonographic-guided hydrostatic saline enema reduction has been shown a good alternative. Operative reduction is the alternative in patients with complications or multiple failed reduction attempts .After fluoroscopic attempted reduction of an ileocolic intussusception, a persistent intraluminal filling defect may be seen in the cecum, posing a diagnostic dilemma in differentiating a residual or recurrent intussusception, a pathological lead point or a residual edematous ileocecal valve. Post-reduction sonography may solve this dilemma showing a \u2018smaller\u2019 donut/target sign  compared"}
+{"text": "Several endoscopic modalities are used to treat colonic diverticular bleeding (CDB), a predominant lower gastrointestinal bleeding typeA 49-year-old man presented with a chief complaint of bloody stools. Contrast-enhanced computed tomography revealed extravasation from the descending colonic diverticulum. We diagnosed him with CDB and performed emergency colonoscopy.When a descending colonic diverticulum was aspirated and inverted, a visible vessel was found. Active bleeding occurred due to suction stimulation, and the diverticulum was identified as the bleeding source . EndoscVideo\u20061\u2002Endoscopic hemostasis of colonic diverticular bleeding by combining endoscopic band ligation and clipping.Endoscopic clipping was performed by placing a hemostatic clip  onto the responsible vessel within the diverticulum. The endoscope was removed, and an EBL device  was attached to its tip.\u200aIt was then reinserted and directed toward the diverticulum marked with a clip.\u200aThe diverticulum was aspirated with the clip into the EBL device and the elastic O-band was released . No rebClipping involves grasping the exposed blood vessel part, whereas EBL involves grasping the root of the blood vessel. Therefore, the novel EBL-C combination treatment provided a stronger and more reliable hemostatic effect than that of each treatment alone . The clThis is the first reported case describing the EBL-C method for hemostasis of CDB. The EBL-C method could be a simple alternative for CDB treatment with less risk of rebleeding compared with EBL or clipping alone, if confirmed in a large case series.Endoscopy_UCTN_Code_TTT_1AO_2AD"}
+{"text": "Persistent hypoxemia during veno-venous extracorporeal membrane oxygenation (VV-ECMO) for supporting acute respiratory distress syndrome (ARDS) patients is a clinical challenge for intensive care medical providers. Prone positioning is an effective strategy to treat persistent hypoxemia; however, placing a patient in a prone position is resource intensive with significant risks to the patient. We present a patient with severe ARDS receiving VV-ECMO who underwent verticalization therapy and subsequently recovered pulmonary function. Veno-venous extracorporeal membrane oxygenation therapy (VV-ECMO) is a modality to support patients with acute respiratory distress syndrome (ARDS) when traditional positive pressure ventilation has failed. The institution of VV-ECMO allows the patient to maintain end-organ oxygenation while clinicians prescribe an appropriate lung protective strategy. In patients with inadequate oxygenation despite optimizing the extracorporeal membrane oxygenation (ECMO) settings, prone positioning (PP) has been proposed to improve oxygenation through improved lung mechanics and gas exchange ,2.PP is logistically difficult and associated with pressure sore development with potential for severe complications such as inadvertent decannulation or extubation . VerticaWe present the first reported case of VT\u00a0to improve oxygenation in a VV-ECMO patient with severe ARDS resulting in a successful outcome.2) woman with no significant past medical history other than attention deficit disorder and anxiety presented to an outside hospital (OSH) with worsening respiratory status. She had been initially treated for influenza as an outpatient, yet her respiratory status declined over seven days at the OSH, requiring mechanical ventilation. She was transferred from the OSH via ambulance for further management and to evaluate the need for ECMO.A 31-year-old 160-pound 5'7\"  of the chest showed severe multifocal consolidation with right upper lung necrotizing lesions  for 45 to 60 degree-VT. The patient underwent VT twice daily for thirty minutes per session. The hemodynamic profile during VT was stable, with blood pressures of 140/80 mmHg and heart rates of 100 beats per minute on average during VT sessions.The decisions regarding the duration and degree of VT were based on patient tolerance. Due to deconditioning, achieving more than 60 degrees of VT was limited by her lower extremity weakness. Similarly, sessions longer than 30 minutes were not tolerated due to leg muscle fatigue. During VT sessions, the degree of sedation utilizing infusions of propofol and fentanyl was targeted to a Richmond Agitation-Sedation Scale (RASS) score of zero to negative one, indicating that the patient was alert and calm .The patient sustained an oxygen saturation above 90 percent for approximately three hours after each VT without changes to the ventilator or ECMO settings. VT sessions continued two to three times daily for one month. As the patient's pulmonary status improved, she was successfully weaned from ECMO and decannulated approximately seven weeks post-cannulation. The patient was discharged from the intensive care unit two weeks later to a long-term acute care hospital. Her chest radiograph two months post-discharge demonstrated a resolution of pneumonia (see Figure Refractory hypoxemia is a treatment problem in patients with severe ARDS who require VV-ECMO. PP has been advocated successfully in VV-ECMO patients to improve oxygenation ,2. GianiGiven the potential risk for position-related pressure sores or more severe complications such as inadvertent decannulation or extubation, alternatives to PP could be a useful therapeutic option for intensivists caring for ARDS patients . VerticaThe mechanism for improving oxygenation in VT likely involves improved pulmonary mechanics and improvements in matching ventilation and perfusion. The major risk of VT would be a negative impact on hemodynamics due to worsening preload. Our patient demonstrated a slight reduction in blood pressure and an increased heart rate during VT sessions, yet hemodynamics were stable, and no interventions were necessary for blood pressure management.VT has not been previously reported for refractory hypoxemia in the setting of ARDS requiring VV-ECMO. We report the first case in the literature of VT to achieve improvement in arterial oxygenation in this setting.Managing refractory tissue hypoxemia during VV-ECMO therapy for ARDS patients is a clinical challenge for intensive care physicians. Previously reported proposed changes in patient positioning, such as PP, are effective yet logistically challenging and associated with risks and complications. VT is potentially an effective yet technically less demanding alternative to PP in the setting of VV-ECMO for ARDS patients."}
+{"text": "The pineal lesion affecting melatonin is a rare cause of central precocious puberty by decreasing the inhibition of hypothalamic\u2013pituitary\u2013gonadal axis. Germ cell tumor secreting human chorionic gonadotropin is a rare cause of peripheral puberty.A 5.8-year-old male presented facial hair and phallic growth, deepened voice, and accelerated growth velocity for 6 months. The elevated human chorionic gonadotropin level with undetectable gonadotropin levels indicated peripheral precocious puberty. Brain imaging revealed a pineal mass and further pathology indicated the diagnosis of teratoma. During chemoradiotherapy with operation, the elevated human chorionic gonadotropin level reduced to normal range, while the levels of gonadotropins and testosterone increased. Subsequently, progressing precocious puberty was arrested with gonadotrophin-releasing hormone analog therapy. Previous cases of transition from peripheral precocious puberty to central precocious puberty were reviewed. The transitions were caused by the suddenly reduced feedback inhibition of sex steroid hormones on gonadotropin releasing hormone and gonadotropins.For patients with human chorionic gonadotropin-secreting tumors, gonadotropin levels increase prior to sex steroid decrease, seems a sign of melatonin-related central PP related to melatonin. Central nervous system neoplasm is considered as one of the important etiologies of precocious puberty (PP). The neoplasm in proximity to the hypothalamic-pituitary region or intracranial radiotherapy focused on this region  may actiA 5.8-year-old boy was admitted to our hospital with a 6-month of facial hair and phallic growth, deepen voice and accelerate growth velocity. The Tanner stage was II for genital development and II-III for pubic hair. Both side testicular volumes were 4 mLby Prader. Family history of PP was denied. The serum sex hormone profile indicated prepubertal levels of gonadotropins with basal LH\u2009<\u20090.1IU/L  and basal FSH\u2009<\u2009below 0.1 IU/L , and pubertal testosterone level . His height reached 129 cm  with a high serum insulin like growth factor-1 level (+\u20093.5 standard deviation scores) in National-specific charts . Other aWe systematically searched PubMed database with \u201ccentral PP\u201d and \u201cperipheral PP\u201d from inception through July 1st, 2022. No language restrictions were imposed. A hand search through reference lists of relevant primary and review articles was also performed for completeness. Each of the two review authors (HC and C-Y M) independently screened articles for inclusion based on title and abstract and reviewed relevant articles as full text. Disagreement during the review process was resolved by consensus through involvement of a third review author (L-Y Z). A total of 25 original articles involving 51 patients with the transition from peripheral to central PP were reviewed and summarized (16\u201341) (Table Transition from peripheral PP to central PP is rare, which means activating GnRH or inhibiting gonadotropin inhibitory hormone after a period of overexposure to steroids. This transition has been reported in patients with Leydig cell tumors \u201324, adreIn the present study, we describe a young boy with a pineal germ cell tumor and peripheral PP who later developed central PP. Initial peripheral PP of the patient due to serum hCG, which binds to the LH receptor and then acts on the testicular Leydig cell to excessively promote testosterone synthesis. The elevated hCG level in serum and CSF inidicated the diagnosis of iGCT. The residual in pineal lesion after induction chemotherapy indicated the diagnosis of mixed iGCT and following histological results indicated the teratoma component. During the initial 2 courses of chemotherapy, although the hCG level returned to normal range, the patient\u2019s LH and FSH levels increased synchronously with the stably elevated testosterone. Compared to previous cases where patients\u2019 central PP commonly developed after months or even years of peripheral PP regression, the abnormal change in gonadotropin and sex steroid hormone of this patient suggested a probable mechanism different from loss of negative feedback to the gonadotropins Fig. . In our Clinicians caring for young patients with pineal hCG-secreting tumors should be alert to the secondary central PP, although most hCG-induced peripheral PP would regress after the tumor was eliminated. Gonadotropin levels increasing prior to sex steroid suppression may be a a sign of melatonin-related central PP. It is highly recommended to assess the function of hypothalamic\u2013pituitary\u2013gonadal axis by testing hormones during the treatment period of pineal hCG-secreting tumors."}
+{"text": "Proximal metal stent migration during or after endoscopic ultrasound-guided hepaticogastrostomy  scan revealed dilatation and infection of the cystic bile duct in left lobe of the liver , and heAfter tract dilation, we tried to place a 6-mm fully covered self-expandable metal stent (SEMS). However, the edge of SEMS on the gastric side migrated into the abdominal cavity. After unsuccessful attempts to retrieve the stent endoscopically via the puncture site, surgical intervention was deemed necessary. We placed two guidewires orally from the gastric fistula into the abdominal cavity so that surgeons could find the gastric fistula  and retSurgical salvage intervention for a migrated metal stent during endoscopic ultrasound-guided hepaticogastrostomy.Video 1Endoscopy_UCTN_Code_CPL_1AL_2AD"}
+{"text": "Correction to: Internal and Emergency Medicine 10.1007/s11739-023-03203-0In the original article under the section NAFLD and metabolic dysfunctions the word \"painful\" was incorrectly written as \"painless\".Also, the small gramatical error \"are\" changed to \"is\" under the section Conclusions and future perspectives.The original article has been corrected."}
+{"text": "The inferior vena cava draining to the left atrium is a rare congenital anomaly. Patients usually present with hypoxia and dyspnoea. This condition is usually diagnosed by echocardiography and sometimes by CT scan.\u00a0Here we report two cases that presented with normal saturation and their surgical management. It is very rare for the inferior vena cava (IVC) to empty into the left atrium (LA) when the normal atrial configuration (situs solitus) is present . It can The first case is a six-year-old male child who was incidentally diagnosed with ostium secundum atrial septal defect (OSASD). Physical examination revealed a resting saturation of 99% in room air and a systolic murmur. His electrocardiogram (ECG) and chest radiograph were normal. A transthoracic echocardiogram revealed a 17 x 20mm OSASD with IVC draining into LA  using an oblique autologous pericardial patch. The patient tolerated the procedure well and was discharged a few days later, asymptomatic and with normal oxygen saturation. Echocardiography on a one-month follow-up showed unobstructed SVC and IVC draining into RA Figure .The second case involves a four-year-old female child who was also incidentally diagnosed with ostium secundum atrial septal defect (OSASD). Physical examination revealed a resting saturation of 99% in room air and a systolic murmur. ECG and chest radiographs were normal. A transthoracic echocardiogram revealed a 20 mm posterior OSASD with IVC draining into LA Figure .Left-sided superior vena cava draining into the coronary sinus was also noted. Intraoperatively all margins of the interatrial septum were well formed. It was noticed that the IVC was opening into the LA and IAS was malaligned. The IVC was then baffled into the RA using an oblique autologous pericardial patch. The patient tolerated the procedure well and was discharged three days later, asymptomatic and with normal oxygen saturation. Echocardiography taken at the one-month follow-up showed unobstructed SVC and IVC draining into RA.Gardner originally identified the unusual congenital vascular condition known as abnormal IVC draining into the left atrium in 1955 . Most paWe present two rare cases of IVC draining into LA presenting with normal saturation. Normal saturation thus doesn\u2019t rule out anomalous systemic venous drainage. CT angiography is useful but not necessary to make a diagnosis. Surgery can be planned if the echocardiography is convincing enough. Utmost care should be taken while closing an OSASD and anomalous opening of the IVC into the LA should be ruled out in every case by identifying the opening of the IVC into the RA."}
+{"text": "A major tenet of environmental cleaning is to focus on high-touch surfaces (HTS). HTS in the patient\u2019s proximity have high rates of contamination, yet cleaning compliance of HTS remains low particularly when the patient is present. This quality improvement (QI) project aimed to use stakeholder input to modify a HTS cleaning checklist.Figure 1).This pilot project used a Plan-Do-Check-Act cycle to modify and evaluate a daily cleaning checklist across acute and long-term care settings at one Midwestern VA Hospital  and b. extent of surface cleaning .Two pre-intervention focus groups  were conducted to understand stakeholder perspectives and barriers to daily cleaning to inform modifications to the cleaning checklist. Participants viewed the graphic and discussed patients\u2019 and EMS\u2019s possible notions upon EMS entering the patient room. The groups were then asked how these insights could be addressed during the cleaning process. Recurrent themes of stakeholder\u2019s perceived barriers to cleaning are depicted in Pre- and post-intervention observations of daily cleaning compliance of 10 HTS showed a significant improvement of 38%  to 72%  (p = 0.011).Two EMS interviews were conducted post-intervention to evaluate checklist usability. Emergent themes were discomfort with cleaning any surface near the patient while the patient was in the bed and with the use of the modified cleaning pattern due to discordance with previous training and practicesGraphic ExerciseCleaning Pattern Mental ModelModified ChecklistModified ChecklistCurrent checklists do not address contextual factors of navigating the environment surrounding patients in bed. HTS cleaning rates may be improved by modifying checklists based on input from local stakeholders. Future research is needed to evaluate modified cleaning processes to facilitate daily cleaning of occupied patient rooms.All Authors: No reported disclosures"}
+{"text": "Lichen planus is a chronic inflammatory disorder affecting skin and mucosal surfaces. There are multiple variants of lichen planus described in the literature. We report a case of inverse lichen planus in a healthy 50-year-old male who presented to our dermatology clinic with multiple violaceous to hyperpigmented patches affecting both axillae and groin for three months. A skin biopsy confirmed the diagnosis of lichen planus. The patient subsequently developed nail dystrophy affecting his fingernails consistent with nail lichen planus. Early recognition and treatment of nail lichen planus is important to prevent irreversible scarring. Lichen planus is an idiopathic inflammatory skin disorder that typically presents with pruritic, polygonal, violaceous papules and plaques on flexor surfaces of forearms, wrists, genitalia and oral mucosa . There aInverse lichen planus is a rare variant of lichen planus that presents with pink to violaceous patches and plaques affecting axillae, groin and inframammary areas . HyperpiNail lichen planus has been reported in up to 15% of patients with lichen planus .A 50-year-old male presented to the clinic with a three-month history of itchy rash over both axillae and groin. No other skin, mucosal, scalp, or nail involvement at initial presentation. He had no past medical history and no systemic symptoms. Physical examination revealed multiple violaceous to hyperpigmented patches, with no secondary changes.A punch biopsy was taken from the left axilla revealed band-like lymphocytic infiltrates at the dermo-epidermal junction with hyperkeratosis, hypergranulosis and necrotic keratinocytes (Civatte bodies) visible at the lower epidermis Figure .The patient was started on tacrolimus 0.1% ointment twice daily for two\u00a0months which resulted in improvement of the lesions with only post-inflammatory hyperpigmentation Figures -3. One yInverse lichen planus is a rare variant of lichen planus with unusual morphological presentation affecting the axillae, inguinal folds and inframammary areas . Sites oThere can be an overlap between inverse lichen planus and lichen planus pigmentosus. Lichen planus pigmentosus typically presents as hyperpigmented macules and patches affecting sun-exposed sites .\u00a0In our The literature review\u00a0showed only a few reported cases of Inverse lichen planus -12. NoneNail lichen planus is an inflammatory process that affects the nail unit . TreatmeLichen planus is a chronic inflammatory papulosquamous disorder. Inverse lichen planus is a rare variant affecting intertriginous areas.\u00a0Treatment of nail lichen planus can be challenging and early intervention should be considered to prevent irreversible nail damage."}
+{"text": "Late atrial arrhythmias after catheter ablation for atrial fibrillation occur in up to 30% of post-ablation patients and are increasingly encountered by emergency physicians. However, diagnosing the exact mechanism of the arrhythmia on the surface electrocardiogram (ECG) remains challenging due to atrial scarring leading to heterogeneous P-wave morphology.A 74-year-old male with a history of prior catheter ablation for atrial fibrillation presented with palpitations and subacute symptoms of heart failure. The patient\u2019s ECG revealed narrow complex tachycardia with more P waves than QRS complexes. The differential diagnosis included typical flutter, atypical flutter, and focal atrial tachycardias with 2:1 conduction block. P waves were positive in V1 and across all precordial leads . This favors atypical flutter originating from the left atrium over typical cavotricuspid isthmus-dependent right atrial flutter. Transthoracic echocardiogram showed a reduced ejection fraction due to tachycardia-mediated cardiomyopathy. The patient underwent a repeat electrophysiology study and ablation, which confirmed the presence of an atypical flutter circuit using the mitral annulus, known as perimitral flutter. Repeat catheter ablation resulted in maintenance of sinus rhythm. At follow-up, his ejection fraction recovered.Recognizing ECG findings suggestive of atypical flutter impacts initial emergency department decisions and triage as atypical flutter post-atrial fibrillation ablation is frequently resistant to rate-controlling medications and often requires cardiology and/or electrophysiology consultation if available. Catheter ablation with pulmonary vein isolation is increasingly used in the management of paroxysmal atrial fibrillation (AF). Post-ablation late atrial tachycardias are common, occurring in up to 30% of patients.A 74-year-old male with a history of symptomatic drug-refractory paroxysmal AF treated with a catheter ablation with pulmonary vein isolation 14 years prior and a second catheter ablation two years prior, presented to the emergency department (ED) with three months of progressive shortness of breath and palpitations. Upon presentation, he was afebrile, his heart rate was 137 beats per minute, respiratory rate was 18 breaths per minute, blood pressure was 106/76 millimeters of mercury, and oxygen saturation was 90% on room air. Cardiovascular examination revealed tachycardia with normal heart sounds and no murmurs, rubs or gallops. Jugular venous pressure was elevated. Pulmonary exam was negative for rales, and there was no lower extremity edema.The ECG  revealedCPC-EM CapsuleWhat do we already know about this clinical entity?Late atrial arrhythmias after atrial fibrillation ablation occur in up to 30% of post-ablation patients. However, the diagnosis remains challenging due to heterogeneous P wave morphology.What makes this presentation of disease reportable?This case highlights the electrocardiogram (ECG) findings suggestive of atypical flutter in a patient with prior catheter ablation.What is the major learning point?The absence of precordial transition favors atypical flutter originating in the left atrium in the post-ablation patient, among other ECG findings.How might this improve emergency medicine practice?Atypical flutter is often resistant to control medications. Symptomatic patients presenting with atypical flutter warrant early consultation or referral to cardiac electrophysiology.A transthoracic echocardiogram (TTE) revealed a severely reduced ejection fraction of 20% without valvular disease or wall motion abnormalities. The patient was started on amiodarone and underwent direct current cardioversion. An electrophysiology study revealed perimitral isthmus flutter. Delayed atrial arrhythmias post-AF ablation present a challenge as the degree of atrial scarring and location of prior radiofrequency ablation sites result in variable P-wave morphology. Most post-ablation arrhythmias are caused by either macroreentry or localized microreentrant atrial tachycardias (circuits <3 centimeters in diameter), and true focal AT due to an ectopic focus is less common.5Typical atrial flutter is defined as a macroreentrant circuit (most often counterclockwise) around the tricuspid annulus, using the CTI.3Atypical atrial flutter refers to macroreentrant tachycardias that are not CTI-dependent. Atypical flutter circuits can originate in the left or right atrium, usually around an atrial scar in patients with structural heart disease.However, an electrophysiology study is needed to map the exact reentrant circuit. Flutter wave polarity in the inferior leads does not separate typical from atypical flutter but rather indicates that the macroreentrant circuit initially activated the superior right atrium with subsequent superior to inferior right atrial activation.A notable feature in 5Distinguishing LA atypical flutter from an arrhythmia originating in the right atrium impacts clinical management as atypical flutter is often resistant to rate-controlling and antiarrhythmic medications and frequently requires repeat catheter ablation.5Late post-ablation arrhythmias are increasingly common as the number of catheter ablation procedures performed for AF increases. The presence of upright P waves across all precordial leads favors atypical flutter from the left atrium over typical CTI dependent right atrial flutter. Once recognized, atypical flutter, including perimitral flutter, is often resistant to rate and rhythm controlling medications. Patients with atrial fibrillation or typical flutter who are asymptomatic once rate controlled or who spontaneously convert in the emergency department are often appropriate for outpatient follow-up with primary care, with cardiology follow-up based on symptoms and clinical course. Symptomatic patients presenting to the ED with atypical flutter warrant early consultation or referral to cardiac electrophysiology for definitive diagnosis and management."}
+{"text": "Heteroresistance is a phenotype in which a clinically susceptible bacterial isolate contains less susceptible subpopulations. Unexpectedly high levels of treatment failure for cefiderocol, a novel antibiotic designed to treat multidrug-resistant infections, have been attributed to this phenomenon.To determine prevalence of cefiderocol heteroresistance amongst clinical isolates at a North London tertiary care centre and study the population dynamics upon exposure to the antibiotic.n\u200a=\u200a146) were screened for cefiderocol susceptibility by standard disc diffusion and Etest assays. Isolates were classified based on EUCAST breakpoints for cefiderocol susceptibility. Heteroresistance was confirmed by performing modified-population analysis profile (mPAP) assay in iron-depleted Mueller Hinton II agar. MIC values were determined by broth microdilution (BMD) assay as per EUCAST guidelines. The heteroresistant isolates and their corresponding less susceptible subpopulations were serially passaged in media with sub-inhibitory concentrations of cefiderocol as well as in cefiderocol-free medium. The changes in frequency and/or susceptibility in the heteroresistant subpopulation were detected using mPAP.Gram-negative clinical isolates  and twenty-two resistant (15.06%) isolates were identified. Cefiderocol susceptibility of the heteroresistant isolates after five passages in cefiderocol-free medium partially reverted to that of the parent population. However, this phenomenon was not observed in the cohort that was first passaged in cefiderocol-containing medium before passages in cefiderocol-free medium. When heteroresistant populations were passaged in cefiderocol-containing media at 0.25\u00d7 MIC values, no MIC changes were observed after five serial passages; however, the proportion of less susceptible subpopulations increased by 1.2 logThe prevalence of heteroresistance to cefiderocol was around 7% amongst clinical isolates. The heteroresistant phenotypes were unstable unless exposed to cefiderocol. Such exposure may also increase the MIC and/or frequency of less susceptible cells within the heteroresistant population. This amplification can continue even after removal of antibiotic pressure. Developing methods for detecting heteroresistance to cefiderocol in clinical laboratories is essential. Clinicians need to take this phenomenon into account when planning treatment regimens to optimize the effectiveness of this invaluable addition to the antimicrobial armamentarium."}
+{"text": "Chromoendoscopy is mainly used in gastrointestinal endoscopy to enhance the visibility of mucosal abnormalities in the digestive tract, by applying stains to the mucosa during endoscopy. The most commonly used stain in chromoendoscopy is indigo carmine, which can highlight subtle changes when sprayed onto the mucosa. Indigo carmine staining is also expected to be useful for the diagnosis of biliary diseases on peroral cholangioscopy (POCS). However, because the bile duct lumen is usually filled with bile or saline during POCS, it is difficult to spray the indigo carmine. In addition, the safety of spraying indigo carmine in the bile duct is unclear.This report presents the first case demonstrating the usefulness of virtual indigo carmine chromoendoscopy (VIC) on POCS using a \u201ccycle-consistent adversarial network\u201d (CycleGAN), an artificial intelligence technology which can convert white-light images to VIC images. VIC makes it easier to recognize the margins and surface irregularities of malignant lesions on POCS.\u200aA 74-year-old man was admitted to our hospital with jaundice. Computed tomography showed wall thickening at the distal bile duct. Endoscopic retrograde cholangiopancreatography showed a main lesion at the distal bile duct extending into the left hepatic duct . We theVideo\u20061\u2002Virtual indigo carmine chromoendoscopy (VIC) on peroral cholangioscopy using a \u201ccycle-consistent adversarial network\u201d (CycleGAN), an artificial intelligence technology which can convert white-light images to VIC images.Endoscopy_UCTN_Code_CCL_1AZ_2AI"}
+{"text": "Aortic knuckle calcification is a condition where there is deposit of calcium in aortic valve causing reduced blood flow through the same. The condition usually presents in old age as a complication of rheumatic heart disease or Infective Endocarditis. Risk factors include old age, raised blood pressure and coronary heart disease. A 60-year-old female came with chief complaints of breathing difficulty for one month (grade 2 dyspnea) along with chest pain for two days. There was a history of rheumatic fever five years ago and was treated with a ten days course of penicillin. On examination, her blood pressure was found to be 150/100mmHg. Chest X-ray was taken and it showed aortic knuckle calcification. The patient was started on anti-hypertensive drugs and rheumatic fever prophylaxis and was planned for surgical valve replacement after 3 months."}
+{"text": "One-year follow-up revealed the absence of clinically relevant infection with patency of the graft and the absence of biochemical inflammatory markers.Infectious aortic disease is a challenging life-threatening disease in cardiovascular surgery. A 70-year-old man patient presented with an infected infrarenal aortic pseudoaneurysm and right iliac artery- left iliac vein fistula (arteriovenous fistula). He underwent total infected tissues excision, debridement,  Infectious pseudoaneurysms of the abdominal aorta are rarer than endograft infections. However, complications, including septicopyemia and rupture, are usually dramatic, resulting in high morbidity and mortality . This reA 70-year-old man was diagnosed with an impending rupture of an infected infrarenal abdominal aortic pseudoaneurysm with AVF Fig.\u00a0. He presin situ reconstruction with a self-made pericardial graft was performed  for at least 6 months. CTA showed a patent abdominal aorta without pseudoaneurysm or any infection symptom after a 1-year follow-up (Fig.\u00a0in situ reconstruction with prosthetic grafts or homograft replacement is a common therapeutic alternative [in situ reconstruction due to better patency. In situ reconstruction can achieve immediate limb revascularization, avoid groyne and axillary incisions and decrease long-term graft occlusion and amputation rates.Infected infrarenal aortic pseudoaneurysm with AVF is an infrequent but severe complication and is unlikely to improve with conservative treatment. Open surgical repair is the most established option for the definitive eradication of the native aortic infection. Extraanatomical or ernative , 3. Extrin situ reconstructions of the aorta using pericardiac graft with great omental coverage and AVF repair to prevent leakage.The most suitable graft material for repairing infected aorta remains controversial. Cryopreserved allografts or autologous deep femoral vein grafts are optimal alternatives with low risk of reinfection and better survival rates. However, the availability of allografts is the main limiting factor for usability , 5. HarvIn situ reconstruction with a self-made pericardial patch followed by prolonged antibiotic therapy was effective and safe for native aortic pseudoaneurysm with AVF."}
+{"text": "Increased uptake is associated with aneurysm expansion and adverse clinical events. The effect of endovascular aneurysm repair (EVAR) on aortic disease activity and sodium [18F]fluoride uptake is unknown. This study aimed to compare aortic sodium [18F]fluoride uptake before and after treatment with EVAR.In patients with abdominal aortic aneurysms, sodium [18F]fluoride positron emission tomography-computed tomography angiography was performed in patients with an infrarenal abdominal aortic aneurysm undergoing EVAR according to current guideline-directed size treatment thresholds. Regional aortic sodium [18F]fluoride uptake was assessed using aortic microcalcification activity (AMA): a summary measure of mean aortic sodium [18F]fluoride uptake.In a preliminary proof-of-concept cohort study, preoperative and post-operative sodium [18F]fluoride uptake was markedly reduced in the suprarenal , neck  and body of the aneurysm  while it remained unchanged in the thoracic aorta .Ten participants were recruited (76\u00b16 years) with a mean aortic diameter of 57\u00b12\u2009mm at time of EVAR. Mean time from EVAR to repeat scan was 62\u00b121 months. Prior to EVAR, there was higher abdominal aortic AMA when compared with the thoracic aorta . Following EVAR, sodium [18F]fluoride uptake is a promising non-invasive surrogate measure of aneurysm disease activity.EVAR is associated with a reduction in AMA within the stented aortic segment. This suggests that EVAR can modify aortic disease activity and aortic sodium [ Endovascular aneurysm repair durability is limited by the development of endoleaks and this necessitates the use of life-long postoperative surveillance programmes.In abdominal aortic aneurysms, sodium [18F]fluoride uptake on positron emission tomography.This study demonstrates that endovascular aneurysm repair leads to a reduction in microcalcification activity in the abdominal aorta which can be detected as a reduction in aortic sodium fluoride is a positron emission tomography (PET) radiotracer which binds to the deposited hydroxyapatite crystals and can detect aortic microcalcification. In the Sodium [18F]Fluoride Imaging of Abdominal Aortic Aneurysms (SoFIA3 study (NCT02229006), aortic sodium [18F]fluoride uptake specifically localised to abdominal aortic aneurysms and was associated with more rapid aneurysm expansion. This was independent of age, sex, baseline diameter, body mass index, blood pressure, smoking, renal function or peripheral arterial disease. During follow-up, aneurysms with the highest sodium [18F]fluoride uptake expanded more rapidly and patients were most likely to require elective abdominal aortic aneurysm repair (because they reached the threshold of 55\u2009mm) or to have experienced aneurysm rupture.Aortic aneurysm formation is characterised by medial wall atrophy and degeneration which may be triggered by an initial inflammatory response.18F]fluoride PET-CT is a non-invasive marker of aortic aneurysm disease activity which predicts disease progression and clinical outcomes, we hypothesised that aortic sodium [18F]fluoride uptake would be reduced after successful EVAR implantation. In an exploratory proof-of-concept study, we undertook repeated sodium [18F]fluoride PET-CT in participants of the SoFIA3 study who had undergone EVAR.Given that sodium [18F]Fluoride Imaging in Abdominal Aortic Aneurysms study (NCT02229006). Participants had an asymptomatic abdominal aortic aneurysm and were under ultrasound-based surveillance. Patients who had undergone successful elective EVAR were invited for recruitment into the PET-EVAR Study (Predicting Endoleaks Following Endovascular Aortic Aneurysm Repair Using Sodium [18F]Fluoride).The study population consisted of patients recruited into the Sodium fluoride intravenously, and 60\u2009min later they were imaged on a hybrid 128\u2013slice PET-CT scanner . A low-dose attenuation correction CT scan was performed , followed by acquisition of PET data at 10\u2009min intervals in three or four bed positions to cover the thoracic and abdominal aorta. A contrast-enhanced aortic CT angiogram  was performed on the same scanner immediately after PET acquisition. This was preceded by a non-contrast CT aortic calcium score at the second visit. Static PET-CT images were reconstructed with correction applied for attenuation, dead-time, scatter and random coincidences, using an optimised iterative reconstruction algorithm .At each of the two study visits, participants underwent a clinical assessment prior to imaging. Patients were then administered a target dose of 125 MBq of sodium fluoride uptake within the abdominal aorta. This reduction was prominent in the regions of the abdominal aorta covered by the stent graft and was not apparent in the thoracic aorta. This suggests that EVAR protects the aortic aneurysm from rupture by providing a physical barrier and by reducing aortic aneurysm disease activity within the aortic wall itself.EVAR is associated with shrinkage of the abdominal aortic aneurysm sac: a key morphological indicator of procedural success.18F]fluoride uptake correlates with progression of coronary calcification18F]fluoride uptake and aneurysm disease activity.Calcification is a marker of disease burden and disease progression in coronary artery disease. Coronary sodium Ffluoride18F]fluoro-2-deoxyglucose, where patients whose aneurysm diameter increased, had demonstrated lower radiotracer uptake on baseline PET-CT 9 months previously.18F]fluoride, detects microcalcification, which is increasingly becoming a specific and reliable marker of disease activity within the aorta. Sodium [18F]fluoride uptake quantifies microcalcification within the aortic media of patients with thoracic aortopathy18F]fluoride uptakes in the cohort occurred in a patient with a type 2 endoleak and sac enlargement. Although the small cohort size is insufficient to draw definitive conclusions, it does provide promising preliminary data to suggest that high aortic sodium [18F]fluoride uptake may reflect disease activity. As an indicator of reduced aneurysm metabolic activity, suppression of uptake could confirm or predict treatment efficacy of EVAR and may have a role in a select group of patients who demonstrate sac expansion on routine screening.An increase in aneurysm diameter and a change in radiotracer uptake over time has previously been observed using 2-[18F]fluoride binding. Irrespective of the mechanism, our findings highlight the potential of PET to provide an imaging biomarker of treatment efficacy in abdominal aortic aneurysm disease, especially for EVAR but potentially also for other future treatment interventions. Conversely, failure to suppress aortic sodium [18F]fluoride uptake may herald the development of complications and endoleaks not yet visible on CT. Speculatively, it could guide baseline patient selection for EVAR if intense uptake at baseline heralds likely future treatment failure, and is the subject of an ongoing prospective study (NCT04577716).The reduction in AMA we observed following EVAR suggests insertion of the stent graft can decrease aneurysm disease activity. The mechanism of such reduced disease activity has not been addressed by our study, but this could plausibly include reducing biomechanical stress within the aortic wall, preventing the build-up of further luminal thrombus or inflammatory mediators or providing a physical barrier to luminal blood pressure which could otherwise exacerbate aneurysmal dilatation. In turn, these processes could lead to a reduction or cessation in further degeneration in the aortic media which leads to reduced deposition of hydroxyapatite crystals and a reduction in surface area for sodium fluoride uptake has shown excellent levels of agreement with conventional PET quantification methods,This is a small single centre proof-of-concept study, with the small sample size a result of recruitment of only those patients from the original SoFIA18F]fluoride uptake localises to the diseased regions of abdominal aortic aneurysm disease and predicts development of aortic macrocalcification. Successful EVAR is associated with a marked reduction in aortic sodium [18F]fluoride uptake and microcalcification activity which is most prominent in the stented regions of the aorta. Although it requires future prospective validation and evaluation, this technique holds promise as a marker of aneurysm disease activity and treatment efficacy and may have clinical implications in personalised EVAR surveillance.In conclusion, aortic sodium ["}
+{"text": "Editorial on the Research TopicCase reports in general cardiovascular medicine: 2022In this 2022 Topic and Case Reports, an international collection of case reports is presented that aims to contribute to the advancement of understanding of personalized approaches to the prognosis, diagnosis, and treatment of cardiovascular disease. This editorial features the collection of Case reports published in Frontiers in Cardiovascular Medicine  in 2022. In total 33 papers are published in this Research Topic. Case reports of the contributions in this special issue highlight unique cases that present with an unexpected diagnosis, treatment outcome, or clinical course. Hereby, reports on this issue can not only describe the cases' clinical presentation, diagnostic process, and treatment but also provide important experience and treatment strategies to manage patients with similar conditions. Following are the Case Reports that are published in the General Cardiovascular Medicine Section of the year 2022 .\u2013Amiodarone-Induced Multi-Systemic Toxicity Involving the Liver, Lungs, Thyroid, and Eyes: A Case Report .Amiodarone is a widely used anti-arrhythmia drug despite its side effects on various organs. However, cases of simultaneous toxicity of different organs in one patient have been rarely reported. This report describes an original case that multi-systemic amiodarone organ toxicity occurred in high-risk patients. This study provides important information for the diagnosis and treatment of amiodarone toxicity that could be useful for both physicians and researchers, as well as guideline makers in amiodarone administration.\u2013The Diagnostic Challenge of Eosinophilic Granulomatosis With Polyangiitis Presenting as Acute Eosinophilic Myocarditis: Case Report and Literature Review .Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare disease that is typically associated with infection and drug factors. It commonly affects multiple organs in the body and manifests with various discomforting symptoms. EGPA-associated eosinophilic myocarditis is rare but can lead to death if left untreated. This report describes a case with this rare disease cured by timely treatment with systemic and oral corticosteroids. The description in this report provides critical clinical features and therapy strategies that can be useful for physicians to identify and treatment of this disease.\u2013Case Report: Intravascular Ultrasound-guided Intervention for Anastomosis Stenosis of the Left Main Coronary Artery Post-Cabrol Technique .This study reports a case of acute myocardial infarction that is successfully treated with intravascular ultrasound (IVUS)-guided percutaneous coronary intervention (PCI). This is the first report that combined PVCI with virtual IVUS. The observations in this paper provide important information for physicians about how to evaluate plaque composition and conduct PCI in patients with chronic inflammatory diseases like Beh\u00e7et's disease.\u2013Aortic Coarctation Associated With Hypertrophic Cardiomyopathy in a Woman With Hypertension and Syncope: A Case Report With 8-Year Follow-Up .Coarctation of the aorta (CoA) and hypertrophic cardiomyopathy (HCM) are two irrelevant cardiovascular diseases . This re\u2013Case report: Myocarditis following COVID-19 protein subunit vaccination .This study reports a case of myocarditis following ZF2001 vaccination in a female patient. This report describes the patient's clinical symptoms and immunohistochemical characteristics of heart sections. Though some patients with myocarditis following COVID-19 vaccination were vaccinated types of vaccines have been reported. Limited knowledge has been known about the association between vaccination and myocarditis in subunit vaccines against COVID-19. The report here suggests that physicians should consider the potential link between vaccination and myocarditis in clinical diagnosis. Also, investigating the specific mechanism underlying myocarditis after vaccination should be significant to guild the development of a new generation of subunit vaccines.\u2013Case report: Aggressive progression of acute heart failure due to juvenile tuberculosis-associated Takayasu arteritis with aortic stenosis and thrombosis .Takayasu arteritis (TA) is a chronic granulomatous vasculitis of unknown pathophysiological mechanisms. The report describes a case of tuberculosis-associated TA who fail to survive after surgery. In this paper, the authors share their clinical experience in the diagnosis of TA and what they could learn from the case. The information provides in this paper can offer important knowledge for physicians to timely diagnose TA at an early stage with few typical features.\u2013Case report: Changes in the levels of stress hormones during Takotsubo syndrome . Inverted Takotsubo Syndrome With HELLP Syndrome: A Case Report .Takotsubo syndrome is a sudden, transient, acute episode of left ventricular dysfunction, usually triggered by physical or emotional stress . These t\u2013Decisive diagnostic clue for infectious abdominal aortic aneurysm caused by Arthrobacter russicus in a diabetic elderly woman with renal dysfunction: A case report and literature review .Arthrobacter russicus that is successfully treated with a combination of surgery and long-term antimicrobial therapy. Arthrobacter russicus is identified as a potential causative microorganism by using 16S rRNA sequencing. This paper indicates that a molecular diagnosis is important for identifying the causative microorganism, in particular in cases of Gram staining and tissue culture-negative IAA.Infectious aortic aneurysm (IAA) is a rare but serious infectious inflammatory disease of the aortic wall with high mortality. This report describes a case of IAA caused by \u2013Disrupting arrhythmia in a professional male wrestler athlete after rapid weight loss and high-intensity training\u2014Case report .It is well-known that physical exercise can induce physiological cardiac adaptions and benefit cardiovascular health , 4. Howe\u2013Myocardial infarction with non-obstructive coronary arteries in a patient double-seropositive for anti-glomerular basement membrane and anti-neutrophil cytoplasmic antibodies: A case report .Anti-neutrophil cytoplasm antibody (ANCA)-associated vasculitides (AAV) and anti-glomerular basement membrane (GBM) disease are rare diseases with high mortality. This report describes a myocardial infarction with non-obstructive coronary arteries (MINOCA) patient with double seropositive for anti-ANCA and anti-GBM antibodies. Limited cases have been reported of anti-GBM disease patients with cardiovascular complications. These observations provide important information for physicians that endothelial injury or systemic inflammation patients with double-positive disease might be at higher risk to develop MINOCA. Further in-depth investigations to understand the clear causality and mechanism are required in the future.\u2013Case Report: Danon Disease: Six Family Members and Literature Review .Danon disease is a rare X-linked dominant genetic disorder characterized clinically by hypertrophic cardiomyopathy, skeletal muscle weakness, and intellectual disability . This re\u2013Case report: Pulmonary arterial hypertension in ENG-related hereditary hemorrhagic telangiectasia .The etiology of pulmonary arterial hypertension (PAH) can stem from various factors and is often multifactorial. It is crucial to implement standardized diagnostic procedures, investigate potential causes, and identify risk factors early on to enhance patient prognosis. In this paper, the authors report a case of hereditary hemorrhagic telangiectasia (HHT) combined with PAH. The clinical presentation, diagnostic process, and treatment of this rare case report provide useful information for physicians to diagnose HHT combined PAH patients. Further studies to better the pathogenesis of PAH in HHT should be of contribution to the timely and accurate diagnosis of this disease.\u2013Case Report: An Unusual Case of Pheochromocytoma .This report describes a female patient with acquired long QT syndrome, which is a rare complication of pheochromocytoma. Limited to the rarity and nonspecific clinical manifestations, diagnosis of pheochromocytoma is difficult. This study provides a successful diagnosis procedure of pheochromocytoma in this reported case and can offer important points for physicians to identify rare causes of common symptoms.\u2013Case Report: Family Curse: An SCN5A Mutation, c.611C>A, p.A204E Associated With a Family History of Dilated Cardiomyopathy and Arrhythmia .SCN5A mutation with various dilated cardiomyopathy (DCM) associated gene mutations result in multiple phenotypes in a 3-generation family. By analyzing clinical data and genetic testing, this report suggests that a combination of SCN5A and PRKAG2 mutation can lead to DCM plus multifocal ectopic Purkinje-related premature contractions and PRKAG2 syndrome. This study discusses the possible causality between gene variants and observed clinical phenotype and indicates that gene diagnosis can offer early intervention to help physicians to improve diagnoses of DCM.This study reports that \u2013Case report: From monkeypox pharyngitis to myopericarditis and atypical skin lesions .In this report, the authors describe a case of myopericarditis which is caused by human monkeypox, which is an endemic disease, infection followed by the onset of atypical skin lesions. This paper presents the clinical presentation, and diagnostic experience of this patient and provides antiviral treatment recommendations for physicians.\u2013Case report: Conquer a complex variant: Coronary-pulmonary artery fistulas, atrial septal defect and bicuspid pulmonary valve, under beating heart surgery .This report describes a rare patient with two coronary artery to pulmonary artery fistula (CPAF) from two branches of the left anterior descending coronary to the main pulmonary artery, coexisting with a bicuspid pulmonary valve and atrial septal defect and treated by on-pump beating-heart surgery (OPBHS). This study discusses the potential origin and reason of this case as well as the clinical advantages of OPBHS. This report is a very complex case that has not yet been previously reported in the literature. This study offers important information for surgeries to treat CPAFs by OPBHS for patients with low surgical risk.\u2013Case report: Coronavirus Disease 2019 (COVID-19) modified RNA vaccination-induced Adult-Onset Still\u2019s Disease with fulminant myocarditis as initial presentation .Several types of vaccines against the coronavirus disease 2019 (COVID-19). In this paper, the authors report a case of an elderly female who is diagnosed with post-vaccination about Adult-Onset Still's Disease after receiving a modified mRNA vaccine (BNT162b2). Adult-Onset Still's Disease is a rare autoinflammatory disease and potentially life-threatening. The report here describes the clinical presentation and diagnosis of this rare Adult-Onset Still's Disease following mRNA vaccines can provide important knowledge for physicians about this disease.\u2013Case report: Sudden cardiorespiratory collapse in a healthy male after coronavirus disease 2019 vaccination at a vaccination center .This paper reports a case of sudden cardiorespiratory collapse in a healthy young male after receiving the Oxford-AstraZeneca (ChAdOx1 nCoV-19) COVID-19 vaccination. This report addresses the importance of careful medical attention by healthcare providers to avoid possible severe adverse events following COVID-19 vaccination which could be certainly useful for healthcare policymakers, and physicians.\u2013Multisystem immune-related adverse events due to toripalimab: Two cases-based review .Immune checkpoint inhibitors (ICIs) significantly prolong survival in patients with advanced cancer. However, immune-mediated adverse events (irAEs) caused by ICIs pose a major threat to patients' lives. In this paper, the authors report 2 patients with advanced tumors suffering from severe multisystem irAEs following treated with toripalimab (anti-PD-1). This report also reviews the Case reports regarding multisystem irAEs based on myocarditis induced by PD-1 inhibitors. Early detection and diagnosis of multisystem inflammation are critical for the management of patients treated with ICIs. This study can provide important experience and critical information for physicians to manage patients undergoing ICIs treatment.\u2013A case report and review of literature: Tuberculous pericarditis with pericardial effusion as the only clinical manifestation .Tuberculosis (TB) remains a serious public health problem worldwide. In this paper, the authors report a case of a patient with Tuberculous pericarditis (TBP) who is admitted to the hospital with massive pericardial effusion. This patient is examined as negative with all routine laboratory tests for the pericardial effusion of unknown origin. This report provides experience and information for physicians to diagnose and treat percardial effuion patients, in particular to those demonstrated as non-TB causes negative.\u2013Case report: A novel surgical technique for rapid valve-in-ring implantation into the native aortic annulus during left ventricular assist device implantation .Left ventricular assist device (LVAD) implantation is an excellent option for treating end-stage heart failure patients . This re\u2013Case report: Severe dry cough associated with superior vena cava syndrome\u2014Caused recurrent chylothorax (Wan).This case reports a patient with uremia who suffered from severe dry cough. This patient is finally diagnosed with superior vena cava and treated by percutaneous balloon dilatation. Chronic coughs, which may be caused by many diseases, are very common syndrome in the respiratory department outpatient clinic. This paper reports a severe dry cough case caused by superior vena cave occlusion-induced recurrent chylothorax can provide information for physicians to diagnose recurring severe cough patients.\u2013Multimodal Imaging for Total Anomalous Systemic Venous Drainage Diagnosis and Preoperative Planning: A Case Report and Literature Review .Total anomalous systemic venous drainage (TASVD) is a rare congenital heart disease . In this\u2013Massive pleural effusion following high-power and short-duration radiofrequency ablation for treatment of atrial fibrillation: A case report and review of the literature .Radiofrequency catheter ablation (RFCA) is a non-pharmacological treatment for drug-refractory atrial fibrillations. Postpericardial injury syndrome (PPIS) is defined as pericarditis or pericardial effusion during myocardial infarction or cardiac intervention. It is widely recognized as a common complication of cardiac surgery, with an incidence ranging from 3% to 30%. Different from previously reported PPIS which is most characterized by pericardial effusion, this report describes a case of PPIS that presents pleural effusion as a main feature after the operation. This case report also systematically reviews the clinical characteristics of PPIS. The study in this paper provides useful reference information for physicians to timely diagnose a patient with massive pleural effusion alone following RFCA.\u2013Case report: Delayed cardiac rupture with congenital absence of pericardium after blunt trauma .As a rare disease with no specific symptoms and signs, the clinical diagnosis of congenital absence of pericardium (CAP) is very difficult. In this paper, the authors report a case of a patient with CAP and present some atypical features which are different from previously reported literature. The clinical presentation and diagnostic process of this patient should be useful to physicians in the diagnosis and treatment of CAP.\u2013Case report: Reducing the duration of positive-pressure ventilation for large mediastinal masses .This report describes two high-risk patients with large mediastinal tumors (MMs) during general anesthesia undergoing tumorectomy by thoracotomy. The perioperative management of patients with large MMs is challenging. This study suggests that patients with large MM should receive positive-pressure ventilation following muscle relaxants given, but that cardiothoracic surgeons should immediately transect the sternum to relieve compression. This study provides important information and experiences for physicians to manage patients with large MMs.\u2013Case report: Metastatic myxoid liposarcoma arising from the right atrium extends as cardiac tamponade\u2014A rare case of atrial oncology . Right atrial cardiac lipoma with distinctive imaging characteristics. A rare case report and literature review .Cardiac lipomas is rare primary cardiac tumors, many of them do not exhibit obvious features and are difficult to identify. These two reports describe patients presenting a lipomas in the right atrium. In these papers, the authors share their experimence in the diagnosis and treatment of cardiac lipomas can provide useful information for physicians.\u2013Successful simultaneous stenting of a pulmonary artery and vein in pulmonary vascular stenosis due to silicosis. Case report and literature review .via clinical symptom presentation and literature review.This report describes a successful stenting of a pulmonary artery and vein in a silicosis-caused pulmonary vascular stenosis patient. In this paper, the authors provide interventional procedure recommendations for this pulmonary vascular stenosis for physicians \u2013An adult female patient with single atrium and single ventricle undergoing appendectomy: A case report .This paper reports an adult female patient with a single atrium and single ventricle undergoing appendectomy. Single atrium and single ventricle is a rare heart disease with very few patients surviving into adulthood. This report describes their associated surgical findings and can share useful experiences for physicians to diagnose patients with similar conditions.\u2013Acute myocardial infarction after inactivated COVID-19 vaccination: a case report and literature review .Many types of vaccines have been developed to restrain the pandemic of COVID-19. This study reports an acute myocardial infarction case following post-COVID-19 vaccination and discusses the potential pathogenesis mechanisms. This study provides clinical experience and recommendations for physicians to manage patients with similar conditions.\u2013Case report: Aortoesophageal fistula\u2014an extremely rare but life-threatening cardiovascular cause of hematemesis .In this paper, the authors report a hematemesis patient with underlying diagnosed esophageal cancer who presents typical aortoesophageal fistula (AEF) clinical features. This report highlights the clinical features and diagnosis process of this extremely rare but life-threatening disease. This paper also provides recommendations for physicians to timely diagnose AEF.In conclusion, the high-quality clinical case contributions presented in this Research Topic have significantly boosted knowledge, diagnosis, and treatment of cardiovascular disease in complex cases."}
+{"text": "Sustained viral suppression in HIV is essential to minimize drug resistance, reduce secondary transmission and improve health outcomes necessary to achieve the UNAIDS 95-95-95 strategy. There is dearth of information on viral suppression among adults in Nigeria. Identifying correlates of sustained viral suppression will inform treatment guidelines especially for people at risk and provide recommendations to policy makers.We collected sociodemographic and HIV-related data from a cross-section of 730 HIV-positive adults receiving antiretroviral therapy from six secondary health facilities in northern Nigeria, between October 2021 and February 2022. Sustained viral suppression was defined according to the Nigerian National Guideline for HIV Prevention, Treatment and Care as a viral load below the detection threshold of less than 20 copies of HIV RNA/ml. Proportion of participants with sustained viral suppression was estimated and a multivariable analysis used to identify independent correlates of sustained viral suppression.The sustained viral suppression rate among HIV-positive adults on ART was 35.7% . Being married  and having secondary education  were significantly associated with sustained viral suppression. Respondents on treatment for 5-10 years  and those taking two or more pills  were more likely to have sustained viral suppression. Previous treatment for opportunistic infection  significantly decreased the likelihood of sustained viral suppression.Sustained viral suppression rates among HIV-positive adults on ART in the six facilities were suboptimal. While being married, taking two or more ART pills and being on treatment for 5-10 years increased the likelihood of having a suppressed viral load, being educated up to secondary level and previous treatment for opportunistic infection decreased the odds of having sustained viral suppression. There is a need to improve viral load monitoring and direct viral suppression interventions towards at risk population.All Authors: No reported disclosures"}
+{"text": "Circulatory shock is defined syndromically as hypotension associated with tissue hypoperfusion and often subcategorized according to hemodynamic profile  and etiology . These shock subgroups are generally considered homogeneous entities in research and clinical practice. This current definition fails to consider the complex pathophysiology of shock and the influence of patient heterogeneity. Recent translational evidence highlights previously under-appreciated heterogeneity regarding the underlying pathways with distinct host-response patterns in circulatory shock syndromes. This heterogeneity may confound the interpretation of trial results as a given treatment may preferentially impact distinct subgroups. Re-analyzing results of major \u2018neutral\u2019 treatment trials from the perspective of biological mechanisms  may reveal treatment effects in subgroups of patients that share treatable traits . In this review, we discuss the emerging literature suggesting the existence of distinct biomarker-based host-response patterns of circulatory shock syndrome independent of etiology or hemodynamic profile. We further review responses to newly prescribed treatments in the intensive care unit\u00a0designed to personalize treatments\u00a0. Circulatory shock incurs a high mortality, with minimal incremental improvements in survival demonstrated by clinical trials in the last two decades \u20134. For tThe initial step in the management of circulatory shock is generally to control the cause of shock . Medical therapy is provided in the form of volume replacement, transfusions, and vasopressors/inotropes to correct hypovolemia, anemia, hypotension and low\u00a0cardiac output. In the case of severe organ dysfunction, patients receive supportive therapies, including renal replacement therapy, mechanical ventilation, and/or mechanical circulatory support  . The \u2018miEmerging translational evidence demonstrates the existence of variability in the host response to circulatory shock syndromes and the existence of potential common \u2018treatable traits\u2019  within subgroups of patients across different forms of shock. Conserved biological signatures occurring across diverse shock subtypes include combinations of endothelial dysfunction, inflammatory cell activation, reactive oxygen species formation, immune dysregulation, neurohormonal dysregulation, activation of coagulation, and fibrinolysis \u201311.It has been hypothesized that heterogeneity in a given etiology or hemodynamic profile of circulatory shock may dilute a demonstrable benefit of specific interventions when applied broadly in clinical trials due to diverse individual treatment response profiles , 12. It (i) distinct and common biological patterns of host response in circulatory shock syndromes and (ii) their response to different established  or novel interventions . This paper is a narrative review from the 2022 Critical Care Clinical Trialists (3CT) Workshop expert panel for circulatory shock endotyping (https://www.3ctmeeting.com/). Our aim is to highlight the main studies in the field and not to provide an exhaustive review of the literature.In this narrative review, we overview the current literature related to Biomolecular heterogeneity is not reflected by non-specific clinical syndromic criteria for patients with critical illness, specifically those with shock. Even if standardized diagnostic criteria for sepsis/septic shock, cardiogenic shock and hemorrhagic shock have evolved over the years, yet substantial underlying heterogeneity exists within populations of patients meeting these definitions.Here, we summarize the main studies using readily available clinical and biological data and/or omics-based biomarkers  to unravel host response heterogeneity within distinct circulatory shock syndromes.. identified four distinct clinical phenotypes of sepsis using readily available clinical and biological data at hospital admission [In a retrospective analysis of sepsis/septic shock cohorts and clinical trials, Seymour et aldmission . The pheIn a prospective observational cohort of 288 sepsis/septic shock adult patients in Uganda, Cummings et al. used unsupervised clustering of 14 soluble host immune mediators, reflective of key domains of sepsis immunopathology , and to whole-blood RNA-sequencing data to identify immune and transcriptional subtypes . The autIn the study of Davenport et al. only\u2009~\u200960% of patients with pneumosepsis had \u201cclassic\u201d immune activation (as many as 40% manifested an immunosuppressed response). In this study, the authors assayed peripheral blood leukocyte gene expression in septic shock patients. The authors used a clustering approach to identify two sepsis response signatures (SRS). SRS-1 had an immunosuppressed phenotype and worse outcome .k-means clustering (a non-model-based clustering technique) to identify three subclasses/phenotypes in a multicenter cardiogenic shock cohort [Zweck et al. recently used k cohort . The thrThese three clusters were replicated by Jentzer et al. with the same six admission laboratory variables in 1498 cardiogenic shock patients, finding differences in echocardiographic markers of cardiac function and long-term survival between groups .In an exploratory study of 107 patients with ST-segment-elevation myocardial infarction and acute heart failure , peripheral leukocyte gene expression patterns (mRNA expression data) were used to identify host-response endotypes. Hierarchical clustering grouped patients in two endotypes based on pathway variability in mediators of inflammation, immune function. Demographic and clinical characteristics did not significantly different across host-response endotypes, suggesting that molecular profiling might be incremental to clinical classifiers alone .Last and not least, Scolari et al. reported that cardiogenic shock patients have a higher frequency of clonal haematopoiesis  than in patients with ambulatory heart failure matched for age, sex, ejection fraction, and heart failure etiology . This co. used a clustering approach to identify distinct immunologic endotypes [In an analysis of a prospective cohort study including 102 severe trauma patients with hemorrhagic shock, Brakenridge et alndotypes . Multipl. used untargeted metabolomics and plasma immune circulating markers in 86 severely ill trauma patients to identify distinct host-response subclasses [Cyr et albclasses . Three hMore and more evidence suggests that the host response to many forms of injury is shared across distinct circulatory shock syndromes. The same biological signatures  were highlighted in circulatory shock with different etiologies using a single-biomarker or a multiple-biomarkers approach.It has been reported in both sepsis/septic shock and cardiogenic shock that levels and rapid changes in circulating bio-adrenomedullin  on admission are associated with worse hemodynamics and organ dysfunction independently from severity of chronic and acute illness and initial lactate level , 25.Similarly, high circulating levels of angiopoietin-2  were reported as associated with organ dysfunction and mortality in distinct populations with cardiogenic shock, septic shock, and traumatic hemorrhagic shock independently from age, comorbidities, and severity scores on admission \u201328.These results support the suggestion of Johansson et al. of a mechanistic link between sympatho-adrenal hyperactivation in circulatory shock independently from the insult and the endothelial phenotype. They defined a potential unifying pathophysiologic mechanism linked to poor outcome as shock-induced endotheliopathy .n\u2009=\u2009167) with matched  healthy subjects and with 133 severely burned patients or 4 healthy adult subjects administered low-dose bacterial endotoxin. Despite different insults, the early genomic changes were highly comparable (>\u200980% of the cellular functions and pathways) between blunt trauma patients, burns, or stressors. These findings demonstrate a common host-response pattern reflective of the large overlap in upstream receptors and signaling intermediates activated by each condition , Toll-like receptor 4 (TLR4), alarmins).In the Inflammation and the Host Response to Injury\u00a0large-scale collaborative research program (Glue Grant), the investigators described the circulating leukocyte transcriptome in critically injured patients with circulatory shock . They co. recently described common injury-induced immune profiles in a large cohort of critically ill patients with different etiologies  [Venet et alsurgery) . The aut. reported in the ShockOmics cohort (n\u2009=\u200937) a similar pattern of differential expression of genes coding for inflammatory and immunoglobulin proteins among patients with sepsis and cardiogenic shock. The overlap in biological patterns suggests shared mechanistic signatures between the two critical illness syndromes [Braga et alyndromes .. used an unsupervised clustering approach across three etiologies of critically ill patients  to identify distinct molecular subclasses based on single cell transcriptomic patterns in circulating leukocytes. The authors identified three clusters reflecting dysregulation in genes involved in DNA repair and RNA processing between the etiologies  with different associated clinical outcomes [Chen et aloutcomes .The U.S. Food and drug administration (FDA) defines predictive enrichment in clinical research as the prospective selection of a study population in which detection of a treatment effect (if one is in fact present) is more likely than it would be in an unselected population . The aimThe selection of patients could be based on a known pathway biomarker or be unsupervised  in case of unknown mechanisms  . This apHowever, as demonstrated in the IMPRESS trial of AMICS that specifically enrolled high-risk cardiogenic shock individuals (>\u200990% of whom were comatose after cardiac arrest), high-risk individuals may not be more likely to respond to a tested intervention if they have competing mortality risks that are not modified by the intervention .Re-analyzing results of major \u2018neutral\u2019 treatment trials in circulatory shock from the perspective of biological mechanisms may allow identification of salutary effects of treatments in subclasses of patients  \u201338. It s. assessed the use of high-affinity polymyxin B hemoperfusion in patients with septic shock to remove bacterial endotoxin from the circulation through selective adsorption [Predictive enrichment can be achieved by classifying patients using a biomarker linked to the tested intervention. In the EUPHRATES trial, Dellinger et alsorption .The authors randomized only patients with an endotoxin activity assay level of 0.60 or higher. Polymyxin B hemoperfusion compared with sham hemoperfusion did not significantly decrease 28-day mortality among the randomized patients.\u00a0In a post hoc analysis of the EUPHRATES trial including high severity of illness (Multiple Organ Dysfunction Score (MODS)\u2009>\u20099) and an endotoxin activity level between 0.6 and 0.89, Polymyxin B hemoperfusion use was associated with an absolute mortality reduction compared to sham patients of 10.7% at 28\u00a0days . These rIn a post hoc analysis of the \u2018neutral\u2019 Sepsis Coagulopathy Asahi Recombinant LE Thrombomodulin trial (SCARLET), the authors reported lower mortality in patients with septic shock associated coagulopathy and elevated coagulation markers  treated with thrombomodulin, suggesting this coagulation pattern could be used to select patients most likely to respond .In another retrospective analysis of the phase III randomized interleukin-1 receptor antagonist trial in Sepsis patients with multiorgan dysfunction syndrome and/or shock, the authors reported in the subclass of patients with macrophage activation syndrome  an association of IL-1 receptor blockade with significant improvement in survival at 28\u00a0days . This siA post hoc analysis of patients enrolled in the ATHOS-3 trial (Angiotensin (AT) II for the Treatment of High-Output Shock) , tested The authors reported that in vasodilatory shock patients with renin concentrations higher than the study population median, angiotensin II infusion significantly reduced 28-day mortality when compared with placebo  which waThe authors hypothesized that the inflammatory host response in circulatory shock may reduce angiotensin-converting enzyme activity, which may lead to decreased conversion of AT-I to AT-II and conversion of AT-I to vasodilatory AT degradation peptides causing persistent hypotension and high renin-levels . They copost hoc\u00a0enrichment strategy based on circulating dipeptidyl peptidase 3 (cDPP3)  may indicate that therapeutic efficacy is most important  in patients with lower cDPP3 levels [.In the AdrenOSS-2 phase 2a biomarker-guided trial, Laterre et al. investigated a non-neutralizing adrenomedullin antibody (adrecizumab) in septic shock patients with high adrenomedullin . The pri3 levels . The sam3 levels .The pathways underlying different circulatory shock syndromes are complex and treatment responses are multifactorial, necessitating multiple biomarkers to identify a significant amount of the variability in response . Limiting ourselves to known biomarkers may not advance much-needed discovery which can instead be promoted using unsupervised clustering approaches .k-means clustering, latent class analysis) may allow the identification of distinct mechanistic signatures underlying the heterogeneous circulatory shock syndromes and the discovery of candidate biotargets  [Patients can be classified using multiple readily available clinical and biological data or more sophisticated high-dimensional biomarkers . The identification of subclasses/subphenotypes using clustering and unsupervised machine learning algorithms  \u201352.In Seymour et al. study, simulation models suggested that the four phenotypes  identified using unsupervised clustering demonstrated proof-of-concept in support for molecular endotypes underscoring treatment effects in septic shock patients . The estIn a post hoc analysis of the VANISH trial including patients with septic shock , genome-In a retrospective analysis of the PROPPR randomized trial including severe trauma patients with hemorrhagic shock which compared transfusion of plasma, platelets, and red blood cells in a 1:1:1 ratio to a 1:1:2 ratio regarding mortality, the investigators applied latent class analysis to identify two trauma subphenotypes (TS-1 and TS-2). They used 36 circulating markers of inflammation, endothelial dysfunction, and coagulation measured prior to patients\u2019 randomization. In patients assigned to TS-2 (lower plasma concentrations of IL-8 and TNF-\u03b1), a 1:1:1 transfusion ratio was associated with significantly reduced risk for 30-day mortality compared to a 1:1:2 approach when adjusted for age, sex, injury severity, and injury mechanism. There was no difference in mortality by treatment assignment when the patients were stratified by severity of illness severity or injury mechanism .A summary of the aforesaid circulatory shock studies with predictive enrichment is represented in Table The identification of distinct host-response subclasses/subphenotypes may further inform mechanisms of persistent organ dysfunction and enable prognostic and predictive enrichment in circulatory shock regardless of the etiology or clinical classification. Secondary analyses of major critical care clinical trials and measurement of biomarkers in longitudinal biobanked samples to identify signals for benefit in a biologically defined subclass could evaluate whether the biological profiles are just capturing different points along patients\u2019 trajectory towards a final common pathway, whether the biological signature is the same for all interventions studied or specific to a targeted intervention and whether the same heterogeneity of treatment effect is seen in other etiologies of circulatory shock.These analyses may support future randomized controlled trials of personalized therapies in circulatory shock patients in which patients are prospectively enrolled based on a biological signature rather than on a non-specific clinical syndrome, such as sepsis, cardiogenic shock, or major trauma that invites empiric therapy. This approach  may be a key step to improve translation of research findings to the bedside for a more personalized critical care medicine. As a result, for example, we could be talking about \u201crenin and/or bio-adrenomedullin-driven shock\u201d, etc., rather than clinically defined \u201csyndrome/etiology\u201d models. We believe that regardless of the triggering etiology, the development of refractory shock and organ failure likely occurs via multiple overlapping conserved pathophysiological mechanisms, and their persistence over time which might be targets for therapy.Identifying distinct biological patterns is promising, but it does not guarantee the distinction of specific pathophysiological processes with causal links to intervention effects that might ultimately allow a personalization of treatment in circulatory shock patients. Diverse influences on these biomarkers are present, and it is unproven how well these candidate markers integrate diverse clinical, genetic, pathophysiologic, and treatment influences. Nevertheless, there is a theoretical advantage that they may summarize these diverse, \u2018upstream\u2019 influences on some extent and represent biologic indicators closer to the patient phenotype.To minimize the risk of categorizing the studied population differently  without capturing the complexity of underlying biological mechanisms, we think it is important to consider the following points. The use of a multi-biomarker approach reflecting diverse pathways involved in circulatory shock in humans  may support comprehensive profiling. Ideally, this approach can be coupled with modeling the dynamic interplay between different actionable biomarkers using unsupervised machine learning  instead of a single-biomarker approach with a single cutoff.Without considering personalized host responses, dozens of promising targeted molecular therapies and efforts to individualize risk prediction have failed to reduce mortality. This parallels oncology clinical research with a high response rate of successful targeted therapies in biomarker-driven patient selection evaluated in early clinical trials \u201357.We suggest the following roadmap as a strategy to advance research in circulatory shock Fig.\u00a0:Fig. 1A First to set up a collaborative, multicenter and interdisciplinary deep subphenotyping platform centered on the biological/molecular drivers of circulatory shock to identify and largely validate distinct mechanistic signatures in circulatory shock . The French and European Outcome Registry in Intensive Care Units (FROG-ICU) is an example of a cohort with a biobank and molecular trait mapping of circulatory shock patients with different etiologies, under one \u201croof\u201d supporting feasibility  , 59.Second, coupling discovery research with clinical trials and develop an integrative subphenotyping approach using unsupervised machine learning and biomarker data to inform effective new therapies in future clinical trials. This may allow signal enrichment and noise reduction and help decrease neutral circulatory shock clinical trials. Developing a harmonized strategy is fundamental with minimal criteria of groups of candidate biomarkers such as inflammatory, immune dysfunction, endothelial injury, organ dysfunction , abnormal coagulation, cell damage and oxidative stress for circulatory shock endotyping. A suggestion of a panel of groups of biomarkers for circulatory shock endotyping is represented in Fig.\u00a0Implementation of biomarker-stratified adaptive clinical trial designs is likely to be an important mechanism to facilitate this approach. Adaptive clinical trials may offer opportunities to better accommodate the possibility of heterogeneous treatment effects into the trial design prospectively\u2014a tool which may better support individualization of clinical care based on host-response profile , 61. ThiMany obstacles need to be overcome to implement biological subclasses/subphenotypes into clinical trials design and daily practice at the bedside. First the important heterogeneity of studies using different clustering approaches and biomarkers. Second, the stability/evolution and overlap of the identified subphenotypes and the interaction between comorbid illnesses and acute subphenotypes which makes it difficult to understand the overlap between subclasses with a poor replicability. Third, the timely serial assignment of subphenotype at the bedside using a simplified clustering/classification algorithm and rapid real-time assays in the ICU . Last anEmerging translational evidence highlights existing heterogeneity regarding the underlying host response between and within circulatory shock syndromes on one hand and demonstrates the existence of potential common \u2018treatable traits\u2019 within subgroups of patients across different forms of shock on the other hand. Further research should focus on these host-response pathways to shift from a cause\u2013consequence model towards a host-response subphenotype model. This could pave the way towards personalized critical care medicine.Traditional shock subgroups defined clinically on basis of etiology and hemodynamic features are incorrectly considered homogeneous entities. Emerging translational evidence highlights the existing heterogeneity regarding the underlying host response between and within circulatory shock syndromes.Accepting the results of neutral clinical trials without taking into consideration the heterogeneity of underlying biological mechanisms and the existence of distinct host-response patterns is a missed opportunity to discover subclasses of patients that may benefit from targeted treatments.Identifying host-response patterns may provide new insights regarding the pathophysiology of circulatory shock and pave the way towards the development of innovative biomarkers and targets of pharmacological therapies. This may allow predictive enrichment to define personalized treatments\u00a0\u00a0and ultimately transform current research and care."}
+{"text": "Xenopus tropicalis as a model organism, the approach should be applicable to genotyping of any organisms.Targeted genome editing is a powerful tool for studying gene function in almost every aspect of biological and pathological processes. The most widely used genome editing approach is to introduce engineered endonucleases or CRISPR/Cas system into cells or fertilized eggs to generate double-strand DNA breaks within the targeted region, leading to DNA repair through homologous recombination or non-homologous end joining (NHEJ). DNA repair through NHEJ mechanism is an error-prone process that often results in point mutations or stretches of indels (insertions and deletions) within the targeted region. Such mutations in embryos are germline transmissible, thus providing an easy means to generate organisms with gene mutations. However, point mutations and short indels present difficulty for genotyping, often requiring labor intensive sequencing to obtain reliable results. Here, we developed a single-tube competitive PCR assay with dual fluorescent primers that allowed simple and reliable genotyping. While we used The online version contains supplementary material available at 10.1186/s13578-023-01042-2. Dear Editor,Xenopus tropicalis as an example.We would like to report a simple and faithful dual color assay for genotyping organisms generated from genome editing. Targeted genome editing is a powerful tool for studying the gene function and underlying molecular mechanisms of almost every aspect of biological and pathological processes. The most popular methods for targeted genome editing are engineered endonucleases, including Zinc Finger Nuclease (ZFN), Transcription Activator-Like Effector Nucleases (TALENs), and Clustered Regularly Interspaced Short Palindromic Repeats/Cas (CRISPR/Cas) system, the prevailing genome editing tool originating from the adaptive immunity system of prokaryotes . The comWe have been studying frog metamorphosis as a model for mammalian postembryonic development and organ regeneration, a period when plasma thyroid hormone (T3) level peaks and adult organ development and maturation occur \u20136. AnuraTo overcome this problem, we hypothesized that a perfectly matched primer  would compete more effectively against a primer with mismatches  when present in the same PCR reaction. Thus, we labelled the mutant-allele specific reverse primer Rm and the wild type allele-specific reverse primer Rwt for HAL2 gene with fluorescent dye IR700 and IR800, respectively. We mixed both primers together in a single tube PCR assay in the presence of the common forward primer F428 (Additional file To test whether primer competition enhanced the PCR specificity in the single tube PCR assay with dual fluorescent primers, we first carried out parallel PCR reactions to genotype HAL2 and MBD3 animals using a single pair of non-fluorescent primers per reaction on serially diluted target DNA templates. We observed significant non-specific amplifications (Additional file Genome editing is a powerful tool used to introduce mutations in targeted genes to study their function and underlying molecular mechanisms. Faithful and simple genotyping is key for the widespread use of such technology and to ensure correct interpretation of the experimental findings. PCR-based detection is an appealing approach as it works reliably on mutations with large indels that lead to significant size differences in the PCR products from wild type and mutant alleles. Additionally, it has the ability to amplify specific alleles with allele-specific primers. However, it is very difficult to design allele-specific primers with high specificity for organisms with small indels or point mutations, which are common mutant types from genome editing. In such cases, PCR often has non-specific amplifications, making this approach unreliable for genotyping. Targeting a region harboring a restriction enzyme recognition site that can be disrupted via genome editing expands the application of PCR-based detection on small indels but requires additional steps to purify and digest the PCR products prior to resolving them through electrophoresis. In recent years, a number of strategies have been developed to genotype organisms with such small indels with limited practical use due to complex designs and/or lengthy assays \u201310. Our These are shown in the supplemental information.Additional file 1. Comparative analysis of regular PCR and competitive single-tube dual fluorescent PCR for genotyping small deletion mutant X. tropicalis animals generated via CRISPR/Cas9-mediated genome editing. Regular PCR with a single genotype-specific primer set in a PCR reaction often leads to non-specific amplification and inconclusive or false genotyping results. On the other hand, competitive single-tube PCR with a mixture of two genotype-specific fluorescent primers and a common primer inhibits non-specific amplification to allow accurate genotyping."}
+{"text": "However, humans spend virtually all their awake hours in a fully light-adapted state. Here we review the evidence for a narrow blue circadian sensitivity curve for light-adapted humans derived from experiments using spectral filtering of light sources, and comparisons of light sources with diverse spectral power distributions. This light-adapted Circadian Potency function permits the development of circadian-protective light for nocturnal use and circadian-entraining light for daytime use.Light exposure at night can disrupt the circadian timing of cellular processes and is associated with a broad range of health disorders. To spectrally engineer lighting which minimizes circadian disruption at night it is necessary to define the precise spectral sensitivity of the human circadian system. Prior attempts have used short monochromatic light exposures in dark-adapted human subjects, or  These studies used dark-adapted subjects with induced pupil dilation [Previous assessments of the spectral sensitivity of the circadian system, based on dilation \u20133, dark-g violet 00\u2013429 nmnd green 00\u2013560 nmdilation , 90 min However, the test conditions of the \u2018dark-adapted\u2019 light-exposure studies are very different than the typically much longer (up to 16+ hours), continuous and fully-adapted exposure of humans to polychromatic white light in everyday life. Because of the initial dark adaptation, the previously reported circadian spectral sensitivity curves may include, in addition to 430\u2013499 nm (blue) wavelength sensitivity, transient 400\u2013429 nm (violet) and 500\u2013560 nm (green) components resulting from cone- and rod-mediated extrinsic inputs to Intrinsically-Photoreceptive Retinal Ganglion Cells (ipRGCs) which decay over the first two hours of extended light exposure.In experiments with longer 6-hour) exposure to monochromatic blue or green light , conducted with initially dark-adapted subjects [-hour expTransient effects may be also seen with violet light exposure, resulting from transitory extrinsic input to ipRGCs from S-cones. Experiments on previously dark-adapted subjects showed that melatonin suppression by monochromatic violet light (420\u2013424 nm) was much larger after 30 minutes (95% suppression)  than aftThe light-adapted human circadian spectral sensitivity curve under normal workplace lighting conditions has now been defined using a) light exposure times of greater than 12 hours instead of brief \u226490 minute light exposures of the dark-adapted eye; b) polychromatic overhead ceiling white light sources, instead of monochromatic lights; c) exposures to illumination levels recommended by the IES Lighting Handbook for work surfaces  ; and d) The first indication that the light-adapted circadian sensitivity curve was narrower than the published dark-adapted curve came from studies using eyeglasses with dichroic cut-off filters . In humaWe explored the spectral boundaries of light-adapted human circadian sensitivity by comparing human subjects illuminated from 20:00 h to 08:00 h overnight by an unfiltered LED overhead light source providing 540 lux illumination at tabletop, and with the same subjects under the light source with dichroic notch filters which either removed all wavelengths between a) 450\u2013490 nm or b) 430\u2013500 nm. The nocturnal pattern of salivary melatonin was suppressed under the unfiltered light source and partially suppressed by the light source with 450\u2013490 nm filter, but the melatonin curve was unsuppressed with the 430\u2013500 nm filter , indicatTo measure the spectral sensitivity of light-adapted human subjects more precisely, we ran a similar 12-hour overnight protocol, using, instead of filtered light, six spectrally diverse polychromatic white LED light sources (A-F). Based on the resulting nocturnal salivary melatonin patterns, a steady-state human spectral sensitivity curve was derived. This Circadian Potency spectral sensitivity curve with a Full Width at Half Maximum (FWHM) of 438\u2013493 nm and peaking at 477 nm  is much in vitro peak sensitivity (479 nm) of human melanopsin [2) monochromatic blue light (480 nm) near that Circadian Potency peak wavelength generates an amplitude of the circadian phase response curve that is comparable to that of a polychromatic light source with much higher irradiance level (3000 \u03bcW/cm2).The Circadian Potency peak wavelength of 477 nm, obtained from light-adapted subjects under extended polychromatic light exposure, is close to the lanopsin , indicatlanopsin  that shoThe human circadian timing system can be disrupted by non-optimal light exposure such as insufficient day light or excessive evening or night light. Light at night is associated with detrimental health effects including compromised mood, sleep and immunity, higher obesity and diabetes risks and higher rates of neuroendocrine sensitive cancers such as breast and prostate cancer \u201317. ConsThe Circadian Potency curve is applicable to real-world situations as it was obtained under typical workplace conditions with light-adapted subjects and extended exposure to polychromatic light.The Circadian Potency spectral sensitivity curve spans a narrower wavelength range (FWHM 438\u2013493 nm) than the rather broad (400\u2013560 nm) range of the \u2018dark-adapted\u2019 spectral sensitivity curves that spread across violet, blue and green wavelengths. Removing this wide wavelength range from the polychromatic (380\u2013780 nm) white light spectrum for the purpose of healthy nocturnal lighting is not practical for manufacturing attractive white or near-white light desired for most human purposes.Further, the narrower Circadian Potency spectral sensitivity curve makes it feasible to engineer energy-efficient nocturnal lighting using energy efficient violet LED dies which would not be feasible according to the \u2018dark-adapted\u2019 sensitivity curve.Defining the specific spectral characteristics of harmful and helpful electric lighting by means of spectral sensitivity curves is important to help spectrally engineer appropriate lighting solutions. The Circadian Potency spectral sensitivity curve  has seveIt allows the use of violet (410\u2013425 nm) LED dies to engineer calorimetrically-balanced white light for nocturnal lighting instead of the conventionally used blue LEDs with ~450 nm peak emissions.The replacement of blue wavelengths by violet wavelengths reduces the negative health impacts of blue-rich nocturnal lighting, while maintaining the positive effects of short wavelength light on alertness and performance ,21, and The fact that the Circadian Potency spectral sensitivity curve suggests relative insensitivity at spectral wavelength below 425 nm is of particular interest:Besides using the Circadian Potency spectral sensitivity curve for spectrally designing healthy nocturnal white lighting, it can be also used for applications to phase shift the circadian clock for purposes of adjusting to shift work or jetlag, or for treating circadian sleep disorders. While specific Phase Response Curves (PRCs), that describe how wavelengths with high Circadian Potency can produce phase delays or phase advances, are not determined, the closest approximation currently available is the type 1 PRC that was developed for monochromatic blue (480 nm) light . The queUnder normal light-adapted conditions with polychromatic white light, the spectral sensitivity of the human circadian system appears to be limited to a narrow band of blue wavelengths with a peak at 477 nm and a FWHM of 438\u2013493 nm. This Circadian Potency function has a narrower sensitivity range than the spectral sensitivity curves previously derived from short exposures to monochromatic lights under dark-adapted conditions. This appears to be because violet and green light effects seen in dark-adapted subjects are transient components that decay with extended exposure to light. The light-adapted Circadian Potency spectral sensitivity function has enabled the development of sensors and spectrally-engineered LED light sources to minimize circadian disruption. It also makes it possible to address the health risks of light exposure at night in our 24/7 society, by alternating between daytime circadian-entraining white light spectra and nocturnal circadian-protective white light spectra without loss of visual acuity."}
+{"text": "A 61-year-old man who had previously undergone pancreaticoduodenectomy underwent subsequent endoscopic ultrasound (EUS)-guided stent placement to bridge the jejunum, pancreatic duct, and stomach as treatment for pancreaticojejunal anastomosis stricture . Stent Video\u20061\u2002Previous endoscopic ultrasound-guided pancreatic duct drainage and stent exchange using the lariat method.A lariat was prepared to facilitate safe removal of the stent during endoscopic intervention from the jejunum where the pancreatic duct had been anastomosed. The wire tip of a snare catheter was grasped using forceps inserted through a single-balloon enteroscope , and thThe scope was subsequently advanced into the jejunum . Then, Endoscopic observation during scope withdrawal confirmed that a few centimeters of the stent were located in the stomach.If the lariat method is not used, there are few strategies by which the previous stent can be safely removed while retaining guidewire routesEndoscopy_UCTN_Code_TTT_1AS_2AD"}
+{"text": "The approval of immune-checkpoint inhibitors (CPI) and mitogen activated protein kinase inhibitors (MAPKi) in recent years significantly improved the treatment management and survival of patients with advanced malignant melanoma. CPI aim to counter-act receptor-mediated inhibitory effects of tumor cells and immunomodulatory cell types on effector T cells, whereas MAPKi are intended to inhibit tumor cell survival. In agreement with these complementary modes of action preclinical data indicated that the combined application of CPI and MAPKi or their optimal sequencing might provide additional clinical benefit. In this review the rationale and preclinical evidence that support the combined application of MAPKi and CPI either in concurrent or consecutive regimens are presented. Further, we will discuss the results from clinical trials investigating the sequential or combined application of MAPKi and CPI for advanced melanoma patients and their implications for clinical practice. Finally, we outline mechanisms of MAPKi and CPI cross-resistance which limit the efficacy of currently available treatments, as well as combination regimens. Malignant melanoma is among the most aggressive solid tumors of the skin that displayed a fast-growing incidence in the last decades , 2. OnceV600) . . V600-mu9\u00a0months .Triple combination therapy has not only been investigated in the metastatic, but also in the neoadjuvant setting. In this setting, CPI or MAPKi are administered prior to definitive surgery. Neoadjuvant treatment regimens for resectable advanced stage III and stage IV melanoma are increasingly coming into focus of clinical investigations given the promising results of the recent OpACIN  and OpACResults from recently presented trials in patients with resectable stage III or oligometastatic stage IV melanoma confirmed these promising results for neoadjuvant Nivo plus relatlimab . The neoDespite the strong efficacy data for neoadjuvant treatment regimens, there remains a need to enhance treatment response for those patients that did not initially show pathological response. Due to the complementary effects of MAPKi and CPI and the high pRR among patients given neoadjuvant DT it has been reasoned that neoadjuvant triple combination therapies might enhance treatment responses in these patients. However, preliminary results have yet only been reported for the NeoTrio trial NCT02858921), a randomized trial that compared the neoadjuvant single-agent pembrolizumab with the sequential application of pembrolizumab with DT or the concurrent application of DT plus pembrolizumab in patients with resectable BRAF-mutant stage III melanoma. In particular it has been reported that pRR and pCR were highest in the triple combination arm as compared to the sequential arm or the single-agent arm . However858921, aAs higher toxicity levels\u00a0of triple therapies may limit their applicability it has been reasoned that a sequential treatment of CPI and MAPKi may reduce overall toxicity but exert similar efficacy rates. However, initial investigations testing sequential regimens with vemurafenib followed by IPI, provided disappointing results in terms of efficacy with ORR of only 32.6%, although tolerability was substantially improved . In addiV600 mutant metastatic melanoma, recent evidence rather showed that the up-front use of CPI before MAPKi results in better survival outcomes [Optimal treatment sequencing strategies have first been evaluated in retrospective studies demonstrating that responses to second line therapy were typically worse than responses to first-line treatment, regardless of treatment modality , 114. Whoutcomes \u2013123.V600-metastatic melanoma patients [V600-mutated melanoma responsiveness to MAPKi [These favorable outcomes for the upfront use of CPI have also been confirmed by two pivotal randomized-controlled phase II/III trials  confirmed superior 2-year OS rates (73% vs. 65%) for the sequential regimen with upfront IPI plus Nivo as compared to upfront encorafenib plus binimetinib in a cohort of 209 patients with advanced BRAFmelanoma . Howevermelanoma .V600-mutant melanoma patients. In accordance with previous results reported in the SECOMBIT trial, preliminary data indicate that an early switch from vemurafenib and cobimetinib to atezolizumab is feasible and safe, although tumor-control achieved during run-in was maintained only in a subset of patients on subsequent CPI monotherapy [As compared to the aforementioned trials evaluating optimal treatment sequencing upon disease progression, trials using the technique of planned switch from MAPKi to CPI rather evaluated overall treatment efficacy regardless of disease progression. Here, a single-arm phase II trial comprising 46 patients with advanced melanoma reported that an initial 6\u00a0week lead-in phase of vemurafenib before starting IPI 10\u00a0mg/kg was associated with a lower rate of severe liver enzyme elevations, but yet promising response rates and median OS of 18.5\u00a0months . In addiotherapy   and an increase in immunosuppressive myeloid cells that could be overcome by direct modulation of the TME via DC maturation and expansion as well as inhibition of the MAPK pathway [The relevance of the immunosuppressive myeloid cell compartment for melanoma cross-resistance was further explored by Steinberg and coworkers who reported that BRAFi resistance was associated with an increasing influx of MDSC into TME that relied on MAPK pathway reactivation and downstream production of myeloid-cell derived CCL2 that could be reversed by the addition of an MDSC blocking C\u2013C chemokine receptor type 2 antagonist . These d pathway .Last, Peng and coworkers showed that the loss of the tumor-suppressor PTEN and subsequent activation of the phosphoinositide 3-kinase (PI3K)/protein kinase B pathway promoted immune resistance in melanoma patients via reduction of T cell infiltration of the tumor and an increase of immunosuppressive cytokines such as VEGF that attract tolerogenic DC, MDSC and Treg . ImportaV600-mutant melanoma patients. Nonetheless, subgroup analyses and preliminary results from trials evaluating triple combination regimens in patients with MBM suggested that patients with higher disease burden and rapidly progressing disease might derive a greater benefit from these treatment regimens. Emerging biomarker analyses might help to better identify this patient population, i.e., it has been reported that particularly patients with a high CD4/CD8 T cell ratio at baseline and a higher circulating tumor (ct)DNA shedding derived a significant benefit from triple combination therapy with spartalizumab, dabrafenib plus trametinib as compared to the DT comparator group [V600-mutant melanoma. However, prospective clinical trials evaluating triple combination regimens compared to combined checkpoint blockade with IPI plus Nivo as an active comparator are required to adequately address this issue and might particularly delineate their efficacy in specific cohorts of patients including those with more aggressive disease, MBM or those\u00a0that are refractory towards CPI. Also, these trials might yield more comprehensive data on the efficacy of a short-term run-in of BRAFi/MEKi on the premise of inducing rapid responses before adding CPI in patients with rapidly progressive disease. Regardless of the recent advances in the field of MAPKi/CPI combination therapies an urgent need remains to establish additional treatment options as secondary acquired resistance towards these agents will affect approximately 50% of patients in the long-term and thus poses a vital issue for both treatment options as responses to second-line treatments remain low [The introduction of CPI and MAPK-targeted therapeutics has considerably improved the treatment options for melanoma patients , 140. Thor group . Meanwhior group , 124. Whmain low ."}
+{"text": "Vaginal mesh exposures and infections are recognized complications of open and laparoscopic sacrocolpopexy performed for vault prolapse. In severe cases, complete sacrocolpopexy mesh removal may be necessary. This case report presents a 72-year-old woman with previous mesh sacrocolpopexy who presented with infected mesh and recurrent vaginal bleeding despite multiple attempts at surgical transvaginal mesh excision. A life-threatening massive hemorrhage occurred intra-operatively. After several failed attempts to control bleeding, hemorrhage Occluder\u2122 Pins were successfully placed by vascular surgery to control presacral veins. Although an exceedingly rare complication, anticipation and rapid management of life-threatening bleeding are critical to save life during complicated mesh removals. \u2022Mesh infections are rare but serious complications of abdominal sacrocolpopexy.\u2022Complete removal of infected mesh may be necessary and carries high risks of complications.\u2022Sudden bleeding during infected mesh removal may require a multi-disciplinary approach for treatment.\u2022Hemorrhage Occluder\u2122 Pin placement may be necessary to control presacral bleeding. Re-oper studies ,4. For t studies . A new t studies . DependiThis case report presents a completely infected SCP mesh requiring open removal. A sudden and cataclysmic bleed occurred from large presacral veins during surgery, prompting an emergency massive transfusion protocol and a vascular surgery consultation. Hemorrhage Occluder\u2122 Pins were placed to control this bleeding and save the patient's life.2A 72-year-old woman, gravida 4 para 3, presented to the emergency department with increased vaginal bleeding and worsening abdominal and back pain. The patient had a history of gastroesophageal reflux (GERD), chronic back pain, and recurrent urinary tract infections (UTI) as well as a past surgical history relevant for a cholecystectomy, total abdominal hysterectomy (TAH), bilateral salpingo-oophorectomy (BSO) for endometriosis in her late thirties, and a mesh sacrocolpopexy (SCP) with midurethral sling placement (MUS) at the age of 56. She underwent subsequent transvaginal mesh excision surgeries for recurrent vaginal bleeding at ages 57 and 59.). The original procedure was resumed once hemostasis was achieved and the patient was stabilized. The infected mesh was completely removed down to the vaginal cuff exposure. The removed specimen showed an abscess pocket with a thick capsule and copious amounts of purulent material  may havDuring pelvic trauma or colo-rectal surgery (proctectomy), bleeding can arise from important veins coursing on the surface of the sacrum or from the foramina of sacral basivertebral veins. A multidisciplinary approach requiring seven surgeons was necessary to stop presacral bleeding in the case of one colo-rectal surgery . This tyA review of the literature indicates rare prior reports especially in the past decade due to the rapid acceptance of robotic surgery for SCP during which venous bleeding can be easier to control. However, robotic technology is not yet available everywhere and certain re-operations are not amenable to a robotic approach.Z-suture along with a warm sponge compression were enough to stop the bleeding. The patient did not require a blood transfusion. The last abdominal sacrocolpopexy case report to date with intra-operative hemorrhage that required the use of pins was in 1991 by Timmons et al. [In prior literature, Nygaard et al. reported a 4.4% rate of hemorrhage, blood transfusion, or both during abdominal sacrocolpopexy, while Rondini et al. found a 3.7% rate of overall intra-operative complications but did not differentiate between types of complications ,12. In as et al.  Several s et al. ,16.4The teaching point of this case report is to alert pelvic reconstructive surgeons to the availability of these Hemorrhage Occluder\u2122 Pins designed to handle massive bleeding from sacral venous plexuses and to reinforce the importance of a multi-modality approach to achieve hemostasis and save life."}
+{"text": "A 66-year-old woman presented with a right femoral false aneurysm following an aortobifemoral bypass for lifestyle-limiting claudication. A computed tomography (CT) angiogram revealed features of complete aortobifemoral graft infection. A two-stage procedure was performed. The first hybrid stage involved the excision of only the femoral components and covered stenting of the aortic stump, along with recanalization of bilateral native iliac systems. The second stage, six weeks later, involved aortic stent and graft explant via midline laparotomy with aortic bovine pericardium patch repair . Follow-up imaging demonstrated no residual infection, and the patient remained without complication at the 12-month follow-up. This\u00a0novel approach utilizes hybrid surgical techniques and modern bioprosthetic material to safely manage an infected\u00a0aortobifemoral bypass graft. Prosthetic material infection following aortoiliac or aortofemoral reconstruction is one of the most challenging complications in vascular surgery . Extra-aWe present a previously undescribed technique that utilizes modern bioprosthetic material and hybrid surgical techniques to provide low morbidity lower limb revascularisation and removal of infected prostheses.\u00a0A 66-year-old woman presented with fevers and a painful\u00a0indurated right femoral mass following elective aortobifemoral bypass grafting for lifestyle-limiting claudication performed 18 months prior. At the time of presentation, she was free from claudication.\u00a0A computed tomography (CT) angiogram demonstrated a large right femoral false aneurysm as well as fluid collection along the entire length of the graft  to prevent potential aortic stump \"blow out\" at a later stage. Two large bore corrugated drains were placed in each groin and removed one week post-operatively following no further drain output.\u00a0Repeat CT angiography performed one week post-operatively demonstrated no infective recollection surrounding both common femoral arteries and no aortic false aneurysm. A moderate aortic collection was still present; however, its appearance was unchanged from the initial pre-operative CT. The patient was discharged on postoperative day six.Six weeks following the initial procedure, the patient underwent removal of the final infected aortic graft. This was performed via a midline laparotomy. A moderate amount of suppuration was identified surrounding the remaining aortic graft component. The graft was excised in its entirety, and following an explant of the aortic V12 stent, the aortic anastomotic defect was closed with a Xenosure\u00ae bovine pericardium patch . Completion of digital subtraction angiography (DSA) demonstrated a patent aortoiliac system with no complications (Figure The management of an infected aortobifemoral prosthetic graft is one of the most challenging problems facing vascular surgeons. Traditional management of infected aortobifemoral grafts requires graft explant and extra-anatomic bypass, typically by axillobifemoral bypass grafting . High moThe method described in this case report\u00a0represents a novel use of hybrid techniques to maintain lower limb perfusion while negating the need for an extra-anatomic bypass. In the case of our immunosuppressed patient, avoiding axillobifemoral bypasses was ideal for minimizing the use of further prosthetic material, while our staged approach also allowed\u00a0time for drainage and resolution of\u00a0infection\u00a0prior to the insertion of the bovine pericardium patch. It should be noted that native racanalization may not be technically possible in all scenarios, which limits the generalizability of our approach.The use of a bovine pericardium patch to repair aortic anastomosis has also not been previously described.\u00a0Although the patient has demonstrated no recurrent infection at 12 months, the success of this case report is limited as it is unclear if the bovine pericardium patch will remain infection-free in the longer term.Infected aortofemoral grafts are one of the most feared complications facing vascular surgeons today. The advent of hybrid vascular surgery has presented new solutions to this challenging problem. Our case describes a novel approach of staged infected graft explant followed by interval in-situ endovascular reconstruction, which may be a safer alternative to traditional extra-anatomical bypass grafting. Our technique should be considered in immunosuppressed patients, where the use of further prosthetic material should be avoided. The XenoSure\u00ae bovine pericardium patch is also emerging as a\u00a0biological alternative to prosthetic grafts for arterial reconstruction in infected fields. Further randomized control trials comparing bovine pericardium to an autologous vein or other prosthetic material are needed to prove their role in vascular infection."}
+{"text": "The impact of providing cognitive pharmacy services following hospital discharge has been studied with various results. This study is specifically focused on comprehensive medication management services delivered postdischarge in an interprofessional team environment to patients aged greater than\u200965 years.To determine if delivery of comprehensive medication management services postdischarge will prevent hospital readmissions or emergency department visits within 6 months following discharge in patients aged greater than\u200965 years. Secondary endpoints included 30-day and 60-day postdischarge events.This was a prospective group matched-controlled study of patients aged greater than\u200965 years with selected diagnoses identified as high risk for readmission. The intervention group received comprehensive medication management that was provided face-to-face in the patient\u2019s primary care clinic within 2 weeks of discharge.No statistically significant difference was found between intervention and control groups in hospital readmissions or emergency department visits at 30 days, 60 days, or 6 months after discharge. No statistically significant difference was seen in mortality between groups.Provision of comprehensive medication management services did not reduce emergency department visits or readmissions in this study. This study was limited by multiple other changes occurring in the health system during the time of this study that potentially confounded results. In addition, the study may have been too small to detect a difference."}
+{"text": "Tardigrades are known for their remarkable ability to withstand extreme stresses . HoweverRamazzottius varieornatus using a previously established specific antibody (TardiVec are vectors designed to express exogenous proteins, such as GFP, under the control of the ~1-kbp upstream sequence of the target genes. As demonstrated, this 1-kbp segment drives distinct tissue-selective expressions depending on the target genes . Corresp4antibody  in Fig. antibody B\u2013E. Thisantibody . The TarUsing TardiVec provides another notable advantage to enable live imaging the in vivo distribution changes of target proteins in desiccating tardigrades. An earlier study has shown that RvCAHS3 form numerous filaments in both human and insect cells under water-deficient stress . Using TIn conclusion, the expression system using TardiVec provides valuable opportunities for tardigrade research. It is also recommended to consider the limitations in recapitulating the endogenous expression pattern and the difficulty in observing fine structures in desiccated tardigrades. Confirmation using alternative methods will solidify the findings about these aspects."}
+{"text": "Ocular lymphatic vessels play major physiological role in eye homeostasis and their dysfunction can contribute to the progression of several eye diseases. In this study, we characterized their spatiotemporal development and the cellular mechanisms occurring during their ontogenesis in the mouse eye.Whole mount immunofluorescent staining and imaging by standard or lightsheet fluorescence microscopy were performed on late embryonic and early postnatal eye mouse samples.We observed that the ocular surface lymphatic vascular network develops at the early postnatal stages (between P0 and P5) from two nascent trunks arising at the nasal side on both sides of the nictitating membrane. These nascent vessels further branch and encircle the whole eye surface by sprouting lymphangiogenesis. In addition, we got evidence for the existence of a transient lymphvasculogenesis process generating lymphatic vessel fragments that will mostly formed the corneolimbal lymphatic vasculature which further connect to the conjunctival lymphatic network. Our results also support that CD206-positive macrophages can transdifferentiate and then integrate into the lymphatic neovessels.Several complementary cellular processes participate in the development of the lymphatic ocular surface vasculature. This knowledge paves the way for the design of new therapeutic strategies to interfere with ocular lymphatic vessel formation when needed. The formation of a lymphatic trunk that further branches and encircles the entire ocular corneolimbal and conjunctival surface was described.C57BL6/J wild type mice were used, in accordance with the statements of the ARVO  for the animal use guidelines in ophthalmology and vision research. The project was ethically approved by the French Ministry for Research and Education (agreement no. APAFIS 13689-2018022110161501 v2). Whole eyeballs from late embryos (E18.5), early postnatal neonates (P0 to P5), 11- and 30-day-old mice were collected by careful dissection, taking care to preserve the conjunctival and ocular surface tissues.Indirect immunofluorescence experiments were performed essentially as previously described.Light sheet fluorescence microscopy (LSFM) imaging was performed using a light Sheet ZEISS Z1 microscope  and ZEN Black software. The whole eyeballs were placed in the sample chamber either after embedding into 1% agarose or after fixation with superglue to a home-made sample holder. The LSFM images shown are two-dimensional reconstructions (maximum intensity projections) of series of acquired Z-stack images.The imaging of whole mount immunostainings of the anterior eye were performed after cutting into four quadrants and flat mounting of the eye anterior segment with Fluorsave reagent .\u2013,,The spatiotemporal ocular surface lymphatic vessel formation was observed by LSFM imaging of the lymphatic vessel endothelial hyaluronan receptor 1 (LYVE-1) immunofluorescent staining. LYVE-1 represent a powerful antigenic marker to visualize the ocular surface lymphatic vasculature.,The quantitative analysis confirms that the development of the LYVE-1-positive ocular surface lymphatic vessel network is achieved at early postnatal steps (from E18.5/P0 to P4/P5), and the delayed formation of the ventral network compared to the dorsal one . AlthougLymphangiogenesis, which corresponds to the sprouting and the formation of new vessels from preexisting ones, appears to constitute an important cellular mechanism involved in the expansion of the nascent LYVE-1\u2013positive trunks that emerge adjacent to the nictitating membrane from P0 A. IndeedAlthough sprouting lymphangiogenesis appears to be a major process for corneolimbal and conjunctival lymphatic network expansion, a lymphvasculogenesis process could also be involved. One can observed the independent formation of LYVE-1\u2013positive isolated cell clusters that develop cord-like structures. These cell clusters, which are also Prox-1 positive, which establishes their lymphatic identity, are mainly seen at the surface of the cornea above the corneolimbus. Such LYVE-1\u2013positive and Prox-1-positive lymphatic cell clusters are illustrated in ,,Several macrophage subtypes expressed LYVE-1 at different expression levels.The presence, at early developmental stages, of many single LYVE-1 and CD206-positive cells in close proximity with the sprouting lymphatic neovessels A,\u00a08B, isTo know whether these macrophages can transdifferentiate into ocular lymphatic endothelial cells, we looked at the potential existence of cells expressing a mixed macrophage-lymphatic phenotype at P0/P1, during the early steps of lymphatic vessel formation. Some cells constituting the sprout were found to highly express LYVE-1 and concomitantly some remaining CD206 expression, whereas scattered macrophage at the vicinity display high CD206 and low LYVE-1 expressions A\u20139C. DouIn this study, we characterize the spatiotemporal and cellular mechanisms of development of the ocular surface lymphatic vascular system in the mouse. We confirmed that the timing of the ocular surface lymphatic vessel organogenesis occurs mostly during early postnatal steps, between P0 and P5, as previously described.,Actually, we provide novel insights in the characterization of the cellular mechanisms involved in the generation of the ocular surface lymphatic network. In addition to sprouting lymphangiogenesis, our results bring the evidence for the involvement of lymphvasculogenesis. This process appears to be mainly responsible for the formation of the corneolimbal lymphatic vascular plexus. Several lymphatic vessel segments arise at the surface of the cornea. They will migrate and connect with the conjunctival developing network and further encircle the ocular globe at the basis of the cornea. These two different morphogenetic cellular mechanisms are in accordance with the cellular mechanisms known to be involved in lymphatic vessel development in other mouse organs.,\u2013,,,,We analyzed whether a third cellular mechanism for ocular lymphatic vessel formation could involve cells of the myeloid/macrophage lineage. Indeed, macrophages are key modulators of both angiogenesis and lymphangiogenesis processes either during tissue repair and remodeling or in pathological situations, including eye diseases. This is mainly achieved by the secretion of angioactive or lymphangioactive growth factors such as VEGF-A and FGF2Our results also provide some evidence that during early developmental processes, resident M2-like macrophage could contribute to the formation of new lymphatic vessel of the ocular surface by direct incorporation into the lymphatic neovessel. The question to know whether it corresponds to true macrophage transdifferentiation and/or to lymphatic endothelial mimicry awaits further investigation. Nevertheless, a lymphatic reprograming of macrophages does not appear before their physical integration into a lymphatic sprout. Indeed, in contrast to what was described by Maruyama et al.,In conclusion, the ontogenesis of the ocular surface lymphatic vessel network formation appears to be more complex than previously reported. Our results indicate that the ocular surface lymphatic network develops by several different but complementary morphogenetic processes: sprouting from a lymphatic trunk originating behind the nictitating membrane but also differentiation of isolated lymphatic progenitors to develop lymphatic-committed cell clusters. Our results also support that macrophages can contribute by their direct integration in the expanding lymphatic vessels. Our results strongly suggest that M2-polarized tissue-resident LYVE-1\u2013positive macrophages could transdifferentiate into lymphatic endothelial cells to constitute new lymphatic vessels. This is in accordance with the existence of myeloid-lymphatic progenitors which have been postulated to express M2-macrophage specific markers."}
+{"text": "The HIV Organ Policy Equity (HOPE) Act allows persons living with human immunodeficiency virus (HIV) infection to accept HIV-positive donor organs. Risk of superinfection or viral recombination resulting from the transmission of a genetically distinct donor HIV-1 strain may be a concern. It is unknown if transplantation from acutely infected donors pose additional risk. Analysis of viral quasispecies from donor and recipient samples provides an opportunity to evaluate the transplanted kidney as a viral reservoir and explore the potential for viral superinfection or recombination in the recipient.(Table 1). Single genome amplification of the HIV-1 env gene was performed with viral RNA extracted from recipient urine and plasma and viral DNA from donor kidney cells, recipient PBMC and renal cells. We constructed phylogenetic trees assessed recombination probabilities.A 63-year-old HIV-positive recipient with focal segmental glomerulosclerosis and suppressed viral load (< 20 copies/mL) on antiretroviral therapy (ART) with dolutegravir and lamivudine, received a kidney from an acutely infected deceased HIV-positive donor env sequence was amplified from the recipient\u2019s urine 30 hours post-transplant suggesting transfer of donor virus to recipient. Donor virus became undetectable on subsequent visits while recipient was maintained on ART. Notably, a third virus was detected 1.5 months post-transplant in urine-derived renal tubular epithelial cells and 5 months post-transplant in urine which was genetically distinct from previously detected donor and recipient strains . This third strain did not have genetic features suggestive of recombination. Our findings suggest potential superinfection in the donor or recipient.A new, genetically distinct We documented presence of three unrelated HIV strains within a transplanted recipient and within different viral reservoirs. Donor and recipient recombination did not occur. In acutely infected donors, when the transfer of virus within the kidney occurs, ongoing virologic suppression can be achieved if appropriate ART is maintained. Additional long-term monitoring of viral populations in the recipient is important to fully assess any clinical and virologic implications of this finding.All Authors: No reported disclosures"}
+{"text": "Investigate the effect on visitors' greenspace engagement by retro-fitting wayfinding, to create a looped walking route, within an urban park.rd March \u2013 3rd May 2021) to determine public perceptions of wayfinding's role for recreational physical activity within the urban park and explore what information should be included on wayfinding.\u20031. An online-survey was distributed (23th March \u2013 26th August 2021) and follow-up (29th August 2021 \u2013 29th August 2022). A QR code accessed intercept survey was provided on the wayfinding to understand route-user visitation habits.\u20032. Automated and manual counts were monitored on footpaths where the new wayfinding was installed at baseline  valued the detachment from the urban environment that the park provided, which gave positive experiences to wellbeing, mental health, and social connections. Wayfinding was valued by irregular park users to help them confidently explore the park.Phase 3: Interviewees (Retro-fitting wayfinding in an urban park helps irregular users engage in the greenspace and wayfinding design needs to integrate with the natural environment to keep contrast with urban environments. The project illustrated the value of qualitative methods within natural experimental studies to capture intervention impacts.University of Northampton"}
+{"text": "Centers for Disease Control and Prevention (CDC) guidance recommends coordinated multifacility interventions to contain selected MDRO, such as carbapenem-resistant Enterobacterales (CRE). A mathematical model using data from a northeastern state estimated these interventions would lead to 76% relative reduction in CRE prevalence in a hospital network connected through patient transfers, but whether results would be similar using data from another state is unclear.We used Tennessee (TN) surveillance and hospital discharge data to estimate CRE transmissibility and patient transfers in a deterministic compartmental model to simulate regional spread of CRE. Simulations were initialized with the first clinical detection of CRE in the hospital with the most outgoing transfers. Interventions were initiated in facilities that detected CRE and those sending or receiving the largest numbers of patients to/from these facilities, including: 1) biweekly point prevalence surveys; and 2) enhanced infection control implemented immediately on CRE detection. We assumed interventions reduced intrafacility transmission by 20%. Surveys stopped after 2 consecutive negative rounds in a facility . We ran simulations using 2 patient transfer networks: 1) all hospitalized patients; and 2) CRE surrogates  .https://www.dartmouthatlas.org) connected by direct and indirect patient transfers with up to 365 days of intervening community stays. Patient transfer data were sourced from the 2018-2019 TN Hospital Discharge Database. Patients who were not admitted to another facility after being discharged in 2018 were attributed to transfers into the HRR corresponding to the hospital\u2019s address. Each circle represents a short-term acute care hospital (STACH), each square represents a long-term acute care hospital (LTACH), and each triangle represents an HRR. The arrow represents the direction of transfers between hospitals. Node sizes correspond to the number of registered beds, and color represents the Emergency Medical Services (EMS) regions where the facility is located.In the multi-facility SIS model, we assume hospitals are at constant occupancy. Each bed was occupied by either an infectious (I) or susceptible patient (S). (b) Interventions outlined in the simulations followed the recommendations of the Interim Guidance for a Public Health Response to Contain Novel or Targeted Multidrug-resistant Organisms (MDROs). Initial detection at the facility with the highest number of outgoing transfers followed by immediate containment efforts and reduced transmissibility in intervened hospitals by 20% by day 30. Simulations were run 35 times. Each run randomly selected a transmissibility value derived from the distribution in our estimates derived from CRE surveillance data in TN.CRE case counts 3 years after importation and interventions were 21% lower (interquartile range [IQR]: 20\u201323%) than without interventions using the transfer network of all hospitalized patients; interventions were required in 52 (36%) of 144 hospitals. Simulations in the CRE surrogate network resulted in a 26% (IQR: 20\u201338%) CRE case reduction and interventions in 32 (24%) hospitals.The estimated CRE prevalence reduction achieved through simulating CDC guidance-recommended interventions in TN was lower than estimates using data from a different state, likely due to state-specific differences in patient transfer network structure and transmission parameters. Containment guided by transfer patterns of patients clinically similar to CRE-infected patients rather than all hospitalized patients requires interventions in fewer hospitals to achieve a comparable impact.Peter F. Rebeiro, PhD, MS, Gilead: Advisor/Consultant|Janssen Pharmaceuticals: Advisor/Consultant|National Institutes of Health: Grant/Research Support"}
+{"text": "Bipolar Disorder (BD) has been suggested to be a risk factor for development of Parkinson Disease. Psychiatric drugs used as standard treatment of BD includes many drugs that are known to induce drug-induced parkinsonism (DIP).Clinical differentiation between PD and DIP is a clinical and scientific crucial result. It might be aided by functional neuroimaging of the dopaminergic nigrostriatal pathway.123I-ioflupane dopamine transporter SPECT. Imaging data of BD patients with pathological nigrostriatal pathway were further compared to a population of de-novo PD patients.Twenty consecutive BD patients with parkinsonism were clinically assessed and underwent Four BD patients had abnormal scans; they had higher putaminal binding ratio and putamen-to-caudate ratios than PD patients, despite similar motor symptom burden.in our initial results, up to 20% of BD patients with parkinsonism might have an underlying dopaminergic deficit, which is higher than excepted in the general population. This evidences supports that BD represents a risk factor for subsequent development of neurodegenerative parkinsonism.None Declared"}
+{"text": "Over-the-scope clip to the rescue: solution for duodenal perforation from migrated biliary stent. Iatrogenic perforation of the duodenum caused by biliary stents is a rare adverse event of ERCP.A 66-year-old man was referred to our institution to resume management of choledocholithiasis and indeterminate biliary stricture. Eighteen months prior, he had jaundice secondary to bile duct stones and mid-distal common bile duct stricture for which he underwent ERCP and plastic stent placement. The COVID-19 pandemic led to delay in the necessary follow-up.www.giejournal.org). The fluoroscopic image confirmed the perforation and approximately 1 cm of the stent extended outside the duodenal lumen. The defect measured 4\u00a0mm in diameter  (diameter ; Video 1diameter ; Video 1diameter ; Video 1diameter ; Video 1diameter ; Video 1A postprocedural CT scan showed no evidence of drainable fluid collection or extraluminal gas ; Video 1A 71-year-old woman presented to an outside hospital with painless jaundice requiring ERCP and bilateral plastic biliary stent placement. Five days later, she was referred to our hospital for duodenal perforation from a migrated biliary stent with retroperitoneal fluid collection seen on a CT scan. She underwent a similar approach with removal of the stent via rat-tooth forceps and primary endoscopic closure of the duodenal defect with tissue ablation with argon plasma coagulation and OTSC closure ; Video 1A 71-year-old woman with metastatic pancreatic adenocarcinoma presented with septic shock and encephalopathy, and she was found to have a migrated biliary stent with duodenal perforation. Her course was complicated by multiple intra-abdominal abscesses, extensive pneumoperitoneum ; Video 1She underwent an ERCP that showed a migrated biliary stent causing opposing duodenal wall perforation. The defect site was ablated and an OTSC mended the perforation. Antibiotics were continued and she underwent percutaneous drain placement with radiology. There were no immediate adverse events and she had improvement in pain and mentation.Duodenal perforations from migrating plastic biliary stents are rare; however, they can be significantly morbid when they occur. While the presentations and time intervals between original stent placement to identification of\u00a0duodenal perforation differed among the 3 cases ; Video 1Dr Phan is a consultant for Boston Scientific, Olympus, and Noah Medical. All other authors disclosed no financial relationships."}
+{"text": "Congenital cytomegalovirus infection (cCMV) is the leading cause of non-hereditary sensorineural hearing loss and can cause other long-term neurodevelopmental disabilities. To consider antiviral treatment, it is important to differentiate between symptomatic and asymptomatic patients by early infancy. However, it is difficult to identify neurological complications in some cases. This study aimed to identify candidate plasma biomarkers for neurological complications of cCMV during the neonatal period using proteome analysis.This study retrospectively enrolled five patients with asymptomatic cCMV and nine patients with symptomatic cCMV, including those with hearing loss and/or abnormal brain imaging. Plasma samples were obtained during the neonatal period. After extraction of 14 high-abundant proteins from the plasma, proteins were digested by trypsin. The peptides were analyzed by liquid chromatography\u2013mass spectrometry using an Orbitrap Fusion mass spectrometer. Protein quantification was performed using Proteome Discoverer. Levels of differently expressed proteins were validated by enzyme-linked immunosorbent assay.In total, 456 proteins were identified and quantified. Levels of 65 proteins were significantly higher in patients with symptomatic cCMV than in those with asymptomatic cCMV. The top two enriched categories for these proteins according to pathway enrichment analysis were \u201ccomplement and coagulation cascade\u201d and \u201cinflammatory response.\u201d In contrast, levels of 30 proteins were significantly higher in patients with abnormal brain imaging. Plasma levels of fms-related receptor tyrosine kinase 4 (FLT4) were significantly higher in patients with symptomatic cCMV than in those with asymptomatic cCMV. Moreover, levels of plasma peptidylprolyl isomerase A (PPIA) were significantly higher in patients with abnormal brain imaging than in those without.Proteome analysis showed that the proteins related to inflammatory response pathways were upregulated in patients with symptomatic cCMV. FLT4 and PPIA can be used as novel diagnostic biomarkers for neurological complications of cCMV to enable early therapeutic intervention with antiviral agents.All Authors: No reported disclosures"}
+{"text": "A 39-year-old woman presented with localized urticaria following N95 respirator use in a COVID-19 unit. After approximately 15 minutes of wear, she developed pruritus on her face, without associated angioedema or dyspnea. She had no history of cutaneous reactions to N95 respirators. Physical examination revealed several wheals with surrounding erythema limited to the area occluded by the N95 respirator . On eval1 Symptoms typically self-resolve within an hour. Antihistamines can be used in symptomatic dermatographism. The pathogenesis is likely related to vasoactive mediators released by mast cells as elevated serum levels of histamine have been associated.2 Differential diagnoses including pressure urticaria and contact dermatitis can be ruled out based on inciting factor, timing of onset and resolution with antihistamines.Dermatographism is characterised by the development of a wheal and flare reaction after pressure is applied to the skin by stroking or scratching, typically within minutes and persisting up to an hour.3 The recent pandemic has led to increased and extended respirator use. While evidence supports these respirators as offering substantial protection against COVID-19, this case highlights that occupational health departments should be alert for adverse cutaneous reactions that may affect HCWs.4N95 respirators are recommended for healthcare workers (HCWs) who provide care for patients with suspected or confirmed COVID-19 infection."}
+{"text": "The detection of driver gene mutations has become essential for lung cancer; however, insufficient sample sizes make gene panel tests difficult to use. We previously reported that the lung cancer compact panel TM (LCCP) could detect EGFR and MET gene mutations with sputum cytology. To date, the detection of gene mutation using RNA from sputum samples is considered practically difficult. We report a case in which the EML4-ALK fusion gene was successfully detected from a sputum sample using the LCCP that was just released in Japan as a new next-generation sequencing lung cancer panel, CDx."}
+{"text": "An 18-year-old male reported chief complaints of inability to close his right eye. He is a known case of oro-facial plexiform neurofibromatosis for the past 12 years. The patient had undergone a debulking surgery in the right eyelid 2 days back. The patient's left eye had been enucleated 10 years ago. On ocular examination, the right upper eyelid showed upper eyelid mass with 6 sutures post debulking on the upper eyelid with scleral show. The left eye had been enucleated and tarsorrhaphy sutures were present. The patient was managed with topical lubricating eye drops and gel as well as lid patching."}
+{"text": "Mitral interventions remain technically challenging owing to the anatomical complexity and heterogeneity of mitral pathologies. As such, multi-disciplinary pre-procedural planning assisted by advanced cardiac imaging is pivotal to successful outcomes. Modern imaging techniques offer accurate 3D renderings of cardiac anatomy; however, users are required to derive a spatial understanding of complex mitral pathologies from a 2D projection thus generating an \u2018imaging gap\u2019 which limits procedural planning. Physical mitral modelling using 3D printing has the potential to bridge this gap and is increasingly being employed in conjunction with other transformative technologies to assess feasibility of intervention, direct prosthesis choice and avoid complications. Such platforms have also shown value in training and patient education. Despite important limitations, the pace of innovation and synergistic integration with other technologies is likely to ensure that 3D printing assumes a central role in the journey towards delivering personalised care for patients undergoing mitral valve interventions. Heart Team based pre-procedural planning using advanced cardiac imaging is crucial to successful mitral interventions.Cardiac imaging requires users to spatially appreciate structures on 2D projections generating an \u2018imaging gap\u2019. 3D printing can surmount the imaging gap to enhance procedural planning and offer personalised care.Integration of 3D printing technologies with other transformative technologies and large-scale clinical trial data may facilitate widespread clinical translation. Mitral regurgitation (MR) is the commonest heart valve lesion in the developed world and is associated with considerable morbidity and mortality , 2. SurgTranscatheter mitral valve interventions have shown promise as alternative interventions to mitigate the burden of MR in those deemed unsuitable for conventional surgery. Indeed, transcatheter mitral valve repair (TMVr) is now an established treatment strategy with over 100,000 procedures performed globally. Meanwhile, transcatheter mitral valve replacement (TMVR) may offer a viable alternative for those unsuitable for TMVr and in patients with failed surgical bioprostheses, severe mitral annular calcification (MAC) and unsuccessful surgical mitral repair .Despite significant innovation and evolution, surgical and transcatheter mitral valve interventions face considerable technical challenges arising from the anatomical complexities of the mitral valve apparatus and its dynamic interaction with adjacent structures, as well as the heterogeneity within mitral pathologies. Indeed, the saddle shaped mitral annulus has variable dimensions dependent on haemodynamic status and left ventricular (LV) cavity dimensions rendering device sizing challenging. The complex sub-valvular apparatus may hinder device manoeuvrability and risks entrapment. The intimate anatomical relationship between the left ventricular outflow tract (LVOT) and the mitral valve introduces the catastrophic risk of LVOT obstruction in TMVR \u20139. MeanwHeart Team-based pre-procedural planning using advanced multi-modality imaging is crucial for achieving optimal procedural outcomes, especially in transcatheter mitral interventions due to their inherent complexities and challenges. Although advances in cardiac imaging (notably in multi-detector cardiac CT (MDCT) and three-dimensional (3D) transoesophageal echocardiography (TOE)) now enable rendering of highly accurate 3D images of cardiac structures, there are important limitations arising from the lack of dynamic feedback and tactile interaction. Users are also required to spatially appreciate complex 3D anatomical structures on a two-dimensional screen. As such, there is a growing recognition of an \u2018imaging gap\u2019 within structural heart interventions which hamstrings effective procedural planning , 13.The advent and rapid evolution of \u2018transformative technologies\u2019 in medicine- namely 3D printing, computer-aided modelling (CAD), computational modelling, artificial intelligence (AI) and extended realities- have the potential to bridge the imaging void gap in structural heart interventions. They may herald a paradigm shift in procedural planning by facilitating patient-specific modelling of mitral pathologies and guiding interventional strategy thus potentially improving procedural outcomes. The integration and clinical translation of such technologies may hold considerable value for future training, evaluation of novel mitral technologies and facilitate the delivery of personalised cardiac care , 14.This work provides an overview of 3D printing technologies and workflows followed by an appraisal of the current status and future clinical translation of this technology in modelling mitral interventions.Three-dimensional printing transforms digital objects into physical 3D replicas through multi-layered material deposition over a digitally defined geometry. Figure\u00a0A volumetric imaging dataset in DICOM  format is a prerequisite for segmentation. As such, relevant imaging modalities include ECG gated MDCT, 3D echocardiography and Cardiac MRI (CMR) .MDCT is now the modality of choice for modelling mitral interventions particularly in the transcatheter domain. Indeed, advances in MDCT technology have enabled sub-millimetre spatial resolution (0.3\u20130.625\u00a0mm) which can be obtained with rapid image acquisition speeds. Meanwhile, progress in reconstruction algorithms enable highly accurate virtual 3D renderings of cardiac structures. The use of iodinated contrast agents in MDCT still requires caution in those with chronic renal impairment and CT based modelling involves image acquisition throughout the cardiac cycle thereby conferring additional exposure to ionising radiation. MDCT acquisition can also be limited by arrhythmia and low cardiac output states . MDCT en3D echocardiography continues to remain an appealing imaging modality in heart valve modelling due to its widespread availability and cost effectiveness. Additionally, it avoids the use of contrast agents and ionising radiation, the latter of particular significance for younger patient groups \u201323. The The choice of imaging modality requires careful consideration when planning 3D printing as the accuracy and quality of printed replicas are a direct function of the virtues of the imaging modality employed. More recent work has demonstrated the potential of fusion imaging whereby imaging data from multiple modalities can be integrated and then 3D printed to model complex anatomical detail. These techniques seek to offset the limitations of individual imaging modalities and enhance the accuracy and quality of printed replicas .https://www.mitk.org/wiki/The_Medical_Imaging_Interaction_Toolkit) and ITK-snap (http://www.itksnap.org/pmwiki/pmwiki.php) as well as proprietary platforms such as Mimics , Intuition  and Amira  [Volumetric imaging data acquired in DICOM format requires processing such that the region of interest can be isolated in a process known as segmentation. There are a constellation of segmentation platforms available including open-source packages such as 3DSlicer, Medical Imaging Interaction Toolkit (MITK) (husetts) .Segmentation is often a laborious step with a steep learning curve and requires a high degree of imaging and software expertise. Manual segmentation using editing, cropping and extraction is often arduous, time consuming and has high interobserver variability particularly in the context of mitral valve disease which often features complex anatomy. Several automated segmentation tools have been developed for varying applications such as deriving quantitative valve measures and extracting annular and leaflet geometry for physical printing, or virtual modelling. Automated segmentation tools which often rely on region growing and simple intensity thresholding segmentation methods may struggle in characterising boundaries of cardiac structures of similar intensity profiles such as mitral valve leaflets. Semi-automated segmentation techniques therefore are the most frequently utilised where acquired volumetric images initially undergo automated segmentation followed by manual optimisation by the user , 28.Fully automated mitral valve segmentation however has seen advancements using atlas-based approaches and deep learning-based methods. Atlas-based approaches utilize a large database of manually labelled images, which are used to generate a deformable template which can then be guided to the leaflet geometry. Atlas-based methods relying on sparse geometry or landmarks are potentially limited in the amount of patient-specific detail that can be extracted and may be biased towards the atlas geometry , 30. DeeOptimisation of the post segmentation virtual model is often required using dedicated platforms which enables editing and smoothing. Computer Aided Design (CAD) tools may also be employed to process virtual geometries for example colour coding regions of interest. The virtual rendering is then converted into the file formats  which are recognised by 3D printers to enable printing a physical replica of the segmented structure. Alternatively, these file formats can be integrated into virtual platforms for computer-aided mitral modeling purposes. , 33.3D printing technologies are well established having been first introduced by Charles Hull in 1984 by the application of optical technology to rapid prototyping . Figure\u00a0Fusion Deposition modelling (FDM) is the most frequently used technology for cardiovascular 3D printing due to its low cost and ease of use. FDM extrudes molten thermoplastic filaments layer by layer to generate a 3D print. FDM requires the use of a supporting material to provide stability for complex structures during the printing process which can later be removed. FDM printing is limited by low accuracy and offers a poor finish for softer surfaces.Stereolithography (SLA) uses a liquid photosensitive resin which rapidly coalesces when exposed to laser irradiation or light. SLA printers can generate complex structures with high feature resolution (~\u20091.2\u00a0mm) however this printing modality is expensive and is restricted by the limited number of available photosensitive resins , 34.TM by Stratasys) or wax (3D systems) as removable support during the printing process. PJ printers offer high resolution with good quality surface finishes and importantly offer the ability to combine different polymers within a single print. PJ printers therefore show considerable promise in the high-resolution printing of complex cardiac structures with multiple tissue properties such as calcification. PJ printers are currently limited by high cost of hardware and printing consumables.Polyjet (PJ) printers are based on the same principle of photopolymer technology used in SLA printers. PJ printers utilize an extrusion process to push out a photopolymer, which is the primary material used for creating the physical model. This photopolymer subsequently solidifies when exposed to laser or light. Furthermore, PJ printers incorporate a photo-curable gel (PolyJetSelective Laser Sintering (SLS) utilizes a laser to selectively heat and fuse powder-based materials. The SLS process involves converting these materials into particles and subsequently fusing them together in successive layers to form the final 3D printed object. While the primary focus is on powder-based polymers, SLS printers can accommodate a diverse range of materials, including ceramics and metals. Although expensive and resulting in a rough finish, SLS printing allows the generation of highly robust 3D structures .A comprehensive understanding of materials technologies and the properties of native tissues is crucial in creating biomechanically realistic 3D printed models.The mitral valve leaflets comprise of three layers each containing a heterogenous matrix of constituents with different biomechanical properties to serve specific functional requirements. The atrialis layer is covered with endothelium below which lies connective tissue composed of elastin sheets and laminar collagen. The composition of the atrialis layer allows it to sustain the significant tensile deformation forces associated with systole whilst enabling a degree of recoil in diastole. The presence of smooth muscle in the atrialis layer with its attendant innervation enables some modulation of leaflet stiffness. The glycosaminoglycan rich spongiosa underlies the atrialis layer and contains irregularly arranged collagen. The spongiosa layer helps resist the compressive forces from mitral leaflet coaptation by retaining water. The Fibrosa layer contains densely packed collagen fibres aligned parallel to the leaflet free edge and flexibly crimped. At the site of chordal insertion, the fibrosa transitions from a planar to\u00a0a cylindrical arrangement which prevents leaflet kinking by enabling a gradual transition of forces from the chordae and leaflets. The chordae tendineae are complex structures featuring an elastin sheath housing a cylindrical collagenous chord \u201338.Table The development of flexible elastomeric materials such as HeartFlex and TangoPlus along with the advent of polyjet printers which enable manufacture of complex models by blending printing materials  may herald a paradigm shift in towards the direct manufacture of biomechanically realistic mitral replicas capable of being integrated into functional and static mitral modelling for prospective interventions. Wang et al. were one of the first to demonstrate the feasibility of using metamaterials to realistically simulate the stress\u2013strain properties of human valvular tissue. The authors used TangoPlus (simulating human extracellular matrix) embedded with\u00a0VeroBlackPlus (simulating stiff collagen fibres within extracellular matrix) either in sinusoidal or double helix geometries. They then compared the stress\u2013strain relationship of human aortic tissue to TangoPlus alone and the metamaterial incorporating a sinusoidal wave geometry to find the metamaterial to emulate human aortic tissue more closely. The authors also demonstrated that stress\u2013strain relationships of the metamaterials can be \u2018tuned\u2019 by changing the characteristics of the ingrained double helix or sinusoidal patterns In the mitral domain, Vukicevic et al. demonstrated the feasibility of patient-specific manufacture of the entire mitral valve apparatus using metamaterials and their ability to permit implantation of transcatheter devices. Significantly, they attempted to simulate the material properties of surrounding structures and the unique layered microanatomy of mitral leaflets by incorporating different shores (hardness) of TangoPlus. Calcification was modelled using very hard VeroWhite material. The authors compared stress\u2013strain relationships of healthy porcine mitral leaflets to that of two individual grades of TangoPlus and a combination of the two grades to find that TangoPlus was able to model the stress\u2013strain relationship of healthy porcine leaflet tissue within the zone of physiological function and at the transitional region where collagen fibres are recruited . More reAlthough polyjet printing and the development of metamaterials offer promise in realistically simulating mitral behaviour, such technologies are currently expensive and require specialist expertise greatly limiting their wider clinical translation. Moreover, such rigid mitral replicas are unable to reproducibly simulate complete mitral valve tissue properties and therefore essentially serve as morphological displays precluding functional replica evaluation. As such, \u2018soft\u2019 deformable silicone based mitral replicas derived from moulding techniques have been favoured for dynamic mitral modelling and simulation. Moulds are often 3D printed and have patient-specific properties however they lack the anatomical precision of directly 3D printed mitral replicas and therefore offer a heuristic approach to modelling , 41, 43.The translation of 3D printing technology in modelling mitral interventions can broadly be divided into the use of static mitral replicas and in vitro functional platforms.Static replicas seek only to replicate patient-specific anatomy and can be used as adjunctive aids in the comprehension of complex\u00a0mitral anatomy, procedure planning and patient education. In vitro functional platforms seek\u00a0to replicate patient-specific mitral anatomy and the haemodynamic milieu of mitral disease. Functional platforms can serve as research testbeds to study mitral pathophysiology and evaluate novel mitral technologies. They also have the potential to be used for dynamic procedure planning and immersive patient-specific simulation training .Static 3D-printed replicas offer haptic and spatial appreciation of complex anatomy, with potential dividends in procedural planning, especially given the steep learning curves associated with mitral interventions , 47. MorAlthough of value, rigid 3D printed mitral replicas are bound by the current limitations of materials\u00a0technology. As such, directly 3D printed replicas currently preclude surgical instrumentation such as the deployment of annuloplasty rings, suturing and leaflet resection limiting their translational value for surgical planning and simulation. \u2018Soft\u2019 silicone based mitral replicas derived from moulding techniques can simulate the gross properties of mitral tissue whilst being sufficiently deformable to facilitate surgical or trans-catheter instrumentation. The properties of \u2018soft\u2019 mitral replicas may therefore lend themselves more favourably to procedural planning. Indeed, in proof of concept work Nia et al. were able to simulate the prospective surgical repair of a P2 prolapse within a static bench top simulator using a deformable patient-specific mitral replica derived from 3D TOE. The authors were subsequently able to undertake successful real-life surgical repair with no alterations to the simulated surgical technique. Interestingly, note was made of anterior leaflet prolapse on intraoperative saline testing post-repair. This was not apparent on the pre-operative TOE or the simulated model and deemed to be pseudo prolapse which was confirmed on intraoperative TOE. In some instances, junior surgeons have been compelled to intervene upon leaflet pseudo prolapse adversely impacting outcomes. The authors argued that this event revealed the potential value of integrating physical 3D modelling with pre-operative imaging in intra-procedural decision making . SimilarUnlike surgical interventions, transcatheter procedures preclude intraprocedural examination of mitral pathologies therefore depriving interventionalists the opportunity to alter procedural strategy at the point of intervention, making such interventions less predictable than their surgical equivalents. As such, there is arguably greater reliance on preprocedural planning and greater exposure to the limitations of cardiac imaging in transcatheter interventions compared to surgical techniques. Moreover, given their high-risk nature, patients undergoing transcatheter interventions are less likely to be offered surgical \u2018bail-out\u2019 in the event of complications. There has therefore been an evolving interest in integrating 3D printing and modelling into transcatheter Heart Team procedure planning for increasingly complex transcatheter mitral valve interventions. Dankowski et al. were one of the first to apply 3D printing techniques as an adjunct to procedure planning for percutaneous mitral annuloplasty using a static phantom derived from MDCT. They found the printed replica enabled them to accurately examine the underside of the mitral valve and identify the precise location, number and size of papillary muscles which has a bearing on initial crossing wire placement. The degree of basal dilatation was also apparent on the replica therefore guiding optimal placement of Mitralign pledgets. The derived model also allowed characterisation of parameters such as the aortic entry angle into the LV and analysis of subvalvular apparatus to guide equipment selection and placement . More reThere are several key limitations precluding the widespread clinical translation of static 3D printed mitral replicas in procedural planning. The materials employed for printing do not entirely mimic native tissue and therefore the impact of dynamic device-host interaction cannot be accurately modelled especially due to the static nature of modelling which has implications for their use in crucial areas such as sizing prostheses. There is no standardised or validated technique available to manufacture mitral replicas which greatly limits the translational potential of research within this area. As such incorporation into procedure planning especially in complex interventions requires careful consideration. Clinical translation is also precluded by cost, time taken for image processing and printing as well as the lack of widespread expertise in this arena.The integration of static 3D printed mitral phantoms with complementary transformative technologies however, have the scope to greatly enhance their combined efficacy and translational potential.TMVR technologies are in their nascency with a myriad of novel devices available for implantation. Moreover, transcatheter valve-in-MAC and valve-in-ring procedures utilise tissue heart valves tailored for transcatheter aortic valve implantation (TAVI).3D computer assisted modelling (3D-CAM) platforms enable the derivation of static virtual anatomical 3D models of patient-specific mitral pathology using volumetric imaging data. Derived virtual models can then be manipulated to evaluate complex anatomy and assist in aspects of procedural planning such as sizing of prosthesis, predicting the risk of significant complications, and devising appropriate interventional management strategies. Patient-specific static 3D printing has been used to complement 3D-CAM \u201358.TMVR displaces the anterior mitral valve leaflet and changes the geometry of the LVOT with the resulting morphology termed the neo-LVOT. TMVR carries a risk of LVOT obstruction (LVOTO) which can be fatal. 3D-CAM is increasingly being adopted for procedural planning and predicting the risk of LVOTO and has shown good correlation between modelled and real-world procedural outcomes  Fig.\u00a04)4). 3D prIn addition to procedural risk prediction and mitigation, 3DCAM can also be employed to derive an enhanced understanding of patient-specific anatomy and optimise interventional strategy for those undergoing transcatheter mitral interventions. For example, 3DCAM can be used to derive an enhanced appreciation of the anatomical relations of the inferior vena cava, interatrial septum, and mitral annulus which can then be 3D printed to provide the operator a physical evaluation of the interatrial puncture site and an impression of the impact of patient-specific anatomy on delivery catheters and other equipment , 59. 3DCDespite the considerable advantages associated with incorporating 3DCAM in transcatheter mitral intervention planning, it remains a static modelling modality unable to simulate the complex dynamic anatomical changes and flow dynamics inherent to mitral valve diseases. As such, the derived modelling information must be considered within the wider scope of Heart team procedure planning and integrated with other imaging modalities and the clinical context.Mitral valve pathologies are unique in that they can only be fully appreciated within a haemodynamic environment, therefore immediately limiting the value of static physical mitral modelling. As such dynamic ex-vivo models comprising of animal mitral valve tissue integrated into mock circulatory systems (MCS) seeking to emulate human cardiac haemodynamics form the mainstay of functional mitral modelling and allow evaluation of research hypotheses, novel transcatheter devices and operator simulation training .The constituents of an MCS are outlined in Fig.\u00a0The advent of 3D printing offers the prospect of incorporating and dynamically modelling patient-specific mitral valve replicas within an MCS. Such a system however is reliant upon the manufacture of mitral replicas exhibiting the biomechanical properties of human valves and accurate simulation of the haemodynamic milieu of mitral pathologies. The current status of materials and printing technologies preclude direct printing of biomechanically realistic mitral replicas. Patient-specific mitral valves created by casting silicone replicas over rigid 3D printed models have been shown to provide a heuristic approach for modelling mitral pathologies within a mock circulatory system environment. This approach arguably can be seen as a bridging technology until materials technologies are sufficiently mature to allow direct realistic mitral printing.Mashari et al. demonstrated the feasibility of the haemodynamic evaluation of a 3D printed mitral valve after TMVr within an MCS. The authors were able to derive pressure half time values from continuous wave Doppler and chamber pressures through pressure monitoring catheters. The study was limited by the ability of the MCS to only generate sufficient pressures to allow diastolic modelling .In more extensive contemporary work, Ginty et al. semi-automatically segmented 3D TOE data in diastole to derive patient-specific 3D printed PLA moulds of the atrial mitral valve surface. Silicone  was then used to create a patient-specific mitral valve assembly with incorporated gauze fabric shaped to anterior and posterior mitral leaflets as well as flayed braided Dacron threads to replicate six chordae tendinae. Gauze fabric provided additional tensile strength to adequately mimic mitral leaflets, prevent dehiscence within simulated haemodynamic conditions and allowed the application of sutures or clips to simulate mitral valve interventions Fig.\u00a0. BraidedThe availability of a high-fidelity patient-specific mitral valve simulator has significant transformative potential with the scope for integration into Heart Team workflows surrounding patient selection and procedure planning and thus potentially enhancing procedural outcomes and patient safety. Moreover, such a platform has the potential to be integrated with other transformative technologies further expanding its utility. Although promising, dynamic patient specific mitral modelling remains nascent and a considerable distance away from clinical translation. Indeed, studies in this arena are limited and only demonstrate feasibility, therefore larger studies are required for further validation prior to which caution must be applied to its application in clinical practice. Other practical limitations include the time taken to fabricate silicone based mitral replicas and that replica leaflet thickness is greater than native tissue. Moreover, any progress in this arena is contingent on advances in 3D printing technologies and the ability of MCS platforms to accurately model human haemodynamics.Surgical and transcatheter mitral interventions are technically complex and associated with significant intraprocedural neurocognitive demand thereby resulting in steep learning curves which are closely related to procedural volumes. Indeed, cardiac surgeons have been shown to require between 75\u2013125 procedures to overcome the learning curve for minimal access mitral valve repair , 68. Imp. Moreover, given their complex nature, mitral interventions are typically undertaken in specialist centres with relatively low volumes further straitjacketing training opportunities. In the case of transcatheter mitral interventions many senior interventional cardiologists are still in the process of transitioning from coronary intervention and TAVI therefore further reducing the scope of technical training\u00a0available for junior trainees.Currently surgical and transcatheter training is dependent on the apprentice model of supervised learning and the principle of \u2018see one, do one, teach one\u2019 , 71. TheSimulation training may offer junior trainees the opportunity become proficient in basic technical skills before graduating onto an apprentice style model whilst more senior operators can acquire the basic skills required for novel procedures. Simulation training is well established in the surgical domain and has been shown reduce the learning curve particularly in laparoscopic surgery . SignifiLow-fidelity, low-cost physical simulation platforms for surgical mitral valve interventions have been available for some time . Given tImportant progress has been achieved in this endeavour with direct or indirect 3D printing of patient-specific mitral replicas incorporated into either static  or a dynamic mock circulatory system. 3D printing has also been utilised to manufacture precision components for animal based ex-vivo simulators which can be adopted for training.Recent work by Nia et al. with the support of the European Association of Cardiothoracic Surgery is an apt example of how 3D printing and silicone based mitral modelling can facilitate efforts towards the systematic development of a validated mitral simulator which can be incorporated into a wider standardised training programme. The investigators conceived, manufactured, and validated a bench top static minimally invasive mitral simulator based on simulation requirements set out by a panel of experienced mitral surgeons. The simulator comprised of a model thoracic torso with robotic and endoscopic access ports. The torso housed a silicone casted generic mitral valve replica mounted within a 3D printed left ventricle and featured a real-time feedback system for suture depth and width Fig.\u00a0. The autThe integration of 3D printing with other transformative technologies to derive hybrid patient-specific simulation platforms may harbour considerable future translational potential through offsetting limitations of individual technologies, conceivably resulting in a highly optimised platform. Engelhardt et al. demonstrated the feasibility of such a paradigm by first developing a standardised workflow incorporating 3D printing techniques to manufacture patient-specific silicone mitral valve phantoms which included the papillary muscles and chordae tendinae. The authors integrated these replicas within a non-dynamic commercial endoscopic mitral valve repair simulator and demonstrated it to be valuable for training junior surgeons and for patient-specific procedural rehearsal for senior surgeons . In furtThe increasing global volume of transcatheter mitral interventions (primarily edge-to-edge repair) has spurred the development of dedicated physical high-fidelity simulators in this arena with a view to training the next generation of interventional cardiologists and facilitating the transition of the current generation from TAVI to transcatheter mitral interventions. Operators undertaking TEER interventions not only require considerable dexterity but also simultaneously need to process and integrate real-time information from 3D TOE and fluoroscopy whilst maintaining close interaction with a multi-disciplinary catheterisation lab team to deploy repair devices safely and successfully within a beating heart. As such the development of effective high-fidelity physical simulators beyond ex-vivo animal models in this arena is fraught with challenges and in its nascency with 3D printing set to assume a pivotal role. Early work by Vukivecic et al. demonstrated the feasibility of successfully deploying and securing a Mitraclip onto a multi-material patient-specific 3D printed mitral replica- an important prerequisite for any substantive simulator .Meanwhile, Laing et al. validated the ability of a benchtop static simulator comprising of a patient-specific silicone-based heart model (manufactured using 3D printed moulds) mounted within a cylindrical container with port access to accurately display anatomical features and equipment on TOE and fluoroscopy to simulate septal puncture\u2014a particularly demanding and crucial element of mitral TEER . More reBertolini et al. fabricated an alternative TEER simulation platform consisting of a stand mounted translucent 3D printed model of the inferior vena cava, atria, left ventricle (LV) with detachable mitral leaflets. The model was exposed for viewing at key points relevant to TEER to enable visualisation of equipment. Consideration was given to creating realistic haptics with the atria and LV fabricated to a shore hardness of 85A using a blend of Stratasys VeroClear (rigid) and Agilus30 (soft) whilst valve leaflets were printed with pure Agilus30. The blend hardness was selected qualitatively by clinicians following systematic behaviour evaluation of various compositions on cylindrical specimens. The investigators were able to perform four defined procedural steps on the static model  under fluoroscopic guidance. Important limitations include the absence of TOE guidance which is crucial to procedural success in TEER as well as the static nature of platform which therefore fails to emulate the challenges of deploying repair devices on a beating heart . These aImportant progress has been made towards high fidelity physical simulation in mitral interventions, however work in this area remains in its infancy with several prevailing barriers. There remains a lack of a standardised curriculum for technical skills training within interventional training programs, particularly in the transcatheter realm, thereby stifling simulator development due to lack of clarity regarding training requirements. Variable attention has been given to realistic haptics and feedback within simulators, this is partly due to limitations with materials technologies but also due to the absence of systematic quantitative evaluation of materials against native tissue and a limited understanding of cardiovascular biomechanics. Moreover, platforms thus far have largely offered static simulation therefore arguably not fully simulating the haemodynamic complexities of beating heart mitral interventions. Maintaining and employing simulation platforms for training is costly, time intensive and requires specialist infrastructure, which undoubtedly limits their widespread uptake within training programmes. Finally, there is also a lack of large-scale validation studies for platforms described in the literature.Cardiac surgery and transcatheter interventions are associated with significant periprocedural anxiety for patients and their families. Anxiety and distress often stem from a lack of understanding of their cardiac condition and the intervention proposed. Moreover, there is evidence to suggest that peri-procedural anxiety has an impact on outcomes in those undergoing cardiac surgery , 84.3D printed models have the potential to transform patient\u2019s understanding of their pathology and proposed interventions and have been shown to help reduce periprocedural distress and anxiety. Conventional methods of counselling patients regarding their diagnosis and proposed interventions are through diagrams, information leaflets and verbal descriptions. Generic 3D anatomical heart models are now widely available and can be used for counselling patients however these are usually not patient or pathology specific. Hung et al. found the use of a 3D printed patient-specific mitral model in addition to standard patient educational materials to positively impact patient understanding of their condition and enhanced satisfaction compared a control group who were counselled using standard educational materials and a generic 3D printed heart model in a recent randomised questionnaire study . As suchDespite promising studies and the novelty associated with the application of transformative technologies such as 3D printing, the literature surrounding their use constitutes small studies and case series, often without significant quantitive data validating their efficacy, impact on patients\u2019 outcome and cost-effectiveness. Therefore, the benefit of these interventions remains unclear and requires large scale clinical trials. However arguably, the scope for clinical studies in this arena is currently limited by nascency of the technologies involved and the rapid flux of multiple devices on various stages of the translational pathway. Indeed, there remains the prospect of clinical trial data being rendered obsolete by the sheer pace of multi-dimensional innovation and technological advancement in this arena. Further barriers stem from the absence of an overarching consensus framework guiding the standardisation of technical workflows  and the application of 3D printing technology in mitral interventions. The labour-intensive nature of 3D printing workflows which require considerable expertise and capital investment also preclude widespread translation particularly in the absence of uniform financing and reimbursement models in an era of strained health budgets.Clinical trial data could conceivably lay the foundation of governance frameworks for technical workflows, reimbursement, and quality control, ultimately fostering a wider cost-effective, evidence-based approach.In view of the significant technical challenges and the rapid pace of development in the realm of mitral valve interventions, disruptive technologies such as 3D-CAM are likely to see increasing uptake as adjuncts to procedural planning and training.Brisk development continues in materials and 3D printer technologies which will likely shift the paradigm closer to the fabrication of biomechanically realistic mitral valve replicas as demonstrated by the early work using metamaterials. The field of bioprinting continues to receive much attention and holds promise in the fabrication of physiologically and morphologically accurate cardiac tissue. Although of revolutionary potential, this area of research remains in its infancy and is some way from clinical translation, with challenges pertaining to maintaining cell viability and spatial control in the fabrication of complex biological structures as well as tissue functionality and the integration of biofabricated structures within native physiology , 86, 87.The heterogeneity and dynamic nature of mitral pathologies poses a formidable challenge to realistic dynamic biomechanical simulation, particularly as simulation of human cardiac haemodynamics currently relies on MCS which offer limited scope for adjusting physiological variables. Technologies such as computational flow dynamics may enable highly accurate simulation of human physiology and their integration with dynamic physical modelling may offer considerable future dividends in mitral modelling .Extended realities technologies harbour early promise in the arena of mitral valve modelling and intervention particularly in surgical training, virtual proctoring, and procedure planning. There is also the tantalising prospect of intraprocedural integration as demonstrated by Chu et al. where augmented reality optimised intraprocedural TOE guidance facilitated safer NeoChord implantation in a porcine model. Mixed r3D printing technologies carry considerable promise in aiding procedure planning, patient selection, operator training and ultimately delivering personalised care in the rapidly expanding domain of mitral valve interventions. They also appear amenable to synergistic integration with other rapidly evolving \u2018transformative technologies\u2019 such as extended realities, machine learning and computational modelling, thereby enhancing the potential clinical dividends particularly in the crucial remits of procedural outcomes and patient safety. However, it is important to appreciate the current limitations with this technology, and caution is required in its widespread application to the clinical decision-making process at this stage. Indeed, 3D printing technologies in the context of heart valve disease remain in their infancy with further advancements required, particularly in\u00a0the realm of materials technologies to achieve high fidelity simulation of valvular tissue properties and biomechanics. Whilst the use of these technologies currently remains sporadic, there is no doubt about their potential to enhance personalised patient care and procedural outcomes in an area of rapidly expanding clinical need."}
+{"text": "Squamous cell carcinoma predominates as the most common malignant lesion of the oropharynx with human papilloma virus-associated disease now predominant over tobacco-related oropharynx cancer. Other rare malignant pathologies can manifest as visible neoplasms in these anatomic sites with varying degrees of symptoms such as dysphagia, odynophagia, otalgia, aspiration, hemorrhage, weight loss and dyspnea. We present a case of a rarely encountered primary oropharyngeal sarcoma managed by single-port transoral robotic resection and a selective cervical lymph node dissection followed by adjuvant radiotherapy.  Awareness of head and neck address neoplasms has vastly increased in the age of human papilloma virus (HPV)-related oropharyngeal squamous cell carcinoma (OPSCC). HPV-related OPSCC now accounts for the majority share of oropharynx malignancy as opposed to HPV negative OPSCC with an incidence of ~4.6 cases per 100\u2009000 individuals in the United States . This shHowever, other malignant pathologies do manifest in the lymphatic-rich environment of the oropharynx including salivary carcinomas, lymphomas and sarcomas. Clinicians must be vigilant to recognize less commonly encountered malignant pathologies in these anatomic sites. This surgical case report describes a rare primary tonsillar malignancy managed by primary transoral robotic surgery (TORS).A 37-year-old Latino male presented with a 1-month history of an enlarging, painless right tonsillar mass noticed during routine oral self-care. He self-referred to our tertiary care academic otolaryngology-head and neck surgery clinic with a clearly visible right tonsillar 1\u00a0cm violaceous exophytic mass arising from the tonsil tissue into the oropharyngeal lumen. An in-office transoral biopsy was performed.His social history was notable for active vaporized nicotine use and prior polysubstance abuse. He identifies as a homosexual male in a monogamous relationship with multiple prior sexual partners. He started pre-exposure prophylaxis (PREP) for human immunodeficiency virus (HIV) with a combination of pharmacologic emtricitabine/tenofovir 2 months prior to the onset of the lesion. As part of initiating this PREP regimen, he received screening testing which was negative for HIV by serology and polymerase chain reaction (PCR) testing.Staging imaging by positron emission tomography-computed tomography (PET-CT) showed right tonsil avidity and a suspicious level IIb ipsilateral node  and B. RThe initial in-office transoral biopsy specimen returned as Kaposi\u2019s sarcoma with immunohistochemical positivity for CD31, CD34, Vimentin and Human Herpes Virus 8. The case was discussed in our multi-disciplinary head and neck oncology tumor board, which recommended locoregional control by transoral robotic resection and selective neck dissection, given his HIV negativity and lack of immunocompromising risk factors.He declined an elective neck dissection despite the avid ipsilateral level II node out of concern for the transcervical incision necessary to perform the lymphadenectomy portion of the procedure. We counseled the patient that in addition to gaining accurate staging and even therapeutic lymph node resection, the transcervical approach allows for ligation of the external carotid arterial system to mitigate postoperative catastrophic hemorrhage risks , 4. UltiHe underwent transoral robotic-assisted right radical tonsillectomy by a single-port technique  in conjunction with an ultrasound-guided needle biopsy of the right level II suspicious node. He tolerated the procedure well and was discharged home once demonstrating an adequate oral intake and achieving oral pain control.He presented to the hospital emergency department on postoperative Day 2 with an episode of small volume hemoptysis while at home. He was hemostatic and hemodynamically stable on arrival. His nodal fine needle aspirate also returned that day, showing suspicion for malignancy and identifying spindle cells. The patient was counseled and readily consented to a selective therapeutic neck dissection and external carotid supply ligation to address his nodal disease burden and hemorrhage risk. He was taken to the operating room that evening and underwent an ipsilateral right selective neck dissection of levels II\u2013IV, as well as ligation of the ipsilateral linguofacial trunk of the external carotid system.His final pathology revealed a 1.2\u00a0cm right tonsil Kaposi\u2019s sarcoma primary with clear margins but perivascular lymphoplasmacytic infiltration identified. The nodal dissection revealed Kaposi\u2019s sarcoma in 3 of 42 lymph nodes examined. All nodal deposits were contained within the node and sub-centimeter in volume  and B.He was again presented in review at our institutional multidisciplinary head and neck oncology tumor board with recommendation for adjuvant radiotherapy for additive locoregional control. After completion of adjuvant therapy, he has been followed closely by the head and neck surgical oncology, radiation oncology and medical oncology teams according to the National Comprehensive Cancer Network recommended schedule for a minimum of 5 years post-treatment. He remains to be in a state of disease-free survival at the time of this article, 14\u00a0months post-treatment.Kaposi\u2019s sarcoma is a disease entity typically associated with immunocompromised states, most notably of individuals with HIV/AIDS. Endemic forms of the disease are also well described and characterized in certain ethnic populations. Perhaps the least known at-risk population are HIV seronegative men having sex with men with limited cases reported to date . Limited"}
+{"text": "Cognitive (dys)function after ECT is often considered as a homogeneous phenomenon across patients. However, there are important inter-individual differences, with some patients experiencing residual invalidating cognitive deficits. We present the results of a study combining both group-level and individual-level analyses of cognitive function using an extensive cognitive test battery that was assessed in 73 patients at 5 time points during their ECT care pathway. Furthermore, we explored the presence of distinct subgroups of patients with a similar cognitive trajectory over time after treatment with ECT using Latent Class Growth Analysis.None Declared"}
+{"text": "This is a peer-review report submitted for the paper \u201cExercise-Induced Hypoalgesia Following Proprioceptive Neuromuscular Facilitation and Resistance Training Among Individuals With Shoulder Myofascial Pain: Randomized Controlled Trial\u201dThis paper  aims to 1. Methods: In the procedures section, please add information about possible blinding of the evaluators .2. Discussion: Please try to address the important improvements in the proprioceptive neuromuscular facilitation exercise group in relation to personal interaction with the researcher ."}
+{"text": "A 42-year-old man presented to our emergency department with a history of having swallowed several sewing needles an hour previously. Physical examination showed mild hyperemia of the pharynx and slight abdominal tenderness. Cervical thoracoabdominal computed tomography detected several high density shadows in the stomach and duodenum, without any signs of perforation . GastroGiven that the needles are metal, a magnet grasped by forceps was subsequently used to retrieve them . The fiMagnet-assisted endoscopic removal of ingested sewing needles from the stomach and descending duodenum.Video 1The ingestion of sharp-pointed foreign bodies such as sewing needles is an urgent situation, with an increased risk of perforation. Commonly used retrieval devices for sharp-pointed foreign bodies are forceps or snaresEndoscopy_UCTN_Code_TTT_1AO_2AL"}
+{"text": "Peliosis hepatis remains a rare focal liver lesion with inconclusive imaging features. The unknown pathogenesis represents a wide possible range of etiologies including the breakdown of the sinusoidal borders, a potential hepatic outflow obstruction or dilatation of the central vein of a hepatic lobule. In histopathology, a blood-filled cystlike appearance with sinusoidal dilatation was reported. On ultrasound, B-mode features are not specific demonstrating a irregular, moreover hypoechogenic focal liver lesions. Postcontrast imaging features on Contrast-Enhanced-Ultrasound may mimic a malignant lesion with irregular contrast inflow and washout during late phase. Our case demonstrates a peliosis hepatis with malignant image features on contrast-enhanced ultrasound, ruled out by PET-CT and core needle biopsy with corresponding histopathological workup. Peliosis hepatis is known as a rare disease showing multiple blood-filled parenchymal cysts in parenchymal organs, which may be associated with a wide range of conditions varying from medication or infectious diseases and autoimmune diseases We demonstrate the case of a 79-year old female patient with conjunctival melanoma diagnosed in 2001. The patient was referred to the Department of Cardiology due to dyspnea under cardiac decompensation and subacute pulmonary embolism. Afterwards, the patient was referred to head and neck surgery to further perform imaging for tumor staging. Magnetic resonance imaging was avoided due to an implanted pacemaker.Positron emission tomography / computed tomography (PET/CT) revealed a 4\u00a0\u00d7\u00a03 cm mass in the so-called Riedel-lobe, which is described as a normally absent, tongue-shaped process at the anterior margin of the right liver lobe overhanging the right kidney. The focal liver lesion (FLL) was slightly hypodense compared to the surrounding liver tissue on nonenhanced CT (Hounsfield units: 39 HU vs 59 HU in the surrounding liver tissue of the right lobe) and showed no sufficient contrast enhancement  after injection of 80 ml iodine-based contrast agent A and B. To further characterize the FLL, CEUS was performed by an expert in the field with more than 20 years of experience in this field (EFSUMB Level III). The ultrasound (US) protocol using a high-end US system with 1\u20136 MHz convex array transducer  included color-coded duplex sonography (CCDS) and superb microvascular imaging (SMI) to determine vessel structure. Afterwards, the liver lesion was examined in modified longitudinal and transversal planes with an up-to-date CEUS-specific protocol available at the time of the examination. On B-Mode US, the lesion was inhomogenous and hyperechogenic compared to the surrounding liver tissue A and B. A percutaneous US-guided core biopsy (16 Gauge needle) was performed due to the discordance between CEUS findings and PET/CT findings after an internal discussion of several disciplines. The histopathological report revealed no atypical cells suspicious for malignancy. The hepatic parenchymal specimen showed peliosis-like dilatation of the sinusoids and edematous widened portal fields with a mixed cell inflammatory .Fig. 4HiPeliosis hepatis is known as a rare disease with several underlying conditions, which is a challenge for diagnosis on established imaging modalities. Our case report shows a patient with suspicion of malignancy receiving a PET/CT scan and CEUS with discrepant findings on both modalities.Perfusion pattern of peliosis hepatis in CEUS are quite variable including a variety of B-mode findings with hyper-, iso- and hypoechogenicity In comparison to the results of the study by Dong et\u00a0al., the lesion we present is in congruence with the described arterial hyperenhancement\u2014but our case showed early progressive washout, whereas the authors concluded washout in the very late portal venous phase (after 1 minute) to be characteristic in peliosis hepatis Several contrast pattern findings for peliosis hepatis are known through the literature, including centripetal contrast enhancement mimicking hemangiomas or atypical enhancement patterns not suggestible for any typical FLL \u2022Peliosis hepatis showed strong enhancement with irregular enhancement pattern\u2022Early washout starting after 40 seconds post injection was present\u2022CCDS depicted no macrovascularization, while microvascular imaging revealed some tiny vesselsCatchword phrases:Our patient demonstrated in the case report signed a written informed consent for publication/research purpose."}
+{"text": "Complete obstruction of the bile duct after hepatic resection is rare and extremely difficult to treat. We report recanalization using magnetic compression anastomosis and retrieval of a magnet that migrated into the intrahepatic bile duct.A 77-year-old man developed complete obstruction of the bile duct due to a biliary fistula following hepatic resection for hepatocellular carcinoma . BreaktA thick sheath was inserted into the PTBD route, and one magnet was inserted through the sheath to the site of bile duct obstruction . A 10-mVideo\u20061\u2002Recanalization by magnetic compression anastomosis for complete bile duct obstruction and retrieval of the migrated magnet.There have been several reports of magnetic compression anastomosisEndoscopy_UCTN_Code_CPL_1AK_2AZ"}
+{"text": "Colorectal endoscopic submucosal dissection (ESD) is now widely used for the treatment of colorectal tumors using several strategies. The effectiveness of the pocket-creation method combined with saline immersion has been reported with an improved endoscopic visual field and submucosal approach due to the buoyancy of the lesion and reduced the amount of submucosal injection. Its disadvantages include a poor visual field during bleeding and dissipation of coagulation ability with monopolar devicesHerein, we report a combination of gel immersion ESD and tunneling in a colorectal tumor . A 71-yVideo\u20061\u2002Successful gel immersion colorectal endoscopic submucosal dissection using the tunneling method.Endoscopy_UCTN_Code_TTT_1AQ_2AD"}
+{"text": "An 11-year-old Japanese boy presented to our hospital with intrahepatic biliary duct stones and regional cholangitis. He had undergone cholecystectomy, complete excision of the extrahepatic biliary duct, and Roux-en-Y hepaticojejunostomy for choledochal cysts (Todani classification IVa) at the age of 8 years. Abdominal magnetic resonance imaging confirmed cystic dilatation of the left hepatic duct and the presence of left intrahepatic biliary duct stones .During long school vacations, three separate endoscopic procedures using balloon enteroscopy  were performed to improve the long-term prognosis following the choledochal cyst surgery. During the first session, endoscopic biliary drainage with multiple plastic stents was performed to reduce the size of the stones by abrasion between the plastic stents and the stones, while also avoiding recurrence of the cholangitis . The seVideo\u20061\u2002Three separate endoscopic procedures were performed using balloon enteroscopy to improve the long-term prognosis after choledochal cyst surgery.Postoperative complications of choledochal cysts generally worsen the outcome and represent a major challengeEndoscopy_UCTN_Code_TTT_1AR_2AH"}
+{"text": "Background: Attention-deficit hyperactivity disorder (ADHD) is a condition which has been consistently documented to impact educational outcomes. Children with ADHD are regularly found to have lower educational attainment and increased likelihood of dropping out of school compared to children without ADHD.Objectives: To project the long-term societal economic consequences of reduced educational attainment, as measured by total lifetime earnings, in an untreated cohort of individuals diagnosed with ADHD in childhood, in Germany. In addition, this research aims at illustrating a cost-benefit analysis framework which could be applied to economically appraise the rate of return from investments in hypothetical health interventions targeting ADHD.Methods: Observational ADHD evidence was collated with demographic and human capital economics methods to quantify ADHD\u2019s impact on educational attainment and long-term labour outcome in Germany. The theoretical benefits deriving from effective interventions targeting ADHD were also quantified.Results: It was estimated that the average per capita lifetime earning loss associated with ADHD was \u20ac92,000 suggesting a societal loss of \u20ac2.93 billion from a single cohort . The benefit-cost analysis suggested that reasonably effective intervention may justify considerable investment in ADHD targeted intervention.Conclusions: Considering the broad economic consequences of the condition might suggest that interventions which change the life course of individuals with ADHD could offer cost-savings and influence future economic outputs."}
+{"text": "We investigated thumb joint stability and patient-reported and functional outcomes a minimum of 1 year after flexor digitorum superficialis opponensplasty and ligament reconstruction in 23 thumbs of 20 consecutive children with radial longitudinal deficiency. In total, 15 thumbs had preoperative multidirectional instability in the metacarpophalangeal joint. We reconstructed 22 ulnar and 16 radial collateral ligaments. At follow-up, all the metacarpophalangeal joints were stable ulnarly. Seven metacarpophalangeal joints were unstable radially despite ligament reconstruction but had no related complaints. We recommend the flexor digitorum superficialis opponensplasty as a safe and reliable procedure in hypoplastic thumbs to create stability and augment thumb strength.Level of evidence: IV All patients with a congenital radial longitudinal deficiency (RLD) have thumb hypoplasia , rangingWe began reconstructing type II and IIIa hypoplastic thumbs at Oslo University Hospital in 2009. We used the FDS-ring for the opponensplasty and MCPJ ligament reconstruction in all our patients. The primary aim of this study was to investigate whether we achieved adequate stability for uni- and multidirectionally unstable MCPJs. The secondary aim was to explore patient-reported and functional outcomes.We conducted the study according to the Helsinki declaration and have reported it according to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement . Our insTwo surgeons (MW and INS) carried out all except two of the earliest procedures. We constructed a palmar aponeurosis  or flexoWe checked the patient records for intra- and postoperative complications  and included any adverse events reported by the children or their caregivers.At the study follow-up, a congenital hand surgeon (INS or MW) assessed whether the thumb joints were unstable (yes or no?) or if the first web space was tight (yes or no?). We defined MCPJ and IPJ instability as a lack of a definite endpoint at ligament testing, indicating the need for surgical stabilization. The CMCJ was defined as unstable if we found a positive dorsal shift . The firThe children performed the Thumb Grasp and Pinch Assessment (T-GAP), and a senior paediatric occupational therapist (OT) (ABS) scored the video clips . There aWe used the Pollexograph  to measu2, mobility) and strength . We used our measurements of radial abduction, Kapandji score, MCPJ stability, ROM in the MCPJ and IPJ according to normative paediatric data  populations from the PROMIS website.All the children and caregivers completed together five Patient-Reported Outcomes Measurement Information System (PROMIS) domains validated from the age of 5 years: Parent Proxy Item Bank v2.0 Upper Extremity \u2013 Short Form 8a; Depressive Symptoms \u2013 Short Form 6a; Anxiety \u2013 Short Form 8a; Peer Relationships \u2013 Short Form 7a; and Parent Proxy Scale v1.0 \u2013 Global Health 7\u2009+\u20092 . PROMIS n\u2009=\u20099) and all caregivers assessed the following statements or questions on a visual analogue scale : the thumb works like a thumb; the thumb looks like a thumb; \u2018How often do you (or does the child) use the thumb to pinch versus scissor pinch for small objects?\u2019; \u2018How often do you (or does the child) incorporate the thumb when holding larger objects like a bottle?\u2019 . Only the caregivers were asked \u2018Has the child used the thumb more after surgery?\u2019. The OT and surgeon also rated statements 1 and 2.The children aged >8 years  had a modified Bayne type N/0-1 RLD  in the 2Two children had had secondary bilateral first web releases for recurring tightness before follow-up. We found no complications in the medical records or adverse events reported by the patients or their caregivers.At follow-up, all the MCPJs were stable on the ulnar side, whereas nine were unstable radially ; Table 3The surgeon judged eight first webs to be tight , but onlt-score of 37 (IQR: 28 to 42) in type II thumbs and 35 (IQR: 32 to 50) in type IIIa thumbs, indicating a moderately reduced function. t-scores were normal for the other PROMIS domains . The VAS assessments are presented in Supplementary Table S3 (available online).We found a median PROMIS upper extremity We found satisfactory MCPJ stability after ligament reconstruction with FDS-ring tendon slips in both type II and IIIa hypoplastic thumbs, including those that were multidirectionally unstable before operation. The patient-reported and assessor-measured outcomes were also good after FDS opponensplasty.The main strengths of our study were the consecutive cohort, preventing selection bias and a low attrition bias. As in earlier studies, the main limitations were the cohort size and the lack of preoperative outcome measures. We cannot rule out performance bias, as the assessors had treated most patients.The successful stabilization of the ulnar side but with remaining radial instability in almost half of the multidirectionally unstable MCPJs might be because we routinely reconstructed the UCLs first and thus did not obtain correct tension in the RCLs. We have chosen this reconstruction sequence because the UCL is the most important MCPJ ligament for grip stability. Our proportion of stable joints after ligament reconstruction was comparable to the findings in two studies with an identical ligament insertion technique , and oneA postoperative positive dorsal shift of the CMCJ has also been reported previously . In two We found no detailed reports on the clinical assessment of the first web. There is no agreement on a clinical definition of a tight first web in children, and again we decided to use the surgeon\u2019s subjective assessment. We did not note web tightness at follow-up as a surgical complication, as not all webs can be completely corrected with primary surgery, and recurrence is common in growing children as scar tissue is less flexible.The T-GAP scores we report were predictably better than those reported after index finger pollicization . The ROMOur study indicates that FDS tendon slips are adequate to stabilize most MCPJs, but we cannot rule out an occasional need for primary or secondary joint fusion. The earlier treatment in our unit of mildly affected hypoplastic thumbs with instability and partial thenar aplasia was a ligament reconstruction with free tendon grafts. Palmar abduction and opposition are present in these thumbs, but strength is lacking. Based on the good outcomes in our study, we have expanded our indications of FDS opponensplasties to include these thumbs to strengthen them.Click here for additional data file.Supplemental material, sj-pdf-1-jhs-10.1177_17531934231187813 for Satisfactory thumb metacarpophalangeal joint stability after ligament reconstruction with flexor digitorum superficialis in children with radial longitudinal deficiency by Ida Neerg\u00e5rd Sletten, Jarkko Jokihaara, Anne Birgit Stavenes and Mona Irene Winge in Journal of Hand Surgery (European Volume)Click here for additional data file.Supplemental material, sj-pdf-2-jhs-10.1177_17531934231187813 for Satisfactory thumb metacarpophalangeal joint stability after ligament reconstruction with flexor digitorum superficialis in children with radial longitudinal deficiency by Ida Neerg\u00e5rd Sletten, Jarkko Jokihaara, Anne Birgit Stavenes and Mona Irene Winge in Journal of Hand Surgery (European Volume)Click here for additional data file.Supplemental material, sj-pdf-3-jhs-10.1177_17531934231187813 for Satisfactory thumb metacarpophalangeal joint stability after ligament reconstruction with flexor digitorum superficialis in children with radial longitudinal deficiency by Ida Neerg\u00e5rd Sletten, Jarkko Jokihaara, Anne Birgit Stavenes and Mona Irene Winge in Journal of Hand Surgery (European Volume)"}
+{"text": "At 8 years of age, this patient with cavernous transformation of the portal vein presented with variceal hemorrhage and underwent successful creation of a transjugular intrahepatic portosystemic shunt (TIPS) Fig. A, B. SheHPS complicates a small proportion of pediatric liver disease patients. Potential mechanisms include increased production of vasoactive metabolites due to portal hypertension or decreased hepatic clearance due to liver disease or portal bypass. These metabolites lead to pulmonary vasodilation and the formation of intrapulmonary right-to-left shunts . The dia"}
+{"text": "Scientific Reports 10.1038/s41598-023-45753-5, published online 30 October 2023Correction to: The Acknowledgements section in the original version of this Article was incomplete.\u201cThis work is part of a project funded by the Independent Research Fund Denmark (grant number: 0135 00351B). The authors gratefully acknowledge Marcos Moreno for his insights and discussions, which contributed to the improvement of this manuscript. JMB acknowledges Valentina Espinoza for her invaluable inputs in multiple aspects of this study.\u201dnow reads:\u201cThis work is part of a project funded by the Independent Research Fund Denmark (grant number: 0135 00351B). AT and DM acknowledge support from the Chilean ANID Milenio Grant NCN19_167\u2014Millennium Nucleus CYCLO. The authors gratefully acknowledge Marcos Moreno for his insights and discussions, which contributed to the improvement of this manuscript. JMB acknowledges Valentina Espinoza for her invaluable inputs in multiple aspects of this study.\u201dThe original Article has been corrected."}
+{"text": "A 57-year-old man was presented with severe headache that had persisted for 1 week. He was diagnosed with diabetes mellitus (DM) and was followed up in the internal medicine clinic because of diabetic ketoacidosis, and he had a history of tooth extraction in the right upper jaw 10 days ago. The patient was administered with antibiotics for being diagnosed with orbital cellulitis. A paranasal computed tomography (CT) scan performed before treatment revealed mucosal thickening in the maxillary sinus . Neurolo"}
+{"text": "Diagnostic esophagogastric endoscopy has recently been performed using new sterile single-use disposable endoscopes   due to N-butyl cyanoacrylate (NBCA) is used for emergency endoscopic hemostasis in cases of gastric and ectopic varicesWe report two cases in which sclerotherapy was performed using the Ambu aScope Gastro for treating gastric and jejunal varices .Gastric and jejunal variceal sclerotherapy using the Ambu aScope Gastro.Video 1Case 1 is of a 65-year-old man who was referred for the treatment of gastric varices due to alcoholic cirrhosis. The gastric varices were punctured using a 23-G esophageal varices puncture needle  . Under Case 2 is of a 76-year-old man  who wasThese cases demonstrate the successful use of sclerotherapy with NBCA using the Ambu aScope Gastro. This single-use disposable endoscope prevents the need for costly endoscope repair following NBCA adhesion and provides excellent visibility on fluoroscopic images.Endoscopy_UCTN_Code_TTT_1AO_2AD"}
+{"text": "Invasive fungal infections (IFIs) can cause high morbidity and mortality in immunocompromised patients. Posaconazole is a commonly used triazole antifungal agent for prophylaxis against IFIs in high-risk populations. However, the effectiveness of Posaconazole as antifungal prophylaxis in Allogeneic Stem Cell Transplantation  in Latin-America has not been well described. The aim of this study is to describe the clinical experience with the use of Posaconazole as antifungal prophylaxis in allo-SCT in a high complexity medical center in Latin-America.A retrospective descriptive study was conducted to evaluate the experience of using Fluconazole or Posaconazole as antifungal prophylaxis in patients undergoing Allogeneic Stem Cell Transplant at the Fundaci\u00f3n Valle de Lili in Cali, Colombia between 2012 and 2020. . The primary outcome variable was the incidence of IFI in the first 100 days of prophylaxis.Allogenic Stem Cell Transplant: Methods selectionA Retrospective descriptive study involving the selection of 194 patients who underwent Allogeneic Stem Cell Transplantation, of which 179 patients met the selection criteria for the study.This study analyzed 179 individuals with hematologic malignancies who received prophylaxis with either Posaconazole (n=164) or Fluconazole (n=15). The occurrence of IFI was lower in the Posaconazole group compared to the fluconazole group during the initial 100 days of prophylaxis  . Aspergillus spp were the most frequent microorganisms observed in 3 cases (1.67%). The Number Needed to Treat (NNT) was 8.25, indicating that 8 patients treated with Posaconazole can prevent one IFI that would have occurred with Fluconazole treatment.Comparative analysis of Posaconazole and Fluconazole as antifungal prophylaxis in Allogeneic Stem Cell TransplantationPercentage of Invasive Fungal Infections found in Allogeneic Stem Cell Transplantation during the first 100 days post-transplantation in patients who received prophylaxis with Posaconazole or Fluconazole.This study suggests that using Posaconazole as antifungal prophylaxis reduces the incidence of invasive fungal infections (IFI) in patients undergoing Allogenic Stem Cell Transplantation under real-world conditions and is a safe alternative to be used in low-income settings. Further clinical studies with larger sample sizes are required to confirm these findings.All Authors: No reported disclosures"}
+{"text": "Augmented renal clearance (ARC) has been reported to occur across many critical illnesses but has not been evaluated in critically ill burn patients. The impact of ARC on clinical outcomes within this population remains unknown. We hypothesize that ARC is prevalent in critically ill burn patients and is associated with improved survival.2. Clinical outcomes were compared between patients with and without ARC.We retrospectively reviewed a prospectively-maintained registry of Burn ICU patients from July 2021 \u2013 September 2022 at an academic burn center. We included patients in whom 24-hour urine creatinine collection was performed on admission and excluded patients in whom accurate collection was not performed within 48 hours of admission. Creatinine clearance was calculated for all patients who met inclusion criteria. ARC was determined to occur when creatine clearance exceeded 130 mL/min/1.73m2 (range 37-313), and 7 patients (29%) had creatinine clearance greater than 200. Complication rates were low and were similar between patients with and without ARC .The analysis included 24 patients . The median percentage of total body surface area (TBSA) burned was 25 [10-38]. ARC was present in 17 patients (71%). Mean creatinine clearance was 162 ml/min/1.73mARC appears to be a common phenomenon among critically injured burn patients. While the presence of ARC could be particularly meaningful in this population of patients that often receives massive volumes of resuscitative fluids, the sample size of our study did not permit the detection of statistically significant differences in outcomes between burn patients with and without ARC. Further work must be undertaken to assess the impact of ARC on fluid resuscitation strategies and medication dosing including that of antibiotics and thromboprophylaxis agents.Augmented renal clearance (ARC) has never before been characterized in the population of critically injured burn patients. This topic merits further research, as it could have far-reaching clinical impact relating to fluid resuscitation practices and dosing of renally-cleared medications ."}
+{"text": "Cervical dystonia with concurrent cervical myelopathy is a challenging pathology that requires thoughtful management. A 46-year-old female was referred to our center with this presentation. We elected to perform bilateral globus pallidus internus deep brain stimulation (DBS-GPi) prior to C5 to C7 anterior cervical discectomy and fusion (ACDF) to avoid the potential for dystonic movements to negatively impact cervical fusion. The patient was followed up at three months post C5 to C7 ACDF and nine months post DBS-GPi with complete control of tremor and no radiographic evidence of hardware loosening or malalignment. Though this strategy was successful in treating both our patient\u2019s cervical myelopathy and cervical dystonia, larger studies need to be conducted to optimize the treatment of patients presenting with these concurrent pathologies. Dystonic movement disorders such as cervical dystonia may present with cervical myelopathy. Epidemiologic evidence has revealed that degenerative disorders of the spine associated with dystonia occur earlier in life than normal physiological aging, and disease is often seen at higher cervical levels . This prA 46-year-old female with a primary complaint of neck pain, bilateral upper extremity radiculopathy, paresthesia, and myelopathic gait was referred to our center. She had also been diagnosed with cervical dystonia 15 years prior. She had trialed various medications for her dystonia over many years with no relief. She also received botulinum toxin injections, which resulted in the worsening of her symptoms. The patient also had significant cervical myelopathy due to disc herniations at C5-C6 and C6-C7 with myelomalacia on cervical MRI seen in Figure There is a small but growing body of evidence that suggests the use of DBS and surgical fixation of the spine may provide long-lasting symptom resolution for carefully selected patients. Bilateral DBS-GPi has been shown to improve symptoms of cervical dystonia for over a decade after implantation . It may The co-occurrence of both a dystonic movement disorder and cervical myelopathy presents a unique challenge in terms of surgical management. This case presents a viable surgical strategy for managing this challenging pathology in patients whose symptoms are refractory to medical management for cervical dystonia with concurrent myelopathy. Larger clinical trials could help further establish this paradigm as an effective treatment for these patients while also elucidating the finer details of managing specific deformities in the cervical spine in this concurrent pathology."}
+{"text": "Glioblastoma (formerly named glioblastoma multiforme) is the most common primary central nervous system tumor, representing 45% of all cases and 15% of all intracranial neoplasms [1]. Its typical radiologic findings and localization make it often a lesion easy to diagnose. In MRI it usually appears as an irregularly shaped cystic lesion with ring contrast enhancement in T1-weighted images, localized in subcortical white matter and deep gray matter nuclei of the cerebral hemispheres. It involves more frequently the frontotemporal region followed by parietal lobes [1]. Few articles in literature described cases of intraventricular glioblastomas, defining those as secondary ventricular tumors because of their probable origin primarily from cerebral tissue with consequent transependymal development . Atypical presentations of these tumors make it more difficult to clearly differentiate them from other lesions more commonly located in the ventricular system. We describe a case with a unique radiological presentation: an intraventricular glioblastoma lying entirely within the ventricular walls, involving all the ventricular system, without mass effect or nodular parenchymal lesions. A 56-year-old woman with history of ankylosing spondylitis presented with a 2-month drug-resistant headache and short-term memory loss. Brain MRI showed an enhancing multinodular lesion with dissemination along the walls of all the ventricular system Fig. . Total bThe integrated histological diagnosis with molecular analysis was compatible with glioblastoma IDH-wildtype, grade 4 according to CNS WHO 2021 criteria  is the most common primary central nervous system tumor representing 45% of all cases and 15% of all intracranial neoplasms [The peculiar distribution following only the ependymal lining instead of white matter tracts is anecdotic, but it may support the hypothesis that the glioblastomas\u2019 cell of origin (COO) is a neural precursor cell located in the subventricular zone (SVZ) along the lateral ventricular walls. Lee and Manzano stated that possible alternative origins of intraventricular glioblastomas could be the septum pellucidum or the fornix, both components of the limbic system : the invWe here present this case because of its uniqueness: to our knowledge no such cases with subependymal distribution in all ventricular walls, without nodular appearance or mass effect on brain parenchyma, has been described in literature."}
+{"text": "Endoscopic retrograde cholangiopancreatography (ERCP) is challenging in patients with surgically altered anatomy; in these cases, balloon-enteroscope-assisted ERCP can be performedVideo\u20061Advantages of a dual-channel multi-bending endoscope for endoscopic retrograde cholangiopancreatography in patients with Billroth II reconstruction.The M-scope can overcome even acute angles by bending in two places sequentially . On reaBiliary cannulation can be challenging in patients with Billroth II anatomy because of high papillary mobility or its angle relative to the scope. The dual channel of the M-scope facilitates simultaneous holding and pulling of the papilla and biliary cannulation . This sPerforming sphincterotomy is often difficult in cases of altered anatomy because scope position adjustments are not straightforward. These adjustments are made easier by utilizing both bending sites . FurtheIf these features were incorporated into the balloon endoscope, it could further facilitate ERCP in cases with altered surgical anatomy.Endoscopy_UCTN_Code_TTT_1AR_2AK"}
+{"text": "To optimize the process to obtain bacterial DNA directly from human urine and blood samples to produce high-quality genomic data using long-read Nanopore sequencer.Escherichia coli or Klebsiella pneumoniae and corresponding isolates were collected from the microbiology diagnostics laboratory. DNA isolation optimization was performed testing three different sample volumes and seven DNA extraction kits. DNA concentration was quantified with Qubit fluorometer. Nanopore sequencing was performed on a MinION Mk1C device in R9.4.1 flow cells using the Rapid Barcoding Kit. Bacterial species and antimicrobial resistance (AMR) genes were determined with EPI2ME ARMA pipeline. Genomes were assembled with Flye, polished with Medaka and remaining human contigs removed with Krakentools. Bacterial isolates from the same samples were also sequenced using Illumina technology. Illumina and Nanopore assemblies were quality checked with Quast, Kraken was used to identify bacterial species, MLST for multilocus sequence typing and ABRicate with ResFinder database to detect AMR genes.A total of 22 blood cultures and 24 urine samples positive for E. coli). A variety of clinically relevant AMR genes were detected, such as dfrA and bla\u00a0CTX-M genes, which matched the phenotypic antimicrobial susceptibility testing results. Comparison of genomic assemblies obtained through Nanopore sequencing of 10 urine samples and Illumina sequencing of the corresponding clinical isolates showed a high degree of matching, validating Nanopore sequencing as an alternative option to support diagnosis and treatment choice.A total of 72 DNA extractions from 24 urine and 22 blood samples with different kits were performed to find the optimal extraction protocol for each sample type. DNA from urine samples was isolated from 5 mL, while 1 mL was best for blood cultures. We found that the host depletion step prior to DNA extraction using MolYsis basic 5 Kit (VH-Bio) was essential. DNA from urine samples was extracted with GenElute Bacterial Genomic DNA Kit (Merck) and QIAamp Biostic bacteremia Kit (Qiagen) was best to allow successful bacterial genome sequencing for blood samples. Bacterial isolates from 11 urine and 1 blood sample (out of 54 sequenced) were successfully sequenced. In all 12 cases, the highest percentage of bacterial reads matched with the causative organism found during routine microbiology diagnostics (We have successfully optimized the protocols to extract and sequence pathogenic bacterial DNA directly from blood and urine samples. Short-read sequencing confirmed results acquired by Nanopore sequencer, endorsing long-read sequencing in clinical settings to support timely diagnosis and treatment."}
+{"text": "Blunt trauma predominantly affects the right adrenal gland (3) owing to its proximity to vertebrae and drainage through the inferior vena cava (4); the patient\u2019s left-sided injury could be attributed to situs inversus. As with other reports (4), this case was nonoperative and successfully managed in the primary care setting. Our incidental discovery of situs inversus highlights one potentially disastrous consequence of estimating injury severity based on conventional anatomical features and eschewing diagnostic imaging.A 43-year-old man presented to our primary care clinic with back pain and contusions following a motorcycle accident. Contrast-enhanced computed tomography revealed complete situs inversus, left upper rib fractures, left adrenal enlargement, and no evidence of extravasation or other organ damage. The left adrenal gland measured 3.1 cm along the major axis : arrow aNoneAll authors contributed to patient care. YH conceived the idea for the study and wrote the manuscript. NH contributed to the editing of the manuscript.An IRB approval is not required because this is a case report.Written informed consent was obtained from the patient for publication."}
+{"text": "Cytomegalovirus (CMV) infection in renal transplant recipients (RTR) impacts morbidity, mortality, and graft survival. Patients are risk-stratified based on their CMV serostatus as low risk (D-/R-), moderate risk (R+), and high risk (D+/R-). Most transplant centers conduct surveillance for CMV reactivation using quantitative nucleic acid testing (qNAT) at regular intervals for a fixed duration after transplantation. Antiviral treatment decisions are often guided by quantitative DNAemia. We hypothesize that the change in the qNAT platform to a newer, more sensitive assay lead to earlier CMV detection, longer antiviral treatment durations, and no difference in one-year all-cause mortality in moderate and high CMV risk RTR.We conducted a cohort study comparing RTRs monitored with the historical higher lower limit of quantification (LLOQ) qNAT  to the newer lower LLOQ qNAT assay . Patients were stratified by CMV serostatus for direct comparisons among moderate and high CMV risk patients. CMV viral load monitoring occurred at least monthly post-transplantation. Primary outcomes were antiviral treatment duration and time to detection of CMV DNAemia.Both the moderate and high CMV risk groups tested with the lower LLOQ qNAT assay exhibited lower peak viral loads and lower first detected viral loads (Table 1). Comparing moderate risk groups, lower LLOQ patients experienced longer CMV DNAemia and corresponding antiviral treatment durations. All-cause mortality risks were not significantly different between the lower LLOQ and higher LLOQ moderate risk patients. In Kaplan Meier analyses, moderate risk patients tested using the lower LLOQ qNAT assay had CMV reactivation detected earlier following cessation of antiviral prophylaxis compared with patients tested using the higher LLOQ assay.Table 1Lower LLOQ and higher LLOQ moderate and high-risk group comparisons for follow up time, CMV DNAemia incidence rate, peak CMV DNAemia, first CMV viral load detected, CMV DNAemia duration, and duration of antiviral treatment. Means, standard deviations, and t-tests are reported where applicable.Moderate Risk KM ComparisonKaplan Meier curve analysis comparing time to first episode of CMV DNAemia for higher LLOQ moderate risk patients (n=523) with lower LLOQ moderate risk patients (n=505) over a one year follow up period after transplantation. A log-rank test was performed and shows a statistically significant difference  in time to CMV DNAemia between the two groups. The median survival for the lower LLOQ group was 300 days and could not be calculated for the higher LLOQ group given that the survival probability was greater than 50% at the end of the study period.High Risk KM ComparisonKaplan Meier curve analysis comparing time to first episode of CMV DNAemia for higher LLOQ high risk patients (n=103) with lower LLOQ high risk patients (n=90) over a one year follow up period after transplantation. A log-rank test was performed and showed no significant difference  in time to CMV DNAemia between the two groups. The median survival for the lower LLOQ group was 335 days and could not be calculated for the higher LLOQ group given that the survival probability was greater than 50% at the end of the study period.qNAT assays with a lower LLOQ result in earlier CMV DNAemia detection and longer antiviral treatment durations in moderate-risk RTRs without affecting all-cause mortality. These findings have important implications for healthcare associated costs and antiviral stewardship.All Authors: No reported disclosures"}
+{"text": "Biliary access in patients with altered anatomy represents a limitation of endoscopic retrograde cholangiopancreatography (ERCP), with Roux-en-Y reconstruction being one of the most challenging postoperative variantsA 64-year-old woman with a history of a choledochal cyst treated with bile duct resection and hepaticojejunostomy 25 years previously was referred with recurrent cholangitis due to an anastomotic stricture and large intrahepatic stones. Previous anastomotic stricture dilation had not prevented further stone formation, and surgical revision was not considered an optimal option. Percutaneous transhepatic drainage (PTD) was performed, with an 11-Fr sheath placed, which was followed by cholangioscopy  . A signVideo\u20061\u2002Percutaneous cholangioscopy with placement of a biodegradable stent for stone disease on a background of a postanastomotic biliary stricture.Remodeling of the anastomotic stricture was attempted using an endoscopic balloon-expandable biodegradable stent system . A cholangiogram confirmed the presence of residual stone burden above the anastomotic stricture . An extPercutaneous cholangioscopy combined with biodegradable stent placement represents a novel approach in the management of stones above biliary strictures in patients with surgically altered anatomy.Endoscopy_UCTN_Code_TTT_1AR_2AG"}
+{"text": "Dear Editor, on the prognostic role of platelet-leukocyte indices incongenital cardiac surgical subset with pulmonary hypertension (PH) is indeedinteresting, and the authors should be congratulated for their admirable endeavors.However, I wish to bring forth few additional insights into the topic that could bebeneficial to the readers of the BJCVS.The recently published \u201cRetrospective Evaluation of Platelet-Leukocyte Indices andCardiac Surgical Outcomes in Acyanotic Heart Disease Patients with PulmonaryHypertension (REPLICA-PH)\u201d study by Walian et al.,3. While Walian et al. have evaluated neutrophil-lymphocyte ratio (NLR),platelet-lymphocyte ratio, and systemic immune-inflammation index (SII = neutrophil\u00d7 platelet/lymphocyte) in their retrospective analysis, Fois et al. recently described other hematologicalinflammatory indices such as the systemic inflammation response index (SIRI = NLR\u00d7 monocyte) and the aggregate index of systemic inflammation (AISI = NLR \u00d7platelet \u00d7 monocyte or SII \u00d7 monocyte) in the setting of coronavirusdisease 2019 (or COVID-19).Inflammatory prognostication using hematological cell lines is an evolving field with thenovel composite indices being increasingly studied across diverse clinicalscenarios. Hence, a comparative account of SIRI and AISI in the favorable andpoor-outcome groups in the Walian et al. analysis could have added an incremental value.Recent research outlines monocyte corpuscular lineage as an important contributor to anongoing systemic inflammatory process\u201cerr on either side of the pulmonarycapillary\u201d. The provision of the PVR data could have substantiated theauthors\u2019 proposition of inflammatory links of proliferative remodeling of pulmonaryvasculature in the congenital cardiac surgical subset with an underlying increasedpulmonary blood flow.Moreover, the lack of data on pulmonary vascular resistance (PVR) in the index of theretrospective study also deserves equal attention. The research group circumspectlylabels the study cohort to be suffering from preoperative PH and not pulmonary arteryhypertension, refraining to , future researchendeavors exploring haematological inflammatory prognostication in a dedicated syndromicsubset can yield potentially interesting results.Although the authors excluded multisystem syndromic association from theiranalysis"}
+{"text": "Cognitive (dys)function after ECT is often considered as a homogeneous phenomenon across patients. However, there are important inter-individual differences, with some patients experiencing residual invalidating cognitive deficits. We present the results of a study combining both group-level and individual-level analyses of cognitive function using an extensive cognitive test battery that was assessed in 73 patients at 5 time points during their ECT care pathway. Furthermore, we explored the presence of distinct subgroups of patients with a similar cognitive trajectory over time after treatment with ECT using Latent Class Growth Analysis.None Declared"}
+{"text": "Ankylosing spondylitis (AS) is a chronic inflammatory disease involving the sacroiliac joint and axial spine. AS may render the ankylosed spine prone to trauma and cause an increased frequency of associated epidural hematomas in spine fractures. Herein, we report a rare case of L5 chance fracture and epidural hematoma in a 27-year-old female patient with AS. She was treated surgically but without bone fusion or decompressive laminectomy due to the neurologically intact status despite significant neural compression by the spinal epidural hematoma (SEH). We believe that conservative treatment with close observation of neurological status may be effective in SEH presenting with mild neurological symptoms despite significant neural compression. Ankylosing spondylitis (AS) is a chronic inflammatory disease of the sacroiliac joint and axial spine that is closely linked to human leukocyte antigen (HLA)-B27 . ChronicA 27-year-old female patient with a 5-year history of AS was admitted to the emergency room (ER) with severe low back pain (LBP) radiating to both lower extremities. She had a history of accidental fall from chair on the same day. She had been treated with selective Cox-2 inhibitor and TNF-\u03b1 antagonist to alleviate pain and to recover physical functions for 2 years before accident. Medical treatment was continued through consultation with rheumatologist. Despite severe LBP and radiating pain, neurological examination revealed no bilateral motor or sensory deficits in the legs. The deep tendon reflexes were normoreactive, and there were no neurological abnormalities related to cauda equina syndrome such as bladder or bowel dysfunction. Simple radiography and computed tomography (CT) revealed a discontinued ossified paraspinal ligament and Chance fracture of the L5 vertebra extending into the posterior elements Fig.\u00a0. MagnetiAS is an inflammatory rheumatic disease involving the bones and ligaments of the spine. The most characteristic features of AS are syndesmophytes and ankylosis, resulting in ossification of the entire spine. Another important feature is low bone mineral density as a result of chronic inflammation and diffuse atrophy . These tLower lumbar fractures accompanying SEH are extremely rare, even in patients with AS. We believe that close observation and medical management can be an effective way to cause spontaneous regression of SEH in patients presenting with mild neurological symptoms."}
+{"text": "These processes are crucial for the proper function of excitable and non-excitable cells. Keeping plasma K+ within such a narrow range is a constant challenge because the extracellular [K+] can be easily disturbed either by potassium intake as daily intake can be equal to the overall amount of extracellular [K+], or by intra-to-extracellular K+ shift given the intracellular [K+] is much higher than the extracellular [K+]. Hence, dyskalemia is common and occurs in many conditions . In thisure see . The Chosure see . Further+ secretion takes place in the distal nephron and is mediated by K+-secreting channels of small and big conductance . ROMK and BK are exquisitely regulated by dietary K+ intake, a regulation that also involves the potassium counteranion  is essential in regulating BK protein levels. The authors found that the knockdown of SPAK decreased, whereas SPAK overexpression increased BK protein abundance. The stimulatory effect of SPAK requires inhibiting BK lysosomal degradation, mediated by ERK1/2 signaling. They showed that SPAK-KO mice exhibit decreased BK channel abundance and a total absence of BK current in the cortical CD\u2019s principal cells (PCs). Their study expands a previously suggested model in which WNK1 activates BK by inhibiting its ERK1/2-mediated lysosomal degradation   , indicat"}
+{"text": "We present findings on cine magnetic resonance imaging (MRI) using steady-state free precession (SSFP) pulse sequences in a patient with pulmonary arteriovenous malformation (PAVM). The technique has the advantage of demonstrating the pulsation of lesions during the cardiac cycle on cine images. It may not replace but may complement other MRI sequences in the characterization of pulmonary lesions in selected cases. To our knowledge, no prior video of cine images of PAVM has been provided in the literature. Pulmonary arteriovenous malformation (PAVM) is an abnormal communication between pulmonary arteries and pulmonary veins, creating a right-to-left shunt.\u00a0PAVMs are usually associated with hereditary hemorrhagic telangiectasia (HHT), inherited in an autosomal dominant pattern There is an estimated cerebral abscess risk of 5%-19% and a 9%-18% risk of ischemic stroke in those who manifest PAVM [Transthoracic contrast echocardiography (TTCE) is the preferred initial screening test. This test allows for potential shunt identification in suspected PAVM cases. TTCE has a high sensitivity and negative predictive value of 97% and 99%, respectively. Unfortunately, it has a high false positive rate and cannot localize lesions . ContrasA 53-year-old female with a history of acute ischemic stroke had an extensive workup, including transesophageal echocardiogram (TEE), which suggested a patent foramen ovale (PFO). However, there was no PFO demonstrated on intracardiac echocardiography (ICE) imaging during attempted closure. A bubble study performed during ICE showed a late crossing of bubbles suggesting a pulmonary shunt. CTPA\u00a0demonstrated a simple PAVM\u00a0in the right middle lobe\u00a0Figures ,\u00a02A-2D.Incidentally, this PAVM appeared as a pulsating lesion on cine cardiac MRI images using steady-state free precession (SSFP) sequences Video .Classification of PAVMs is based on the number of feeding arteries. The simple type has one segmental feeding artery, whereas the complex type has two or more segmental feeding arteries . This clCT techniques, without and with contrast, are most commonly used in the initial evaluation and follow-up of patients with PAVM or risk of developing PAVM. Cumulative radiation dose may be substantial in patients with HHT secondary to repeated diagnostic and therapeutic interventions .SSFP cine MRI sequence may not replace currently used MRI sequences since this sequence type and protocol is typically used for a small field of view rather than the entire lungs. It may complement currently used MRI sequences by demonstrating pulsation of the lesions on cine images.The unique feature of the technique may help the characterization of pulmonary lesions since certain vascular and non-vascular abnormalities may mimic PAVM . Non-vasSSFP cine MRI demonstrates potential in aiding initial diagnosis and follow-up of PAVM in conjunction with other MRI sequences. Optimization of the technique and comparative studies are required to determine the value of this technique to complement established MRI sequences in selected cases."}
+{"text": "Plummer-Vinson syndrome (PVS) or Paterson-Brown-Kelly syndrome is a rare clinical condition characterized by the triad of esophageal webs/stenoses, iron-deficiency anemia, and progressively worsening dysphagia. It occurs mostly in Caucasian women in the fourth to seventh decades, particularly in northern countries. Esophageal webs and stenoses can be encountered during endoscopic evaluation for the patient\u2019s complaint of dysphagia. Esophageal stenoses are characterized as simple or complex. A stenosis should be considered refractory once the patient has undergone several sequential dilatations within short intervals, optimized treatment for potential underlying causes (eosinophilic esophagitis or acid reflux), and after neuromuscular causes have been excluded. Glucocorticoid injection into a stenosis during an endoscopic dilation session has been proven to be beneficial as the initial treatment modality of refractory nonmalignant esophageal stenoses. We present a case of a 39-year-old woman with refractory esophageal stenosis in the setting of PVS which was successfully treated with serial endoscopic glucocorticoid injections while she received oral iron supplementation. To our knowledge, there are no previous cases of esophageal stenoses associated with PVS in the literature requiring endoscopic glucocorticoid injection for successful resolution. Plummer-Vinson syndrome (PVS) or Paterson-Brown-Kelly syndrome is a rare clinical condition characterized by the triad of esophageal webs/stenoses, iron-deficiency anemia, and progressively worsening dysphagia . When thA 39-year-old woman presented to our clinic complaining of weight loss of 3.2 kg associated with dysphagia for three months. Her past medical history was significant for hypothyroidism, chronic menorrhagia, and gastroesophageal reflux disease. She had a surgical history of laparoscopic cholecystectomy and a prior cesarean section. She reported progressively worsening dysphagia to solid foods and pills with chronic heavy menstrual periods. She was referred to a gynecologist due to chronic menorrhagia and was treated with intramuscular medroxyprogesterone acetate every 12 weeks which stopped the episodes of menorrhagia. Due to pill dysphagia, she was started on ferrous sulfate solution 220 mg orally twice daily and she remained adherent with iron supplementation throughout her entire clinical course. Her weight was 47.6 kg (baseline 55-60 kg). The complete blood count and iron panel were obtained before and one month after oral iron supplementation (Table A prior esophagogastroduodenoscopy (EGD) performed four years ago for dysphagia was normal. A repeat EGD was performed where she was found to have a benign-appearing 8 mm stenosis due to an upper esophageal web which was located 15 cm from the incisors  balloon dilator.\u00a0Biopsies of normal-appearing esophageal mucosa in the upper and lower third of the esophagus were negative for eosinophilic esophagitis (EoE) showing\u00a01-2 eosinophils per high-power field (15 or more eosinophils per high-power field is diagnostic of EoE).\u00a0She had a total of three sessions of endoscopic dilation in two to three-week intervals without improvement of the stenosis beyond 10 mm.\u00a0On her fourth EGD, the upper esophageal stenosis was dilated to 15 mm with a TTS balloon  during all esophageal dilations.\u00a0With each endoscopic dilation, she reported improvement in her symptoms and eventually returned to a regular diet.\u00a0Wireless pH monitoring over a 48-hour period (off of acid-suppressive medication for seven days) was done after the patient declined catheter-based pH monitoring and was negative for pathologic acid reflux .\u00a0There was no gastrointestinal cause for anemia found on subsequent colonoscopy and small bowel video capsule endoscopy. Following medical therapy with iron supplementation and endoscopic therapy with triamcinolone\u00a0and progressive TTS balloon dilations, she was found to have a weight of 64 kg (an increase of 20.9 kg from nadir).Esophageal stenosis should be considered refractory once a patient has undergone several sequential dilatations within short intervals, optimized treatment for potential underlying causes (eosinophilic esophagitis or acid reflux), and after neuromuscular causes have been excluded . NonmaliThere is a lower risk of stenosis recurrence and fewer sessions of serial endoscopic dilation associated with endoscopic glucocorticoid injection. A meta-analysis  involving 176 patients with refractory esophageal stenoses, glucocorticoid injection plus endoscopic dilation resulted in a lower risk of stenotic recurrence  = 0.51-0.81) and fewer endoscopic dilation sessions compared with dilation alone  [In the iron-deficient state in PVS, the gastrointestinal tract is susceptible and rapidly loses iron-dependent enzymes due to a high cell turnover, which leads to mucosal degeneration and web formation. Alternative proposed etiologies include genetic predisposition, malnutrition, and autoimmune processes . FollowiIt is unclear if the etiology of the stenosis influences the effect of steroid injection . The useOur success with regard to treating benign esophageal stenosis in our patient highlights the importance of considering endoscopic glucocorticoid injection as an initial treatment for refractory benign esophageal stenoses.To our knowledge, there have not been any previous cases of esophageal stenoses associated with PVS in the literature requiring endoscopic glucocorticoid injection for successful resolution. This case also shows the safety and feasibility of performing endoscopic triamcinolone injections for nonmalignant esophageal strictures, especially in the community-based hospital setting where access to metal, plastic, or biodegradable esophageal stents may be limited."}
+{"text": "Endoscopic omental packing (EOP) is a technique used to close gastric perforations and is particularly useful for large defectsPerforation occurred during ESD for gastric cancer in the greater curvature of the lower body. Although conventional EOP was performed  and subVideo\u20061\u2002Endoscopic omental packing in combination with the clip-and-snare method using pre-looping technique for gastric perforation.The patient\u2019s subsequent clinical course was good and scarring of the post-ESD ulcer was confirmed .CSM-PLT represents a simple and reliable method for EOP. Previous reports demonstrated the effectiveness of EOP for gastric wall closure after endoscopic full-thickness resectionEndoscopy_UCTN_Code_CPL_1AH_2AZ"}
+{"text": "A 7-year-old girl with sickle cell trait was admitted with inability to bear weight and a painful rash. Examination demonstrated retiform purpura (RP) of the right leg Fig. A with teRP presents as branching purpuric patches and develops when dermal and subcutaneous blood vessels are compromised by vessel wall damage or lumen occlusion causing pain, necrosis, and ulceration . Underly"}
+{"text": "Teaching Point: High-pressure injection injuries are clinically significant injuries which may be underappreciated on initial physical exam and which require a high index of suspicion and early clinical intervention to avoid negative outcomes. A 46-year-old female presented to the ER with diffuse swelling of the left hand after attempting to fill a balloon from a helium tank. The patient\u2019s distal thumb exhibited a punctate entry wound, pale tense skin, and absent capillary refill. Radiographs showed extensive diffuse subcutaneous emphysema consistent with helium insufflation  injury. High-pressure injection injuries are caused by high-pressure delivery devices such as paint guns or pressurized gas tanks . Injury"}
+{"text": "Magnetic resonance imaging (MRI) is the primary methodfor noninvasive investigations of the human brain in health, disease, anddevelopment but yields data that are difficult to interpret whenever themillimeter-scale voxels contain multiple microscopic tissue environmentswith different chemical and structural properties. We propose a novel MRIframework to quantify the microscopic heterogeneity of the living humanbrain as spatially resolved five-dimensional relaxation\u2013diffusiondistributions by augmenting a conventional diffusion-weighted imagingsequence with signal encoding principles from multidimensional solid-statenuclear magnetic resonance (NMR) spectroscopy, relaxation\u2013diffusioncorrelation methods from Laplace NMR of porous media, and Monte Carlo datainversion. The high dimensionality of the distribution space allowsresolution of multiple microscopic environments within each heterogeneousvoxel as well as their individual characterization with novel statisticalmeasures that combine the chemical sensitivity of the relaxation rates withthe link between microstructure and the anisotropic diffusivity of tissuewater. The proposed framework is demonstrated on a healthy volunteer usingboth exhaustive and clinically viable acquisition protocols. To measure and map thecellular architecture and molecular composition of the living human brain isa challenging experimental endeavor that promises far-reaching implicationsfor both clinical diagnosis and our understanding of normal brain function.Over recent decades, magnetic resonance imaging (MRI) methods have beencrucial for the progress of neuroanatomical studies .Most clinical MRI applications rely on detecting More detailed information can be obtained by taking into account that eachMRI voxel comprises hundreds of thousands of cells with potentiallydifferent properties, implying that the per-voxel signal may includecontributions from multiple microenvironments with distinct values of theMRI observables. To resolve the various microenvironments within a singlevoxel remains a highly challenging problem of vital importance for theprogression of quantitative MRI studies. The signals from heterogeneousmaterials are often approximated as integral transformations ofnonparametric distributions of relaxation rates or diffusivities, which may be estimated by Laplaceinversion of data acquired as a function of the relevant experimentalvariable . Within the context of humanbrain MRI, the components of the distributions have been assigned to waterpopulations residing in specific tissue microenvironments such as myelin and tumors . The powerto resolve and individually characterize the different components can beboosted by combining multiple relaxation- and diffusion-encoding blocks andanalyzing the data as joint probability distributions of the relevantobservables . These ideas follow the principlesof multidimensional nuclear magnetic resonance (NMR) spectroscopy and formthe basis for multidimensional Laplace NMR which has become routine in thefield of porous media  and is now being combined with MRI . Recently, similar relaxation\u2013diffusioncorrelation protocols have been translated to in vivo studies using model-basedrather than nonparametric data inversion . So far, relaxation\u2013diffusion correlation studieshave relied on the Stejskal\u2013Tanner experiment , a pulsed gradient spin-echo (PGSE) sequence that has been inuse for more than 50\u00a0years and where the signal is encoded for diffusionalong a single axis using a pair of collinear gradient pulses. Thelimitations of the conventional experimental design become apparent whenconsidering a white matter voxel comprising anisotropic domains withmultiple orientations. When projected onto the measurement axis defined bythe magnetic field gradients, the combination of diffusion anisotropy andorientation dispersion gives rise to a broad distribution of effectivediffusivities  that is challenging toretrieve with nonparametric Laplace inversion and, most importantly,impossible to differentiate from a spread of isotropic diffusivities. Consequently, despite the fact that therelaxation\u2013diffusion correlation yields more detailed information thanconventional quantitative MRI, the inherent limitations of theStejskal\u2013Tanner experiment prevent unambiguous discrimination betweenisotropic and anisotropic contributions to the diffusivity distributions aswell as model-free resolution of tissue microenvironments for heterogeneousanisotropic materials such as brain tissue.We have recently shown that data acquisition and processing schemes forcorrelating isotropic and anisotropic nuclear interactions inmultidimensional solid-state NMR spectroscopy  can be translated to diffusion NMR , relaxation\u2013diffusion correlation NMR, and diffusionMRI , yielding nonparametric diffusion tensordistributions  with resolution of multipleisotropic and anisotropic diffusion components. These \u201cmultidimensionaldiffusion MRI\u201d methods  rely onvarying both the amplitude and orientation of the magnetic field gradientswithin a single encoding block in order to mimic the effects of samplereorientation  and rotor-synchronized radiofrequency pulse sequences  in multidimensional solid-stateNMR to target specific aspects of the tensorial property being investigated.Here, we incorporate these ideas into a clinically feasiblerelaxation\u2013diffusion correlation MRI protocol to quantify the microscopicheterogeneity of the living human brain. The suggested acquisition andanalysis protocols resolve tissue heterogeneity on a five-dimensional spaceof transverse relaxation rates and axisymmetric diffusion tensors thatreport on the underlying chemical composition and microscopic geometry.Nonparametric relaxation\u2013diffusion distributions are obtained for each voxelin the three-dimensional image using Monte Carlo data inversion to deal withthe nonuniqueness of the Laplace inversion and estimate the uncertainty ofquantitative parameters derived from the distributions. Subvoxel tissue environmentsare resolved without limiting assumptions on the number or properties of theindividual components and are characterized with statistical measures that haveintuitive relations with the local microstructure.22.1Figure\u00a01a displays a pulse sequencewherein the signal Throughout the signal encoding process, the relaxation and diffusion ofwater are both affected by molecular exchange between chemically differentsites and interactions with cell membranes. Averaging all these complexeffects into sets of effective relaxation rates and apparent diffusiontensors, subvoxel composition can be reported as a collection ofindependent tissue microenvironments, each of which is characterized by aset of  was scanned on a Siemens MagnetomPrisma 3T system equipped with a 20-channel-receiver head coil, and capableof delivering gradients of 80\u202fmT\u202fmhttps://github.com/jsjol/NOW,last access: 1\u00a0November\u00a02019), including compensation for theeffects of concomitant gradients . This procedure yielded a pair of asymmetric gradient waveforms lasting30.8 and 25.0\u202fms, separated by approximately 8.0\u202fms. Linear encoding and gradient waveforms shown inFig.\u00a01. The depicted waveforms give fourdistinct A total of 852 individual images were recorded at different combinations of have beenreviewed in both general  and magneticresonance  literature.While classical inversion methods can be successfully used to estimate the5D The procedure described above is performed voxel-wise, resulting in an arrayof spatially resolved Following the works of Prange and Song , we replace traditional regularization constraints with an unconstrained Monte Carlo approachthat estimates voxel-wise ensembles of https://github.com/JoaoPdAMartins/md-dmri(last access: 25\u00a0February\u00a02020) .Inversion of the 45\u202fmin dataset took The nonparametric Monte Carlo inversion procedure was implemented in MATLABand is publicly available in our GitHub repository: 33.1The proposed acquisition protocol translates into distinctive signal decaycurves for each of the main components of the human brain. Indeed, voxelsencompassing either white matter (WM), gray matter (GM), or cerebrospinal fluid (CSF) are all characterized by clearly distinct signal patterns . The observeddifferences can be used to infer the gross Spatially resolved 5D Voxels containing pure GM or WM are characterized by clusters ofAs evidenced by Fig.\u00a02c, pure GMvoxels yield bimodal distributions that feature a nearly symmetric spread ofcomponents around the 3.2The The three maps in the first column of Fig.\u00a03 provide a rough spatial overview of the principal tissue types: The maps displayed in Fig.\u00a03 can also beused to identify voxels containing WM3.3A more detailed picture of intra-voxel heterogeneity is obtained by dividingthe distribution space into smaller subspaces (\u201cbins\u201d). In line with earlydiffusion MRI works , we definethree bins that loosely capture the diffusion properties of theGlobal and bin-resolved averages for all the analyzed voxels of the entire3D image matrix are compiled in Fig.\u00a05,where per-voxel average means of The minor differences between the relaxation rates of the thin and thickcomponents are also observed in the scatter plots ofFig.\u00a05. A more detailed analysis showsthat distinct All bin-resolved The 3.4The acquisition protocol discussed thus far can be inserted without furtheralterations in research studies of brain disease, where subjects arerecruited for long scan sessions. However, the associated 45\u202fmin scan timeimpedes its use outside of a clinic-research setting. To assess thepotential for clinical translation of the proposed framework, we compare theperformance of the exhaustive 45\u202fmin protocol with that of an abbreviatedprotocol, compatible with the time frame of most clinical applications. Tothis end, we included two different 5D relaxation\u2013diffusion MRI protocols ina single imaging session: the 45\u202fmin protocol described in the Methods section, andan abbreviated 15\u202fmin protocol whose details are contained in theSupplement. The two acquisition protocols were consecutively used withoutrepositioning the volunteer.The abbreviated dataset was inverted with the Monte Carlo algorithmdescribed above. The resulting 5D 4The proposed framework resolves intra-voxel heterogeneity on a 5D space oftransverse relaxation rates The protocol presented in this work shows promise for neuroanatomy studiesdealing with the resolution of specific microscopic features such as nervefiber-tracking through heterogeneous voxels  orfree water mapping . Within a clinicalsetting, disentangling different tissue signals is expected to be useful forpathological conditions associated with intra-voxel tissue heterogeneity,e.g. tumor infiltration in surrounding brain tissue, inflammation of cerebraltissue, or replacement of myelin with free water. In the latter example, theproposed echo times lead to an almost complete decay of the signalcontributions from myelin domains, meaning that the effects of axonaldemyelination would have to be probed indirectly by tracking a reduction ofthe signal fraction from anisotropic subvoxel components.Several approaches have been introduced in the diffusion MRI literaturewhere subvoxel composition is investigated by devising signal models withincreasingly complex priors and constraints . While such models can be used toinvestigate the conditions mentioned in the above paragraph, the attainedconclusions will be heavily dependent on the assumptions used to constructthe model . Hence, erroneousconclusions may be derived whenever the presupposed MR properties differfrom the underlying microstructure . Thislimitation is alleviated in the present framework where subvoxelheterogeneity is quantified with nonparametric distributions that areretrieved from the data with minimal assumptions on the underlying tissueproperties. Moreover, the vast majority of diffusion MRI models has been sofar implemented with conventional Stejskal\u2013Tanner sequences, which are knownto convolve the signal contributions from Besides resolving the various microscopic domains within a voxel, we werealso capable of observing subtle differences in component-specificrelaxation rates. As mentioned before, this information is unattainable withclassical multi-echo At the cellular level, the translational motion of water inside the humanbrain is influenced by interactions with macromolecules and partiallypermeable membranes forming compartments with barrier spacings ranging fromnanometers for synaptic vesicles and myelin sheaths to micrometers for theplasma membranes of the axons. The diffusion of water during the 0.1\u202fstimescale of MRI signal encoding is thus affected by a myriad of complexphenomena that are not explicitly accounted for in Eq.\u00a0(2). Instead, we use the well-established approachof approximating the micrometer-scale water displacements as a distributionof anisotropic Gaussian contributions . Themeasured diffusivities may depend on the exact choice of experimentalvariables if the timing parameters of the gradient waveforms match thecharacteristic timescales of displacements between cellular barriers or molecular exchange between tissue environmentswith distinctly different diffusion properties . Byaugmenting our acquisition protocol with an experimental dimension in whichthe spectral profiles of the gradient waveforms are comprehensively varied, microscopic barrier spacings could in principle be estimated byexplicitly including the effects of restricted diffusion in the kernel ofEq.\u00a0(2). Here we chose to minimize the influence oftime dependence by designing waveforms with similar gradient-modulationspectra.In the previous section, we mentioned that prolate . Recently, Veraart et al.\u00a0(2017) estimated subtle differences in This work introduces and demonstrates a novel MRI framework, in which themicroscopic heterogeneity of the living human brain is characterized via 5Dcorrelations between the transverse relaxation rate 10.5194/mr-1-27-2020-supplementThe supplement related to this article is available online at:\u00a0https://doi.org/10.5194/mr-1-27-2020-supplement."}
+{"text": "Specialist palliative care (PC) is a limited resource, best conserved by identifying persons most likely to benefit from a PC consult. Little guidance is available for clinicians on whether/ when to consult PC. The authors previously developed empirically-derived consult criteria to guide burn providers in specialist PC consultation, refining them by expert panel input.A modified three-iteration Delphi process was employed to revise and develop consensus on empirically-derived PC consult criteria in burn patients. Eligible participants (N=202) were identified by (a) having published on burn and PC (b) presented nationally on burn and PC or (c) nomination by the study team as having equivalent expertise in the field.Forty-three individuals participated in Iteration 1; n=34 (79%) in Iteration 3, which rank-ordered three versions of criteria and invited further revisions. Consensus eliminated the most parsimonious version. Expert review panelists integrated feedback, yielding a consensus list with 6 criteria for PC consultation and 6 criteria for consideration of PC consult. Consult criteria include patient/family request; conflicted or unclear goals of care; and high modified Baux/SCORTEN scores. Criteria for consideration include no longer meeting milestones; assistance with symptom management; or cardiac arrest.Consensus among burn and PC providers enhances validity and supports clinical use to guide burn providers on patients most likely to benefit from specialist PC consultation. Future research should prospectively explore whether adherence to the criteria is associated with improved outcomes and potential further revision.Provides guidance on PC consultation and may be used to examine outcomes."}
+{"text": "When removing large flat colonic polyps (LFCPs) en bloc endoscopic submucosal dissection (ESD) may be suitable; however, it requires significant expertise and a long procedural time. The use of a conventional monopolar snare for endoscopic mucosal resection (EMR) of large lesions increases the risk of deep mural injuryThe Dragonare dedicated bipolar soft snare  has a unique mechanism where one electrode is at the tip of the snare and the other at the sheath, which allows uniform cauterization of the tissue. The soft nature of the snare allows stabilization of its tip at the distal margin of the lesion while opening the snare, thereby enabling en bloc resection of LFCPs. This requires a slower cutting technique compared with monopolar devices. Herein, we report two cases in which EMR was performed using the bipolar soft snare (26\u200amm) for LFCPs .Video\u20061\u2002Two cases in which endoscopic mucosal resection is performed using a dedicated bipolar soft snare (26\u200amm) for large flat colonic polyps.The first patient was a 78-year-old man who had a 25-mm nongranular laterally spreading tumor (LST) found in his descending colon . AlthouThe second patient was an 86-year-old man who had a 30-mm granular-type LST found in his ascending colon . InjectBEMR with dedicated snares could be a new alternative when treating LFCPs. ESD can be replaced with BEMR for eligible polyps.Endoscopy_UCTN_Code_TTT_1AQ_2AD"}
+{"text": "A 25-year-old man with recently diagnosed acquired immunodeficiency syndrome (AIDS) was referred for consultation because of multiple intraoral lesions that had developed within past 2 months. Physical examination revealed diffuse multinodular purplish-red lesions with spontaneous bleeding affecting both the maxillary and mandibular gingiva . Histopa,KS is a multifocal angioproliferative disorder associated with HHV-8All procedures involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards."}
+{"text": "Magnetic resonance imaging-guided prostate biopsies have revolutionized the detection of clinically significant prostate cancer (csPCa) within the last decade . Using aThe authors of the study presented here have done a well thought out analysis to determine the distance between systematic cores containing csPCa and the ROI in 505 consecutive patients undergoing TB plus SB . This prIn 2019, the PIRADS-committee recommend TB of the ROI and a 5-mm penumbra for PIRADS 4 and 5 lesions . MoreoveIn conclusion, this study significantly contributes to the understanding of perilesional sampling in men undergoing prostate biopsy. However, confirmatory studies are needed to show if a risk-group based approach by PIRADS-score and PSA density has the potential to set up TB plus perilesional sampling biopsies as a new standard."}
+{"text": "However, in case of preoperatively confirmed lymph node metastasis to the neck, patients are generally precluded surgery. The concurrent palliative treatment approach is associated with a limited 1 year survival of 32\u201339%. An alternative treatment approach would be neoadjuvant chemoradiotherapy followed by robot-assisted minimally invasive esophagectomy (RAMIE) with three-field lymphadenectomy, including the cervical lymph nodes. Whether this would be feasible and safe for the Western population was unclear up to now.Esophageal cancer remains a devastating disease, of which the incidence is increasing.2 Moreover, postoperative complications are comparable to those reported after curative treatment by high-volume centers and randomized trials. Overall 1 year survival was higher (85%) than reported for palliative treatment approaches, though this was not a primary endpoint for this study. An important finding was the high rate of interval metastasis in patients presenting with concomitant celiac trunk lymph node metastasis as well as poorly differentiated tumors. Additionally, patients rarely had cervical lymph node metastasis contralateral to the preoperatively detected cervical lymph node metastasis.This study shows that robot-assisted minimally invasive esophagectomy (RAMIE) with three-field lymphadenectomy is feasible in patients with resectable esophageal cancer presenting with cervical lymph node metastasis in a Western population.3 followed by restaging before entering the NODE treatment. The other patients will receive upfront the NODE protocol as described here. A bilateral cervical lymph node has been found unnecessary and will be replaced by a unilateral dissection. This study will compare the survival of patients who receive this treatment protocol with palliatively treated patients in the population.The results of this study will be used to design a nationwide multicenter study. In this prospective cohort trial, patients with celiac trunk metastasis or poorly differentiated tumors will first receive a potent systemic therapy [fluorouracil + leucovorin + oxaliplatin + docetaxel (FLOT) combined with trastuzumab for Her2-Neu-positive tumors] combined with immunotherapye"}
+{"text": "Medicare Part D prescription drug plans must offer medication therapy management (MTM) services to qualified enrollees. Eligibility criteria used by plan sponsors are restrictive, and fewer than 10% of Part D enrollees receive MTM services. The extent to which plan criteria identify beneficiaries most at risk for suboptimal medication use is unknown.To (a) evaluate potential underuse of and poor adherence to evidence-based medications used in the treatment of Medicare beneficiaries with diabetes, heart failure, and chronic obstructive pulmonary disease (COPD) over 3 years; (b) determine whether MTM eligibility criteria used by the modal Part D plan in 2011  identified Part D enrollees at greatest risk for underuse of and poor adherence to these drugs; and (c) demonstrate how sensitive MTM eligibility is to variations in criteria levels.Study subjects were selected from a 5% random sample of Part D enrollees with 1 or more of these diseases in 2006 and followed through 2008 or death. Longitudinal patterns of exposure and adherence to angiotensin-converting-enzyme inhibitor/angiotensin receptor blockers, beta-blockers, and COPD controller drugs were tracked comparing patterns for enrollees meeting/not meeting the modal 2011 MTM eligibility criteria.Use of evidence-based medication was consistently suboptimal for every disease cohort studied. Higher rates of exposure and adherence were observed among those with high drug spending taking multiple Part D drugs. Current MTM criteria were found to target beneficiaries with above average utilization of evidence-based medication and to exclude those with more problematic utilization patterns. We estimate that lowering the maximum required drug count from 8 to 2 would increase the percentage of beneficiaries eligible for MTM by two thirds.Our findings suggest that MTM eligibility criteria are not optimally targeted to capture underuse of and poor adherence to evidence-based medications. Policymakers should weigh the pros and cons of loosening restrictive MTM eligibility criteria to target patients with potentially greater needs."}
+{"text": "E. coli MutT protein, that degrades 8-oxodGTP to prevent the incorporation of potentially miscoding 8-oxodG during DNA replication [E. coli, MutT counteracts spontaneous mutagenesis and mutT mutants have one of the highest known spontaneous mutation rates. Consistent with a similarly powerful antimutagenic role, enhanced nucleotide pool editing in human or mouse cells overexpressing hMTH1 significantly reduces the extremely high spontaneous mutation rates that result from a defect in DNA mismatch repair [in vivo overexpression of hMTH1 in transgenic C57BL/6J mice (hMTH1-Tg mice) protects them against age-related increases in micronucleus frequency [The universality and inevitability of the aging process suggests that the underlying mechanisms are likely to be similar across animal species and that data from animal models can therefore potentially inform human aging. Recent experiments using an engineered mouse strain indicate a plausible role for the early acquisition of oxygen-related mutations in the aging process. Altered mitochondrial function and increased steady-state levels of reactive oxygen species (ROS) feature in several models of cellular senescence and aging. In general, cellular macromolecules  are regarded as the targets for damage by ROS. The nucleotide pool that provides DNA replication precursors is also a significant ROS target and oxidation damage to deoxynucleoside triphosphates is now implicated in influencing longevity. The major product of oxidation in the nucleotide pool \u2013 8-oxo-7,8-dihydrodeoxyguanosine triphosphate (8-oxodGTP) \u2013 is mutagenic. Human cells encode a nucleotide hydrolase hMTH1), the homolog of the , the homh repair . hMTH1 ah repair  and its h repair . In addirequency .hMTH1 overexpression in young hMTH1-Tg mice has a surprising impact on their general metabolism - including mitochondrial metabolism and the TCA cycle . At two The protective effect of hMTH1 overexpression is confined to young mice and the behaviour of adult (7-month-old) animals is strikingly different. By this age WT mice maintained on a normal laboratory diet appear free of stress related to nucleotide precursor oxidation and hMTH1 overexpression in the hMTH1-Tg mice has no detectable effect on their liver metabolome. Furthermore, a 5-week HFD challenge to these adult mice elicits little in the way of metabolic changes or other oxidative stress markers. The responses of adult WT and hMTH1-Tg mice are closely similar and the protective effect of hMTH1 overexpression is redundant in these adult mice.The canonical nucleotide hydrolase activity of hMTH1 is antimutagenic. Since the effects of its overexpression appear to be largely confined to young mice, it seems likely that this is related to the developmental pattern of these mice. The birth weights, subsequent growth rates and adult bodyweights of WT and hMTH1-Tg mice are indistinguishable. In both genotypes, growth is extremely rapid between conception and around 10 weeks after birth during which time the animals attain more than 80% of their final body mass . In WT min vitro models [The involvement of mutagenesis in aging is not straightforward. Aging affects everyone. By analogy, although only approximately one in three people will be diagnosed with cancer \u2013 a mutation-driven pathology - all three individuals will inevitably succumb to aging. Clearly the cancer paradigm of selection of key \u2018driver\u2019 mutations is unlikely to apply to aging. An alternative possibility is that all mutated genes are potential contributors to aging. They might do this via detrimental effects on the proteome that worsen with time. The altered primary sequence of a protein expressed from a mutated gene increases its risk of misfolding and misfolded proteins are highly susceptible to oxidation and aggregation. The powerful impairment of cellular systems by misfolded and oxidized proteins has been extensively documented in o models . Proteino models . On thisThe enhanced longevity of hMTH1-Tg mice is consistent with the prevention of early-life ROS-related mutations via nucleotide pool cleansing. It remains to be experimentally determined whether a reduced mutational burden extends their healthy lifespan by slowing the time-dependent accumulation of toxic misfolded and oxidized protein aggregates."}
+{"text": "Leiomyomas are benign smooth muscle tumors, and retroperitoneal leiomyomas without coexisting uterine leiomyomas are extremely rare. Mitotically active leiomyomas, which are leiomyomas with increased mitotic activity, are rarely observed in postmenopausal women, except under the influence of exogenous hormones. This report presents a rare case of a retroperitoneal mitotically active leiomyoma in a postmenopausal woman. The patient presented with an abdominal mass and underwent surgical resection of the retroperitoneal tumor. Pathological examination revealed a mitotically active retroperitoneal leiomyoma with 31 mitotic figures per 10 high-power fields. The patient did not experience recurrence during the 2-year follow-up period. This case highlights the need to consider retroperitoneal mitotically active leiomyomas in postmenopausal women and suggests that myomectomy can prevent their recurrence. Leiomyomas are benign smooth muscle tumors that represent the most common gynecological neoplasms ; howeverAn 82-year-old woman with an abdominal mass was referred to our hospital. She had previously undergone ovarian mucinous cystadenoma with bilateral salpingo-oophorectomy 3 years prior, and had uterine leiomyoma. Abdominal contrast-enhanced computed tomography revealed a well-defined heterogeneously enhanced mass near the left ovarian artery and ureter . No signDuring surgery, we observed a retroperitoneal tumor with a smooth surface at the back of the sigmoid mesentery . The tumPathological reports revealed a smooth muscle tumor with 31 mitotic figures per 10 high-power fields, but lacking cytologic atypia and tumor cell necrosis . Based oThe patient was doing well at the outpatient follow-up at 2\u00a0years, with no recurrence.The lessons learned from this case are as follows: (i) retroperitoneal mitotically active leiomyomas can occur in postmenopausal women and (ii) myomectomy does not result in tumor recurrence.Retroperitoneal mitotically active leiomyomas can be observed in postmenopausal women. Leiomyomas are non-cancerous monoclonal tumors that arise from smooth muscle cells and fibroblasts that can exhibit various types of smooth muscle differentiation. Although various atypical localizations of leiomyomas have been reported, growth in the retroperitoneum is extremely rare . AdditioEven after myomectomy of the retroperitoneal mitotically active leiomyoma, no recurrence or metastasis was observed during follow-up. In general, classic leiomyomas have the following features: mitotic index of <5 mitotic figures per 10 high-power fields, mild cytologic atypia and no tumor cell necrosis, whereas a diagnosis of leiomyosarcoma requires at least two of the following three features; mitotic index of \u226510 mitotic figures per 10 high-power fields, moderate to severe cytologic atypia or presence of tumor cell necrosis . SeveralIn conclusion, this case report indicated that mitotically active leiomyomas can occur after menopause and are curable by myomectomy without the need for postoperative chemotherapy or pelvic radiotherapy. Further studies are required to determine the optimal treatment for mitotically active retroperitoneal leiomyomas."}
+{"text": "The COVID-19 pandemic prompted healthcare organizations around the country to rapidly set up infusion centers that were solely dedicated to delivering outpatient COVID-19 monoclonal (mAb) and antiviral infusions. We capture the process of setting up these mAb infusion centers from the perspectives of key stakeholders. These lessons learnt may inform or refine actions in future pandemics.A realist interview approach was undertaken to evaluate the effectiveness of the program development with ten key stakeholders and healthcare workers who were involved. In contrast to traditional interviewing methods where a straight question leads to a straight answer, realist interviewing involves capturing the interviewees\u2019 experiences through conversations of teaching and learning. We interviewed ten key stakeholders and healthcare workers who were involved with developing the mAb infusion process from Dec 13th, 2021, to Jan 19th, 2022, over online videoconferencing.A causal mechanism diagram using a context-mechanism outcome configuration was identified. There was a rapid development of multiple infusion sites over a short time frame with dynamic staffing and patient appointment models leading to rapid increases in mAb infusion capacity in southwestern Virginia.Figure 1.Causal mechanism diagram using a CMO configuration for the successful attributes leading to eligible patients treated with monoclonal antibodies.Strong clinical leadership, a robust communication and feedback framework and shared goals were identified by stakeholders as pivotal in the success of a COVID-19 monoclonal antibody infusion program for a health care system. Pandemic preparedness strategies should hardwire and leverage these features for resiliency.All Authors: No reported disclosures"}
+{"text": "These signs are the characteristic of fibroblast growth factor 23 (FGF23)-related hypophosphatemic osteomalacia, and the serum FGF23 levels were high . Although she was suspected to have tumor-induced osteomalacia, systemic venous samplings of FGF23 and 111In-octreotide somatostatin receptor scintigraphy were unable to identify the tumor. Her symptoms and multiple uptake on bone scintigraphy almost disappeared after initiating active vitamin D and phosphate replacement , (2)lacement . AlthougNone Naoya Fujita wrote the first draft. Yosuke Ono suggested improvements and revised the manuscript.Written informed consent was obtained from the patient to publish this report in accordance with the journal\u2019s patient consent policy."}
+{"text": "An ectopic pregnancy occurs when an embryo implants outside of the uterus, usually in a fallopian tube. When detected early, treatment is often with a medication called methotrexate. When methotrexate does not work, surgery is required. A recent clinical trial of ectopic pregnancy treatment  found that adding a drug called gefitinib to methotrexate did not reduce the need for surgery. We have used data from the GEM3 trial, combined with data collected 12 months after the trial finished, to investigate post-methotrexate pregnancy outcomes. We found no difference in pregnancy rates, pregnancy loss rates and recurrent ectopic pregnancy rates between those treated medically only and those who subsequently also needed surgery. The surgical technique used also did not affect pregnancy rates. This research provides reassurance that women with ectopic pregnancies treated medically who need surgery have similar post-treatment pregnancy outcomes to those treated successfully medically. Pre-treatment counselling for women with unruptured tubal ectopic pregnancies considering their treatment options requires the provision of information on post-treatment pregnancy outcomes, including rates of ectopic pregnancy recurrence. Current UK NICE early pregnancy guidelines are based on low-quality evidence and estimate the long-term ectopic pregnancy recurrence rate at ~18.5% . FurtherWe describe subsequent pregnancy outcomes in women with tubal ectopic pregnancy managed with methotrexate using data from a UK multicentre randomised controlled trial comparing methotrexate and gefitinib vs methotrexate and placebo for the treatment of tubal ectopic pregnancy . Follow-up data from both randomisation groups  were combined owing to no between-group differences in subsequent pregnancy outcomes .This project was supported by funding from the This study is a follow-up analysis of participants from the GEM3 trial (ISRCTN Registry ISRCTN67795930).SCM drafted the manuscript. CAM analysed the data. All authors reviewed and contributed to the final manuscript."}
+{"text": "A 74-year-old male was admitted to the emergency department with cutaneous lesions on his face resembling raccoon eyes and lesions on his neck and shoulders . He had Primary amyloidosis involves the extracellular deposition of amyloid protein in various tissues, causing multiorgan damage . Raccoon"}
+{"text": "Intraoperative aortic valve evaluation should be accurate in valve-sparing root replacement to minimize postoperative aortic valve regurgitation. Ascending aorta de-clamping and weaning of cardiopulmonary bypass are required in intraoperative transoesophageal echocardiography. Aortic valve endoscopy aids in the magnification of structures and enables image sharing within the operative team. While a rigid endoscope and saline infusion line are directly inserted from the Valsalva graft end, a Kelly clamp is needed for graft gap closure, affecting the valve morphology due to graft deformation. The accurate inner pressure of the neo-Valsalva sinus cannot be measured in this method. We propose a technique to accurately evaluate aortic valve conformation using a balloon blunt-tip system that enables aortic valve evaluation under the measured pressure and without Valsalva graft deformation. Valve-sparing root replacement is advantageous over the Bentall technique and provides excellent long-term results [1]. Valve-sparing root replacement is advantageous over the Bentall technique and provides excellent long-term results . IntraopIn conventional endoscopic evaluation, the endoscope and saline infusion line are directly inserted from the Valsalva graft end, and Kelly clamps are used for gap closure. However, observing the natural aortic valve morphology is difficult because NVS is deformed by clamping and endoscope operation Fig.\u00a0A. FurtheThe Kii balloon blunt-tip (BBT) system  is a camera port used for laparoscopic surgery Fig.\u00a0B. With aA 60-year-old man, diagnosed with non-communicating DeBakey type-II aortic dissection, was referred to our hospital. A dilated aortic root and ascending aorta with tears were observed on four-dimensional computed tomography angiography. Echocardiography revealed mild-to-moderate AR. After performing median sternotomy and establishing cardiopulmonary bypass, an aortic cross-clamp was placed near the innominate trunk to induce cardiac arrest. The aortic annulus diameter and non-coronary cusp-left coronary cusp commissure height were 26 and 24\u2009mm, respectively. A 26-mm Gelweave\u2122 Valsalva graft  was selected.After partial aortic arch replacement, the root reconstruction was resumed. After placing the Valsalva graft, we evaluated the aortic valve using the BBT system. The NVS was marked to orient the valvular cusps. The balloon and softgel cone were positioned to facilitate closure; the inner BBT cylinder was removed before insertion into the graft. The balloon was gently inflated to fix the BBT on the graft tubing and to close the NVS; a rigid endoscope was inserted.Saline infusion and manometric lines were connected to stopcock of the BBT system. Saline was infused into the NVS to achieve a 70-mmHg pressure Fig.\u00a0A. The aoIntraoperative transoesophageal and postoperative transthoracic echocardiography revealed no residual AR.The BBT system is universally used in laparoscopic surgery. Balloon size can be regulated according to the graft diameter and the graft can be sufficiently closed. Using the balloon and softgel cone together, the distal end is closed without deformation. The system\u2019s stopcock facilitates saline infusion into NVS and simultaneously measures inner pressure. This technique allows us to evaluate the morphology of aortic valve not only without graft deforming but also under artificial diastolic pressure. That provided the opportunity to correct cusp prolapse or commissure fixed position and might improve the quality and increase the reproducibility of valve repair.To avoid mechanical injury to the aortic valve, the graft\u2019s tube portion should be maintained above the commissure fixation point Fig.\u00a0C and 25\u2009The BBT system facilitates simple and accurate physiological evaluation of valve-sparing root replacement."}
+{"text": "A 12-year-old Caucasian male presented to the clinic with a displaced, segmental left clavicle fracture involving the distal clavicle after falling from a zip line.\u00a0He was treated non-operatively in a sling and returned to normal activities without restrictions after three months.\u00a0At one year, the patient was able to maintain his pre-injury baseline function without limitations of his left shoulder.\u00a0While no clear guidelines for operative treatment of segmental clavicle fractures in the adolescent population exist in the current literature, this report illustrates an excellent patient outcome following conservative therapy of a segmental clavicle fracture involving the middle one-third and distal clavicle in a young adolescent with open physis. Clavicle fractures are common pediatric injuries in which the majority are treated non-operatively . The annA 12-year-old Caucasian male with no significant past medical history presented to the clinic with a closed left clavicle fracture after falling from a zip line 12 days prior. A physical exam showed a deformity over the left clavicle without appreciable skin tenting or neurovascular injury. Initial radiographs were obtained demonstrating a displaced, segmental clavicle fracture involving the middle one-third and distal clavicle, lateral to the coracoid  with mid-diaphyseal clavicle fracture malunions after non-operative treatment. All patients in the given study presented with an initial fracture displacement greater than 2 centimeters and were followed for two years. The authors concluded that radiographic malunion in adolescents does not result in clinically meaningful loss of shoulder motion or strength . A retro.2 years Although non-operative management has traditionally been the treatment of choice for pediatric clavicle fractures, there has been a recent increase in operative management. As patients enter adolescence they become more active than adults, gradually lose their remodeling potential, and may experience greater functional impairment from residual disability. The initial displacement of a clavicle fracture is an important factor in treatment decision. Initial fracture shortening of >20mm is associated with nonunion and unsatisfactory results . A CanadA disparity exists amongst surgeons regarding the treatment of adolescent clavicle fractures as shown by a survey of 302 members of the Pediatric Orthopaedic Society of North America (POSNA). Surgeons were nearly unanimously in favor of non-operative treatment in younger patients. However, regarding isolated segmental clavicle fractures, treatment preferences were split between operative and non-operative management with surgeons more likely to operate on adolescents age 16-19 years than age 12-15 years. Additionally, surgeons with less than five years of experience were more likely to choose operative treatment .Clavicle fractures in the adolescent population have no clear consensus on treatment, particularly when considering the 12-15-year-old age group. Currently, no literature supports the age range at which surgeons should adopt more aggressive treatment options related to fracture characteristics. This report demonstrates that a segmental clavicle fracture involving the middle one-third and distal clavicle in a young adolescent with open physes may be managed conservatively with good outcomes."}
+{"text": "Intraductal papillary neoplasm of the bile duct (IPNB) is a type of epithelial tumor characterized by papillary proliferation within the bile duct. It is defined histologically as a papillary or villous neoplasm covering the delicate fibrovascular stalks within the bile ductsThe patient was a 79-year-old man referred to our hospital for detailed examination of intrahepatic bile duct dilatation. Marked dilatation of the left intrahepatic bile duct and a suspected intrahepatic bile duct tumor were observed on contrast-enhanced computed tomography and magnetic resonance cholangiopancreatography . EUS coVideo\u20061\u2002Detective flow imaging (DFI), a novel imaging technique for low velocity blood flow, is used to identify the fibrovascular stems in intraductal papillary neoplasm of the bile duct (IPNB) that could not be detected by conventional imaging modalities.To our knowledge, this is the first report on the use of DFI to detect dendritic vessels within an intrahepatic bile duct tumor. DFI, which can capture tumor hemodynamics not detectable by conventional blood flow imaging, may be useful in differentiating intrahepatic bile duct tumors, including IPNB.Endoscopy_UCTN_Code_TTT_1AS_2AD"}
+{"text": "Molecular genetic testing confirmed a de novo heterozygous pathogenic variant in TCS2. The patient was commenced on everolimus and has had no complications.A 32-year-old man with a known diagnosis of tuberous sclerosis presented with early satiety and abdominal discomfort. Investigations revealed multiple large angiomyolipoma arising from and surrounding both kidneys. Axial and coronal true fast imaging with steady state precession magnetic resonance imaging (MRI) scans  showed tAngiomyolipomas are a common feature of tuberous sclerosis, occurring in 60\u201380% of patients  and are"}
+{"text": "Physical education is an important context to contribute students\u2019 physical activity in childhood and adolescence. However, negative physical education experiences may have a long-lasting association on students\u2019 willingness to participate in physical activity. The associations between students\u2019 anxiety in physical education and physical fitness have not been previously investigated. The aim of this longitudinal study was to analyse associations between physical education anxiety and physical fitness through five years.Participants of this study included 1147 Grade 5 students  (mean age: 11.27(0.32) years) at the baseline measure. These participants were measured annually between Grades 5 to 9. The Finnish version of the Physical Education State Anxiety Scale  was used to measure cognitive anxiety in physical education. Physical fitness was measured by 20meters shuttle run test (cardiorespiratory fitness) and curl-up and push-up tests (muscular fitness). Sex, BMI and peak height velocity was used as covariates in the analysis. Associations between study variables were measured by the Random Intercept Cross-Lagged Panel Model using Mplus statistical software.Between level results (squared multiple correlations) of the analysis demonstrated that cognitive anxiety was related to cardiorespiratory (-.32) and muscular fitness (-.34) over five years. Additionally, sex , BMI (.16) and peak high velocity (-.23) had significant associations with cognitive anxiety.This study revealed that cognitive anxiety in physical education has an influence on student\u2019s physical fitness longitudinally. These findings were similar between anxiety and cardiorespiratory fitness and between anxiety and muscular fitness. Results demonstrate that negative physical education experiences have an association on cardiorespiratory and muscular fitness from late childhood to adolescence. Constructs of the Self-determination theory  and Achievement goals theory (task orientation) are helpful when implementing positive pedagogy in physical education.Finnish Ministry of Education and culture funded this study."}
+{"text": "Allergic Rhinitis is a common Ear, Nose and Throat disorder. Asthma and Allergic Rhinitis are diseases with similar underlying mechanism and pathogenesis. The aim of this survey was to highlight current treatment trends for Allergic Rhinitis and Asthma.A questionnaire was emailed to all registered consultant members of the British Association of Otorhinolaryngologists - Head and Neck Surgeons regarding the management of patients with Allergic Rhinitis and related disorders.Survey response rate was 56%. The results indicate a various approach in the investigation and management of Allergic Rhinitis compatible with recommendations from the Allergic Rhinitis and Its Impact on Asthma guidelines in collaboration with the World Health Organisation.A combined management approach for patients with Allergic Rhinitis and concomitant Asthma may reduce medical treatment costs for these conditions and improve symptom control and quality of life. The definition of Allergic Rhinitis (AR) was formulated by Hansel in 1929 [The nasal passage and paranasal sinuses are an integral part of the respiratory tract and patients may have rhinitis without sinusitis, but not sinusitis without rhinitis, hence the term rhinitis has been replaced in modern ENT literature by the more accurate term rhinosinusitis . AR and The aetiology of AR is multi-factorial and the diagnostic and therapeutic choices remain diverse. The aim of this questionnaire survey was to highlight the treatment trends in the management of AR amongst UK-based otolaryngologists.A questionnaire (Appendix 1) was emailed via ENT UK to the email addresses of all registered consultant members of the British Association of Otorhinolaryngologists - Head and Neck Surgeons (BAO-HNS). Survey recipients were asked 1) about their familiarity with the Allergic Rhinitis and Its Impact on Asthma (ARIA) guidelines in collaboration with the World Health Organisation (WHO), 2) about the type of investigations, treatment regimes and follow-up arrangements for AR patients and 3) about whether they give to patients advice leaflets on life style changes including education and allergen avoidance. All participants had the opportunity to answer anonymously.A total of 551 questionnaires were emailed. There were 309 replies (56% response rate). All consultants were familiar with the association between AR and Asthma but only 63% of the respondents were familiar with the ARIA guidelines. Seventy seven (25%) of otolaryngologists managed AR patients of which a 20 - 30% proportion had associated symptoms or a diagnosis of Asthma . Only nine consultants (3%) arranged pulmonary spirometry Figure .Fifty six per cent of otolaryngologists preferred the management pathway of starting treatment and then discharging AR patients to General Practitioners (GPs) for further follow-up. However three (1%) consultants managed and subsequently referred AR patients to a respiratory physician Figure .In total two hundred and forty (78%) of otolaryngologists provided patient leaflets on life-style changes including education and practical tips on allergens avoidance .Figure AR is a multi-factorial disease with a worldwide disabling effect on all individuals irrespective of age and ethnic background. In 2001 the ARIA in collaboration with the WHO workshop published guidelines for healthcare professionals in order to highlight the latest updates on the aetiology of AR emphasizing the association between AR and Asthma and proposing a management algorithm .Risk factors for AR include a combination of environmental and genetic interactions . The diaAn overwhelming 99% of UK ENT consultants use intra-nasal steroids to treat AR. This trend is supported by several studies demonstrating that intra-nasal steroids are the most efficacious and cost effective first line treatment for AR ,13.et al in a cochrane review showed sublingual immunotherapy to be a safe and effective option in managing AR [et al in a recently published meta-analysis advocate the use of allergen injection immunotherapy as an effective treatment with a low risk of adverse effects in the management of AR [Allergen specific immunotherapy for AR was first described in 1911 by Noon and involves the administration of a gradually increasing quantity of an allergen extract . Patientaging AR . Furthernt of AR . Howevernt of AR .The importance of educating patients or carers with advice leaflets with information regarding AR including allergen avoidance cannot be over emphasised and was actively supported by 78% of responders of this survey. This enables individuals to be actively involved in the management of their disease resulting in an overall improvement in patient satisfaction, treatment compliance and outcomes . Such prInterestingly, only 3% of otolaryngologists arranged pulmonary spirometry and 1% of all respondents referred AR patients to a respiratory physician for management of any associated lower respiratory tract pathology. Several studies though have demonstrated that AR patients with no underlying Asthma do have impaired pulmonary function and reversible airway obstruction ,22. In aThis survey demonstrates as expected a diverse approach to the management of Allergic Rhinitis. An interesting finding of the survey is that despite good evidence on the relationship between Asthma and AR, most otolaryngologists often do no think \"outside the specialty\", for example they would rarely use spirometry as a diagnostic aid.A combined treatment strategy of allergen avoidance, pharmacotherapy, immunotherapy and education applied to patients with AR and concomitant Asthma as recommended by the ARIA guidelines may reduce medical treatment costs and improve symptom control and quality of life.The authors declare that they have no competing interests.RSN: Primary Author of manuscript. PDK: Assistant Author of manuscript and Editing. EGT: Contribution to Literature Search and Proof Reading. AK: Senior Clinician and contribution to Proof Reading and Editing. DKN: Assisted writing manuscript and designing questionnaire. All authors read and approved the final manuscript.Dear colleague,Pease could you complete this survey with your responses and return it by clicking the SUBMIT button below. We thank you for your valuable time in completing this survey.1. Are you familiar with the association between Allergic Rhinitis and Asthma?\u2022 Yes\u2022 No2. Are you familiar with the Allergic Rhinitis and its impact on Asthma (ARIA) guidelines in collaboration with the World Health Organisation?\u2022 Yes\u2022 No3. What proportion of your patients with Allergic Rhinitis have got symptoms or diagnosis of Asthma?\u2022 <10%\u2022 10 - 20%\u2022 20 - 30%\u2022 30 - 40%\u2022 40 - 50%\u2022 >50%4. If you suspect Allergic Rhinitis what investigations would you consider ?\u2022 None\u2022 Skin prick test to known allergens\u2022 Serology tests e.g. RAST, IgE\u2022 Peak flow meter (air flow litres/minute)\u2022 Pulmonary spirometry5. If you suspect Allergic Rhinitis in a patient which of the following management plans would you consider?\u2022 Start treatment and review\u2022 Start treatment and discharge patient to GP for follow-up\u2022 Start treatment and refer to a Respiratory Physician6. If you suspect Allergic Rhinitis which of the following would you use for treatment ?\u2022 Antihistamine - oral\u2022 Antihistamine - intra-nasal\u2022 Steroid - intra-nasal\u2022 Steroid - intra-bronchial\u2022 Steroid - oral\u2022 Decongestant - oral\u2022 Decongestant - intra-nasal\u2022 Anti-cholinergic (Ipatropium Bromide)\u2022 Anti-leukotriene\u2022 Specific Immunotherapy - sublingual\u2022 Specific Immunotherapy - subcutaneous7. How long do you prescribe nasal sprays for\u2022 3 months\u2022 6 months\u2022 >6 months8. What is the frequency of nasal spray administration do you prescribe ?\u2022 Two puffs once a day\u2022 Two puffs twice a day\u2022 Other (please specify)9. Do you provide leaflets for patients about life-style changes including education and avoidance of allergen(s)?\u2022 Yes\u2022 NoThe pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1472-6815/11/3/prepub"}
+{"text": "Due to theoretical importance of nuclear quadrupole resonance data [17O and 14N- NQR parameters. The studies reported in this work were undertaken to establish whether the NQR method could be used to derive a rational structure-activity relationship for these inhibitors. These findings open up useful applications for this family of inhibitors, considering the vast number of alternative disease related proteases that may exist.Increasing numbers of HIV infected patients along with severe treatment-associated complications and related deaths make the AIDS pandemic . These ince data  for char"}
+{"text": "A 29-year-old female patient with Ebstein anomaly was referred to our division for drug-resistant symptomatic wide-complex tachycardia. Her preprocedural electrocardiograms showed a sinus rhythm without delta wave and a wide-complex short RP tachycardia with a rate of 150 bpm during palpitation. During conventional electrophysiologic study earliest local activation times during the tachycardia were obtained from the right parahisian region . A few sTo the best of our knowledge, this is the first case whose parahisian atrial tachycardia was ablated from the aortic cusp using cryothermal energy. Cryoablation from the aortic cusps should be considered to ablate the arrhythmia focus when RFA threatens the normal conduction system or vital anatomical structures ."}
+{"text": "The interface between titanium dioxide and biological solution is relevant for the bioactivity of titanium implants. Adhesion phenomena between inorganic solids are of general interest for mineralization and bone formation processes.6 atoms in the 10-100 ns range and ab initio molecular dynamics wit 100-200 atoms for some ps.Such interfaces are complex systems with many constituents including the hydroxylated metal oxide support, hydrocarbon contamination, ionic water solution and a variety of biopolymers. Our computational methods comprise classical molecular dynamics with around 102 on Ti metal may be commensurate and crystalline [\u2022 Electronic structure calculations show that even very thin layers of TiOstalline . A varie2 is in practice screened by hydrocarbons, which may enhance inflammatory complications of implants [\u2022 The oxide is hydroxylated and its surface charge density correlates with the pH-value. The highly hydrophilic TiO\u2022 Sequence specific protein adsorption on inorganic surfaces was found in several experiments on inorganic surfaces, even though no key-lock mechanism is conceivable. We propose two effects : (i) Con\u2022 Close to solids water has an ordered structure, which only slightly depends on the surface charge density. These layers hinder protein adsorption. A major difference to the bulk is the reduced water mobility there."}
+{"text": "The selection tool deriving from this analysis may allow an optimal use of the available treatment strategies in these patients.In radically resected gastric cancer the possibility to predict the site of relapse could be clinically relevant for the selection of post-surgical management. We previously showed that specific tumour integrins genotypes are independently associated with either peritoneal or hematogenous metastases (ITGA and ITGV). Recently VEGF and VEGF-R polymorphisms have been demonstrated to potentially affect tumour angiogenesis and the metastatic process in gastric cancer. We then investigated the role of VEGFs and VEGF-R genotyping in determining either peritoneal carcinosis or hematogenous metastases in radically resected gastric cancer patients. Tumour genotyping for integrins (ITGA and ITGV) was also performed according to our previous findings. Genotyping for VEGF-A, VEGF-C, VEGFR-1,2,3 and ITGA and ITGV was carried out on pT4a radically resected gastric tumours recurring with either peritoneal-only carcinosis or hematogenous metastases. 101 patients fulfilled the inclusion criteria: 57 with peritoneal carcinomatosis only and 44 with hematogenous spread only. At multivariate analysis, intestinal histology and the AC genotype of rs699947 (VEGFA) showed to independently correlate with hematogenous metastases (p\u200a=\u200a0.0008 and 0.008 respectively), whereas diffuse histology and the AA genotype of rs2269772 (ITGA) independently correlated with peritoneal-only diffusion (p\u200a=\u200a<0.0001 and 0.03 respectively). Our results seem to indicate that combining information from genotyping of rs699947  The global outcome for radically resected gastric cancer patients remained substantially unchanged across the years in western Countries, with a 5-years survival rate ranging between 15% and 35% of all cases In western Countries only a modest survival benefit, has been observed for adjuvant chemotherapy mainly in pooled analyses and the beneficial effect of chemoradiotherapy seemed limited to patients receiving an inadequate clearance of the lymphatics Peritoneal carcinosis may be the first site of relapse in approximately 40 to 50% of patients undergoing radical resection ITGA) and rs11902171 (ITGV) may represent a critical asset in the definition of high risk gastric cancer patients for peritoneal carcinosis In a previous analysis we found that Genotyping of rs2269772  superfamily has been identified to critically influence angiogenesis in solid tumours. Published data suggest that in presence of tumour angiogenesis-related factors distant metastases are more likely to occur Interestingly it has been also demonstrated that the angiogenic phenotype may differ between intestinal-type and diffuse-type gastric cancer. In different analyses intestinal-type tumours seem in fact more biologically dependent on angiogenesis than diffuse-type tumours Single-nucleotide polymorphisms (SNPs) in the vascular endothelial growth factors (VEGF) and VEGF receptors (VEGF-R) genes have been correlated to tumour neoangiogenesis through different biological mechanisms. In patients with colorectal cancer specific SNPs in the VEGF-R2 have been shown to significantly influence microvessel density Tumour lymphangiogenesis is strictly dependent on the biological activity of the VEGFC and the VEGF-R3 Predicting the location of recurrence amongst high risk individuals may allow for tailored adjuvant approaches. We therefore examined the role of tumour VEGFs and VEGF-Rs polymorphisms in determining either peritoneal carcinosis or hematogenous metastases in radically resected gastric cancer patients. Clinical data and SNPs results for tumour VEGFs, VEGF-Rs and integrins have been analysed with the aim to suggest a biologically-driven profile to be employed as a tool for the appropriate treatment selection in the appropriate patient.th TNM.The patients study population was selected from a central database including patients affected by gastric cancer, operated in four different Institutions of our Region. Classification of the T, N and M-factors was made according to the numeric system introduced by the 7Only patients who had recurred within 2 years, with either peritoneal-only carcinosis or hematogenous metastases after curative gastrectomy for a pT4a gastric adenocarcinoma, who did not receive adjuvant chemotherapy and whose tumour specimen was available were selected for tumour genotyping. Patients with either distant metastases at the time of diagnosis or presence of exfoliated tumour cells in peritoneal lavage obtained during laparotomy were excluded from analysis. We decided to restrict our analysis to patients with pT4a tumours as this group of patients is at higher risk for peritoneal diffusion and is often considered for locoregional treatment such as intraperitoneal chemotherapy. However a not negligible proportion of these patients does not recur locally and therefore a selection tool in this setting would be a particularly valuable asset for the treating physicians. Since most recurrences are registered within 2 years from diagnosis we chose to exclude patients recurring after this time period in order to obtain an homogenous population.Follow-up of both groups  occurred at three-months intervals. Follow-up consisted of physical examination, a complete blood count, chest radiography and US of the abdomen or CT scanning as clinically indicated. The site and date of first relapse and the date of death were recorded.This study was approved by Ethical committee AOU Ospedali Riuniti \u2013 Umberto I of our institution. All patients provided informed written consent.VEGF and VEGF-R genotyping was performed on formalin-fixed paraffin-embedded tissue block (about 30 mg) of primary gastric cancer samples.Paraffin wax was removed with xylene and the samples were washed twice with 100% ethanol. DNA was isolated from the deparaffinised tissue using the RecoverAll\u2122 Total Nucleic Acid Isolation Kit for FFPE Tissues , according to the manufacturer\u2019s instructions. DNA from each sample was then eluted in 120 \u00b5l of eluting solution.http://pupasuite.bioinfo.cipf.es/index.jsf - version 2.0.0, bioinfo 2008), the CIPF Single Nucleotide Polymorphism database (dbSNP) generated by the National Center for Biotechnology Information (http://www.ncbi.nlm.nih.gov/SNP) and by review of the medical literature, using the following criteria:Single nucleotide polymorphisms (SNPs) within each gene were selected using the Pupasuite software ;the minor allele frequency was above 10% ;the genetic polymorphism was established and well-documented.Further considerations drove the selection of SNPs for our study. A correlation between the presence of a specific allele on a polymorphic site and the expression of the respective protein has been previously documented for VEGF Globally we assumed that selected SNPs had impact on protein expression and therefore on biological function.Selected SNPs were as follows: six polymorphisms in the VEGFA gene , two in VEGFC , two in VEGF-R1 (FLT1) , four in VEGF-R2 (KDR)  and three in VEGF-R3 (FLT4) . Chromosomal locations, positions and biological effects of investigated VEGF and VEGFR SNPs have been summarised in SNP genotyping was performed by TaqMan technology, using SNP genotyping products (Applied Biosystems). Polymerase chain reaction (PCR) was performed and genotypes were analysed on the 7300 Real-Time PCR System (Applied Biosystems) using an ABI Prism 7300 Sequence Detection System software . Each reaction contained 0.2 \u00b5l of total genomic DNA. Genotyping was performed by laboratory personnel blinded to patient status, and a random 10% of the samples were repeated to validate genotyping procedures.All SNPs genotyped had to present an overall call rates of \u226590% to be included in our analysis.ITGA and G and C genotypes of rs11902171, ITGV) was conducted as previously described Genotyping for tumour integrins independently associated with either peritoneal or hematogenous metastases in our previous analysis  and each VEGF and VEGF-R polymorphism.Tested variables included sex , age (<65 yrs vs. \u2265 65 yrs), absence or presence of lymph node metastases (pN0 vs. pN+), type of lymphadenectomy (D1 vs. D2), tumour histology according to Lauren\u2019s classification , lymphatic/blood vessels invasion (presence vs. absence), the clinical Center where surgery was performed, integrins genotyping  in the 2 groups  was calculated with a 95% confidence interval. A significant level of 0.05 was chosen to assess the statistical significance.www.statgen.ncsu.edu/powermarker).All polymorphisms were examined for deviation from Hardy-Weinberg equilibrium using the Powermarker v. 3.25 package (www.statgen.ncsu.edu/powermarker). LD was estimated using r2, with r2\u200a=\u200a1 indicating complete LD and r2\u200a=\u200a0 indicating absent LD.Linkage Disequilibrium (LD) analysis was also performed using the Powermarker v. 3.25 package . Follow-up data were available for all patients included. Follow-up consisted of physical examination, a complete blood count, chest radiography and US of the abdomen or CT/MRI scanning as clinically indicated. Only patients who exclusively developed either peritoneal carcinosis or hematogenous metastases during the entire course of their disease were considered.All patients underwent radical surgery (R0) for pT4a gastric cancer, regional lymphnodes were negative for metastases (pN0) in 23 patients (23%). Most of the patients underwent a D2 lymphadenectomy . Pathology report showed intestinal histology in 51 cases (51%) and diffuse histology in 50 patients (49%) . Fifty-sAll SNPs genotyped presented an overall call rates of \u226590%.Repeated samples for genotyping validation confirmed results obtained by previous analysis in all cases.VEGFA), the AC genotype of rs699947 (VEGFA) and the GG genotype of rs7993418 (FLT1) resulted more prone to hematogenous metastases  (Gastric tumours showing the AA genotype of rs10434 (ctively) . No corrAnalysis of the remaining VEGF and VEGF-R polymorphisms did not show any correlation with either peritoneal carcinosis or hematogenous metastases .Globally results for tumour integrins genotyping confirmed our previous findings.ITGA) resulted less prone to peritoneal carcinosis , whereas the AA genotype of rs2269772 (ITGA) was more frequently associated to peritoneal carcinosis . The CC genotype of rs11902171 (ITGV) was more frequently associated to peritoneal carcinosis . On the contrary, patients with the GG genotype of rs11902171 in the ITGV gene developed peritoneal carcinosis less frequently than hematogenous metastases .Patients tumours with the GG genotype of rs2269772 , whereas tumour intestinal histology was linked to hematogenous metastases  .At multivariate analysis, intestinal histology and the AC genotype of rs699947 (VEGFA) showed to independently correlate with hematogenous metastases, whereas diffuse histology and the AA genotype of rs2269772 (ITGA3) independently correlated with peritoneal-only diffusion (p\u200a=\u200a0.001). Odds ratio results for these latter factors confirmed their role in guiding tumour cells through the metastatic process toward the peritoneum or hematogenous sites .The introduction of multiple therapeutic options for the post-surgical management of radically resected gastric cancer patients has opened the question of optimal patients selection. Unfortunately a critical limiting factor for the potential of these treatment choices is represented by the lacking of clinical and biological factors able to predict the site of recurrence. The containment of disease with a locoregional treatment such as intraperitoneal chemotherapy may be in fact inadequate in patients at high risk for hematogenous metastases and should be better reserved to patients most likely to recur with peritoneal-only diffusion. On the other hand in patients more likely to recur with hematogenous metastases adjuvant chemotherapy may represent a more effective strategy.In our experience the rs699947  polymorphism is independently related to a higher risk of hematogenous metastasis with an OR 8.08 . SNPs in the promoter region of the VEGF gene have been already demonstrated to affect patients outcome in colorectal, breast and gastric cancer As previously described the rs2269772  genotype of tumour integrins confirmed to be independently relevant in determining peritoneal diffusion of gastric cancer cells [10). This finding deriving from a multivariate analysis including tumour-angiogenesis related factors strongly suggests that this specific tumour integrin polymorphism should be considered in future studies. On the contrary our analysis could not confirm the role of tumour integrins in determining hematogenous diffusion. We know from previously published analyses that upregulation of integrins sub-classes could enhance neoplastic cells motility and VEGF expression Tumour histology resulted a further factor independently able to identify the gastric cancer potential to determine either peritoneal or hematogenous metastases. Nonetheless tumour histology alone does not seem sufficient to accurately predict the metastatic sites. In our experience, similarly to previous reports, a relevant proportion of patients developed peritoneal carcinosis or hematogenous metastases independently from tumour histology. Similar considerations could be applied to the presence of tumour serosal involvement and/or exfoliated cancer cells in peritoneal lavage. Not all gastric tumours with serosal infiltration will eventually develop carcinosis and a negative peritoneal lavage unfortunately does not exclude a future peritoneal diffusion Globally we believe that genotyping for specific VEGFA and integrin genes may represent a critical asset in the definition of the metastatic diffusion for radically resected gastric cancer patients. Radically resected gastric cancer patients at high risk for peritoneal recurrence may be optimal candidates for intraperitoneal therapy, whereas if the risk of hematogenous metastases is predominant systemic chemotherapy may represent a better option. The selection tool deriving from this analysis may then allow an optimal use of the available treatment strategies and should represent a possible stratification factor in future studies in these patients."}
+{"text": "The neonatal Fc receptor (FcRn) binds immunoglobulin G (IgG), protects it from degradation and can transport IgG from apical to basolateral side of epithelial cells . Previou2 were used for subsequent experiments. Monoclonal IgG was added either apically or basolaterally and after incubation IgG was measured in the culture supernatant using an ELISA that was developed inhouse. To distinguish leakage of IgG through the cell layer from active transport by the cells we used NH4Cl or Chloroquine to block cytoplasmic vesicles.Monolayers of RPE cells, ARPE-19  and human primary RPE cells , were established on Transwell culture inserts using fibronectin coated membranes. Trans-epithelial resistance (TER) measurements were used to evaluate monolayer formation. Plates with an average TER >35\u03a9*cm4Cl and Chloroquine were limited.The highest TERs were observed with ARPE-19 cells, while TERs often remained low with the primary cell cultures. The IgG level that crossed the membrane correlated positively incubation time, but this association was not linear. The observed effects of NHFurther experiments are needed to determine whether there is active transport by the RPEs. Paracellular diffusion will be investigated using dextran and specific blocking antibodies for the FcRn. In addition, experiments will be performed with RPE cells where FcRn is overexpressed or knocked-out."}
+{"text": "Balloon dilatational percutaneous tracheostomy with radial outward dilation minimizes bleeding and injury to tracheal rings . Using tTwenty-five patients including 15 males and 10 females, mean age 61 years, with age range from 23 to 102 years, underwent bedside percutaneous tracheostomy combining real-time ultrasound and the Blue Dolphin technique.The median time for the procedure was 15 (12 to 20) minutes. Targeted placement for the tracheostoma between the second and third or the third and fourth tracheal ring was achieved in 100%. No significant complications  occurred. One fractured tracheal ring was identified using bronchoscopy after the procedure. No conversion into a bronchoscopically guided or into a surgical open technique was necessary.This study demonstrates the feasibility and safeness combining real-time ultrasound guidance and balloon dilatational percutaneous tracheostomy (Blue Dolphin technique) in critically ill patients. In our division, this technique has become the standard bedside tracheostomy procedure because it combines excellent patient safety features with avoidance of intraprocedural tube misplacement, hypoventilation and accidental bronchoscopy damage even in technically difficult cases ."}
+{"text": "The discovery of neutralizing antibodies that are broadly reactive with multiple influenza subtypes is therefore extremely important for the influenza pandemic preparedness, for use either for therapeutic purposes or as the basis of vaccine development. On the other hand, recently studies also suggest that cell-mediated immunity might be critical for cross-subtype protection against influenza virus infection. Using vaccinia virus-based H5 vaccine, we also demonstrated this approach might also capable of inducing cross-subtype protection. Mice received this H5 vaccine had no detectable neutralization antibody against other HA subtypes, suggesting that cell-mediated immunity might be account for the subtype protection. Here, we would discuss our recent findings on these research topics.The continuous antigenic drifts and occasional antigenic shifts enable human influenza viruses to escape the human immune system. Moreover, the frequent occurrence of human H5N1-infected cases and the recent emergency of a novel swine-like human H1N1 influenza virus further reiterate the risk of the introduction of a new pandemic strain to humans through"}
+{"text": "Hox genes impart segment identity to body structures along the anterior-posterior axis and are crucial for the proper development of all organisms. Multiple regulatory elements, best defined in Drosophila melanogaster, ensure that Hox expression patterns follow the spatial and temporal colinearity reflected in their tight genomic organization. However, the precise mechanisms that regulate colinear patterns of Hox gene expression remain unclear, especially in higher vertebrates where it is not fully determined how the distinct activation domains of the tightly clustered Hox genes are defined independently of each other. Here, we report the identification of a large number of novel cis-elements at mammalian Hox clusters that can help in regulating their precise expression pattern.Hox clusters that show poor association with histone H3 in chromatin immunoprecipitation (ChIP)-chip tiling arrays. The majority of these elements lie in the intergenic regions segregating adjacent Hox genes; we demonstrate that they possess efficient enhancer-blocking activity in mammalian cells. Further, we find that these histone-free intergenic regions bear GA repeat motifs and associate with the vertebrate homolog of the GAGA binding boundary factor. This suggests that they can act as GAGA factor-dependent chromatin boundaries that create independent domains, insulating each Hox gene from the influence of neighboring regulatory elements.We have identified DNA elements at all four murine Hox clusters. We further demarcate the precise location of several novel cis-elements bearing chromatin boundary activity that appear to segregate successive Hox genes. This reflects a pattern reminiscent of the organization of homeotic genes in Drosophila, where such regulatory elements have been characterized. Our findings thus provide new insights into the regulatory processes and evolutionarily conserved epigenetic mechanisms that control homeotic gene expression.Our results reveal a large number of potential regulatory elements throughout the murine  Hox genes specify segment identity during development: the unique combination of their expression pattern provides correct positional identity along the anterior-posterior (AP) body axis. The distinct organization of the Hox genes was first defined in Drosophila melanogaster[Hox complexes, however, are distinct from those seen in invertebrates. Through genome duplication events, vertebrates have at least four Hox clusters that are more organized, with all the genes transcribed in the same orientation and arranged more compactly than those in lower organisms [Hox genes. Their temporal order of activation, however, shows a difference; in Drosophila, the expression pattern of all the Hox genes is set simultaneously, while mammals show temporal colinearity by expressing their 3\u2032 Hox genes first and then the more 5\u2032 Hox genes sequentially from anterior to posterior during development [Hox gene regulation is highly dependent on genomic organization. It remains unclear how the colinear pattern of Hox gene expression in mammals is governed to provide discrete segment identity during development. In particular, it is not fully determined how the distinct activation domains of successive Hox genes are defined to maintain this spatial and temporal colinearity of expression. Mouse transgenes bearing regulatory regions of Hox genes faithfully recapitulate their expression domains [Hox gene expression are probably located in close proximity to the genes themselves, interspersed between coding regions within the conserved clusters. This arrangement may also allow enhancer sharing and promoter competition between the vertebrate Hox genes, providing an additional layer of regulatory control [Hox regulatory elements has not been clearly mapped in organisms other than Drosophila, where distinct regulatory domains control gene expression; most importantly, boundary elements flank each regulatory domain and define its limits in the bithorax complex [Hox clusters [anogaster and suchanogaster. Specifirganisms . The ordelopment ,5. These domains ,7, indic control . However complex . Chromat complex ,11. Home complex . Epigeneclusters .Hox clusters using custom-designed high-resolution chromatin immunoprecipitation (ChIP)-on-chip tiling arrays to reveal the presence of novel histone H3-free regions as potential regulatory elements. We show that most of these histone-depleted regions are associated with the vertebrate GAGA factor. Further, almost all intergenic regions at the Hox clusters show the presence of such histone-free regions that bear significant enhancer-blocking activity in human cells. These findings establish an association of the GAGA factor at specific intergenic chromatin structures that act as regulatory elements in mammalian Hox clusters. The observation that some of these regions can function as chromatin boundaries indicates a conserved mechanism of Hox gene expression regulated by distinct chromatin domains of each gene.Here, we have explored the chromatin regulatory features across all four murine Hox clusters, we designed a ChIP-on-chip tiling array including all 39 Hox genes along with their intergenic as well as upstream and downstream flanking regions. Synchronized G0 cells from the mouse C2C12 cell line were used to obtain a homogenous assay system for chromatin analysis, minimizing possible effects of cell type or cell cycle distribution and potential variations in the epigenetic state. Chromatin immunoprecipitation (ChIP) experiments with histone H3 antibodies were then performed for hybridization to the custom-designed tiling arrays.To obtain a complete picture of the epigenetic organization of the four murine Hox clusters in a defined pattern, as outlined for 150 kb of each of the Hox clusters in Figure Strikingly, ChIP-on-chip analysis revealed a consistent pattern of histone depletion at intergenic intervals across all arrays. The H3 \u2018pan\u2019 antibody against the carboxy terminus of histone H3  recognizes all forms of histone H3 and its modifications. We found that the binding of this antibody was depleted at many regions within the HoxA, HoxC, and HoxD clusters while the HoxB cluster showed the lowest occurrence of such regions. The HoxB cluster is different from the other Hox clusters in that the Hoxb13 gene is separated from the rest of the cluster by ~70 kb of DNA, in contrast with the other homeotic genes, which are closely spaced in all four clusters. Although the HoxB cluster maintains colinear expression of all its genes along the A-P body axis, the distant location of Hoxb13 is believed to contribute to its loss of expression along the secondary body axes, presumably owing to the absence of cis-regulatory features in the large intervening region, which also contains highly repetitive DNA sequences [HoxB cluster could explain the absence of HFRs in this part of the complex. The reason behind the low frequency of HFRs in the cluster as a whole is not clear, although it may suggest a relatively low regulatory complexity for this cluster.Nucleosome organization governs the accessibility of chromatin to regulatory complexes, increasing the binding of nonhistone proteins to target sites. Genome-wide chromatin studies have established the presence of regions with altered nucleosome occupancy, which often coincide with known regulatory elements, such as gene promoters, enhancers and transcription start and termination sites . The disequences . This unHox coding regions. A large number of the intergenic HFRs (64 HFRs) were located at intermediate positions between successive Hox genes or downstream to them. Apart from the Hox coding regions, we also checked the positions of intergenic noncoding transcripts as well as all CpG islands known at the Hox clusters. While 16 of the intergenic HFRs were found within noncoding transcribed regions, the remainder showed no overlap with any of these known intergenic features  of which only 9 were genic  enhancer and the \u03b3-neo gene providing antibiotic resistance blocks promoter activation  that showed high enrichment with the core histone H3 antibody.To determine whether any of the newly identified HFRs marked potential boundary elements at the murine n Figure  inset, te effect . We usedboundary  as a posP < 0.0001) in the number of G-418 resistant colonies when cells were transfected with the target HFRs  and boundary elements [Hox clusters also bear such regulatory elements and this study provides a large-scale identification of such potential elements marked by their modified histone occupancy pattern. Not all the elements tested displayed strong boundary potential and it is possible that the enhancer blocking observed in some cases may be the manifestation of some other activity in their native context, as there are many ways that enhancer-promoter interactions can be disrupted [Hox gene expression in mammals.The disruption of histones exposes tructure . Reducedelements . In thisisrupted ,25. Basein vitro colony formation assay suggests their possible association with key regulatory factors at the murine Hox loci. We therefore subjected all the identified HFRs to sequence analysis and found multiple sites for the GAGA binding factor (GAF in Drosophila) at the histone-free regions, with the GAGAG motif appearing as the most frequent significant hit with a motif P < 0.0005 . Enrichment was assayed using multiple primers designed across 18 HFRs, including 13 that had shown high enhancer-blocking activity, as described in Figure Th-POK binding boundary region between Evx2-Hoxd13 characterized previously , positioned within the Hox gene bodies, did not show similarly robust association with the Th-POK antibody  is the best studied vertebrate boundary factor  and  domains . We ther cluster . CTCF ca cluster . It is pox genes .Drosophila, many cis-regulatory elements including boundaries within the homeotic complex are bound by GAF, and evidence suggests that altering the nucleosome occupancy might be a feature of such binding [Drosophila, which remain associated with HS sites regardless of a heat-shock event triggering the activation of the locus [The association of HFRs observed here appears to be specifically with the vertebrate GAGA factor and could possibly be the outcome of the nucleosome-reorganizing potential of GAF and not solely a feature of boundary activity. In  binding . To detehe locus .Hox genes. It remains to be determined if the histone depletion creates accessibility at these sites for enhancer-blocking function or if the GAF binding elements actively serve as anchors for directing the basic chromatin structure by histone disruption at the Hox complexes. dGAF plays a key role in directing chromatin architecture and driving nucleosome reorganization by recruiting remodeling complexes; its mutation has been shown to effect both histone replacement and associated boundary function at Hox complexes in Drosophila[Hox clusters. Since HFRs can provide sites for a multitude of target proteins and GAF can bind to various proteins to form regulatory complexes, looking for interacting partners at these sites will help identify other regulatory features at the HFRs. Taken together, our findings suggest a correlation between GAGA factor association at the histone-depleted regions and chromatin accessibility, providing functional significance to the presence of HFRs in the intergenic regions of mammalian Hox clusters.We hypothesize that the vertebrate GAF-associated intergenic HFRs described here may be important in maintaining the local chromatin conformation of rosophila. The preHox clusters potentially involved in higher-order chromatin regulatory mechanisms. In Drosophila, multiple elements, such as enhancers, insulators, and PREs, form regulatory units that determine and maintain the segment-specific expression pattern of the associated homeotic genes. In mammals, the regulatory elements driving colinear activation and maintenance of Hox expression have not been delineated. In this context, GAGA factor associated histone-depleted regions identified in the intergenic stretches between murine Hox genes suggest sites of potential regulatory function that could help demarcate their domains of expression. We have previously characterized a GA-rich intergenic tract between the Evx2 and Hoxd13 genes conserved among mouse, human, and zebrafish and demonstrated its functional conservation as an enhancer blocker in both transgenic flies and cultured human cells [HoxD locus [Th-POK as the vertebrate homolog of dGAF and indicated its potential to bind and regulate Hox clusters [Hox clusters with GAF recognition sites and Th-POK binding. These results indicate a strong correlation of HFRs associated with Th-POK binding as a general feature of mammalian Hox gene domain regulation and provide mechanistic insights into the possible role of the mammalian GAGA factor in nucleosome reorganization at the Hox clusters, thereby setting the stage for the binding of regulatory proteins to organize chromatin regulatory activities, including boundaries.This study used an epigenetic approach to identify a novel set of DNA elements at murine an cells . The regxD locus ; we havexD locus . We haveclusters . In thisHox genes across species but delineating the conserved organizational features of the Hox clusters can offer remarkable insights into their regulation. In this study, we have been able to identify over 90 such novel regions in the Hox clusters as HFRs and demonstrate the potential of many of the intergenic HFRs to function as chromatin regulatory elements. Our work indicates a genome-wide association for such structures and demonstrates that a lack of enrichment of histone H3 at specific genomic sites in ChIP-on-chip binding assays can serve as a marker for the identification of novel regulatory elements in a context-specific manner.Finally, sequence comparison might not directly identify homologous regulatory elements of the 5 cells/ml in DMEM containing 1.3% methyl cellulose, 20% FBS, 10 mM HEPES, and 1 \u00d7 Penicillin-Streptomycin. Suspended cells were harvested after 48 h, during which time 98% of cells were arrested at the quiescent G0 stage [C2C12 skeletal muscle myoblasts were cultured as described previously . UndiffeG0 stage , by dilu7 synchronized cells. Cells were harvested as described and fixed using 1% formaldehyde (Fisher Scientific) in growth medium for 10 minutes at 37\u00b0C and quenched with 0.125 M Glycine (Sigma). Fixed cells were washed well with 1 \u00d7 PBS containing protease inhibitors at 4\u00b0C and resuspended in 2 ml lysis buffer supplemented with PMSF, DTT, and protease inhibitor cocktail (Roche). Following 15 min incubation on ice, the sample was sonicated using Bioruptor (Diagnode) to obtain fragments of average size 200 bp to 600 bp. The sonicated chromatin was divided into 200 \u03bcl aliquots for chromatin immunoprecipitation (ChIP) using the ChIP assay kit  according to the manufacturer\u2019s protocol. ChIP was performed on precleared chromatin from 106 cells using rabbit polyclonal antibodies against core histone H3 , H3K4me3 , H3K27me3 , Th-POK , or CTCF . Unenriched input fraction was retained as control in each case. ChIP and input samples were subjected to array hybridization or real time qPCR assays to determine enrichment.Chromatin was crosslinked and isolated from 10Hox clusters was designed with 60-mer probes  tiled continuously with a 10 bp overlap between consecutive probes for high resolution (Agilent Technologies). Repeat masking was used to avoid repeat sequences and other probes with cross hybridizing potential. Dual-color microarray hybridization experiments were carried out according to the manufacturer\u2019s protocol. Briefly, samples recovered from the enriched fraction and unenriched whole cell extracts (input DNA) from two parallel experiments were independently pooled to obtain optimal yields for direct array hybridization, thus minimizing bias introduced during ligation-mediated PCR amplification of DNA fragments. The pooled enriched and input fractions were directly labeled with Cy5 and Cy3 dyes, respectively, using an Agilent Genomic DNA labeling kit (5190\u20130449) and hybridized onto the mouse custom arrays at 65\u00b0C for 40 h followed by washing. Scanned microarrays were submitted for background subtraction and data extraction to Agilent\u2019s Feature Extraction. Normalized enrichment values for the probes were identified using DNA Analytics software. Probe data were normalized using default blanks subtraction and intra-array dye-bias median normalization and P values were assigned to groups of neighboring probes using the Whitehead error model.A custom mouse genome microarray chip representing 1.1 Mb of the mouse genome consisting of the four The ChIP-on-chip signals were normalized with input DNA signals hybridized to the same arrays and the NLRs of the probes thus obtained were visualized on the Mouse NCBI37/mm9 Assembly in the UCSC genome browser . AdditioHox clusters from the histone H3 tiling array were used to identify unenriched genomic stretches using an in-house PERL script. The extent of each target region was determined based on a defined cut-off for the number of consecutive probes that showed a negative NLR value with the histone H3 antibody. Briefly, the probe dataset from each cluster was divided into groups of five contiguous probes and each was classified as a \u2018low enrichment\u2019 group if at least three probes in the group had an NLR <0. Continuous blocks of low enrichment groups were extended until two or more consecutive high enrichment groups were encountered or if a genomic distance >200 bp was encountered between successive probes. These poorly enriched genomic stretches were classified as histone H3-free regions or HFRs and subjected to further analysis for ChIP-qPCR , NLR values of the probes within the Hox genes and all noncoding transcripts (downloaded from the Tromer database) using Geneious [Genomic sequences of HFR stretches from each of the clusters were extracted from the mouse reference assembly MGSCv37-C57BL/6J of NCBI build 37.2 and subjected to motif search analysis using the MEME Suite of tools . The HFRGeneious .Hox clusters were amplified as test fragments from mouse genomic DNA using primers designed with Xho 1 restriction sites at their 5\u2032 ends  at the Hox clusters (x axis). (A) Large stretches of histone H3 unenriched probes showing negative NLR values across all the arrays are highlighted by boxed regions. Map of all the HFRs (green boxes) further identified by bioinformatics analysis of the probe binding data is presented at the bottom for each cluster. (B) H3K4me3 and H3K27me3 peaks called in the custom tiling arrays show that the HoxB and HoxD clusters are highly enriched for the H3K27me3 mark in G0 cells, as reported previously for proliferating myoblasts and myotubes [HoxA and HoxC clusters do not share this feature but show some association with H3K4me3. These trends are comparable with those seen in the ChIP-seq data from ENCODE using C2C12 cells (brown tracks). Genomic scale bar is indicated at the top. Figure S2. Map of GAGA motifs and CTCF sites across Hox clusters. Schematic map  depicting the location of all the GAGA motifs identified by sequence analysis as well as the CTCF sites identified by ChIP-seq in C2C12 cells from the mouse ENCODE project as obtained from the UCSC genome browser . Green boxes indicate HFRs while red bars mark GAGA motifs and grey bars mark CTCF sites. Blue boxes denote the Hox genes with transcriptional orientation; the large intronic regions of Hoxa3 and Hoxd3 genes have been omitted for clarity. Figure S3. DNaseI HS peaks in context of HFRs at the Hox clusters. Schematic map  depicting the location of all the peaks of DNaseI hypersensitivity identified in skeletal muscle (blue track), mesoderm (black track) and embryonic stem cells (maroon track) from the mouse ENCODE project . Green boxes indicate the HFRs while blue boxes denote the Hox genes with transcriptional orientation; the large intronic regions of Hoxa3 and Hoxd3 genes have been omitted for clarity. Table S1. Classification of HFRs identified in the three histone arrays. Table S2. List of GAGA factor binding motifs at the Hox clusters. Table S3. HFRs overlapping with DNaseI HS sites. Table S4. List of primers for ChIP-qPCR assays. Table S5. List of primers for cloning test fragments for boundary assays.HFRs across all arrays using histone H3 antibodies. Screenshots from the tiling array data obtained using pan histone H3 (blue track), H3K4me3 (pink track) and H3K27me3 (green track) antibodies, visualized using the UCSC genome browser showing normalized log ratio (NLR) values of probes (myotubes ; genes iClick here for fileNormalized log ratio values for probes at Hox clusters.Click here for file"}
+{"text": "The architects of phase I radiochemotherapy development programs impose a semblance of structured radiation \u201cintensity\u201d and adverse event predictability upon radiation-anticancer agent interactions whose natural complexity and improper mixing would otherwise lead to dire health consequences. It is incumbent upon radiation oncology investigators to pledge radiation quality and safety to the participants of radiochemotherapy trials. Measures of radiation quality and safety may be tools to scrutinize radiation-anticancer agent dose and schedule, as well as, radiation field design among diverse radiation delivery platforms. In this article, the merits and demerits of phase I radiochemotherapy quality and safety policies are critiqued considering the current era of rapidly evolving radiation technologies. The traditional first-in-human radiochemotherapy study or phase I investigation often determines the dose and schedule of radiation and investigational anticancer agent combination. This assessment also paints the initial descriptive palette of adverse events linked with the co-administration of the two in a dose-dependent manner. From this parti, we gain an illustrative safety portfolio for radiation-anticancer agent combinations that allow next step study of therapeutic response in phase II or III clinical trials.In an effort to maximize clinical benefit, architects of phase I radiochemotherapy development programs conduct stepwise dose-escalated trials of radiation, of anticancer agent(s), or both together. It has been held in such dose-escalated trials that one accepts an adverse event or toxicity rate of 33% or less in participants, based on the premise that the limited study subject numbers are largely representative of patient cancer groups sharing common traits. Discovery of a toxicity rate target may be done by escalating radiation or anticancer agent dose until two of six  enrollees manifest an adverse event, often a toxicity arising from a pre-determined list. For radiochemotherapy trials, investigators then drop down to the next lower radiation or anticancer agent dose level to enroll additional patients to establish a recommended phase II dose and schedule. This is coined the maximally tolerated dose (MTD). The end product is a radiation-anticancer agent combination recommended for phase II or III clinical testing. Here, we focus on stepwise dose-escalated trials but recognize that other radiation-drug discovery formats are part of the anticancer clinical development portfolio -cisplatin (30\u2009mg/m2) regimen  is administered for cisplatin radiochemosensitization  and single-cycle bolus mitomycin C (15\u2009mg/m2) radiochemotherapy (30\u2009Gy in 15 2\u2009Gy fractions) for anal cancer  plus mitomycin C  radiochemotherapy had planned adjustments in treatment intensity  and mitomycin C  radiochemotherapy investigated peer-reviewed dose-painted intensity modulated radiation therapy (IMRT)  has brought new challenges for assurance of radiation quality and safety. These technologies along with adaptive radiotherapy and image guided radiotherapy (IGRT) rely on treatment volume definitions which are still in development in many disease sites. In radiochemotherapy centers and cooperative groups known for excellence in the quality delivery of radiation, rapid review of cases allows for uniform definition of radiation volumes and dose delivered over elapsed times specified in clinical trial protocols with little variation. Real-time monitoring of these advanced radiation delivery platforms merits our serious and respectful scrutiny. Treatment volumes are not as easily defined by bony anatomy as is seen in 2 and 3-D treatment volumes and can be variable depending on differing patient anatomy. Hence these platforms should not earn our uncritical acceptance. Arguably, these platforms offer expectantly substantial reduction in radiation-related adverse events but should not be used clinically in deference to rigorous quality assurance by all users. Also, it is prudent within a single phase I radiochemotherapy trial to have a uniform radiation platform by all investigators. Enrolling trial participants into a phase I radiochemotherapy trial that allows radiation treatment by conventional radiation or by IMRT would cloud the interpretation of observed radiation-drug adverse events, possibly raising issues of falsely concluding a safe relationship exists when it truly may not. Mixing technologies on a phase I radiochemotherapy trial may also invalidate the historical radiation-specific technology adverse event data upon which the trial was predicated. Observed toxicity on down-the-line phase II or phase III studies may also be influenced by \u201cany\u201d form radiation delivery. More study is needed and guidelines for safety and quality assurance are emerging for these new technologies and utilization in phase I radiochemotherapy studies should only be considered once these guidelines are confirmed in other venues.Making radiation-anticancer agent discovery safer and of optimal quality is the goal of phase I radiochemotherapy programs. Implementing the layers of quality control such as dose checks, timetables, uniformity in treatment portal/treatment volume design, and brachytherapy application, and with timely critical feedback are musts in high-performing phase I radiochemotherapy programs. In the context of radiochemotherapy, the architects of clinical trials must layout plans intended to balance the safe selection and concise use of radiation-anticancer agent combinations.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Charadriiformes infected in Delaware Bay this host population does not appear to significantly contribute to the North American AIV diversity sampled in Anseriformes. In contrast, influenza viruses sampled from Anseriformes in Alberta are representative of the AIV diversity circulating in North American Anseriformes. While AIV may be restricted to specific migratory flyways over short time frames, our large-scale analysis showed that the long-term persistence of AIV was independent of bird flyways with migration between populations throughout North America. Analysis of long-term surveillance data provides vital insights to develop appropriately informed predictive models critical for pandemic preparedness and livestock protection.Wild birds have been implicated in the emergence of human and livestock influenza. The successful prediction of viral spread and disease emergence, as well as formulation of preparedness plans have been hampered by a critical lack of knowledge of viral movements between different host populations. The patterns of viral spread and subsequent risk posed by wild bird viruses therefore remain unpredictable. Here we analyze genomic data, including 287 newly sequenced avian influenza A virus (AIV) samples isolated over a 34-year period of continuous systematic surveillance of North American migratory birds. We use a Bayesian statistical framework to test hypotheses of viral migration, population structure and patterns of genetic reassortment. Our results reveal that despite the high prevalence of  Anseriformes) and shorebirds (Charadriiformes), the ecological and evolutionary dynamics of avian influenza A virus (AIV) in these hosts is poorly understood. Comparative genomic analysis of AIV data revealed that the high prevalence of Charadriiformes infected in Delaware Bay is a reservoir of AIV that is phylogenetically distinct from AIV sampled from most North American Anseriformes. In contrast, influenza viruses sampled from Anseriformes in Alberta are representative of the remaining AIV diversity sampled across North America. While AIV may be restricted to specific migratory flyways over short time frames, our large-scale analysis showed that this population genetic structure was transient and the long-term persistence of AIV was independent of bird flyways. These results suggest an introduced virus lineage may initially be restricted to one flyway, but migration to a major congregation site such as Alberta could occur followed by subsequent spread across flyways. These generalized predictions for virus movement will be critical to assess the associated risk for widespread diffusion and inform surveillance for pandemic preparedness.Despite continuous virological surveillance (1976\u20132009) in wild waterfowl ( Migrating wild birds have been implicated in the spread and emergence of human and livestock influenza, including pandemic influenza and highly pathogenic H5N1 avian influenza Anseriformes infected with influenza A virus have hampered migration, these hosts vector influenza viruses vast distances It is estimated worldwide that over 50 billion birds migrate annually between breeding and non-breeding areas Anseriformes and Charadriformes gene pools where birds from both continental regions commingle and therefore the threat posed by introduction of H5N1 to North America remains. However, once a virological threat has entered the North American bird population there is little information regarding how that virus may behave or diffuse between spatially distant migratory bird populations.Recent efforts to assess invasive virological threats have focused on increased surveillance and early detection of introduced viral strains ad hoc approaches. This is largely due to a critical lack of knowledge of viral movements between different host populations The prediction of viral spread and disease emergence, as well as formulation of preparedness plans has generally been based on In this study we identified 20 discrete regions in North America where influenza viruses have been systematically collected from wild birds to determine whether the viral population was structured according to host migratory flyways, and rates of gene flow between these populations. Avian influenza viruses were isolated annually throughout our surveillance in Alberta, Canada and Delaware Bay, USA and an additional 287 genomes were sequenced. Using full genome data we characterize the reassortment dynamics, spatial diffusion patterns and evolutionary genomics of influenza A viruses in North America collected over a 25-year period from migratory birds.Avian influenza H3 viruses were among the most frequently isolated influenza subtype from our surveillance in Alberta, Canada and Delaware Bay, USA AnseriformesCharadriiformes were sampled, H3 viruses were detected in only 7 years (ntax\u200a=\u200a69) from 24 years of surveillance  and patristic distances for each gene segment (excluding NA) to test differences in reassortment between populations . In thisAnseriformes, throughout the entire surveillance period. One possibility is that this deep divergence is the product of (i) a very large host meta-population and (ii) relatively rare cross-species transmission rate when compared to annual seasonal epidemic dynamics leading to a lack of synchronicity of partial immunity across host species so that more than one lineage can effectively survive long periods of time. Although there was little evidence for geographic structuring of the virus population over extended periods, an obvious exception is a single lineage that has circulated for more than 10 years in birds sampled from Delaware Bay . The tMRCA of Lineages I and II was estimated to be \u223c1942 . The mechanism for maintenance of this deep divergence remains unknown, as viruses from both lineages have co-circulated in geographically overlapping host populations, primarily ware Bay .Ancestral state reconstruction of virus geographic location suggests that the population of Lineage II was localized in southeast Alberta prior to migrating to other locations across all North American flyways . HoweverWe next estimated rates of viral migration between discrete geographic locations treating each gene as an independent dataset to capitalize on the extra historical information generated by genetic reassortment. While each gene segment analysed supported lateral diffusion between migratory flyways over time, analysis of migration paths using single gene segments yielded contradictory answers , S7, S8.th state termed \u201cOther\u201d, that maintained phylogenetic tree structure. The \u201cOther\u201d state included taxa isolated prior to 1998 where few geographic locations were sampled and locations where few isolates were encountered over the surveillance period We further analyzed all publically available PA, PB1, PB2, NP and M sequence data from wild aquatic birds isolated between 1985\u20132009 in North America. The HA, NA and NS gene segments were not included in this analysis due to the deep divergence between the subtypes Anseriformes' social behavior in persistence of the virus population.Our goal was to understand the migration dynamics and diffusion patterns of influenza virus in their natural hosts by utilizing over 30 years of continuous systematic surveillance data. We show that our surveillance within Alberta, which includes convergence points for all four migratory flyways Charadriiformes stopover annually to feed in highly dense congregations. Our results showed limited genetic diversity coupled with high prevalence of infection indicating an epizootic in Charadriiformes that does not play a significant role in the shaping the sampled AIV diversity within North American Anseriformes. Even though this hotspot is not representative of gene pool diversity, these viruses are ultimately derived from the same population of viruses common throughout North America. The transmission of viruses between populations of birds is most likely occurring where migratory Anseriformes and Charadriiformes commingle, possibly in South and Central America or Arctic breeding grounds. The role of Charadriiformes in the persistence and transmission of influenza A viruses therefore warrants further study, especially on a more comprehensive spatial scale.The site at Delaware Bay has been identified as a hotspot for avian influenza A viruses We show that the long-term persistence of the influenza A virus gene pool in North American wild birds may be independent of migratory flyways. Although virus migration could be restricted within a flyway over short time periods, our results show strong support for longer-term lateral diffusion of viral lineages between host populations. In our study, data points were not assigned to a flyway but discrete sites were assigned and used to inform within and between flyway migration rates using tip-dated time-dependent phylogenetic reconstructions. While this does contradict previous work by Lam et al Subtype specific host distribution, geographic state definition and host ecology may also be a source for the differences observed between the two studies The data used in our analysis included collections from resident and short distance migratory birds Using our model for virus transmission generalized predictions for movement of an introduced Eurasian virus and the associated risk for widespread diffusion can be inferred. An introduced virus lineage to Alaska might initially be restricted to the Pacific Flyway, but migration to a major congregation site such as Alberta could occur with subsequent spread across flyways occurring shortly after. While the establishment of introduced lineages into North America may be rare, introduction and reassortment events with Eurasian and North American strains probably occur more frequently than detected The development of fully resolved ecological and viral risk models depend upon the continued long-term active surveillance in major bird congregation zones. While the resolution and detection of migration events has been enhanced with increased surveillance in recent years, critical information for wild bird surveillance remains sparse. This is especially evident as no sampling in Central and South America was available for this study. A comprehensive understanding of spatial diffusion patterns of viruses introduced to wild animal populations is critical for the development of preparedness plans in response to emerging viral threats.Anas platyrhynchos), northern pintail (Anas acuta), and blue-winged teal (Anas discors) with these three species accounting for 93% of the total specimens. Other species (listed in decreasing rank order of samples obtained) include redhead (Aythya americana), green-winged teal (Anas crecca), american wigeon (Anas americana), gadwall (Anas strepera), canvasback , lesser scaup (Aythya affinis), american coot (Fulica americana), northern shoveler (Anas clypeata), bufflehead , cinnamon teal (Anas cyanoptera), common goldeneye , ruddy duck (Oxyura jamaicensis), greater scaup (Aythya marila), hooded merganser (Lophodytes cucullatus), and wood duck (Aix sponsa).Systematic influenza surveillance has been conducted in ducks in Alberta, Canada since 1976, and in shorebirds and gulls at Delaware Bay (Delaware and New Jersey) since 1985. Ducks were sampled post-breeding and prior to southern migration during July through early September at various wetlands in the following regions of Alberta: Vermilion (1976\u20131978), Grand Prairie/Fairview , Edmonton/Stettler , Brooks (1992\u20131995), and High River . Sampling occurred during duck banding operations conducted by the Canadian Wildlife Service after ducks were captured in swim-in bait traps. Birds banded in Alberta have been recovered in all four North American flyways but most mallards are recovered in the Central and pacific flyways. In 1984 samples were also collected from ducks captured in decoy traps during late April to early May in the Vermilion area. Overall, the majority of samples were obtained as cloacal swabs  and tracheal/oropharyngeal specimens accounted for most of the remaining samples . Hatch-year ducks were sampled more frequently than after-hatch-year ducks . A variety of duck species were sampled \u2013 primarily dabbling ducks. The most abundantly sampled species are mallard (Charadriiformes \u2013 shorebirds and gulls - were collected in May at Delaware Bay from ruddy turnstone (Arenaria interpres), red knot , semipalmated sandpiper , sanderling , and dunlin  starting in 1985 and continuing to the present. Samples were also obtained from breeding colonies of gulls \u2013 primarily laughing gull (Larus atricilla) and herring gull (Larus argentatus). It is during this period in May that shorebirds (waders) are migrating north from South America to their breeding grounds in the Canadian Arctic. Delaware Bay serves as a stopover point where the birds can re-fuel on the abundance of eggs deposited by the coincident spawning of horseshoe crabs (Limulus polyphemus).Fecal samples from Although most of the 10,350 samples obtained were from freshly deposited feces on beaches we also collected 213 cloacal swabs from captured birds spanning the years 1986\u20131989 and 2000. A subset of 440 samples was collected outside of the May surveillance period at the following times; September 1985, September and November 1986, and June-September 1988. It should be noted that from 1988 through 2002 multiple swabs  were combined to constitute a single sample vial. In the years prior to 1988 most sample vials contained an individual swab, and all samples since 2003 have been from single fecal deposits.Approximately 19 sample sites were established around Delaware Bay and varied from year-to-year. Six sites were used on the west side of Delaware Bay in Maryland and Delaware from 1985 through 1989. Sampling was performed at 13 sites on the east side of the bay in New Jersey in all years. The majority of the swabs were derived from fecal deposits and therefore it was not possible to identify the species that served as the source of the sample in over half of the specimens. However, the birds tend to congregate in groups of like species, and gull feces were easily discriminated from other bird droppings, therefore in many instances we could attribute the source of the sample to a particular species. Otherwise the sample was considered \u201cshorebird\u201d or \u201cgull\u201d.Swabs were collected using a dacron tipped applicator and placed in transport medium containing 50% phosphate buffered saline and 50% glycerol adjusted to pH 7.2 and supplemented with penicillin G, streptomycin, polymyxin B, gentamycin, and nystatin. In Alberta the duck swabs were placed immediately in liquid nitrogen and returned to the laboratory. Shorebird samples from Delaware Bay were immediately placed on ice and shipped to the laboratory within 6 days of collection. Storage of the specimens prior to testing was at \u221270\u00b0C.Viruses were isolated in 10-day-old embryonated chicken eggs as previously described Through exploratory examination of surveillance records from Alberta and Delaware Bay we determined that H3 subtype viruses have been most frequently isolated throughout the time period 1985\u20132009. We therefore focused our sequencing efforts on this time period and randomly selected 200 viruses for full genome sequencing. This data was further supplemented with an additional 100 viruses randomly selected for genomic sequencing of various subtypes.All samples were sequenced using a high-throughput Next-Generation sequencing pipeline at the JCVI that includes the 454/Roche GS-FLX and the Illumina HiSeq 2000. Viral RNA was first reverse transcribed and amplified by multi-segment RT-PCR (M-RTPCR) One library was prepared for sequencing on the 454/Roche GS-FLX platform using Titanium chemistry while the other was made into a library for sequencing on the Illumina HiSeq 2000. The sequence reads from the 454/Roche GS-FLX data were sorted by barcode, binned by sample, trimmed, searched by TBLASTX against custom nucleotide databases of full-length influenza A segments downloaded from GenBank to filter out both chimeric influenza sequences and non-influenza sequences amplified during the random hexamer-primed amplification. For each sample, the filtered 454/Roche GS-FLX reads were then binned by segment, and de novo assembled using CLC Bio's clc_novo_assemble program. The resulting contigs were searched against the corresponding custom full-length influenza segment nucleotide database to find the closest reference sequence for each segment. Because of the short read length of the sequences obtained from the barcode-trimmed Illumina, HiSeq 2000 these were not subjected to the TBLASTX filtering step. Both 454/Roche GS-FLX and Illumina HiSeq 2000 reads were then mapped to the selected reference influenza A virus segments using the clc_ref_assemble_long program.At loci where both GS-FLX and Illumina sequence data agreed on a variation (as compared to the reference sequence), the reference sequence was updated to reflect the difference. A final mapping of all next-generation sequences to the updated reference sequences was then performed. Any regions of the viral genomes that were poorly covered or ambiguous after Next Generation sequencing were PCR amplified and sequenced using standard Sanger sequencing approach.Through sequencing, some of these selected viruses have been identified as more than one isolate (\u201cMixed\u201d in table S3). The direct sequencing method does not allow us to determine which internal gene segments are associated with which subtype. Furthermore, some variants could not yield unique gene sequences for each potential virus identified. Hence, some mixed variants contain more than 8 associated sequences, but fewer than 16. As such, these were not included in the analysis of genomic reassortment patterns. Other variants could not be completely sequenced and have subsequently been submitted as \u201cDraft.\u201d Out of the 300 variants submitted for sequencing, 287 full genomes have been completed. All data generated for this study has been made publicly available via the Influenza Virus Resource at NCBI We analyzed 1441 genomic sequences of influenza A viruses in wild birds  as this was the most commonly isolated subtype throughout the surveillance period in both Alberta and Delaware Bay. Secondly, we analyzed all publically available PB1, PB2, PA, NP, M gene segments (excluding recent introductions from Eurasia) to estimate the viral migration patterns across the entire population of birds regardless of subtype. HA, NA and NS genes were not included due to the deep divergence between subtypes. This latter analysis resulted in a dataset of more than 1300 sequences for each of the five genes included.While the phylogeny and substitution rates were separate for each gene, based on a joint migration process a single migration matrix was estimated. We used a reversible continuous-time Markov chain model to estimate the migration rates between geographical regions and the general patterns of avian influenza A virus circulation in different populations We used multidimensional scaling plots to visually assess the strength of reassortment in Alberta and Delaware Bay. In this analysis the tree-to-tree variation in branch lengths is visualized as a cloud of points where the centroid of the cloud represents the mean from the 500 trees used in the analysis. Here we assume that gene segments with similar evolutionary histories will occupy the similar locations in the 2-dimensional Euclidean space where the cloud of points should overlap. We used two metrics to assess the degree of reassortment of the influenza A virus populations in the two discrete sampling regions: the time to the most recent common ancestor (tMRCA) or patristic distances calculated from a posterior distribution of trees. From a posterior distribution of phylogenetic trees we estimated the tMRCA for influenza A viruses sampled in each location from each gene during each year and computed the correlation coefficient of the tMRCAs between each pair of trees. This method of tree to tree comparisons has been applied to seasonal influenza A viruses In our data sets there was a sparseness of sampling through time, especially in Delaware Bay. Therefore we encountered high levels of uncertainty where no clear pattern was discernable and zero distances between trees resulted in computational errors by using the tMRCA to estimate phylogenetic uncertainty between gene trees. To overcome this we computed the correlation matrix of the pairwise tree distances. Here we calculated the correlation coefficient for each pair of trees using the patristic distances between every taxon, where the patristic distance is the sum of branch lengths between two nodes. The dissimilarity matrix was obtained by calculating one minus the correlation matrix.All animal experiments were performed following Protocol Number 081 approved on August 19, 2011 by the St. Jude Children's Research Hospital Institutional Animal Care and Use Committee in compliance with the Guide for the Care and Use of Laboratory Animals, 8th Ed. These guidelines were established by the Institute of Laboratory Animal Resources and approved by the Governing Board of the U.S. National Research Council.Figure S1Neighbor joining phylogenetic tree produced from an HKY85 nucleotide substitution model optimized distance matrix from all available H3-HA data, including sequences generated in this study. The major lineages; Oceania, Eurasia, and North American Lineages I and II are indicated to the right of the tree. Bootstrap supports for these major lineages are indicated on the tree. The scale bar indicates nucleotide substitutions/site.(PDF)Click here for additional data file.Figure S2http://tree.bio.ed.ac.uk/software/figtree/). Also applies to figures S3, S4, S5, S6, S7, S8.H3 Hemagglutinin gene tree nexus file. Temporally structured maximum clade credibility phylogenetic tree showing the mixing of avian influenza A virus isolated from North American wild birds for each individual gene dataset. Ancestral state changes recovered from the discrete phylogeographic analyses are indicated by color changes at tree nodes. Purple bars on nodes indicated 95% confidence intervals of date estimates. Trees with taxon labels and node annotations can be viewed in FigTree (available from (TREE)Click here for additional data file.Figure S3PB2 gene tree nexus file.(TREE)Click here for additional data file.Figure S4PB1 gene tree nexus file.(TREE)Click here for additional data file.Figure S5PA gene tree nexus file.(TREE)Click here for additional data file.Figure S6NP gene tree nexus file.(TREE)Click here for additional data file.Figure S7M gene tree nexus file.(TREE)Click here for additional data file.Figure S8NS gene tree nexus file.(TREE)Click here for additional data file.Figure S9A) Mean migration rate per MCMC step within flyway migration rates vs Mean between flyway migration jointly estimated from a subsampled dataset of (PDF)Click here for additional data file.Figure S10Relationship of migration rate and distance. A) Mean statistically supported rates vs distance between discrete migration sites; B) Median statistically supported rates vs distance between discrete migration sites; C) All Mean migration rates vs distance between discrete migration sites; D) All Median rate indicator vs distance between discrete migration sites.(PDF)Click here for additional data file.Figure S11Interactive Google Earth Supplementary Data. GenBank Accession numbers and specific location of virus sampling for all sequences used in this study in the 5\u00b0 Latitude by 5\u00b0 Longitude square used to define the discrete character for ancestral state reconstruction.(KML)Click here for additional data file.Figure S12http://tree.bio.ed.ac.uk/software/figtree/). Also applies to figures S13, S14, S15, S16.PB2 gene tree nexus file used to estimate joint migration. Interactive Tree files. Temporally structured maximum clade credibility phylogenetic tree with all available data used to jointly estimate the migration patterns summarized in (TREE)Click here for additional data file.Figure S13PB1 gene tree nexus file used to estimate joint migration.(TREE)Click here for additional data file.Figure S14PA gene tree nexus file used to estimate joint migration.(TREE)Click here for additional data file.Figure S15NP gene tree nexus file used to estimate joint migration.(TREE)Click here for additional data file.Figure S16M gene tree nexus file used to estimate joint migration.(TREE)Click here for additional data file.File S1http://beast2.cs.auckland.ac.nz/index.php/Main_Page).BEAST2 executable xml file detailing the parameters for the joint estimation of the single migration rate matrix from independently generated phylogenies (BEAST2 available from (TXT)Click here for additional data file.Table S1Host Avifauna most frequently infected with influenza A virus summarized from the Centers of Excellence for Influenza Research and Surveillance North American wild bird surveillance efforts reporting from 2007.(DOC)Click here for additional data file.Table S2GenBank Accession numbers, isolation date and location of virus sampling for additional sequences from public databases used in this study.(DOC)Click here for additional data file.Table S3Associated geographic metadata and exact date of sampling of newly sequenced avian influenza A viruses.(DOC)Click here for additional data file.Table S4Number of taxa included per protein coding region to estimate average migration dynamics between discrete regions.(DOC)Click here for additional data file.Text S1Supplementary information describing flyways and bird behavior.(DOC)Click here for additional data file."}
+{"text": "Estrogen Receptor (ER) is the defining feature of luminal breast cancers, where is functions as a transcription factor. The traditional view of ER getting recruited to promoters of target genes is too simplistic. The recent discovery of ER-DNA interaction regions from ER+ breast cancer cell lines has revealed that ER rarely associates with promoter regions of target genes and instead associates with enhancer elements significant distances from the target genes. The genomic mapping of ER binding events also revealed the enrichment of DNA motifs for Forkhead factors. The Forkhead protein FOXA1 (HNF3a) was subsequently shown to bind to ~half of the ER binding events in the genome and was required for ER to maintain interaction with DNA. We have extended on these findings to map ER binding events in primary breast cancers and distant metastases. We find context dependent ER cis-regulatory elements (cistromes) that give insight into underlying transcriptional networks. These differential ER binding profiles correlate with clinical response in ER+ breast cancers. We experimentally explore the binding dynamics between drug sensitive and resistant contexts and identify properties that govern ER binding differences. These data suggest that ER-DNA interactions are dynamic and can be modulated by changes in FOXA1. We are currently exploring mechanisms that mediate FOXA1-DNA interactions, in order to better understand ER transcriptional activity in breast cancer biology."}
+{"text": "Treating acute ischaemic stroke patients with iv-rtPA is of overall benefit. An associated increase in the risk of symptomatic intracranial haemorrhage (SICH) may cause considerable harm. We investigated (i) whether novel or existing prediction models could predict SICH or poor functional outcome in rtPA treated patients and (ii) whether ischemic stroke patients at either a high predicted risk of SICH or poor functional outcome experienced less benefit from rtPA.We used the IST-3 trial data, an international, multicentre, open treatment randomised trial of rtPA versus control in 3035 acute ischemic stroke patients. We developed and internally evaluated a multivariate logistic regression model for SICH following rtPA including variables identified as important in a systematic review. We compared the discrimination (area under the receiver operating characteristic curve (AUROCC)) of our model with those existing in the medical literature. We calculated the absolute risk reduction of death or dependency with rtPA in patients at a low, medium or high predicted risk of SICH or poor functional outcome with each model.Our model had similar discrimination for SICH (AUROCC 0.68 95% CI: 0.63-0.74) to nine previously developed models . There was no evidence that patients at high predicted risk of SICH or poor functional outcome after stroke derived less benefit from rtPA.We found no evidence to support a stratified approach in administering rtPA to acute ischaemic stroke patients at a high predicted risk of intracranial haemorrhage or poor functional outcome."}
+{"text": "Target-based drug discovery must assess many drug-like compounds for potential activity. Focusing on low-molecular-weight compounds (fragments) can dramatically reduce the chemical search space. However, approaches for determining protein-fragment interactions have limitations. Experimental assays are time-consuming, expensive, and not always applicable. At the same time, computational approaches using physics-based methods have limited accuracy. With increasing high-resolution structural data for protein-ligand complexes, there is now an opportunity for data-driven approaches to fragment binding prediction. We present FragFEATURE, a machine learning approach to predict small molecule fragments preferred by a target protein structure. We first create a knowledge base of protein structural environments annotated with the small molecule substructures they bind. These substructures have low-molecular weight and serve as a proxy for fragments. FragFEATURE then compares the structural environments within a target protein to those in the knowledge base to retrieve statistically preferred fragments. It merges information across diverse ligands with shared substructures to generate predictions. Our results demonstrate FragFEATURE's ability to rediscover fragments corresponding to the ligand bound with 74% precision and 82% recall on average. For many protein targets, it identifies high scoring fragments that are substructures of known inhibitors. FragFEATURE thus predicts fragments that can serve as inputs to fragment-based drug design or serve as refinement criteria for creating target-specific compound libraries for experimental or computational screening. In drug discovery, the goal is to identify new compounds to alter the behavior of a protein implicated in disease. With the very large number of small molecules to test, researchers have increasingly studied fragments  because there are fewer possibilities to evaluate and they can be used to identify larger compounds. Computational tools can efficiently assess if a fragment will bind a protein target of interest. Given the large number of structures available for protein-small molecule complexes, we present in this study a data-driven computational method for fragment binding prediction called FragFEATURE. FragFEATURE predicts fragments preferred by a protein structure using a knowledge base of all previously observed protein-fragment interactions. Comparison to previous observations enables it to determine if a query structure is likely to bind particular fragments. For numerous protein structures bound to small molecules, FragFEATURE predicted fragments matching the bound entity. For multiple proteins, it also predicted fragments matching drugs known to inhibit the proteins. These fragments can therefore lead us to promising drug-like compounds to study further using computational tools or experimental resources. Fragments in this context refer to low-molecular-weight small molecules usually 120\u2013250 Daltons in weight Fragments tend to bind in the millimolar to micromolar range and require sensitive experimental screening techniques, including protein crystallography et. al. took a ligand fragment-centric view and calculated the residue preferences of different fragments et. al. took a protein residue-centric view and determined the fragment preferences of the side chains of Asp, Glu, Arg, and His However, the growing database of structural data for protein-small molecule complexes provides an opportunity for empirical data-driven approaches to fragment binding prediction in silico fragment binding predictors/evaluators. Using information from the Protein Data Bank, we created a knowledge base linking local protein structural environments to the small molecule fragments they bind. Given structural environments from a target protein, FragFEATURE compares them to the knowledge base to find similar structural environments and identify statistically preferred fragments. For a variety of protein-ligand complexes, we demonstrate the method's ability to predict fragments that are substructures of the bound ligands. We also present six case studies (three in main text and three in supporting information) of fragment predictions corresponding to known inhibitors. These fragment predictions can help identify promising compounds from compound libraries. Such compounds have potential to form favorable interactions with the protein target due to the presence of the fragment but require additional evaluation as other moieties in the compounds may prevent binding. Predicted fragments are also starting points for fragment-based drug design. Furthermore, knowledge of fragments favored by a protein pocket could give insight to lead optimization by suggesting favorable chemical groups. FragFEATURE thus powerfully leverages empirical knowledge of protein-fragment interactions to predict fragments for a target protein structure.Here, we describe FragFEATURE, a novel fragment binding predictor that overcomes many of the limitations of existing The knowledge base is the underlying source of information for fragment predictions. We mined 34,000 protein-ligand complexes from the PDB (01/01/2013 snapshot) to create a knowledge base of local protein structural environments (microenvironments) annotated with the small molecule substructures (fragments) they bind . In the To capture protein information, we used FEATURE To capture fragment information, we divided 16,000 PDB ligands into overlapping substructures ranging from three to thirteen heavy atoms in size . These fFragFEATURE predicts fragments preferred by the microenvironments of a protein pocket . It usesWe validated FragFEATURE on four nucleotide and four non-nucleotide ligands and found strong ability to predict fragments matching the ligand bound. The nucleotides included adenine (ADE), adenosine-5\u2032-diphosphate (ADP), flavin-adenine dinucleotide (FAD), and nicotinamide-adenine dinucleotide (NAD). The non-nucleotides included thiamin (VIB), thiamine diphosphate (TPP), pyridoxal-5\u2032-phosphate (PLP), and triclosan (TCL). These compounds tested FragFEATURE on ligands of different frequency , flexiblFragFEATURE predicted fragments for 9,392 ligand-binding pockets  and we aFor the previous analysis, we used observed ligand-binding pockets. In other applications of FragFEATURE, the location and extent of the ligand-binding pockets may be unknown. In those cases, both pocket definition and conformation may alter the microenvironments used by FragFEATURE to make predictions. To determine the sensitivity to non-ideal microenvironments, we tested computationally predicted pockets fPocket  from botWe investigated the potential utility of FragFEATURE fragment predictions for drug discovery. In the following case studies, FragFEATURE rediscovered fragments of inhibitors for the analyzed protein targets. These \u201cdrug-relevant fragments\u201d can inform different research approaches including virtual screening, high-throughput experimental screening, or fragment-based drug design.Pseudomonas aeruginosa is an opportunistic bacterium that infects immunocompromised patients \u221229 for the microenvironments proximal to the nicotinamide moiety of NAD (i: 140 nM) and is available in the PDB bound to exotoxin A . A crystal structure of staurosporine-bound DAPK1  that interact with the protein target. It relies solely on the target's 3D structure and can be applied to any protein with a solved structure or high quality homology model. Additionally, the structural space of protein pockets is small, with the PDB showing good coverage of pocket space Other methods for identifying compounds for a protein target include using information from (1) known bioactive compounds for the target, (2) compounds that bind to homologs of the target, and (3) compounds that bind to proteins non-homologous to the target but share binding specificity (i.e. bind similar endogenous ligands as the target). Such compounds can serve as valuable starting points in drug discovery Fragments predicted by FragFEATURE may overlap with available binding information for the target or be intuitive to a researcher with expertise in structure-based or fragment-based drug design. However, FragFEATURE provides a systematic statistical framework within which to interpret a fragment prediction along with the structural evidence for the prediction. FragFEATURE uses fragment information from proteins with low sequence identity to the target protein. The retrieved nearest neighbor protein structures may highlight unexpected local structural similarity. Shared fragment preferences between proteins can provide an opportunity for polypharmacology The FEATURE software Microenvironment centers correspond to residue side chains or backbone atoms. For the side chain centers, we use those defined by PocketFEATURE To determine microenvironment similarity, we adopted the approach used by PocketFEATURE x and y) as the ratio of shared properties to non-zero properties. Like PocketFEATURE, we define shared properties as those whose difference is less than the standard deviation of the property. If c is the number of shared properties and a and b the number of non-zero properties in vector x and y respectively, the Tanimoto coefficient (Tc) is as follows: We use PocketFEATURE's Tanimoto coefficient to perform similarity comparisons between microenvironments of the same type (e.g. backbone oxygen to backbone oxygen). This Tanimoto coefficient measures the similarity between a pair of microenvironment vectors , we retrieve all protein X-ray crystallography structures with resolution less than 3 \u00c5. We then select the structures bound to small molecules, ignoring small molecules less than three heavy atoms, greater than 100 heavy atoms, or corresponding to commonly used buffers and crystallization agents. PDB ligands with over 100 heavy atoms tended to produce errors with either PUG SOAP or SMSD. For the resulting protein-ligand complexes, we calculate the location of all pseudo atoms (see Feature Microenvironments). We then use a distance cutoff to identify protein atoms/pseudo atoms \u201cinteracting\u201d with the ligands, keeping side chain atoms/pseudo atoms within 5 \u00c5 and backbone atoms within 4 \u00c5 of a ligand heavy atom. The shorter distance cutoff for the backbone atoms helps exclude atoms participating in intra-protein hydrogen bonding and thus not involved in ligand binding. We converted the collected protein atoms/pseudo atoms into microenvironments using FEATURE and divided them into 23 types (see Feature Microenvironments). By definition, each microenvironment is \u201cinteracting\u201d with one or more ligand heavy atoms. For each ligand heavy atom interacting with a microenvironment, we retrieve its associated fragment list and take the union of these lists as the microenvironment's associated fragments . This prGiven a query microenvironment, we compare it to knowledge base microenvironments of the same type. This allows us to sort the knowledge base by similarity to the query using the Tanimoto coefficients. We then filter the knowledge base for homology by first removing microenvironments from proteins homologous to the query. Of the remaining microenvironments, we keep only the most similar microenvironment for microenvironments from homologous proteins. This ensures the final knowledge base microenvironments are non-homologous to the query and to each other. We define homology as \u226550% sequence identity as pre-computed by the PDB. This produces a query-specific non-homologous knowledge base ordered by microenvironment similarity to the query.k most similar non-homologous microenvironments (k nearest neighbors) and their corresponding fragment list. For each fragment in these lists, we calculate a hypergeometric p-value. This requires the number of neighbors selected (k), the number of neighbors binding the fragment (m), the number of microenvironments in the non-homologous knowledge base binding the fragment (M), and the number of microenvironments in the non-homologous knowledge base (N). The hypergeometric p-value . We take the most significant fragment predicted for a microenvironment and compare it to the microenvironment's fragment list to determine its validity (correct/incorrect). We then use the predicted fragments' p-values and validity labels to compute a precision recall curve for each microenvironment type. The area under the precision recall curve (AUPR) serves as a measure of overall performance. An AUPR approaching 1.0 indicates similar microenvironments bind similar fragments.We selected eight ligands to validate FragFEATURE's performance: adenine (ADE), adenosine-5\u2032-diphosphate (ADP), flavin-adenine dinucleotide (FAD), nicotinamide-adenine dinucleotide (NAD), pyridoxal-5\u2032-phosphate (PLP), triclosan (TCL), thiamine diphosphate (TPP), and thiamin (VIB). For the ligand-bound structures, we retrieved all structures from the PDB in complex with the validation ligands. For the ligand-free structures, we retrieved all protein-only structures from the PDB homologous (95% sequence identity) to the ligand-bound structures.Three types of pockets are of interest: observed ligand-binding pockets, predicted pockets from ligand-bound structures, and predicted pockets from ligand-free structures. An observed ligand-binding pocket contains the side-chain atoms within 5 \u00c5 and backbone atoms within 4 \u00c5 of any validation ligand heavy atom. A predicted pocket for a ligand-bound or ligand-free structure is the atoms forming the largest pocket predicted by fPocket. fPocket performs pocket detection for each protein chain individually with the ligand information removed. Protein atoms comprising the different pockets are then passed to FEATURE to calculate their microenvironments. Microenvironments centered on a pseudo atom are calculated if any of the atoms contributing to the pseudo atom location are part of the pocket (see FEATURE Microenvironments).N spatially proximal microenvironments. However, given that some microenvironments in the set may not be informative for fragment prediction, we also create all subsets of size N\u20131 to 2 microenvironments . Fragments with a hypergeometric p-value for all microenvironments within a set are consensus fragments regardless of the hypergeometric p-value. We keep only consensus fragments to ensure agreement and coherence among the microenvironments of a set. For each consensus fragment, we use Fisher's method to combine the hypergeometric p-values  and the structures homologous to the query. This helps take into account that proteins may bind multiple ligands at a given site. We retrieve PDB structures sharing at least 95% sequence identity to the query and use BLAST+ Fragment predictions arise from microenvironment sets and are correct, incorrect or no information . CorrectEach fragment prediction is made by a set of microenvironments with each microenvironment using fragment information from the five nearest non-homologous neighbors. A subset of these nearest neighbors contributes to the fragment prediction (e.g. bind the predicted fragment). We calculate the percent sequence identity between the query structure and this subset of nearest neighbor protein structures. We analyze the most significant correct fragment prediction for each test structure, so test proteins without a correct fragment prediction are excluded from analysis. To determine the percent sequence identity between a pair of proteins, we use BLAST+ to align their amino acid sequences. We consider alignments that fail to cover at least 20% of the smaller protein or that possess an alignment E-value \u226510 (default) as failed alignments.Computation time varies with the size of the pocket of interest as measured by the number of microenvironments comprising the pocket. The process begins with an input list of atoms defining the pocket and ends with an output file of fragment predictions. The ligand-binding pockets generally possess five to fifty-five microenvironments. We select eleven pocket sizes to cover this range evenly and time five pockets for each pocket size to obtain computation time as a function of pocket size . ComputaFigure S1FEATURE microenvironments.(DOCX)Click here for additional data file.Figure S2Breakdown of knowledge base microenvironments.(DOCX)Click here for additional data file.Figure S3Ligand fragmentation.(DOCX)Click here for additional data file.Figure S4Breakdown of knowledge base fragments.(DOCX)Click here for additional data file.Figure S5Fragment prediction for single microenvironments.(DOCX)Click here for additional data file.Figure S6Microenvironment set definition.(DOCX)Click here for additional data file.Figure S7Chemical moieties of the validation ligands.(DOCX)Click here for additional data file.Figure S8Fragment evaluation.(DOCX)Click here for additional data file.Figure S9Sequence identity between test proteins and nearest neighbor proteins.(DOCX)Click here for additional data file.Figure S10Comparison of observed ligand binding pockets and predicted pockets.(DOCX)Click here for additional data file.Figure S11FragFEATURE performance on predicted pockets.(DOCX)Click here for additional data file.Figure S12Fragment prediction and validation for Abl tyrosine kinase.(DOCX)Click here for additional data file.Figure S13Fragment prediction and validation for protein kinase A (PKA).(DOCX)Click here for additional data file.Figure S14Alternative fragments for PDB ligands I5S, M77, and TZ1.(DOCX)Click here for additional data file.Figure S15Microenvironment similarity of nearest neighbors.(DOCX)Click here for additional data file.Figure S16FragFEATURE computation time.(DOCX)Click here for additional data file.Table S1Prevalence of validation ligands across 50% sequence identity clusters.(DOCX)Click here for additional data file.Table S2Breakdown of protein pockets tested.(DOCX)Click here for additional data file.Table S3PDB ligands supporting the benzamide prediction for exotoxin A.(DOCX)Click here for additional data file.Table S4PDB structures supporting the benzamide prediction for exotoxin A.(DOCX)Click here for additional data file.Table S5Protein names of PDB structures supporting the benzamide prediction for exotoxin A.(DOCX)Click here for additional data file.Table S6Sequence identity between PDB structures supporting the benzamide prediction for exotoxin A.(DOCX)Click here for additional data file.Table S7PDB structures supporting fragment 13509097/benzamide prediction for DAPK1.(DOCX)Click here for additional data file.Table S8Sequence identity of PDB structures supporting fragment 13509097/benzamide prediction for DAPK1.(DOCX)Click here for additional data file.Table S9PDB ligands supporting the benzamide prediction for DAPK1.(DOCX)Click here for additional data file.Table S10PDB structures supporting fragment 1049/241 prediction for aPKC.(DOCX)Click here for additional data file.Table S11Sequence identity of PDB structures supporting fragment 1049/241 prediction for aPKC.(DOCX)Click here for additional data file.Text S1Similar microenvironments bind similar fragments.(DOCX)Click here for additional data file.Text S2FragFEATURE predicts fragments of bound ligands using predicted protein pockets.(DOCX)Click here for additional data file.Text S3FragFEATURE predicts fragments of unbound ligands using predicted protein pockets.(DOCX)Click here for additional data file.Text S4Inhibitor fragment predictions for cholix toxin.(DOCX)Click here for additional data file.Text S5Inhibitor fragment predictions for Abl tyrosine kinase.(DOCX)Click here for additional data file.Text S6Inhibitor fragment predictions for protein kinase A.(DOCX)Click here for additional data file.Text S7Expanding the knowledge base beyond the information in the PDB.(DOCX)Click here for additional data file.Text S8FragFEATURE and ligand/fragment affinity.(DOCX)Click here for additional data file.Text S9Microenvironment independence assumption.(DOCX)Click here for additional data file.Text S10Multiple hypothesis correction.(DOCX)Click here for additional data file."}
+{"text": "Integration of retroviruses occurs in most genomic regions with weak but statistical significant preferences for target site sequences. HIV-1 preferentially targets genes, particularly the transcriptionally active ones. Avian sarcoma and leukosis viruses (ASLV) integrate with only slight preference for genes while murine leukemia virus uniquely favors integration in close proximity to upstream or downstream transcription start sites. Genomic features as well as the \u201cepigenetic landscape\u201c at the site of integration are crucial for the outcome of each integration event, i. e. stable long terminal repeat-driven expression of the provirus or silencing and transcriptional suppression. The current availability of assembled genome sequences with epigenomic characteristics and reliable cloning of retrovirus integration sites enables to study the interplay between transcription signals of the retrovirus and enhancing or suppressive influences of the adjacent cellular DNA.We studied the integration sites of ASLV-derived vectors integrated into normal or DNA methylation-deficient human cells. Integration sites from cell clones containing single provirus were cloned and their genomic features as well as epigenetic landscape were correlated with expression or silencing of the provirus. Dnmt3b turned out to be the major player in silencing the long terminal repeat-driven transcription. Proviruses integrated into H3K4me3-rich CpG islands associated with promoters of active genes display long-term stability of expression and are resistant to the transcriptional silencing after over expression of Dnmt3b. Stability of expression and resistance to the silencing decreases with the distance from transcription start site. By contrast, proviruses integrated into the intergenic regions tend to the spontaneous transcriptional silencing even in DNA methyltransferase-deficient cells."}
+{"text": "Ion channels facilitate the diffusion of specific ions across neuronal membranes. If large enough, this movement of charge creates currents that may change the membrane potential. Biophysical models of membrane potential assume the trans-membrane currents flow within an \u201cequivalent electrical circuit\u201d in which ion channels are represented by resistors arranged in parallel. The functions representing the trans-membrane currents mediated by channels are typically written using Ohm's law. It is possible to describe channel-mediated currents by taking diffusion into consideration , but suc"}
+{"text": "Cell behavior in the presence of nanomaterials is typically explored through simple viability assays, but there is mounting evidence that nanomaterials can have more subtle effects on a variety of cellular functions. Previously our lab demonstrated that gold nanorods functionalized with polyelectrolyte multi-layers inhibited rat cardiac fibroblast-mediated remodeling of type I collagen scaffolds by altering fibroblast phenotype and the mechanical properties of the collagen network. In this work, we examine a possible mechanism for these effects: adsorption of cellular proteins by the nanorods. Mass spectrometric and gel electrophoresis of media collected from cultured cells suggests that a number of proteins, some of which mediate cell-cell and cell-matrix interactions, adsorb onto the surface of these nanoparticles in vitro. Polyethylene glycol coating of the nanorods largely mitigates protein adsorption and fibroblast-mediated collagen remodeling. These results suggest that adsorption of proteins by nanorods could have a significant effect on cell functions, including fibroblast-mediated matrix remodeling. Gold nanomaterials have received considerable attention for use in biomedical applications due to their unique optoelectronic properties Previously, we reported that gold nanorods coated with polyelectrolyte multilayers terminated with anionic poly(styrene sulfonate) (PSS) substantially altered the matrix-remodeling behavior of neonatal rat cardiac fibroblasts in type I collagen gels in vitro model for tissue and also the native ECM of the cells in the phenotype study In addition to the effects nanorods have on cells themselves, possibly via the protein corona, nanorods also alter the physical properties of the matrix that surrounds them. We quantitatively examined the effects of polyelectrolyte-coated nanorods on the polymerization and mechanical properties of type I collagen hydrogels, frequently used as an Here, we report the composition of the protein corona adsorbed onto polyelectrolyte-coated gold nanorods from culture media conditioned by rat cardiac fibroblasts. We demonstrate differential binding of proteins to nanorods that bear positively or negatively charged functional groups. Furthermore, the hypothesis that adsorbed proteins actually cause behavior changes in fibroblasts was tested using \u201cprotein-resistant\u201d coatings on the nanoparticles as functional controls. Reduced protein adsorption to these \u201cresistant\u201d particles was observed along with a reduction in nanomaterial-induced cellular behavior. Taken together, these experiments support the notion that the protein corona that surrounds nanomaterials provides a molecular mechanism to influence cell behavior.4.3H20), sodium borohydride (NaBH4), ascorbid acid, poly sodium salt , poly, poly, and ultrapure hexadecyltrimethylammonium bromide (CTAB) were obtained from Sigma-Aldrich . All other chemicals were purchased from Sigma unless otherwise noted and all solutions were prepared with 18 M\u03a9 resistivity water using a Millipore Biocel ultrafiltration system .Chloroauric acid . Transmission electron microscopy was performed on a JEOL 2100 Cryo-TEM instrument . Light scattering and zeta potential analysis were performed on a Brookhaven Instruments ZetaPALS machine .Gold nanorods  were prepared in aqueous solution using a seed-mediated surfactant-directed approach previously described and purified by centrifugation and washing 9 and 1010 rods) were incubated in conditioned media overnight at 37\u00b0C followed by centrifugation to separate them from the media. After washing with phosphate buffered saline, bound proteins were eluted using 1 M NaCl, separated on a 4\u201320% gradient sodium dodecylsulfate\u2013polyacrylamide gel electrophoresis (SDS-PAGE) gel  and silver stained using the Silver Quest staining kit (Invitrogen) as per manufacturer\u2019s instructions. To identify specific proteins bound to the nanorods, samples were sent to ProtTech  where they were reduced using dithiothreitol, alkylated with iodoacetamide (20 mM), trypsin digested, and analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS) using a system with a high performance liquid chromatography reverse phase C18 column coupled to an ion trap mass spectrometer . Protein identification was determined using the Non-Redundant Protein Database from GeneBank with ProtTech\u2019s ProtQuest software package.Neonatal rat cardiac fibroblasts were isolated from 3\u20134 day old Sprague Dawley pups as previously described 9 nanorods/gel were re-suspended in the HEPES buffer prior to preparing the collagen mixture. Fibroblasts  were combined with the neutralized collagen and added in 100 \u00b5L aliquots to the wells of 96 well microtiter plates and allowed to polymerize for 1 hour at 37\u00b0C in a 5% CO2 humidified incubator. After polymerization, culture media was added to each well and the gels were manually detached from the wall of the well. Gels were photographed after 24 hours in culture with a Canon EOS Rebel digital camera and gel areas were measured using ImageJ. Statistical analysis was conducted using a Student\u2019s T-test in Microsoft Excel.Three dimensional collagen gels containing neonatal cardiac fibroblasts seeded with PSS, PDADMAC or PEGylated gold nanorods were prepared as previously described \u03b1-smooth muscle actin (\u03b1-SMA)  and control gene acidic ribosomal phosphoprotein (ARBP) . Data were analyzed using the fold change method incorporating primer efficiency with the REST2009 program .Three gels per condition were pooled, solubilized in Trizol (Invitrogen) and RNA isolated using the RNeasy Micro RNA kit with on column DNase I digestion as recommended by the manufacturer . RNA concentrations were determined using a BioRad Experion system with standard sensitivity RNA chips and 50 ng of total RNA was used to prepare cDNA using the iScript cDNA synthesis kit . PCR reactions were carried out using iQ Supermix (BioRad) with primers specific for rat In our previous experiments, the presence of PSS-coated gold nanorods in fibroblast-seeded three-dimensional collagen gels led to reduced gel contraction by the fibroblasts and corresponding changes in gene expression 9 PEGylated (350 or 5000 MW PEG) or PSS- or PDADMAC-coated rods/gel were prepared and allowed to contract for 24 hours To confirm that protein adsorption was involved in mediating differences in collagen gel contraction, gels containing cardiac fibroblasts and 5.6\u00d710To test our hypothesis that the protein binding characteristics of the nanoparticle coating are the mitigating factor in the observed changes in fibroblast behavior, PDADMAC-, PSS- and PEG-coated nanorods were exposed to fibroblast conditioned culture media and the adsorbed proteins identified. The procedure used to isolate and characterize nanorod-bound proteins is outlined in LC-MS/MS analysis of protein eluates revealed that the nanorods adsorbed a more diverse population of proteins than originally expected based on the electrophoresis data. On average, PSS- and PDADMAC-coated nanorods bound almost twice as many unique proteins as PEG-terminated nanorods . CompariIn a combination of four independent analyses, 37 unique proteins were identified which bound to the PSS-coated nanorods while 45 unique proteins adsorbed to PDADMAC-coated nanorods . Of thesThe data in Based on the modest effects that the PEGylated nanorods had on fibroblast-mediated gel contraction and gene expression, the protein adsorption characteristics of these particles were also examined to determine if the minimal changes in gel contraction observed were due to the non-fouling and minimally adsorptive characteristics of the PEG coating. As shown in An examination by species of origin indicated that most of the proteins identified as being associated with the nanorods were of bovine origin, and therefore due to the serum used in the culture media. However, biglycan was of rat origin, therefore produced by the fibroblasts, and was found in the protein fractions binding to both cationic and anionic nanorods but not PEGylated particles. Biglycan is a small ECM proteoglycan found in most connective tissues, and it is known to influence cell-ECM interactions and to modulate cell bioactivity by binding collagen and multiple growth factors, including members of the transforming growth factor \u03b2 (TGF\u03b2) superfamily The local concentration of biglycan in the heart has been shown to influence cardiac fibroblast development in 6-week-old mice  A number of investigators have begun to examine the role that protein adsorption onto nanomaterials has on biological effects of nanomaterials The results of this study offer insight into a possible mechanism by which polyelectrolyte-coated nanorods disrupt the matrix remodeling behavior of cardiac fibroblasts. The ability to bind proteins on the surface of the nanomaterials which can modulate the ECM remodeling behavior of fibroblasts suggests that nanoparticles could serve as novel therapeutic agents in the regulation of wound healing. If the protein adsorption process could be tailored for particular proteins, one could envision regulation of cell behavior by colloidal nanomaterials, by analogy to how fixed nanostructured substrates guide cell behavior.Figure S1Size Distribution of Adsorbed Proteins. PEG-, PSS-, and PDADMAC- coated nanorods showed a similar distribution of bound proteins based upon the protein size.(JPG)Click here for additional data file.Table S1Complete list of unique proteins identified which bound to PSS-, PDADMAC-, and PEG-coated nanorods. Three proteins identified as binding to PDADMAC-coated nanorods were of human origin and discounted as contamination since no human products were added to the cell culture media.(DOCX)Click here for additional data file."}
+{"text": "Molecular parameters of key interest for monitoring the efficacy of anti-malaria interventions are those that quantify effects on transmission or incidence of infection and disease.molFOI is easily detected despite a background of ongoing infections.Vaccine trials provide regular follow-up samples of both comparator groups. In addition, the clinical episodes are detected and sampled. Provided the spacing of follow up surveys is in the range of 2-8 weeks, the force of infections (FOI) can be determined by genotyping all consecutive samples of all study participants. The molecular FOI is defined by new parasite clones appearing per time interval. Individual clones are identified using highly polymorphic molecular markers in conjunction with high resolution typing. Simultaneously, blood samples from trial participants become available for RNA based detection and quantification of gametocytes by qRT-PCR. Vaccine effects on gametocyte prevalence can be detected by targeting gametocyte-specific transcripts.We have evaluated RNA sampling techniques for malaria field surveys. Collecting samples directly into RNAprotect solution gave best results. Gametocytes were detected by qRT-PCR using marker pfs25.P. falciparum clones aquired per time per individual host, corrected for imperfect detectability [In our cohort studies asexual parasites were genotyped using marker msp2 and fragment sizing by capillary electrophoresis ,2. In thtability .P. falciparum infection dynamics were estimated based on high precision genotyping data from cohort studies or from a clinical trial with repeated follow up bleeds at intervals between 2 weeks and 2 months. The full time-series of presence and absence of clones in consecutive samples from one individual forms the basis from which molFOI, duration of infection, and clone detectability were estimated.Molecular parameters describing the molFOI in vaccinated children from the Combination B vaccine trial was significantly reduced in vaccine recipients only for parasites carrying a 3D7-type msp2 allele corresponding to 3D7 MSP2 component of Combination B.molFOI as an outcome measurement in vaccine trials and to collect and preserve in the field trial setting in parallel blood samples useful for RNA extractions for monitoring vaccine effects on transmission stages.We demonstrated proof of concept of this approach in a vaccine trial of the Combination B malaria vaccine. We propose to consider the"}
+{"text": "The existing cluster kernel methods based on neighborhoods and profiles and the Markov clustering algorithms are currently the most popular methods for protein family recognition. The deviation from random walks with inflation or dependency on hard threshold in similarity measure in those methods requires an enhancement for homology detection among multi-domain proteins. We propose to combine spectral clustering with neighborhood kernels in Markov similarity for enhancing sensitivity in detecting homology independent of \u201crecent\u201d paralogs. The spectral clustering approach with new combined local alignment kernels more effectively exploits the unsupervised protein sequences globally reducing inter-cluster walks. When combined with the corrections based on modified symmetry based proximity norm deemphasizing outliers, the technique proposed in this article outperforms other state-of-the-art cluster kernels among all twelve implemented kernels. The comparison with the state-of-the-art string and mismatch kernels also show the superior performance scores provided by the proposed kernels. Similar performance improvement also is found over an existing large dataset. Therefore the proposed spectral clustering framework over combined local alignment kernels with modified symmetry based correction achieves superior performance for unsupervised remote homolog detection even in multi-domain and promiscuous domain proteins from Genolevures database families with better biological relevance. Source code available upon request. Contact:  The remote homology detection from available protein sequences is one fundamental problem in comparative genomics. With higher sequence similarity, several panoply of methods can detect homologs accurately. However detecting remote homologs with subtle sequence similarity still remains a challenging problem.In general, there are three categories of methods to solve this problem \u2013 simple approaches based on sequence similarity like BLAST or Smith-Waterman Recently, the discriminative kernel methods with SVMs like mismatch string kernels To compute the sequence distances, some groups utilized Connected Component Analysis(CCA) The semi-supervised protein clustering achieved efficiency earlier, introducing the neighborhood vector over profiles in cluster kernels by Symmetry is an inherent feature to enhance recognition and reconstruction of shapes and objects. It reflects to be powerful for recognizing homolog protein clusters in kernel space. In In this work, at first we develop new valid Mercer kernels based on similarities explicitly in local alignment methods like BLAST and PSI-BLAST. We present two positive semi-definitive local-alignment kernels based on the singular-value decompositions of respectively MCL similarity scoring and position-specific scoring matrices (profiles). The Markov cluster similarity kernel further with the neighborhood feature vectors is enhanced. Furthermore incorporating the mismatches with profiles the diagonal dominance issue problem is reduced. This enables more accurate detection of remote homologs boosted by similarity deemphasizing multi-domain proteins. To reduce promiscuous domain problems, we further incorporate the spectral clustering approach over kernel matrices to alleviate inter-cluster edges implicitly selecting the leading eigenvectors from \u2018global\u2019 distances without using any hard-threshold. Finally, we introduce the modified-symmetry based correction over the homolog distributions in Hilbert space. This reduces number of singletons (represented as outliers) and classifies multi-domain proteins into more biologically-significant clusters with closest nearest-neighbor homologs from different domains. Contradicting with earlier discriminative approaches, this approach detects remote homology among unlabelled multi-domain proteins without any prior annotation. Local-alignment kernels or Markov similarities are combined cascadingly with neighborhoods in spectral clustering, which are further enhanced by modified-symmetry based correction.We experiment all our kernel frameworks over the multi-domain proteins from Genolevures Yeast database In this section, we briefly describe existing state-of-the-art cluster kernel methods for remote homolog proteins detection and the modified symmetry based distance measure for clustering.In semisupervised learning, To project the selection of closely related neighbor sequences through evolution from PSI-BLAST profiles in mismatch kernel, Among the different distance measures for clustering like Euclidean, Pearson correlation or Spearman distance, none can detect symmetrical overlapping clusters. Su and Chou Candida glabrata, Eremothecium gossipii, Kluyveromyces Lactis, Yarrowlo lipotytica, Zygosaccharomyces rouxii, Saccharomyces kluyveri, Kluyveromyces thermotolerans, Debaryomyces hansenii, Saccharomyces cerevisiae) The Genolevures database explores nine complete genomes .However utilizing the HSP (high-scoring segment pair) score of BLASTP results directly resembles the functionality of mismatch string kernel II). A related protein structure kernel, based on MAMMOTH score To explore the statistically significant alignments produced by BLASTP with the position-specific score matrix (http://micans.org/mcl/) The Markov Cluster algorithm(MCL \u2013 III).We incorporate the neighborhood probabilistic representation of each input sequence over the above explained MCL similarity scores, following earlier neighborhood mismatch kernel IV).To construct the kernel based on profile information, we generate a variant kernel with MCL similarity and PSI-BLAST profile-based scores. Following the profile mismatch kernel based on spectrum kernel V, VII) and similarly the combined IV, VI). Therefore our combined local alignment kernels , which are the tensor products The position specific scoring kernels are based on the singular value decompositions and therefore, are Mercer's kernels. Again the neighborhood similarity kernel and mismatch profile kernel are also proved to be Mercer kernels. We define the kernels combining For unsupervised classification, we apply the spectral clustering method directly to the combined local alignment cluster kernel matrices without using a transductive setting like in This algorithm also constructs the Markov transition matrix as used in Markov Clustering algorithm (MCL) The modified-symmetry based distance measure Furthermore to prove the non-negative definiteness in spectral kernel with modified symmetry, for arbitrary Therefore the spectral kernel matrix with modified symmetry norms is itself positive semidefinitive in nature. Alternatively, let IX, XI) and combined PSI-BLAST kernel with OMCL NM and OMCL MP kernels as respectively kernels .Accordingly, we correct the combined spectral kernel results with modified symmetry with reallocating proteins to a cluster with its optimal modified symmetry distance norm less than the pre-defined threshold In this section the framework for the experiments and comparative results of all local alignment kernels and combined spectral kernels after modified symmetry based correction are described. The comparative study of the clustering solutions of the existing string Several frameworks have been implemented for demonstatating the performance of twelve different kernels proposed in this article. The I), PSI-BLAST kernel(II), OrthoMCL Neighborhood Mismatch III) and OrthoMCL Mismatch Profile IV) to classify the multi-domain protein families of our dataset with mean ROC and mean ROC50 scores. These results show that IV) performs best over all other methods indicating the influence of profiles in homolog detection. All the modified local alignment kernels outperforms simple score based kernels in this experiment. As an illustration, the distribution of ROC50 scores for all local alignment-based kernels is shown in III), IV) kernels retrieve approximately two times more ROC50 scores than the two simple score based BLASTP(I) and PSI-BLAST(II) kernels for similar number of families.VI) and VIII) kernels provide respectively ROC values V) and VIsI) kernels. VIII) outperforms all other methods with the highest ROC50 score of I) and PSI-BLAST (II) kernels cannot successfully perform in the absence of sufficient positive training data for a huge unlabelled protein database VI) and VIII) kernels combined with the proposed II) consistently show superior performance while significantly outperforms other combined kernels.In order to investigate the performance of our spectral kernels over simple alignment kernels, we combine all modified local alignment kernels using normal product. Combining X, XII).In the unsupervised setting of homolog detection, the simple score based kernels do not show very strong performance in comparison with the combined modified spectral alignment kernels. Incorporation of the modified symmetry based cluster correction imporves the performance further see  for unlaIX, X, XI, XII). These results show that X, XII), consistently outperform other combined kernels with higher ROC50 values.VI, VIII). The points fall approximately near evenly above and below the diagonal, indicating similar performance of both methods. However there exists more points on upper triangle of the VIII). I) and its improvement after combination with the XI). For most of the families, the XI) provides higher ROC50 scores than simple I). All the experiments demonstrate the utility of combined spectral kernel approaches with modified symmetry corrections in the remote homolog detection.We have presented and experimentally evaluated twelve spectral kernels for remote homology detection that classify protein sequences in comparison with the explicit evaluation of modified symmetry based proximity norm. These kernels measures sequence similarity on the unlabelled data. For this unsupervised protein family classification approach, we focus on our spectral clustering approaches with combined local alignment score-based valid kernels. This approach performs competitively with state-of-the-art neighborhood I), PSI-BLAST (II) and newly experimented OrthoMCL scores for kernel formations . After combined with neighborhood similarity and mismatch profile features , our proposed Mercer kernels provide significant solutions after introducing modified symmetry based updating  in spectral clustering results.Weston et al in I, II) proves to be a valid kernel for homology detection. Second, as discussed earlier in coperation of previously detected OrthoMCL scores to reduce the \u201crecent\u201d paralog effects in BLASTP/PSI-BLAST results gains significance. The neighborhood similarity and the mismatch profile kernel over OrthoMCL scores  also proves to be significant in comparison with earlier cluster kernels, reducing the diagonal dominance issue with arbitrary lower magnitude distribution of diagonal values. Third, we do not need to diagonalize the matrix of all labelled and unlabelled data as in Four major observations can be made by analysing different experiments presented in this article. First, the direct use of local-alignment based BLASTP and PSI-BLAST scores to create a kernel matrix with singular value decomposition  and XII) kernels respectively provide Dunn's index values of VII) and VIII) kernels in We evaluate the clustering solutions for all kernels objectively by measuring five validity measures Dunn, Davies-Bouldin, Kruskal, Rand and Jaccard indices as defined in III) and IV) kernels over those values I) and II) kernels, shows the significance of the Markov cluster similarity scoring kernels considering neighborhood similarity and mismatch profile respectively. The Rand index III), V) and VI) kernels respectively with increasing values of VI), X), VIII) and XII) kernels respectively further show the significance of modified symmetry based corrections over the clustering solutions provided by the combined local alignment spectral kernels. This shows superiority of the combined kernels even over local alignment kernels proving The increasing values of We evaluate the clustering solutions of our proposed kernels comparatively with those of the already-existing linear The homologous protein family detection tool within Hemiascomycete yeast complete genomes are appreciated in genomics to detect the conservation of function. Therefore, we propose a computational approach for computing local alignment based Mercer kernels utilizing Markov similarity to reduce \u201crecent\u201d paralog effects. Introducing profile mismatching and neighborhood feature vectors in combined Mercer kernels for spectral clustering, effectively escalates remote homolgy detection from unlabeled protein sequences database. We experiment the corrections by the modified symmetry based proximity norm producing improved clusters with reduced outliers/singletons and selecting more biologically significant domains for multi-domain proteins. Our position specific scoring kernel combined with the modified symmetry based corrections, achieves state-of-the-art prediction performance in the context of unsupervised homology detection. When combined with Markov cluster similarity kernels in well-known neighborhood feature space and considering neighborhood mismatch based on profiles, this approach performs superiorly over other cluster kernels. Therefore to detect the homologs among multi-domain proteins, our spectral clustering approach with combined local alignment kernels results in clusters having better more biological significance. We suggest that this is achieved due to the incorporation of the modified symmetry based corrections in kernel space.Table S1List of 23 multidomain family names used from Genolevures database.(TXT)Click here for additional data file.Table S2PSI-BLAST kernel matrix.(TXT)Click here for additional data file.Table S3OrthoMCL Neighborhood Mismatchkernel matrix.(TXT)Click here for additional data file.Table S4OrthoMCL Mismatch Profilekernel matrix.(TXT)Click here for additional data file.Table S5Combined+kernel matrix.(TXT)Click here for additional data file.Table S6Combined+kernel matrix.(TXT)Click here for additional data file.Table S7Combined+kernel matrix.(TXT)Click here for additional data file.Table S8Combined+kernel matrix.(TXT)Click here for additional data file.Table S9ROC50 scores obtained over all families.(PDF)Click here for additional data file.Table S10ROC scores obtained over all families.(PDF)Click here for additional data file.Table S11ROC50 scores obtained after modified symmetry based correction over all families.(CSV)Click here for additional data file.Table S12ROC scores obtained after modified symmetry based correction over all families.(CSV)Click here for additional data file."}
+{"text": "Hypertension (HTN) is a major worldwide cause of stroke, heart failure, myocardial infarction, and chronic kidney disease. Human genetics offers the potential to identify novel physiologic mechanisms that underlie blood pressure (BP). BP is a heritable trait but until recently genetic factors that influence BP at the population have been difficult to identify.NPPA-NPPB locus to identify genetic variants that influence atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) [NPR3 encoding the natriuretic peptide clearance receptor [NPR3 SNP has recently been reported to be associated with taller stature in humans [We used a candidate gene association study of common variants across the de (BNP) . The minde (BNP) . Recentlreceptor . The minn humans , consistn humans  or apparn humans  in NPR3.The ANP-BNP/pGC/cGMP axis is important in the regulation of BP in humans. Further ongoing GWAS studies have identified additional novel loci. Human genetics can offer an entr\u00e9e into the physiologic determinants of blood pressure at the population level and point to therapeutic opportunities to reduce the morbidity and mortality due to HTN."}
+{"text": "A 40-year-old gentleman came to surgical OPD with chief complaint of crampy abdominal pain since last 12 days. He had complaint of occasional vomiting. Physical examination was not contributory. On per rectal examination, finger was stained with blood. His past surgical and medical history was not significant. His vitals were normal. After routine investigations, Barium enema was advised and it showed the findings revealed in What is the diagnosis?Which are the common lead points for Colocolic intussusceptions?How to differentiate between non-lead point and lead point intussusception?Enumerate the signs of intussusception on USG?Barium enema revealed typical claw sign in left lumber region suggestive of colocolic intussusceptions.Colocolic intussusception in the adults is almost always due to pre-existing disease like carcinoma or polyp.Abdominal CT scan with contrast helps in differentiating non-lead point and lead point intussusception.Transverse section revealed \u2018Doughnut sign and longitudinal section showed Bull\u2019s eye and pseudo kidney sign.3"}
+{"text": "Apis mellifera, are able to distinguish mixtures where both odors arrive at the same time (synchronous mixtures) from those where odor onsets are staggered (asynchronous mixtures). Surprisingly, this ability persists down to an onset delay of only 6 ms.Insects have a remarkable ability to identify and track odor sources in multi-odor backgrounds. Recent behavioral experiments show that this ability relies on detecting millisecond stimulus asynchronies between odors that originate from different sources . HoneybeOn this poster we explore this surprising ability in a model of the honeybee antennal lobe. We hypothesize that a winner-take-all inhibitory network (see Figure We present a detailed data-driven model of the bee antennal lobe that reproduces a large data set of experimentally observed odor responses  and demo"}
+{"text": "Tubercular spinal epidural abscess (SEA) is is a devastating infectious disease. Its presence without associated osseous involvement may be considered an extremely rare scenario. We present a rare case of tubercular SEA complicated by paraplegia in an immune-competent 58-year-old male patient. MRI shows a multisegmental posterior collection of epidural fluid extending from C7 to L2 vertebral level and displaces the ventrally located thecal sac, without any evidence of vertebral involvement. The patient made an uneventful recovery following surgical decompression and antitubercular chemotherapy. The diagnosis was confirmed by histopathological demonstration of Mycobacterium tuberculosis in drained pus. Such presentation of tubercular SEA has not been reported previously in the English language based medical literature to the best of our knowledge."}
+{"text": "Demand for critical care services is increasing yet a comprehensive understanding of how critical care nurses - the largest group of ICU direct care providers - impact outcomes remains unclear. The purpose of this study was to determine how critical care nurse education  and ICU work environment influenced 30-day mortality of mechanically ventilated older adults.A multi-state cross-sectional nurse survey was linked to hospital administrative data and Medicare claims (2006 to 2008). The final sample included 55,159 mechanically ventilated older adults in 303 hospitals. Logistic regression modeling was employed to jointly assess the relationship of critical care nurse education, work environment and staffing on 30-day mortality while adjusting for hospital and patient characteristics and accounting for clustering.A 10% increase in the proportion of ICU nurses with a bachelor's degree or higher was associated with 2% lower odds of death while controlling for patient and hospital characteristics. Patients cared for in better work environments experienced 11% lower odds of risk-adjusted death than those cared for in poorer ICU work environments.Patients cared for in hospitals with a greater proportion of bachelor's prepared ICU nurses and in better ICU work environments experienced significantly lower odds of death. As the demand for critical care services increases, attention to the education level of ICU nurses and ICU work environment may be warranted to optimize currently available resources and potentially yield better outcomes."}
+{"text": "A winch-capable helicopter emergency medical service (HEMS) offers several advantages over standard rescue operations. Little is known about the benefit of physician winching in addition to a highly trained paramedic. We analysed the mission profiles and interventions performed during rescues involving the winching of a physician in the Greater Sydney Area HEMS (GSA-HEMS).All winch missions involving a physician from August 2009 to January 2012 were identified from the prospectively completed GSA-HEMS electronic database. A structured case-sheet review for a predetermined list of demographic data and physician-only interventions (POI) was conducted.2 scores were more likely to receive a POI when compared with those with normal RTSc2 (P = 0.03). The performance of POI had no effect on median scene times . See Tables We identified 130 missions involving the winching of a physician, of which 120 case sheets were available for analysis. The majority of patients were traumatically injured (90%) and male (85%) with a median age of 37 years. Seven patients were pronounced life extinct on the scene. A total of 63 POI were performed on 48 patients. Administration of advanced analgesia was the most common POI making up 68.3% of interventions. Patients with abnormal RTScOur high POI rate of 40% coupled with long rescue times and the occasional severe injuries supports the argument for winching doctors. Not doing so would deny a significant proportion of patients time-critical interventions, advanced analgesia and procedural sedation."}
+{"text": "In this brief report, we share our observations on a splitted Dexamethasone implant (Ozurdex) which we discovered a week after the injection. It is likely that implant splitting neither changes the efficacy of the implant nor creates a mishap for the patient. Dexamethasone implant (Ozurdex) is approved for eyes with posterior uveitis and macular edema associated with retinal vein occlusions , 2. Very A 68-year-old man received a Dexamethasone implant (Ozurdex) for macular edema due to nonischemic type central retinal vein occlusion at our institution Figures . The imp The implant is preloaded into a specially designed single use applicator that promotes easy and controlled drug delivery. Thereby, the slow release provides long-term effectivity and less steroid-related side effects. First, Rishi et al.  reported Implant splitting may not be a rare occurence but Ozurdex splitting most possibly do not change the effectivity of the implant or create a mishap for the patient."}
+{"text": "Transgenic tumor models provide the closest animal approximation of human cancer development and progression, and a challenging treatment model. The orthotopic location of these tumors presents challenges in testing radiation therapies because conventional radiation models using patient linear accelerators or untargeted units with selective shielding are difficult or impractical in transgenic tumor models. We have tested CT-guided radiation therapy using a Small Animal Radiation Research Platform to treat transgenic MMTV-PyMT mammary tumors. Image guiding permits close targeting of tumors with no measurable toxicities at single tumor doses tested up to 20Gy. We demonstrate that tumor treatment results in a dose-dependent control of mammary tumors. Histology illustrates destruction of invasive carcinoma in the mammary gland with remaining tissue features of premalignant disease due to ongoing transgene-driven tumorigenic progression in other mammary cells. We demonstrate progressive expansion of CD11b+Gr1+ myeloid cells detectable in the blood of mice that correlates with tumor progression, and that focal treatment of mammary tumors with radiation therapy reverses this myeloid expansion without affecting systemic T cell numbers. The result is an improved systemic myeloid cell: T cell ratio in treated mice, which has been associated with improved immune function in many animal models of cancer. This platform provides an approach to study hypofractionated radiation therapy in authentic animal models of tumor progression without causing systemic lymphopenia and permits experiments investigating the interaction between radiation therapy and endogenous immune responses in transgenic and orthotopic tumor models."}
+{"text": "Adult T-cell leukemia/lymphoma (ATLL) is highly chemotherapy resistant. The combination of AZT and interferon (IFN) is a first line treatment option for the leukemic forms of ATLL. We and others have demonstrated AZT/IFN can effectively suppress ATLL long-term; however, these drugs fail to eradicate malignant ATLL clones. At our institution we have recently established a clinical trial for ATLL using AZT/IFN in combination with the inexpensive histone deacelytase (HDAC) inhibitor valproic acid (VPA) during the maintenance treatment phase. Histone acetylation can result in HTLV-I promoter activation and viral transcription. We hypothesized that HDAC inhibitors would re-activate latent HTLV-I in ATLL cells harboring intact provirus and help eliminate residual disease after cytoreductive treatment. We have exciting preliminary data which suggest we can achieve this. So far, we have enrolled 13 subjects with acute-type ATLL in our study. We observed a serial decrease in clonal ATLL disease followed by molecular clearance by multiplex PCR in one subject after VPA treatment. We had not seen such effect previously in long-term responders treated with AZT/IFN alone. Using fresh ATLL cells from this subject we augmented HTLV-I expression and induced cell death ex vivo after treatment with the newer HDAC inhibitor vorinostat. We are currently testing other newly available HDAC inhibitors in our pre-clinical models. The dual anti-neoplastic and viral inducing roles of HDAC inhibitors can be exploited in the treatment of ATLL. This exciting approach may help advance the cure for this disease. We will present our interim clinical trial results at the conference."}
+{"text": "A novel approach to increase erythropoietin (EPO) using oxygen has been reported in healthy volunteers. The purpose of this study is to investigate whether the EPO increase is sufficient to induce erythropoiesis.We compared exposure to daily versus every other day oxygen administration on haemoglobin variation during a 12-day period. Each subject underwent the two protocols at a 6-week interval period to achieve the same baseline values.P < 0.001). These data provide demonstration of an enhanced production of erythrocytes.See Figure The normobaric oxygen paradox seems effective to increase haemoglobin in non-anaemic healthy volunteers assuming there is a sufficient time interval between the two oxygen applications. This could permit interesting clinical applications in perioperative medicine as an adjunct therapy to EPO for blood predonation."}
+{"text": "Pseudomonas aeruginosa is a human opportunistic pathogen. It can cause infection of immunocompromised people or people suffering from cystic fibrosis, which is often fatal. Bacterial colonization of human tissues is mediated by interaction of bacterial surface proteins \u2013 lectins \u2013 with cellular surface carbohydrates. PA-IIL is Pseudomonas aeruginosa tetrameric lectin, which contains two calcium ions in each binding site and recognizes fucosylated oligosaccharides [Bacterium charides . SaturatTwo different approaches for identification of promising compounds were employed. Subset of drug-like molecules was docked into the PA-IIL binding site by Autodock Vina  and Dock"}
+{"text": "Drosophila sensory neurons, we focused on a subset that were targets of the transcription factor Fd3f, which regulates functional specialization of mechanosensory cilia. Bioinformatic enrichment for known ciliary domains as well as orthologous protein-protein interaction network modelling provided a list of putative ciliary genes for further functional characterization. One such candidate, CG31320, has been initially characterized in Drosophila. Little is known about this gene, except the encoded protein contains HEAT repeats \u2013 belonging to an armadillo-like fold family associated with intracellular transport. In situ analysis confirms that CG31320 mRNA is highly expressed in the ciliated chordotonal neurons. RNAi-mediated knock-down resulted in abnormal chordotonal ciliary morphology and locomotory defects, consistent with impaired mechanosensory cilium function. Currently, we are studying whether the ortholog Heatr2 is also required for mammalian cilia. Protein localization studies suggest that Heatr2 plays a role in trafficking to primary cilia. RNAi knock-down and protein interaction studies using mammalian cells are underway to functionally dissect Heatr2 roles; results will be presented. We are generating a Heatr2 conditional mouse mutant to investigate its function in different types of cilia and sperm flagella. We present a multisystem experimental pipeline for functional characterization of novel genes expressed in cilia as well as putative ciliopathy candidates.The structural and functional roles of many of the 800-1000 proteins that make up the microtubule core and specialized membranes of cilia and flagella are poorly understood. Following from our recent expression study to identify putative ciliary candidates in"}
+{"text": "Compressed sensing with PCA based coil compression is a promising way to obtain high quality radial perfusion images without incurring the high computation cost and memory requirements associated with large multi-coil arraysImaging with large coil arrays is desirable for rapid imaging and high signal to noise ratio. Compressed sensing (CS) is a promising way to accelerate myocardial perfusion imaging . HoweverDynamic cardiac perfusion data at rest and stress were acquired using a 32-channel cardiac coil on a Siemens 3T scanner using a 2D radial turboFLASH sequence . The acqCS reconstruction using temporal and spatial total variation constraints (STCR)  was perfFigure 1 shows 32-channel images and the five compressed coil images. Five compressed coil images are sufficient for accurate reconstruction, as seen in Figure 2 which compares CS reconstructions on the original and compressed channel data. With coil sensitivity weighting, streaks  are reduced for original and compressed channel images. Images and time curves from compressed coils match well with those from all 32 coils. Reconstruction time for four slices and 250 time frames using compressed channels took ~26 min and was ~6 times longer for the 32-channel data.Compressed sensing with coil compression is a promising and efficient way to obtain high quality cardiac perfusion images using large coil arrays.Ben B. and Iris M. Margolis Foundation."}
+{"text": "Long-term use of mechanical ventilators may lead to ventilator-induced diaphragmatic dysfunction (VIDD) and increase the duration of weaning from MV . It was Two juvenile pigs were anesthetized with propofol (150 to 250 \u03bcg/kg/minute) and ventilated (VENT) with an assist control mode MV (Nellcor Puritan Bennett 840). Using fluoroscopy, a novel multipolar neurostimulation catheter  was threaded into the left internal jugular vein and advanced to the junction of right atrium and the superior vena cava using a modified Seldinger technique. The successful capture of the right and left phrenic nerves was confirmed by fluoroscopic visualization. Peak airway pressures (PAWP) and blood gases were determined after 10 minutes MV (MV), MV and stimulation applied together (MV+STIM) and stimulation only (STIM).2 and PO2 confirmed that adequate ventilation and oxygenation can be provided by the system, while PAWP could be reduced  was noted while peak airway pressures were reduced. During STIM there was no discernible paradoxical movement of the diaphragm. In addition, PCOed Table .It was possible to capture and stimulate both phrenic nerves using a minimally invasive approach to support respiration and sustain blood gases at physiological levels. This development could help wean MV-dependent ICU patients earlier. Further long-term studies are needed to assess the full potential of this novel system."}
+{"text": "Large or giant intracranial aneurysms can simulate brain tumors clinically and radiologically by virtue of their progressive mass effect. Unlike aneurysms from alternative locations, those arising from the distal posterior inferior cerebellar artery (PICA) are uncommon. We report a patient who experienced progressive hemiparesis with magnetic resonance imaging findings suggestive of an infratentorial ependymoma. Intraoperatively, a thrombosed large aneurysm of the distal PICA was unexpectedly encountered. The aneurysm was clipped and the patient did not develop any permanent neurological deficit. This case illustrates the radiological nuances of large aneurysms and infratentorial ependymomas. Three-dimensional contrast-enhanced magnetic resonance angiography can be falsely negative and the importance of the \u201ctarget\u201d sign is emphasized. One should be cognizant of this possible diagnosis for patients with midline fourth ventricular lesions in order to reduce surgical risk. Aneurysms arising from the posterior inferior cerebellar artery (PICA) are uncommon and constitute 0.5 to 3.0% of all intracranial aneurysms . While mA 79-year-old woman, with a history of hypertension, presented with dizziness and progressive left side weakness for two months. There was neither headache nor symptoms to suggest raised intracranial pressure. She found it increasingly difficult to walk and required assistance.Physical examination revealed left hemiparesis of medical research council (MRC) power grade 4/5. Deep tendon reflexes were equivocal and muscle tone was normal. Cranial nerve palsy, cerebellar signs, and papilloedema were not detected.Computed tomography revealed a midline hyperdense posterior fossa lesion that displaced the fourth ventricle and compressed the pontine-medullary junction of the brainstem . There wA suboccipital craniotomy was performed and the telovelar approach was planned for tumor excision. Exploration of the cerebellomedullary fissure revealed a fibrous encapsulated 3\u2009cm extra-axial lesion that indented the floor of the fourth ventricle. Upon microsurgical dissection, it transpired that the lesion was a saccular aneurysm arising from the telovelotonsillar segment of the left PICA with no perforator incorporation . ClippinThe posterior inferior cerebellar artery has five segments: 1) the anterior medullary segment; 2) the lateral medullary segment; (3) the telovelomedullary segment containing the caudal loop ending at the cerebellar tonsils; (4) the telovelotonsillar segment from the medial aspect of the tonsils to the roof of the fourth ventricle containing its cranial loop; and (5) the cortical segment that supplies the cerebellar vermis and hemispheres . Accordi the late the anteDistal PICA aneurysms are uncommon and their pathogenesis is a matter of debate \u20133. WhileOur patient demonstrates how a large partially thrombosed distal PICA aneurysm can mimic an infratentorial ependymoma both clinically and radiologically. Most large distal PICA aneurysms rarely rupture and seldom cause thromboembolic events due to the rich anastomotic arterial supply of the inferior cerebellum. Their presentation is similar to posterior fossa neoplasms inducing chronic brainstem or cerebellar compression . DeficitRadiologically infratentorial ependymomas can share common characteristics with partially thrombosed distal PICA aneurysms. Both are predominantly midline lesions located near the fourth ventricle. They can appear iso- or hypointense on T1W imaging and elicit heterogeneous contrast enhancement with significant perilesional vasogenic edema. Almost half of all ependymomas demonstrate T1- and T2-weighted signal heterogeneity due to areas of necrosis, cystic change, repeated hemorrhage, or calcifications . LamellaThe most significant radiological feature for this patient was the presence of the \u201ctarget\u201d sign. Best demonstrated on gadolinium contrast T1W imaging, it represents enhancement of the aneurysm wall as well as within the cavity of a partially thrombosed aneurysm . This isClipping is an effective means of treating distal PICA aneurysms, as they are often superficial and surgically easily accessible. Most patients have good functional outcomes as described in several operative series , 18, 19.The clinician must be aware of the limitations of 3D MRA in identifying thrombosed aneurysms. We recommend meticulous multiplanar evaluation of contrast T1-weighted MRI for the \u201ctarget\u201d sign in older patients with midline fourth ventricular mass lesions. Catheter angiography is recommended in suspected cases and if they remain undetectable one should be cognizant of this possible diagnosis when surgically treating such lesions."}
+{"text": "Taenia solium antibody was positive at high titers. A T2 sagittal magnetic resonance image of the brain showed numerous circumscribed lesions with visible scolices and involving adjacent soft tissues (T. solium. Disseminated cysticercosis has the potential to cause severe clinical manifestations.2Human cysticercosis is an important cause of seizures in the developing world. A small subset of patients acquires heavy infections with large numbers of lesions disseminated throughout the brain and skeletal muscle. tissues . Cystice"}
+{"text": "Local field potential in-vivo recordings often show oscillations with frequencies ranging from < 1 Hz to 100 Hz. The underlying mechanism could change across frequency bands but likely involves network interactions such as recurrent synaptic excitation-inhibition loops. Particularly fast rhythmic activity in the beta and gamma range is thought to be caused by synaptic inhibition . In addiHere we investigate how the dynamics of such neuronal adaptation currents contribute to synaptically generated spike rate oscillations and resonance properties in recurrent networks of excitatory and inhibitory neurons. Based on a network of sparsely delay-coupled adapting spiking model neurons we take a mean-field approach using the Fokker-Planck equation to analyze oscillatory network activity. In the limit of slow adaptation timescales we obtain population spike rates and membrane potential distributions . To alloFor constant external input we find that fast oscillations stabilize if recurrent inhibition is slower than excitation. The oscillation frequency increases with increasing inhibitory synaptic efficacy and decreasing inhibitory delay. Neuronal adaptation facilitates such network-based oscillations for fast synaptic inhibition and leads to decreased frequencies (see Figure"}
+{"text": "Migraine is a condition which consumes maximum revenue of a family, state & nation & still the suffering goes on. In the world millions are suffering from Migraine .. & having pain killer medicine & suffering from their side effect like kidney failure etc Migraine sufferers may have depression deep down... but psychiatry being a stigma - very few sufferer goes for consultation to psychiatrist. History of migraine needs a long time to listen & the ability to listen ,.... which normally a psychiatrist does not have time to listen the painful past & long details without getting revenue - or fee or financially paid for - so depression goes unnoticed. Depression assessment scale -although available - but very few psychiatrist has a team work in India & most of the countries.1. To see that by treating depression & adding specific group of dietary supplements - is there any effect on frequency severity & relapse? 2. Frequency of pain killer - can it be reduced & patient be saved from kidney failure?1. Used exclusion criteria ..... where no other cause of migraine found...all investigation within norm. 2. After assessment treated with antidepressant & CBT & specific group of dietary supplememt. In follow up video of their statement regarding frequeny was noted & use of pain killer was recorded.1. 50 patients dropped out of the study. 2. 450 completed the study. 3. 90% of patients reported a 90% reduction in the use of pain killer. 4. 100% reported that CBT helped them. 5. 10% of patients reported a mixed picture of attacks but reported reduced severity.Migraine patient may have depression underlying which if addressed can be a useful method to reduce severity of migrane attacks. If stigma of mental health or depression can be reduced - will benefit migraine patient. Nti depressant therapy coupled with CBT & specific group of dietary supplement plays an important role in treatment of migraine ."}
+{"text": "Medulloblastoma with extensive nodularity is a rare subtype of the most common malignant childhood brain tumor and has been associated with more favorable prognosis. The authors report the case of a 10-month-old girl with a posterior fossa tumor of excessive nodularity with decreased diffusivity on diffusion-weighted magnetic resonance imaging sequences and robust grape-like postgadolinium contrast enhancing features. The unique neuroradiographic features were confirmed by histopathology and a diagnosis of medulloblastoma with extensive nodularity was made. This case highlights the importance of recognizing this unique medulloblastoma subtype preoperatively, as the more favorable outcome may preclude less aggressive medical management. Primary childhood central nervous system brain tumors occur at an incidence of 5.0 cases per 100,000/person-years in the United States according to data from the Central Brain Tumor Registry \u20136. NeuroA 10-month-old full term female presented to our hospital following a 4\u20136 month history of delayed motor milestones and enlarging head circumference. She had an external ventricular drain placed at an outside hospital prior to arriving at our institution. Her neurological examination revealed mild limited upgaze and moderate axial hypotonia without obvious dysmetria. Magnetic resonance imaging (MRI) examination of the brain revealed a very large posterior fossa tumor with decreased diffusivity on diffusion-weighted imaging (DWI) and apparent diffusion coefficient (ADC) sequences Figures . On T2-w2 of residual tumor postmaximum surgical resection. The newly stratified molecular classification of medulloblastoma has revealed distinct subsets of children who have better prognosis in spite of their young age. Among these children are those with either nodular desmoplastic or extensive nodularity. The distinguishing feature at the histologic level is those patients with extensive nodularity have an expanded lobular architecture of the classic reticular free zones that are enlarged with neuropil. Previously termed \u201ccerebellar neuroblastoma\u201d medulloblastoma with extensive nodularity belongs to a molecular subgroup driven by sonic hedgehog pathways. The neuroradiographic features of this medulloblastoma with what we describe as \u201cexcessive\u201d nodularity are important to recognize as these children may be cured with chemotherapy alone and spared from the neurocognitive consequences of radiation therapy. While a similar finding of medulloblastoma with \u201cextreme\u201d nodularity has been reported [The five-year overall survival of children with average risk medulloblastoma who are treated with a combination of craniospinal radiation and chemotherapy approaches 90%. Currently average risk is defined as age greater than 3 years at diagnosis, negative CSF or leptomeningeal spread, and less than 1.5\u2009cmreported , we feel"}
+{"text": "This paper describes a rare finding of an inguinal ovary in an adult woman who presented with pelvic pain. Inguinal ovary may occur if the gubernaculum fails to attach to the uterus or if the canal of Nuck remains open during fetal development.The online version of this article (doi:10.1186/2193-1801-2-545) contains supplementary material, which is available to authorized users. Ovary within the inguinal canal is occasionally seen in infants, but is rare in adult women. This paper describes a woman with an inguinal ovary who presented with pelvic pain. We review the literature and discuss its embryological background.A 33 year-old-woman presented with pelvic pain on a background of longstanding left sided iliac fossa pain, which was exaggerated by constipation and movement. Past medical history included depression, scarred left kidney from recurrent urinary tract infections and surgery for urethral diverticulum. Obstetric history included two vaginal deliveries following subfertility treatment. Ultrasound scan demonstrated an unremarkable retroverted uterus and normal renal tract. The right ovary appeared normal however left ovary was not identified. Diagnostic laparoscopy revealed the left ovary herniating through the left internal inguinal ring Figure\u00a0a-b. The A literature search revealed twelve case reports in adults. The majority presented with a palpable groin mass and they were diagnosed at time of surgery for suspected bowel hernia Additional file 2: Figure S2: Laparoscopic image of left ovary following its removal from the inguinal canal and mesh repair of the hernia. (JPEG 329 KB)Authors\u2019 original file for figure 1Below are the links to the authors\u2019 original submitted files for images."}
+{"text": "Thalidomide is a drug, which has its own place in the history of medicine and has been used in various types of cancers and other chronic inflammatory disorders (erythema nodosum leprosum) but its mode of action as an immunomodulatory drug in acute infections  is not clear. Thus, the present study was designed to investigate its effect on pulmonary innate immune response during acute lung infection in BALB/c mice.Lung innate immune response plays an important role in the clearance of pathogens  from lungs. However, profound activation of innate immune cells  can lead to development of acute lung inflammation or injury observed during pneumonia, acute respiratory distress syndrome (ARDS), or sepsis by producing various proinflammatory cytokines  and molecules . Acute lung inflammation was induced by intranasal instillation of Klebsiella pneumoniae B5055 into mice without any anesthesia and treated with thalidomide (30 mg/kg/day/p.o.) or normal saline orally using a treatment schedule shown to modulate proinflammatory innate immune response. Various proinflammatory  as well as anti-inflammatory  cytokines were estimated by ELISA. Pulmonary macrophage-mediated phagocytosis and bactericidal assays were performed. Alveolar macrophages were evaluated in terms of macrophage spreading ability assay. H2O2 production by macrophages was assessed according to the method based on the process of horseradish peroxidase-dependent oxidation of phenol red assay. Neutrophil infiltration to the lungs was determined by histopathological analysis.Animals were divided into four groups  were found to be decreased significantly in the thalidomide-treated group but the levels of IL-10 were found to be significantly elevated.Thalidomide treatment modulated proinflammatory function of alveolar macrophages by significantly decreasing their phagocytic potential in terms of phagocytic uptake and intracellular killing, spreading and HThalidomide proved a promising immunomodulatory agent with a potential to modulate aggravated innate immune response observed during acute lung inflammation associated with pneumonia or sepsis caused by Gram-negative bacterial infection."}
+{"text": "Cell structure depends on both matrix strain and stiffness, but their interactive effects are poorly understood. We investigated the interactive roles of matrix properties and stretching patterns on cell structure by uniaxially stretching U2OS cells expressing GFP-actin on silicone rubber sheets supporting either a surface-adsorbed coating or thick hydrogel of type-I collagen. Cells and their actin stress fibers oriented perpendicular to the direction of cyclic stretch on collagen-coated sheets, but oriented parallel to the stretch direction on collagen gels. There was significant alignment parallel to the direction of a steady increase in stretch for cells on collagen gels, while cells on collagen-coated sheets did not align in any direction. The extent of alignment was dependent on both strain rate and duration. Stretch-induced alignment on collagen gels was blocked by the myosin light-chain kinase inhibitor ML7, but not by the Rho-kinase inhibitor Y27632. We propose that active orientation of the actin cytoskeleton perpendicular and parallel to direction of stretch on stiff and soft substrates, respectively, are responses that tend to maintain intracellular tension at an optimal level. Further, our results indicate that cells can align along directions of matrix stress without collagen fibril alignment, indicating that matrix stress can directly regulate cell morphology. Cyclic stretching causes the alignment of several cell types perpendicular to the direction of stretch Experiments involving cells cultured on soft hydrogels have demonstrated that substrate stiffness strongly regulates many cell processes, including cell\u2013cell adhesion Since the stiffness of silicone rubber  were cultured in DMEM (Gibco) supplemented with 10% fetal bovine serum (Gibco), 2 mM L-glutamine (HyClone), 1 mM sodium pyruvate (HyClone) and 1 mM (HyClone) penicillin/streptomycin in a humidified 5%CO2) by incubating 100 \u00b5l of 0.3 mg/ml rat tail collagen type-I (BD Biosciences) in the well and allowing the solution to evaporate. The collagen solution (3 mg/ml) was then added to form a gel within the collagen-coated well as described previously Silicone rubber stretch chambers  were modified to form a circular well (15 mm diameter) by adhering a silicone rubber sheet onto the chambers . The chaCells were cultured on the top surface of the collagen gels and subjected to cyclic stretch by stretching the chambers with two linear motors  as described previously E1) and lateral directions (E2) were computed from the E11 and E22 components of the Lagrangian strain tensor The strain fields produced by the device were determined by tracking the displacement of markers on the collagen gel and silicone rubber surfaces. Strains on the bottom surface of the silicone rubber sheeting were measured by marking membranes at several points with a permanent marker and imaging before and after stretch using nominal stretch values ranging from 2.5 to 12.5%. To quantify the strains on the collagen gel surface, red fluorescent beads  were mixed into the gel prior to polymerization to serve as fiducial markers. Triads of markers in a focus plane in various locations on the surface were selected to compute the symmetric Lagrangian strain tensor at each location. The finite strains in the longitudinal  as described previously The shape of each cell was determined from the background signal of the Alexa 488-phalloidin stained cells. Each cell was fit to an equivalent ellipse using NIH ImageJ software 2-independent media (Hyclone). The stretch device was mounted under the objective of the confocal microscope and subjected to a 10% step change in stretch with images of GFP-actin captured at 10 min intervals.One hour before starting the experiment, the media in stretch chamber was changed to Hyclone L-15 COSignificant differences in order parameters between groups were identified using ANOVA followed by Student-Newman\u2013Keuls posthoc multiple comparisons testing.Two-dimensional strains measured on the surfaces of 500 \u00b5m-thick collagen gels and the supporting silicone rubber membranes were very similar . Strains2) rather than the thick gel. In each case, the cells were subjected to 3 h of 10% cyclic uniaxial stretch at 1 Hz. Consistent with our previous findings using non-confluent and confluent U2OS and bovine aortic endothelial cells on fibronectin-coated silicone rubber We evaluated the effects of stretch on SF organization in non-confluent U2OS cells adhered onto the top of collagen gels. For comparison, experiments were also performed where the cells were adhered on the supporting silicone rubber membranes, but coated with a low concentration of collagen , a transient hold , and subsequent release of the stretch . In eachConsistent with previous findings with NIH 3T3 fibroblasts on soft polyacrylamide gels To observe the dynamic process of SF alignment in cells stretched on collagen gels, we collected time-lapse videos of GFP-labeled actin in U2OS cells. Our results demonstrate that stretch-induced cell and SF alignment are highly dependent on the mechanical properties of the collagen matrix upon which cells are cultured. Cyclic stretch promoted alignment parallel to the direction of stretch cf.  in cellsWe previously reported a theoretical model predicting that SFs reorient perpendicular to the direction of cyclic stretch on matrix-coated silicone rubber to avoid excessive levels of tension acting on actomyosin binding sites The dependence of alignment on cyclic stretch frequency is consistent with previous measurements using U2OS cells and endothelial cells on fibronectin-adsorbed silicone rubber Our results provide evidence that two mechanisms contribute to stretch-induced alignment on soft collagen gels. Prestretched collagen gels are expected to have anisotropic mechanical properties, with greater stiffness in the direction of stretch. The alignment of the cells and SFs along the direction of greater stiffness cf.  is consiIt is interesting to speculate on why the stretch stimulus is only effective on soft collagen gels, but not on collagen-coated sheets cf. . PreviouCells in stretched 3-D collagen matrices are often elongated in parallel with the predominant alignment of collagen fibrils Extracellular matrix geometry and topography at the nanoscale can impact cellular function A recent study by Pang et al. Our results indicate that stretch-induced SF alignment on soft collagen gels is dependent on MLCK, but not Rho-kinase. Rho-kinase and MLCK regulate central and peripheral SF populations, respectively Our findings shed new light on experimental and theoretical observations by other groups on cells stretched on soft 2D and 3D substrates Recent studies by Quinlan et al. In summary, our results clearly demonstrate that cells respond to applied strains in a manner dependent on substrate rigidity. Recent experiments employing high-resolution traction force microscopy on polyacrylamide substrates indicate that focal adhesions individually sample the substrate rigidity and that FAK/phosphopaxillin/vinculin signaling defines the rigidity range over which cells migrate toward regions of higher rigidity Figure S1Silicone rubber chamber with collagen gel before (A) and after stretch (B).(TIF)Click here for additional data file.Figure S2Influence of substrate stiffness on cell elongation during stretch. Representative images of U2OS cells before and after a 10% step stretch depicting cell elongation and change in cell length in the direction of stretching for cells cultured on collagen gels (A) and collagen coated silicone rubber sheets (B) (n\u200a=\u200a3).(TIF)Click here for additional data file.Table S1Influence of substrate stiffness on cell strains during stretch.(DOCX)Click here for additional data file.Video S1Live Cell Microscopy. Time-lapse video depicting data in (AVI)Click here for additional data file."}
+{"text": "Chronic liver diseases are characterized by inflammatory and fibrotic liver injuries that often result in liver cirrhosis with its associated complications such as portal hypertension and hepatocellular carcinoma. Liver biopsy still represents the reference standard for fibrosis staging, although transient elastography is increasingly used for non-invasive monitoring of fibrosis progression. However, this method is not generally available and is associated with technical limitations emphasizing the need for serological biomarkers staging of liver fibrosis. The enhanced liver fibrosis (ELF) score was shown to accurately predict significant liver fibrosis in different liver diseases, although extracellular matrix components detected by this score may not only mirror the extent of liver fibrosis but also inflammatory processes.In this prospective biopsy-controlled study we evaluated the utility of the ELF score in comparison to transient elastography to predict different stages of fibrosis in 102 patients with chronic liver diseases.Both techniques revealed similar area under receiver operating characteristic curve values for prediction of advanced fibrosis stages. Compared to transient elastography, the ELF score showed a broader overlap between low and moderate fibrosis stages and a stronger correlation with inflammatory liver injury.Both the ELF score as well as transient elastography allowed for high quality fibrosis staging. However, the ELF score was less discriminative in low and moderate fibrosis stages and appeared more strongly influenced by inflammatory liver injury. This should be considered when making clinical interpretations on the basis of ELF score values. Liver fibrosis is the consequence of a variety of chronic liver diseases and can result in liver cirrhosis. Early detection of fibrosis progression and development of cirrhosis are crucial for management of patients with chronic liver diseases since advanced fibrosis is associated with clinical complications and formation of hepatocellular carcinoma. Although liver biopsy remains the reference standard for evaluating liver fibrosis, it is limited by sampling errors and risk of complications The liver volume explored by transient elastography is estimated to be 100 times larger compared to liver biopsy and might thus be more representative of the entire organ Extracellular matrix components may not only mirror the extent of liver fibrosis but are also involved in inflammatory processes. For instance, direct immunological impact of HA by regulating inflammatory cell recruitment and release of inflammatory cytokines has been described In the present study we have evaluated the performance of the ELF test against transient elastography for non-invasive assessment of fibrosis in a prospective biopsy-controlled manner. In this context we have analyzed the influence of possible confounders, such as liver inflammation or steatosis, on fibrosis detection by ELF score and transient elastography.16 In addition to the ELF score alanine and aspartate aminotransferase  levels were determined. At the time of blood withdrawal, all patients obtained liver biopsy and liver stiffness measurement using the Fibroscan . The fibrosis stage (F1\u2013F6) was determined according to Ishak et al.We investigated sera from 102 patients  with chronic liver diseases . Serum samples were analyzed for markers of the ELF score, including tissue inhibitor of matrix metalloproteinase 1 (TIMP-1), hyaluronic acid (HA), and amino-terminal propeptide of type III collagen (PIIINP). The proprietary assays developed for the ELF test by Siemens Healthcare Diagnostics Inc.  were used and analyses were performed on an Immuno-1 auto-analyser . Results were entered into the established algorithm and expressed as score as described.Statistical analyses were performed by using Graphpad Prism 5.0 and SPSS 19.0 software and confirmed by a professional statistician. Data are presented as box plot and whiskers analysis as well as mean \u00b1 standard error of the mean (SEM). The results obtained with the different serum markers or liver stiffness measurements were compared using the Mann-Whitney\u2019s U test. Regression analyses were performed to calculate the Spearman rank correlation coefficient. Receiver operating characteristics (ROC) analysis was calculated. A P value <0.05 was considered significant. A multivariate logistic regression analysis was performed in order to adjust for variables found to be associated with fibrosis.The ELF test was compared with transient elastography for detection of different fibrosis stages in patients with chronic liver diseases (n\u200a=\u200a102). Transient elastography allowed a better discrimination between low  6.9\u00b10.4 kPa) and moderate  and between moderate and high fibrosis stages  or progressed fibrosis/cirrhosis (\u2265F5) with the best compromise sensitivity/specificity. To this end, we performed a ROC plot analysis including all patients (n\u200a=\u200a102) with different fibrosis stages. The cut-off value of transient elastography of 8.5 kPa correctly predicted fibrosis stages of \u2265F2 with a sensitivity of 86% and a specificity of 73%  95%: 0.85\u20130.98; To analyze a potential influence of liver inflammation on ELF score and transient elastography, we performed regression analyses comparing ALT or AST levels with ELF score and transient elastography. Both methods of fibrosis detection significantly correlated with AST and ALT levels Figure 3Chronic liver diseases represent a substantial public health problem with a worldwide mortality of around 800.000 deaths per year Ideally, non-invasive markers of liver fibrosis should be liver-specific and easy to perform with high diagnostic performance (compromise sensitivity/specificity) for accurate fibrosis staging. Among the most studied non-invasive detection methods of liver fibrosis is transient elastography. A prospective study in patients with chronic liver diseases demonstrated that measurement of liver stiffness by transient elastography is a reliable method to predict moderate or severe fibrosis stages, but shows less accuracay to differentiate between lower fibrosis stages according to METAVIR Compared to transient elastography, the ELF score revealed a lower significance (p<0.05) for discrimination between low and moderate fibrosis stages and showed a broad overlapping range for those stages. Nevertheless, AUC values for prediction of relevant fibrosis (\u2265F2) are high for both non-invasive methods with similar sensitivity and specificity. Both transient elastopgraphy and ELF score showed also a comparable high diagnostic accuracy to predict progressed fibrosis/cirrhosis (\u2265F5). The cut off-value of transient elastography for prediction of progressed fibrosis evaluated in this study was nearly the same (17.5 kPa) compared to that (17.6 kPa) of a previous study A recent study showed lower diagnostic performance for transient elastography in detection of liver cirrhosis compared to lower fibrosis stages There is also increasing evidence that liver stiffness is influenced by acute exacerbation of liver disease with ALT flares resulting in overestimation, e.g. up to three fold increase, of liver stiffness values It has been reported that liver stiffness values are higher in subjects with enhanced BMI or metabolic syndrome Our present large biopsy-controlled prospective study showed that the ELF score reveals similar diagnostic accuracy to predict relevant (\u2265F2) or advanced (\u2265F5) stages of fibrosis compared with transient elastography. However, the cut-off values of the ELF score to predict relevant stages of fibrosis are close to the cut-off value for detection of progressed fibrosis whereas the respective cut-off values for transient elastography showed a higher difference. The ELF score appears less discriminative in lower fibrosis stages compared to transient elastography. Furthermore, the ELF score showed a higher correlation with inflammatory liver injury compared to transient elastography. These observations should be considered when making clinical interpretations or decisions on the base of ELF score values."}
+{"text": "Trauma and sepsis can cause acute lung injury (ALI) and Acute Respiratory Distress Syndrome (ARDS) in part by triggering neutrophil (PMN)-mediated increases in endothelial cell (EC) permeability. We had shown that mitochondrial (mt) damage-associated molecular patterns (DAMPs) appear in the blood after injury or shock and activate human PMN. So we now hypothesized that mitochondrial DAMPs (MTD) like mitochondrial DNA (mtDNA) and peptides might play a role in increased EC permeability during systemic inflammation and proceeded to evaluate the underlying mechanisms. MtDNA induced changes in EC permeability occurred in two phases: a brief, PMN-independent \u2018spike\u2019 in permeability was followed by a prolonged PMN-dependent increase in permeability. Fragmented mitochondria (MTD) caused PMN-independent increase in EC permeability that were abolished with protease treatment. Exposure to mtDNA caused PMN-EC adherence by activating expression of adherence molecule expression in both cell types. Cellular activation was manifested as an increase in PMN calcium flux and EC MAPK phosphorylation. Permeability and PMN adherence were attenuated by endosomal TLR inhibitors. EC lacked formyl peptide receptors but were nonetheless activated by mt-proteins, showing that non-formylated mt-protein DAMPs can activate EC. Mitochondrial DAMPs can be released into the circulation by many processes that cause cell injury and lead to pathologic endothelial permeability. We show here that mitochondria contain multiple DAMP motifs that can act on EC and/or PMN via multiple pathways. This can enhance PMN adherence to EC, activate PMN-EC interactions and subsequently increase systemic endothelial permeability. Mitochondrial DAMPs may be important therapeutic targets in conditions where inflammation pathologically increases endothelial permeability. We also set out to determine whether these effects occur via MTD interactions with EC, PMN or both. To study these processes under the most realistic and relevant possible conditions, we created studies that centered on the changes in endothelial monolayer permeability occurring \u2018in real-time\u2019 when human EC were exposed to fragmented whole human mitochondria (MTD) or to purified mtDNA in the presence or absence of human PMN. We then focused on the molecular biologic and cell signaling events that led to the alterations in EC permeability seen in the translational models we had created.Cellular damage due to mechanical trauma, hemorrhage and sepsis can release mitochondrial (mt) damage motifs like mtDNA and formyl peptides. We previously showed that these molecules can trigger inflammation and organ injury  of Beth Israel Deaconess Medical Center, Boston, MA USA. Written consent was obtained from blood donors. The tissue samples obtained for isolation of human mitochondria were portions of surgical pathology specimens that were not needed for diagnostic purposes. All samples were de-identified.Human tissues such as the margins of liver resections, portions of spleens removed due to injury and bone marrow reamed from the femur during fracture fixations were obtained from operations performed at Beth Israel Deaconess Medical Center (BIDMC). Whole mitochondria (mt) were prepared using a mitochondrial isolation kit from Thermo Fisher Scientific . For certain experiments, mitochondrial debris (MTD) fractions were prepared by sonicating whole mitochondria (prepared from human liver) five times for 30 s as previously described 2+]i response in Fura 2-loaded human PMN equal to that induced by 1 nM fMLP 2+ response, does not guarantee identical changes in permeability. This approach is by necessity very different from using commercial agents that are purified and fully characterized, but also reflects real biologic variability.Activity of MTD samples was standardized using a bio-assay based upon the ability of MTD to elicit a i) was monitored with a Basic InCyt Im2 calcium imaging system . 20\u201330 cells were typically selected for each experiment. The ratio of fluorescence at 340/380 nm was used to indicate [Ca2+]i.EC calcium mobilization was determined using a fluorescent calcium imaging system where cells are attached to glass coverslips. Cells were loaded with Fura-2 2 using a Zeiss LSM 510 Meta Live Cell Inverted Confocal System.To visualize localization of mtDNA in HPAEC, human mtDNA was labeled with Alexa 488 using the Ulysis Nucleic Acid Labeling Kit  following the manufacturer\u2019s protocol MTD applied to EA cells showed marked effects in endothelial permeability in the absence of PMN. As shown in MtDNA (25 and 50 \u00b5g/mL) was prepared from mitochondria isolated from human liver and applied to EA cells with and without human PMN present. We note an immediate, dose-dependent rise in monolayer permeability both in the presence and absence of PMN  with or without PMN were also evaluated. As seen in DNA-sensing TLRs are endosomal in location. We therefore next sought to show that mtDNA applied to EC externally was taken up into endosomes. To do this, we applied mtDNA prepared from human liver and freshly labeled with Alexa 488 to HPAEC along with FM4-64, a marker that localizes to endosomes. We then examined live cells under confocal microscopy. As shown in . Protease activity was terminated by heat (75\u00b0C/20 min) prior to treating EC. As shown in In addition to mtDNA, mitochondria contain proteins that EC might sense as alarmins. These could be formylated proteins synthesized in the mitochondria that act on formyl peptide receptors (FPR) like those on PMN, or they could be non-formylated proteins sensed via other mechanisms. We examined the permeability of EC exposed to MTD pre-treated with a protease cocktail or media only 2+]i). We therefore applied MTD to EA cells or HPAEC to evaluate calcium mobilization  the [Ca2+]i increases were very limited.Agonists like thrombin and histamine increase EC permeability in part by increasing cytosolic calcium concentrations ([Ca2+]i transients in response to fMLP despite responding briskly to thrombin stimulation. This suggests the absence of formyl peptide receptors (FPRs)  had no direct effect on EC permeability. Moreover, application of fMLP to EC in addition to MTD or mtDNA had no additional effect on the permeability changes seen (C&D). Thus exposure to mtDNA increases expression of selectins and integrins in both PMN and EC and causes them to adhere to each other.Next, we examined whether enhanced PMN-EC adherence might contribute to the increased permeability observed when PMN and EC were exposed to mitochondrial alarmins. EA cells were treated with mtDNA  for 6 hrs and calcein-loaded PMN were applied to the EA cell monolayers for the last 60 min. Exposure to mtDNA significantly increased PMN adherence to EA cells  and related organ failure syndromes (like ALI/ARDS) are often thought of as reflecting the effects of inflammatory cytokine release on PMN-EC interactions. But cytokine release is the delayed, indirect response to injury seen after intermediate events transduce physical stimuli into immune \u2018Danger\u2019 signals. Similarly, release of known endothelial activators like thrombin is strictly limited to sites of wounding. We hypothesized that MTD released from sites of injury might participate in the acute activation PMN-EC interactions that underlie the increased systemic endothelial permeability typical of SIRS and ALI. In this context, we focused our studies on the effects of mitochondrial DAMPs (MTD) on EC activation and permeability in the presence and absence of PMN. Although the concentrations of these molecules under clinical conditions are difficult to ascertain, we have tried to maintain translational relevance by examining the effects of biologic mixtures of mitochondrial DAMPs removed directly from fresh human cells and used at concentrations that produce similar modest activations of PMN i) are a common mechanism of immune cell activation. We found mtDNA-treated PMN to have an increased Ca2+ influx response to TG  to enhance barrier integrity intracellular S1P synthesis activates store-operated Ca2+ channels. Increases in [Ca2+]i due to SOCE in PMN or EC could then activate pathways leading to increased vascular permeability. Studies by our lab and others have suggested that S1P acts as a second messenger and has an important non-receptor mediated role in the regulation of [Ca2+]i mobilization and cell permeability 2+ store depletion by other signaling agents Such further investigations will involve direct evaluation of intracellular S1P levels as we have shown previously 2+ flux responses may be an important source of the diversity in endothelial responses seen in different vascular beds.The increase in Sphk1 induced by mtDNA treatment (Finally, we show here for the first time that endothelial cell expression of HMGB1 is up-regulated in inflammatory environments and that sterile mitochondrial motifs can activate HMGB1 expression. Although HMGB1 has been thought to act as a late cytokine mediator of sepsis that activates cells via innate immune receptors The ability of DAMPs derived from mitochondria to initiate changes in endothelial permeability has not been previously studied. The events described here are actually responses to a spectrum of molecular species that can act on both EC and PMN. The current work establishes that release of molecular motifs from the mitochondria of disrupted, dead or dying cells may be a critical event in determining early systemic endothelial response to injury. Subsequent studies will be aimed at determining the dominant active agonists and the pathways by which they act."}
+{"text": "The choice of footwear and custom modification of footwear in fast bowling in cricket lacks biomechanical and clinical evidence. This demonstrates that despite professional advice being available, elite fast bowlers continue to wear shoes that may not be appropriate for them. The aim of this study was to investigate the biomechanical effects of three cricket shoes commonly used by fast bowlers and whether footwear modification could play a role in injury.Four male cricket fast bowlers were included in the study. A 20 camera VICON Mx system was used to collect three-dimensional kinematic data. A four segment marker set was used to track and model the lower limb. Four force platforms  were positioned at both back and front foot strike to capture kinetic data. Participants\u2019 perceptions of footwear were measured using a VAS. Freidman two-way ANOVA with post hoc pairwise comparison was used to analyse the differences between shoes. Linear regression analysis was used to correlate predictive outcome measures.P = 0.038) and a significant decrease in front knee joint external rotation moment (P = 0.022) relative to the custom modified shoe (ASICS 490TR). Exploratory regression analysis identified that front foot peak lateral shear force was significantly correlated  to sagittal plane knee joint angle at initial contact. Sagittal plane knee joint angle at initial contact was also significantly correlated  to front foot loading rate.The custom modified cross-trainer (ASICS 490tr) demonstrated the highest participant perception footwear score (mean 9/10 VAS). The conventional cricket shoes (ASICS 170no) demonstrated a significant reduction in front foot lateral shear force (The findings of this research demonstrate that custom modified cricket shoes increase lateral shear force and knee external rotation moment at the front leg. However, the relationship between these findings and injury remain unquantified. Further research must identify the role of footwear in the mechanism of lower limb injury in fast bowlers and what characteristics of footwear correlate to improved footwear VAS scores in regards to comfort, support and performance."}
+{"text": "A variety of complications related to endovascular procedures are being reported. We present an annoying complication implying complete migration of stent-graft of subclavian artery into the aortic lumen.A 61 years old man with abdominal endovascular aortic stent-graft inserted previously, had a saccular aneurysm of descending aorta distal to left subclavian artery and a small dissection flap with saccular aneurysm originating from left subclavian artery. Since the patient refused to have any surgical procedure for left subclavian artery revascularisation, thoracic aortic-stenting for descending aorta just below subclavian origin and a second stent-graft for left subclavian artery just above the orifice was planned. Coverage of left subclavian artery was not preferred aiming to avoid possible cerebrovascular events. During intervention, stent-graft to be inserted inside subclavian artery migrated totally into aortic arch in a perpendicular fashion.Bilateral femoral and left brachial artery accesses were done. A 16x41mm stent-graft was inserted inside left subclavian artery. While insertion with balloon dilatation, stent-graft migrated distally with the balloon forming a partial prolapse into aortic arch. We tried several endovascular maneuvers including inserting a second graft into subclavian artery to stabilize the first one or trying to press this graft with the one inserted into descending aorta, but unfortunately the stent totally migrated into aorta. We catheterized migrated stent with balloon catheter and were able to move the graft with inflated balloon fixing it. Stent-graft and inflated balloon were pulled slowly back together to proximal part of left arm of the previously inserted abdominal aortic stent-graft and stabilized it carefully. Control DSA showed settled graft without any stenosis.We present a bothering complication and an endovascular solution we performed without complication."}
+{"text": "Isometric exercise is a powerful stimulator of the cardiovascular system. Therefore, exercise can be used to unmask subtle cardiovascular changes that are not evident at rest. MRI is a proven method for comprehensive cardiovascular assessment in the resting state. Unfortunately, lack of fast imaging sequences and an appropriate exercise test has prohibited the use of isometric exercise in MRI.We aimed to devise an isometric exercise test for use in MRI in order to comprehensively assess the hemodynamic response to exercise using fast-imaging MRI.A sustained isometric biceps exercise test was devised for the MRI scanner. Ten healthy male volunteers (24 to 44 years) underwent three minutes of sustained isometric exercise using a weight load adjusted to 35% of maximum biceps strength. The hemodynamic response was elucidated during rest, exercise  and recovery . At each time point we obtained 1) aortic flow - spiral prospectively-gated breath-hold phase contrast CMR, 2) LV volumes - real-time radial k-t sensitivity encoding free-breathing CMR and 3) oscillometric upper arm blood pressure. Using this data vascular resistance and compliance was calculated.All participants completed the isometric exercise test. All data sets were complete. Sustained isometric exercise in the MRI scanner produced a marked hemodynamic response Table . Both vaIsometric biceps exercise testing is highly feasible using a MRI safe methodology, which allows exercise in the supine position within the scanner. The test evokes a hemodynamic response that corresponds to isometric exercise conducted outside the MRI scanner. The hemodynamic response can be comprehensively and safely assessed at any point of time during isometric exercise using this exercise methodology together with fast-imaging MRI."}
+{"text": "We report a rare complication after successful Evita Open Plus\u00ae implantation with cardiopulmonary bypass and circulatory arrest complete for total aortic aneurysm treatment.A 71 year old male with aortic aneurysm was referred for consideration of surgery. The patient comes to the emergency department to present an acute left chest pain. He was a history of duodenal ulcer and arterial hypertension. Rx thorax demonstrated mediastinal widening compatible with giant aortic aneurysm. The echocardiogram (TTE) confirmed normal sized cardiac cavities and ascending aortic aneurysm. Aortography presented severe dilatation of ascending thoracic aorta with moderated aortic regurgitation. CT Angiography established supra-aortic ascending aneurysm with maximum dimension of 53 mm, 65 mm arch aneurysm and descending 106 mm in the transverse plane.Upper medial resternotomy, cardiopulmonary bypass and circulatory arrest complete with moderated hypothermia were performed as well as ascending aorta and arch replacement with reimplantation of the supra-aortic trunks by hybrid prosthetic Evita Open Plus\u00ae 33.The patient evolution was favourable. In the control TTE was observed on the left ventricular apex two interconnected cavities support with left ventricular pseudoaneurysm, confirmed by CT angiogram. The patient required a new intervention, performing exclusion of the pseudoaneurysm in the left ventricular (LV) apex with a Teflon patch. After surgery remains stable and was discharged without complications.The total aortic replacement  using hybrid routines are reserved for patients with complex pathology. Iatrogenic LV pseudoaneurysms postoperative may uncommon. In some cases is related to the increase in consistency (due to hypothermia during circulatory arrest complete) of the cannula vent of the LV during extracorporeal circulation."}
+{"text": "Celiac artery compression syndrome is a rare disorder characterized by episodic abdominal pain and weight loss. It is the result of external compression of celiac artery by the median arcuate ligament. We present a case of celiac artery compression syndrome in a 57-year-old male with severe postprandial abdominal pain and 30-pound weight loss. The patient eventually responded well to surgical division of the median arcuate ligament by laparoscopy. Celiac artery compression syndrome also known as median arcuate ligament syndrome is a rare cause of abdominal pain and weight loss. It is caused by compression of the celiac artery by the median arcuate ligament. We report a case of a 57-year-old male who presented to us with this rare diagnostic challenge. Various imaging techniques such as duplex ultrasound, magnetic resonance angiography, computerized tomography angiogram, and visceral angiography can be used to diagnose this condition. Surgical decompression of the celiac artery by division of the median arcuate ligament has been shown to be very effective.A 57-year-old male with past history significant for hepatitis C and chronic abdominal pain with 50 admissions in various hospitals over the last 2 years presented with worsening epigastric and left upper quadrant pain as well as a 30-pound weight loss over one year . The pai9/L, and white blood cells 6.8 \u00d7 109/L. Liver function tests were elevated  likely secondary to Darvocet use, which returned to baseline during his hospital course. Antismooth muscle antibody (ASMA), antinuclear antibodies (ANA) and intrinsic factor blocking antibody were within normal limits. Computed axial tomography (CAT) scan of the abdomen was normal and showed no signs of cirrhosis. Stool hemoccult was positive. Capsule endoscopy was done which showed delayed gastric emptying. Visceral angiogram was done which showed no signs of vasculitis but near complete stenosis of celiac axis secondary to median arcuate ligament compression and retrograde filling of celiac artery , magnetic resonance angiogram (MRA), and computerized tomography angiogram (CTA). However, CT angiogram remains the gold standard. Findings include retrograde filing of celiac artery via gastroduodenal branch of the superior mesenteric artery and poststenotic dilatation.Various treatment modalities have been tried to decompress the celiac artery. Surgical division of the fibers of the median arcuate ligament either by conventional open surgery  or by laparoscopic approach is usually adequate in most patients . RecentlCeliac artery compression syndrome is a rare condition that may present a real diagnostic challenge for the clinician. We presented an unusual case of a 57-year-old male, with the median arcuate ligament compressing on the superior mesenteric artery, thereby causing postprandial abdominal pain and weight loss. Our patient was successfully treated by laparoscopic division of the median arcuate ligament. At least three-fourths of the patients have a good long-term prognosis following the surgical division of the median arcuate ligament ."}
+{"text": "Biologic agents may cause auto-antibody formation and drug induced lupus but no paediatric guidelines exist regarding monitoring of auto-antibodies. The UK Royal College of Nursing Guidance advises checking ANA and anti-dsDNA before starting biologic treatment and repeating anti-dsDNA if concerned.The Alder Hey protocol tested an autoantibody profile Table , 2 3-6 mTo analyse frequency of antibody positivity in rheumatology patients on biologics in order to estimate costs and to devise a rational protocol for test frequency.A retrospective audit of a 2 year period, August 2008 to July 2010. All patients on biologics were included with data on auto-antibodies collated using the hospital computer system.111 children were receiving biologic therapy and 2511 auto-antibodies were tested at a cost of over \u00a326,000.With the exception of ANA antibody, all other antibody tests were usually negative. Those that were positive tended to be non specific  and/or were negative on subsequent testing. The results did not alter patient care yet costs are significant. This audit would suggest that antibody tests are checked too frequently at Alder Hey Hospital. A new protocol in development is likely to recommend testing auto-antibodies annually in the absence of clinical signs / symptoms of lupus."}
+{"text": "High sensitive troponin T (hsTnT) is a highly specific marker of myocardial injury and one of the keystones in the diagnosis of acute coronary syndrome. Although hsTnT is thought to be released by myocardial cell damage, recent studies reported elevated levels after exercise testing and endurance sports. The exact mechanism of this phenomenon is discussed controversially. CMR stress testing is widely used for detection of myocardial ischemia. The kinetic of troponin release after CMR stress testing has not been studied previously.To assess the impact of adenosine and dobutamine CMR stress testing on hsTnT.21 Patients underwent CMR stress testing  for evaluation of coronary artery disease using dobutamine wall motion (13 patients) or adenosine perfusion imaging (8 patients). Standard protocols included dobutamine infusion  to reach a target heart rate [(220-age)*0.85] or adenosine infusion (0.14 mg/kg/min). Blood samples were taken immediately before and 12-24 hours after CMR.At baseline, hsTnT levels of all patients were below the detection limit of 0.010 ng/ml. After dobutamine stress, hsTnT levels raised in 7 patients (54%), of which 3 had evidence of myocardial ischemia in wall motion analysis. 4 patients with an increase in hsTnT did not show ischemia in CMR. Elevation of hsTnT was not detected in any patient after adenosine stress. A significant positive correlation between hsTnT levels and increase in systolic blood pressure after dobutamine stress was observed . Myocardial ischemia  was not associated with the release of hsTnT.HsTnT release seems to be a common phenomenon using different stress testing modalities associated with increased blood pressures. This is supported by previous reports of hsTnT elevation related to increased blood pressure like physical stress testing, whereas adenosine does not alter blood pressure. Therefore, mechanisms different from cardiomyocyte necrosis might contribute to hsTnT release."}
+{"text": "In early development stages of biologicals there is often more than one molecule against a specific target. A careful candidate evaluation is crucial to choose an optimal lead variant for further development. Complex biologicals are typically produced in CHO cells and host cells as well as the process are known to influence important molecule features such as glycan patterns or activity. To streamline the generation of stable producer cell lines we have established an Flp-based RMCE system in our CHO-DG44 platform. RMCE application allows for multi-parallel production of candidate material in the host cell and process background used for the pharmaceutical cell lines. Therefore, the molecular features of this material are expected to match with material that will be derived from a future producer cell line.A replaceable gfp gene cassette was established at random chromosomal integration sites in CHO-DG44 cells. This clone pool was subjected to a primary RMCE with a secreted and complex glycosylated alpha1-antitrypsine (A1AT) reporter. Resulting cells were screened for A1AT producers that have undergone a successful cassette exchange. This strategy allows for selection of a RMCE host cell line that combines transgene expression from highly active genomic loci with superior processing and secretion capabilities.The selected RMCE host cell line is susceptible for cassette exchange with any desired target gene and candidate protein. Successful cassette exchange is enforced by promoter trap and a well defined selection system Figure . For RMCRMCE application results in cell populations showing comparable expression levels of the newly introduced genes as exemplified for individual RMCEs with a gfp reporter and different selection formats Figure . Also, aRMCE was applied to a monoclonal antibody and single cell clones have been generated from the RMCE derived population. Those clones were analyzed together with the original population in fed batch culture using ProBioGen's chemical defined platform medium and process Figure . The RMCIn a second study two variants of a soluble receptor-Fc fusion protein were analyzed for manufacturability. Over a number of individual RMCEs variant #1 was expressed at a ~2-fold higher rate. In a fed batch process the difference was maintained yielding in final titers of 1.2 g/L for variant #1 Figure . The 2-3At minimal effort RMCE application allows for streamlined generation of stable cell lines and production of POC material Figure . ApplyinA robust protocol provides for efficient and reproducible RMCE application for antibodies and single chain proteins.At minimal effort RMCE application enables fast and multi-parallel evaluation of complex biological drug candidates.RMCE application allows for streamlined production of candidate material in the background of ProBioGen's CHO-DG44 platform."}
+{"text": "AIRE, characterized by autoimmune endocrinopathies and mucocutaneous candidiasis. It is accompanied by serum auto-antibodies whose generation has been mainly related to autoreactive T cells escape from tolerance mechanisms. Recent data suggest a T cell independent mechanism implicated in altered peripheral B cell selection and its possible contribution to the pathogenesis of autoimmune disease. Despite these observations, B cell subsets phenotype in these patients is still poorly characterized.Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED) is a rare autosomal recessive syndrome due to mutations in To perform a detailed analysis of B and T cell subsets in a cohort of APECED patients in order to better understand whether an intrinsic alteration in B cell compartment is present. We also evaluated B lymphocytes related cytokines  in patients\u2019 sera compared to age matched control.Flow cytometric analysis of B cell subsets was performed in 12 patients with APECED coming from Sardinia, Italy, compared to age-matched healthy donors. The following B cell subsets were analysed: transitional, na\u00efve, IgM and switched memory and plasmacells; T cell subsets: Treg, CD4 and CD8 T cell subsets  ELISA assay was performed for cytokines determination in sera.Analysis show an altered distribution of the immature peripheral B cells compartment in APECED patients and an increased level of BAFF in patients\u2019 sera. The T cell compartment is skewed towards effector memory T cells.Increasing the knowledge on B cells in APECED patients improves the comprehension of autoimmunity pathogenesis in immunodeficiency and may allow the exploration of the possible clinical efficacy of B cell targeted therapy."}
+{"text": "Drosophila melanogaster female sperm storage is anecessary step in the reproductive process. Amo is a homolog of the humantransient receptor potential channel TRPP2 , which ismutated in autosomal dominant polycystic kidney disease. In flies Amo isrequired for sperm storage. Drosophila males with Amomutations produce motile sperm that are transferred to the uterus but theydo not reach the female storage organs. Therefore Amo appears to be amediator of directed sperm motility in the female reproductive tract but theunderlying mechanism is unknown.Sperm have but one purpose, to fertilize an egg. In various species includingin vivo imaging of dual labelled sperm to demonstratethat Drosophila sperm navigate backwards in the femalereproductive tract. In addition, we show that sperm exhibit hyperactivationupon transfer to the uterus. Amo mutant sperm remaincapable of reverse motility but fail to display hyperactivation and directedmovement, suggesting that these functions are required for sperm storage inflies.Amo exhibits a unique expression pattern during spermatogenesis. Inspermatocytes, Amo is restricted to the endoplasmic reticulum (ER) whereasin mature sperm, Amo clusters at the distal tip of the sperm tail. Here weshow that flagellar localization of Amo is required for sperm storage. Thisraised the question of how Amo at the rear end of sperm regulates forwardmovement into the storage organs. In order to address this question, we usedAmo is part of a signalling complex at the leading edge of the sperm tailthat modulates flagellar beating and that guides a backwards path into thestorage organs. Our data support an evolutionarily conserved role for TRPP2channels in cilia. Drosophila melanogaster, female sperm storage is critical formaximal reproductive success Drosophila female during mating but \u223c80% areexpelled from the uterus when the first egg is laid The evolutionary success of sexual reproduction depends on the ability of motilesperm cells to find an egg and fertilize it. Different animals have evolved distinctand elaborate mechanisms to accomplish this essential task but female sperm storageis a commonly used strategy in species ranging from insects to mammals. InDrosophila males that arelacking the seminal fluid protein Acp36DE are inefficiently transferred from theuterus to the sperm storage organs There is relatively little known about the factors that govern sperm storage in thefemale reproductive tract. In flies, male accessory gland proteins contribute tothis process and sperm derived from Drosophila melanogasterPKD2) PKD2 result in autosomal dominant polycystic kidney diseasein vivo is poorlyunderstood Drosophila males with amo mutations aresterile; they produce motile sperm that are transferred to the uterus but the spermdo not reach the female storage organs We have previously shown that Amo is a sperm enriched protein that is essential forfertility and sperm storage in Drosophila sperm mightswim tail first. We used in vivo imaging of dual labelled sperm todemonstrate that wild type Drosophila sperm do in fact navigatebackwards in the female reproductive tract. In addition, we discovered that spermexhibit activated flagellar beating upon transfer to the uterus. Amo mutant spermremain capable of reverse motility but fail to display hyperactivation, suggestingthat activated flagellar beating is a requirement for sperm storage in flies.In the present study we investigate the role of Amo in sperm motility within thefemale reproductive tract. We show that although Amo is expressed in the endoplasmicreticulum (ER) during earlier stages of spermatogenesis, it is the flagellarlocalization at the tip of the sperm tail, which is critical for making spermstorage competent. This finding coupled with Amo's role in directional spermmovement prompted us to hypothesize that Drosophila males with Amo mutations produce motile sperm thatare transferred to the uterus but do not reach the female storage organs   , and the protein .In contstorage . Althougstorage , it was storage , suggest rescued . Since bDrosophila sperm swimbackwards in the female reproductive tract in vivo. Thispattern of directed motility has not been reported for sperm of any otherspecies.The requirement for Amo at the flagellar tip coupled with its pivotal role indirected sperm motility prompted us to ask how Amo could regulate head firstmovement? We hypothesized that sperm might travel in reverse or tail firstrather than in a forward direction. In order to explore this possibility, weadapted methods that allowed us to assay directional sperm movement within thefemale reproductive tract in real time Drosophila sperm and Amo might act as asensor at the leading edge, serving a distinct pathfinding function. In order totest these possibilities, we generated amo mutant fliesproducing dual labelled sperm and mated these males to wild type female. Wefound that amo mutant sperm still are capable of backwardsswimming, both in the uterus and in the seminal receptacle channels in ciliary structures. In Drosophila sperm travel backwards in the uterusand seminal receptacle. As far as we know, this type of motility has not beenreported for sperm of any other species. One potential rationale for this type ofdirectional movement is that it would permit sperm to \u201cback in\u201d to thefemale storage organs. This is supported by analyses of sperm organization withinthe female seminal receptacle Amo's unique distribution in the flagellum led us to investigate the behaviourof sperm in the female reproductive tract. Our studies reveal several novelfindings. First, we used real-time analysis of sperm expressing red and greenfluorescent proteins in the head and tail respectively to show that shortly aftermating, wild type Drosophila sperm acquirehyperactivated flagellar beating upon transfer to the female uterus. This is similarto mammalian sperm capacitation, a process that \u201cswitches on\u201dspermatozoa, thus rendering them capable of fertilizing an egg Secondly we show that wild type Amo is a logical mediator of sperm motility in Drosophila. In addition to itsfavourable localization in the sperm tail, TRPP2 proteins are calcium permeablenon-selective cation channels In summary we show that Amo localization defines a unique niche at the leading edgeof sperm, which are traveling tail first. Activation of Amo serves to modulateflagellar beating and guides a backward trajectory into the sperm storage organs. Inkeeping with an evolutionarily conserved sensory role for TRPP2 channels in cilia wepostulate that Amo is ideally located to receive cues upon transfer to the femalereproductive tract. The nature of the stimuli to which the TRPP2 channel complexresponds remains a matter of investigation. But in the light of our data and recentevidence from vertebrate models it is tempting to speculate that ligands rather thanmechanical cues are critical for triggering TRPP2-mediated signalling Amo knockout flies (1amo) have beendescribed amo, (CG6504) and approximately 1 kb of 5\u2032 flankingsequence amo (CG6504) genomic rescue construct wasgenerated by site-directed mutatgenesis using standard procedures. We sequencedall constructs to verify that no errors were introduced by PCR. Flies expressingthe wild type and mutant genomic rescue constructs were crossed into theamo null background for analysis of fertility, spermstorage and sperm dynamics. Flies expressing Protamine-B-labelled with redfluorescent protein (ProtB-DsRed) on the third chromosome were kindly providedby John Belote and a line expressing don-juan-GFP (dj-GFP) on the thirdchromosome was obtained from Barbara Wakimoto \u00ae 488 antibodies were used for visualization. Sperm tails were stained with Alexafluor\u00ae-594 conjugated concavalin A  and sperm heads by 4\u2032,6-Diamidin-2-phenylindol(DAPI). Images were recorded using a Zeiss LSM510 confocal microscope .Dissection and preparation of testis and sperm as well as the anti-Amo antiserum(1\u22363000) have been described 1118w (wt) virgin females were performed for5 days. At that time both parents were removed from the vial. The number ofprogeny that eclosed from each vial was counted. Ten vials were scored for eachgenotype.Males of various genotypes were separated upon eclosion and maintained inisolation 3 days prior to mating. Single pair matings with1118w females and mating wasinterrupted after 20 minutes. To analyze the beat frequency, sperm were releasedfrom a seminal vesicle or from a mated-uterus into a Petri dish containingHEPES-buffered saline solution -1-piperazineethanesulfonic acid (HEPES), pH 7.4). Seven areasaround the sperm mass were recorded. Three sperm tails per area were analyzed.One hundred fifty frames were acquired per area at a frame rate of 50 Hz. Spermbeating was recorded on an inverted microscope  witha charge-coupled camera device .Beat frequency was analysed using ImageJ software .Three-day old virgin male and/or female flies were used for these studies. Maleswere mated to \u2212/\u2212amo background) and virgin1118w females were separated for four daysprior to mating. Immediately after termination of mating, female flies wereanaesthetised with CO2 and dissected in HEPES-buffered salinesolution using fine forceps. The lower reproductive tract was removed withoutcompression of the uterus by gently severing the ovipositor from surroundingcuticle and longitudinally opening the mid-ventrum. The digestive tract wassevered close to the anus and the ovaries were removed at the base of thelateral oviducts. Female reproductive tracts were aspirated using a Pasteurpipette and transferred to a 15 \u00b5m slide 2\u00d79 well , containing 70 \u00b5l HEPES-buffered salinesolution per well. Real-time imaging of dual-colour fluorescently labelled spermin the female reproductive tract was performed on a microscope ZEISS LSM 510 DUOequipped with a LD LCI Plan-Apochromat 25x/0.8 glycerine objective . Microscopic analysis was started withinfive minutes after unsolicited termination of mating. Excitation of thefluorophores (GFP and DsRed) was performed at 489 and 532 nm, respectively. Forsimultaneous detection of the red and green fluorescence, the LSM 5 Liveconfocal scanner was used, collecting emitted fluorescence in the range495\u2013525 nm for the dj-GFP fusion protein, and 560\u2013675 nm forProtB-DsRed. 5000 images were recorded per sample at 15 frames per second with512\u00d7512 pixels and a pixel dwell time of 112 \u00b5s. . Image analysis andsperm tracking were performed using Imaris tracking software .Freshly hatched males . Unpairedstudent's t-Test was used for statistical analysis between two groups.Analysis of sperm dynamics and subcellular localization of TRPP2 wild type andmutant transgenes was performed in a blinded fashion.Figure S1Sperm Storage Organs Dissected From Females Mated With Wild Type or\u2212/\u2212amoFlies. A. Schematic model of the female reproductive system.Ovary (ov), spermathecae (sp), seminal receptacle (sr), uterus (ut).B\u2013F. Seminal receptacles dissected30\u201360 minutes after observed mating. Wild type virginfemales were mated to males of different genotypes as indicated:B. Wild type, C.amo\u2212/\u2212,D.amo\u2212/\u2212;P[amo],E.amo\u2212/\u2212D627V],;P[amoand F.amo\u2212/\u2212D627V];P[amo/amo.(TIF)Click here for additional data file.Figure S2Amo Localizes to the Endoplasmic Reticulum (ER) inSpermatocytes. A. Intracellular localization of Amo inspermatocytes . B. Expressionpattern of the ER marker PDI-GFP in spermatocytes. C. Mergedimages.(TIF)Click here for additional data file.Figure S3Amo Expression by Western Blot Analysis. Lysates were preparedfrom male flies of various genotypes and subjected to immunoprecipitationwith anti-Amo antisera. Western blots were probed with anti-Amoantisera.(TIF)Click here for additional data file.Figure S4D627VTransheterozygous Sperm.Subcellular Localization of Amo in Amo/Amo Immunofluorescent labeling of sperm ofthe genotypeamo\u2212/\u2212D627V];P[amo/amo. A. DAPI.B. Concavalin A. C. Anti-Amo. D.Merged image. Scale bar 20 \u00b5m.(TIF)Click here for additional data file.Figure S5Analysis of Sperm Speed in the Uterus. Frequency distribution ofsperm speed in the female reproductive tract .(TIF)Click here for additional data file.Figure S6D627V.Absence of a Dominant Negative Effect of AmoFertility tests using heterozygous+/amo\u2212mutant males show that introduction of one (dark grey bars) or two copies(light grey bars) of transgenic AmoD627V (3rdchromosome) does not result in impaired fertility.(TIF)Click here for additional data file.Video S1Wild Type Sperm in the Female reproductive Tract. Live imagingof wild type sperm bearing dj-GFP and ProtB-DsRed transgenes in the femaleuterus and seminal receptacle. Green fluorescent protein  and red fluorescent protein  were detectedsimultaneously. Isolated sperm head movement (white) in the uterus and theseminal receptacle is also demonstrated.(MOV)Click here for additional data file.Video S2\u2212/\u2212Amo in theFemale Reproductive Tract. Live imaging of\u2212/\u2212amo sperm bearing dj-GFPand ProtB-DsRed transgenes in the female reproductive tract. Sinceamo\u2212/\u2212 sperm donot reach the storage organs, there are no sperm visualized in the seminalreceptacle. There is only background autofluorescence detected. IsolatedSperm head movement (white) in the uterus is also demonstrated.(MOV)Click here for additional data file.Video S3Single Sperm Movement in the Female Reproductive Tract. Liveimaging of a single wild type sperm labelled with dj-GFP and ProtB-DsRedtransgenes in the seminal receptacle is demonstrated. The sperm moves tailfirst.(MOV)Click here for additional data file.Video S4Single Sperm Movement ofamo\u2212/\u2212Sperm in the Female Reproductive Tract. Live imaging of asingle amo\u2212/\u2212 spermlabelled with dj-GFP and ProtB-DsRed transgenes. The sperm movesbackwards.(MOV)Click here for additional data file.Video S5Tracking of Sperm in the Female Reproductive Tract.Representative tracking of sperm heads in the uterus. Each sperm head(magenta) is marked with a dot. The pseudocolor bar at the right representsthe time of tracking during the experiment.(MOV)Click here for additional data file.Video S6Wild Type Sperm in the Female Reproductive Tract. Real-timeimaging of dual-colour fluorescently labelled wild type sperm in the seminalreceptacle and uterus.(MOV)Click here for additional data file."}
+{"text": "This report details the case of 17 year old identical twins who both presented with paroxysmal supraventricular tachycardia (PSVT). Electrophysiological studies revealed atrioventricular nodal reentry tachycardia (AVNRT) in both twins. Successful but technically challenging slow pathway ablation was performed in both twins. This is the first reported case of confirmed AVNRT in identical twins which adds strong evidence to heritability of the dual AV node physiology and AVNRT. A review of the current literature regarding PSVT in monozygotic twins is provided. Paroxysmal supraventricular tachycardia (PSVT) caused by accessory pathways or dual atrioventricular node (AVN) physiology were initially thought to be randomly occurring congenital anomalies.,2 HoweveIdentical female twins were referred with palpitations from a young age. Twin A was first seen in clinic at the age of 13 years. She had been experiencing rapid palpitations since the age of 12. Her palpitations were triggered by activity and occurred roughly x 4-5/month. The episodes were associated with breathlessness and presyncope. Most episodes were terminated with vagal maneuvers with only one episode required intravenous adenosine. Physical exam and echocardiography of twin A were unremarkable. Her resting 12 lead ECG was normal bar left axis deviation. During tachycardia, the12-lead ECG during palpitations showed a narrow complex tachycardia (rate = 180 bpm) with retrograde negative P waves in lead II about 20 ms off the onset of the QRS. Oral metoprolol (25 mg twice daily) reduced the frequency of the episodes but did not abolish them and hence the decision for management with catheter ablation.Twin B was first seen in clinic at the age of 11 years of age. She had experienced palpitations once every 2-3 months since the age of 10. Again the episodes were related to exertion and were associated with shortness of breath and presyncope. The episodes were terminated by lying flat. Examination, echocardiography and resting 12-lead ECG were normal bar left axis deviation. On this occasion, SVT was diagnosed by an external event recorder. Initial management was with vagal maneuvers only until her palpitations became more frequent at the age of 17 when more invasive management was sought.A standard 4 wire study was performed in both patients: decapolar CSL response to coronary sinus from the left subclavian vein, johnson curve quadrapolar catheters to high right atrial and right ventricular apical positions, and a 4 mm non-irrigated tip ablation catheter initially in the His position .Twin A: Basic intervals were within normal limits  applications. Many of the RF applications had to be curtailed due to fast junctional tachycardia with dissociated atrial and ventricular activity . After tTwin B: Baseline intervals were normal ; i.e. a re-entrant origin. PSVT occurs with an incidence of 35 per 100,000 people a year [The major causes of PSVTs are AVNRT (~60%), and AV re-entrant tachycardia (AVRT) (~ 30 %) with smaller contributions from intra-atrial re-entry, micro re-entrant AT and sinus nodal re-entry .PSVT caused by AV accessory pathways or dual AVN physiology were formerly thought to be randomly occurring congenital anomalies due to pathological substrates present from birth.,2 HoweveBack in 1976, Mispireta et al [A similar clinical scenario was reported by Bennett et al . Here idIn more recent studies investigating familial clustering of pre-excitation syndromes, an autosomal dominant pattern of inheritance has been suggested -9. Even The possibility of inheritable AVNRT has been suggested by a couple of case reports. Lu et al demonstrated bystander dual AVN physiology in 16-year-old identical female twins who both have AVRT caused by the same left lateral AV accessory pathway .In the case presented here, the presence of dual nodal physiology with symptomatic AVNRT, similar retrograde jumps in VA conduction  and simiThese 2 instances could justify the presence of AV dissociation during manipulation of the catheters in the slow pathway region or application of RF in the same area.The unique case presented here adds evidence to the inheritability of AVNRT as previously suggested. Further studies of AVNRT involving genetic mapping in correlation with the delineation of the AV nodal arterial supply and histological presence of inferior nodal extensions may be warranted."}
+{"text": "It is well known that migraine attacks can be precipitated by various stimuli. More than 50% of migraine with aura (MA) patients know of at least one stimulus that always or often triggers their MA attacks. The objective of this study was to expose MA patients to their self-reported trigger factors in order to assess the causal relation between trigger factors and attacks.We recruited 27 MA patients who reported that bright or flickering light and/or strenuous exercise would trigger their migraine attacks. The patients were experimentally provoked by either different types of photo stimulation, strenuous exercise or a combination of these two factors. During and following provocation the patients would report any aura symptoms or other migraine related symptoms.Of 27 provoked MA patients 3 (11%) reported attacks of MA following provocation. An additional 3 patients reported MO attacks. Following exercise, 4 out of 12 patients reported migraine, while no patients developed attacks following photo stimulation.Experimental provocation using self-reported natural trigger factors causes MA only in a small subgroup of MA patients. Prospective confirmation is important for future studies of migraine trigger factors and in the clinical management of migraine patients."}
+{"text": "Introduction: The standard non-muscle invasive bladder cancer (NMIBC) endoscopic diagnosis suffers from the frequently unsatisfactory white light evaluation accuracy leading to residual lesions being left behind. Monopolar transurethral resection of bladder tumors (TURBT) is marked by a substantial morbidity rate requiring further amelioration. Methods: Small size tumors (under 1 cm) are feasible for \u201cen bloc\" resection. Bipolar TURBT was defined as being able to challenge the gold-standard status of monopolar resection due to the reduced complication rates. Plasma-button vaporization was introduced as a promising large bladder tumors\u2019 ablation modality. Narrow band imaging (NBI) cystoscopy became an increasingly popular method of enhancing tumor detection. Results: The \u201cen bloc\" resection of small size or thin pedicle tumors provides the conditions for avoiding tumoral tissue scattering. Bipolar resection is characterized by decreased perioperative bleeding risks and faster patient recovery. Plasma-button vaporization gained confirmation as an innovative approach, able to dispose large tumor bulks under complete control while minimizing the associated morbidity. NBI cystoscopy is a useful tool in identifying CIS lesions, small papillary tumors or extended margins of large tumor formations. As a cost-free technique, it may be extensively used both during the NMIBC initial diagnostic as well as during follow-up evaluation protocol. Conclusions: Having in mind the various modalities of ameliorating the bladder cancer diagnostic and treatment, NMIBC management should be tailored in accordance with the particularities of each case. Despite the technological advances achieved in the field of endourology, non-muscle invasive bladder cancer (NMIBC) continues to represent a challenging pathology, generally characterized by disappointing clinical outcomes and alarmingly high recurrence rates. The main reasons behind the relatively unsuccessful NMIBC therapeutic management are represented by the clearly doubtful oncological safety of the transurethral resection of bladder tumors (TURBT) [3] and, despite numerous attempts of improvement, continued to constitute the standard NMIBC treatment alternative during the past 50 years [4]. Moreover, the bladder mucosa endoscopic inspection under simple white light was often described as a rather blunt tool in detecting urothelial malignant lesions, thus creating the premises for leaving behind the future \u201crecurrences\" [5]. From this perspective, TURBT has been characterized as based on the \u201cincise and scatter\" oncologically flawed principle . Our experience during the past 5 years confirmed these findings and imposed bipolar TUR as a standard of \u201cgood clinical practice\" in NMIBC treatment. Bipolar energy is most certainly recommended as the future of TURBT by the growing experience and increasingly numerous reports available in literature [8]. Subjectively speaking, we noticed that, during bipolar TURBT, a cleaner tissue cut is achieved, thus enabling a more accurate and precise tumor ablation to be performed. This feature is particularly useful during the resection of the thinned tumoral bed area, of tumors located on the lateral  or posterior bladder walls implying a high perforation risk as well as in cases of extensive flat lesions widely spread out throughout the bladder mucosa surface. The main advantages of bipolar resection over the monopolar approach are well defined by the published trials: reduced perioperative bleeding risks, superior haemostatic abilities and faster postoperative recovery  but eventually failed to gain acknowledgement in clinical trials. During the past 5 years, the plasma-button vaporization became increasingly popular as an efficient benign prostatic hyperplasia (BPH) treatment and was eventually oriented towards large bladder tumors\u2019 management as well [10]. Endoscopic monopolar vaporization of tumors was at some point introduced as a viable NMIBC therapeutic alternative [11]. From the very beginning, we noticed that the bipolar plasma vaporization technique is able to provide the conditions for a fast, safe and efficient malignant tissue ablation phenomenon to be achieved. In our view, the BPV-BT cases selection criterion was represented by patients preoperatively diagnosed as presenting at least one apparently non-muscle invasive bladder tumor over 3 cm in diameter based on abdominal ultrasound, computer tomography and flexible WLC . The fact that it did not require the instillation of an expensive contrast agent (otherwise the main drawback of the photodynamic diagnostic \u2013 PDD) represented a substantial advantage from the very beginning. Narrow band imaging (NBI) cystoscopy was developed as a complementary method to the standard WLC, aimed to improve the bladder tumors\u2019 detection solely based on an optic technological advancement [14]. Therefore, the vascular structures appear dark brown (capillary vessels) and green (veins), thus contrasting with the pink or white background of normal mucosa [15]. Subjectively, NBI technology was shown to accurately underline the specific vascular architecture of urothelial lesions, thus creating the impression of a three-dimensional visualization of tumors and clearly defining their limits [16].In short, the NBI visualization mode is based on the white light being filtered into 2 discrete centre wavelengths for blue (415 nm) and green (540 nm), otherwise strongly absorbed by hemoglobin and only able to penetrate the tissue surface [17] as well as to our own published data [18], NBI cystoscopy was proved to overcome the standard WLC diagnostic accuracy by finding more tumors. Patients with carcinoma in situ (CIS) lesions particularly benefited from the respective technique , which displayed a substantially increased detection rate in comparison with the white light evaluation [19].  Essentially, both according to literature . In such situations, NBI cystoscopy displayed superior detection rates over WLC in a randomized clinical setting, brought a significant contribution to an improved oncological outcome and reduced medium term recurrence rates being eventually obtained [12].  Moreover, according to our protocols, a special indication for the NBI evaluation is represented by cases of large bladder tumors (over 3 cm), widely acknowledged as associating hardly visible extended tumoral margins  2007-2013, financed from the European Social Fund and by the Romanian Government under the contract number POSDRU/107/1.5/S/82839\"."}
+{"text": "Visual snow has a major impact on patients' quality of life. They describe persistent, dynamic, black & white tiny dots in the entire visual field (main criterion). Additional symptoms might be present. The literature on this condition is scarce -3 and thTo describe the clinical phenotype of patients with visual snow.Preliminary additional criteria for visual snow were generated retrospectively based on an internet-survey. By using telephone interviews, we re-tested these criteria prospectively and collected further information.The survey-data of 120 patients with self-reported visual snow was reviewed to generate preliminary criteria. These were re-tested by interviewing 115 patients. The main criterion  was met by 57 patients. Additional visual symptoms were excessive floaters (84%), persistent after-images (83%), \"hard time seeing at night\" (65%), \"little cells that travel on a wiggly path\" (77%), photophobia (70%), \"moving objects leave trails\" (56%), \"swirls, clouds or waves with eyes closed\" (51%), and bright flashes (51%). Requiring at least one or three of these additional criteria reduced the sensitivity by 2% and 7%. No patient described the visual symptoms consistent with persistent visual aura in migraine. A history of migraine was seen in 54%, with 35% having typical migraine with aura. None of the patients noted intake of illicit drugs prior the onset of visual snow. All ophthalmology tests were non-contributory.(i) Visual snow is a unique clinical syndrome. The main criterion  is almost always associated with at least three additional criteria. (ii) The visual symptoms are distinct from migraine with aura. (iii) The high prevalence of history of migraine (with aura) points to a susceptibility for visual snow in patients with migraine. (iv) Intake of illicit drugs and ophthalmological diseases may not be of pathophysiological relevance."}
+{"text": "Sedimentaion rate is often used to manage pediatric patients with rheumatologic disease. Most management decisions are dependent on studies which have used Wintrobe or Westergren sedimentation rate methodologies. However, these methods suffer from the need for relatively large amounts of blood and long turn-around times. Determination of sedimentation rate using laser kinetic rate determination has allowed calibration to Westergren methods, low volume of blood needed for testing and very rapid results. We sought to compare the Wintrobe method to the ESR Stat method  to determine suitability of the ESR Stat method for patient testing.We performed a prospective comparison between the traditional Wintrobe and ESR Stat sedimentation rates in consecutive pediatric patients at a tertiary care pediatric hospital. Wintrobe and ESR Stat sedimentation data was fitted using a logarithmic model. Outliers were defined as those samples with ESR Stat sedimentation rates greater than 80 mm/hr and Wintrobe sedimentation rates less than 30 mm/hr . Retrospective chart review was performed on all patients undergoing testing.2 = 0.7768) and is seen below. Of interest was the identification of four patients who had apparently normal or mildly elevated sedimentation rates by the Wintrobe method versus an extremely high (greater than 120 mm/hr) by the ESR Stat method. These patients were noted to have lupus or lupus-like syndrome and a history of hemolytic anemia. Non-outlier samples were from patients who did not this combination of disease morbidities.A total of 131 pediatric patients (with one patient undergoing repeat testing because of sedimentation rate discrepancy) were tested. Age range was 18 months to 34 years with 29% being male. A logarithmic model appeared to best fit the data (RDiscrepancies in Wintrobe and ESR Stat sedimentation rates may identify a subgroup of with lupus (or lupus-like syndrome) and a history of hemolytic anemia. Careful consideration of methodology is needed when sedimentation rate testing is performed on pediatric lupus patients.Edward C. Wong: None; Deborah Yuan: None; Claas Hinze: None; Lawrence Jung: None."}
+{"text": "The synergy between synaptic and postsynaptic firing dynamics in shaping neuronal encoding has not been explored. We show that by matching short-term synaptic dynamics with postsynaptic firing class, either stimulus rate or a rate change are encoded. The result may be relevant to understand the function of cortical microcircuits.Short-term synaptic dynamics and firing dynamics of neurons can each be classified into two types. In short-term plasticity, type 1 synapses show release-dependent depression and constant rate of recovery. They appear to encode a stimulus rate change. Type 2 synapses show release-independent depression and faster recovery at higher stimulus frequencies. They can follow the stimulus rate [We investigate if different combinations of synaptic and postsynaptic dynamics can shape neuronal encoding.Using NEURON, we simulated biophysically realistic cells with class 1 or 2 firing dynamics  that recSpiny stellate cells in the layer IV microcircuit preferentially receive inputs from type 1 synapses while star pyramidal neurons receive type 2 inputs . Even th"}
+{"text": "The authors report a case of metastatic gastrointestinal adenocarcinoma to the cervical spine in a patient with acquired immunodeficiency syndrome (AIDS) being treated with antiretroviral therapy. The source of this tumor could not be identified despite a thorough evaluation. A 49-year-old male being treated for AIDS presents with worsening neck pain and left distal arm weakness. MRI demonstrated an erosive mass within the cervical four vertebral body extending through the pedicle on the left side. Patient underwent needle biopsy followed by combined anterior and posterior fusion procedures. Pathology demonstrated metastatic gastrointestinal adenocarcinoma without known primary origin. He is currently undergoing palliative radiotherapy. This is an unusual case of metastatic gastrointestinal adenocarcinoma to the cervical spine. This should be included on the differential diagnosis of spinal lesions in this patient population and may represent a unique tumor in patients with HIV/AIDS who are on immunosuppressive therapy. The authors report an unusual case of symptomatic metastatic gastrointestinal adenocarcinoma without known primary tumor to the cervical spine in a patient with AIDS on chronic antiretroviral therapy.We report the case of a 49-year-old homosexual male being treated for AIDS who presented with worsening neck pain and left distal arm and hand weakness. MRI demonstrated an erosive mass within the C4 vertebral body extending through the pedicle on the left side and causing severe spinal stenosis Figures  and 2. APatient underwent needle biopsy followed by anterior cervical corpectomy and fusion and finally posterior lateral mass instrumentation and fusion . PatholoThe patient was successfully treated for post-operative cerebrospinal fluid collection in the neck with a lumbar drain. His neurological examination returned to its baseline. His CD4 counts remained stable preoperatively and postoperatively. He is currently undergoing palliative radiotherapy with 37.5\u2009Gy over 15 fractions to his cervical spine.AIDS-defining cancers, such as Kaposi's sarcoma, non-Hodgkin's lymphoma, and cervical cancer, are quite common in patients with end-stage AIDS \u20133. Over  Some authors have argued that there is an association between chronic AIDS and human immunodeficiency syndrome (HIV) infection and the occurrence of colonic malignancy . StudiesAbout 10% of all cancer patients develop metastases to the spine , 5. AmonRavalli et al. noted in their seminal report three patients with HIV in less than one year who developed gastrointestinal carcinoma and suggested an increased frequency in this population . GastroiThis case stimulates interest in a possible association between AIDS/HIV, long-term antiretroviral therapy, and metastatic gastrointestinal adenocarcinoma without a clear primary site. We wonder if this particular metastatic gastrointestinal tumor is a unique tumor of the gastrointestinal system that is associated with chronic HIV/AIDS or chronic immunotherapy. In conclusion, this pathology must be kept on the differential diagnosis list in this patient population and further cases must be documented to clearly confirm this association."}
+{"text": "Procalcitonin (PCT) has been studied extensively as a marker of sepsis; however, its clinical utility remains uncertain . Alternan = 87) were enrolled if they fulfilled the 1992 Consensus Statement [n = 31), with 71 healthy controls (HC) for comparison. Blood samples were collected within 24 hours of the surgical procedure or upon admission to ICU for sepsis patients. PCT was measured using a commercially available assay kit (Brahms PCT) and GE assessed using Affymetrix GeneChip Human Exon 1.0 ST arrays, where a set of biomarkers were identified a priori. A Support Vector Machine algorithm was used to calibrate the molecular biomarkers with respect to specific clinical groups. Bootstrap and permutation tests were performed on the difference in area under the receiver operating characteristic curves (AUC ROC) for PCT and crossvalidated posterior probabilities.The dataset was derived from two clinical trials conducted across four tertiary care settings in Australia between 2008 and 2011 (ACTRN12610000465055). Critical care patients , respectively. The differentiating ability of PCT and the SeptiCyte\u00ae Triage biomarker set is demonstrated in Figure The SeptiCyteIn comparison with the diagnostic performance of PCT, a limited set (<10) of molecular biomarkers potentially has a significantly better sensitivity and specificity profile for the detection of sepsis within a mixed systemic inflammatory patient group."}
+{"text": "Marine salterns are artificial multipond systems designed for the commercial production of salt by evaporation of seawater. We report here the metagenomic sequence of the prokaryotic microbiota of a pond with intermediate salinity  of a saltern located in Isla Cristina, Huelva, southwest Spain. Haloquadratum walsbyi and the bacteroidete Salinibacter ruber  on July 2010. The sample was sequentially filtered through 5.0- and 0.22-\u00b5m-pore size polycarbonate filters (Millipore) as previously described . Total eSequences related to 16S ribosomal RNA genes were identified using the Ribosomal Database Project (RDP) . In addiEuryarchaeota (~84%) was the most abundant phylum present in this sample, followed by Bacteroidetes (~8%) and Gammaproteobacteria (~7%), suggesting a decrease of the microbial diversity in salt ponds of salterns when the salinity reaches salt concentrations >20%, being more similar to those found in crystallizer ponds than those found in intermediate-salinity ponds with <20% salts.Further metagenome analysis will contribute increased understanding of the genetic diversity present in marine salterns and particularly in ponds with intermediate salinities where the environmental conditions limit the presence of halophilic bacteria and enhance the growth of haloarchaea.SRP029970.The sequences obtained in this project have been deposited in the NCBI Sequence Read Archive under the accession no."}
+{"text": "Genomic selection (GS) involves selection decisions based on genomic breeding values estimated as the sum of the effects of genome-wide markers capturing most QTLs for the target trait(s). GS is revolutionizing breeding practice for complex trait in domestic animals. The same approach and concepts can be readily applied to forest tree breeding. Trees also have long generation times and late expressing traits. Differently from association genetics that aims at dissecting complex traits in their discrete components, GS precludes the discovery of individual marker-trait associations and focuses on prediction of performance. By capturing the \"missing heritability\" of complex quantitative traits beyond the few effect variants that association genetics has so far typically identified, GS might soon cause a paradigm shift in forest tree breeding. In a prior deterministic study we assessed the impact of linkage disequilibrium (modeled by Ne and inter-marker distance), the size of the training set, trait heritability and the number of QTL on the predicted accuracy of GS . ResultsE. grandis x E. urophylla hybrids clones therefore having an effective population size of Ne= 11. The second population was a progeny trial installed by FIBRIA (FIB) with 232 full-sib families involving 120 elite parents, the vast majority F1 hybrids of E. grandis, E. urophylla, E. globulus and E. maidenii. For the GS study however only the most phenotypically relevant 75 families were used derived from intercrossing 55 parents therefore limiting the effective population size to Ne= 55. A sample of trees was taken in a stratified way from all families to provide a balanced representation of all families with similar numbers of individuals per family. Bark or leaf samples were collected, DNA extracted and genotypes obtained for 783 and 920 trees from CEN and FIB respectively. Genotyping was carried out using a high-throughput genotyping platform developed earlier [Puccinia rust resistance were obtained. Single marker regression association analyses were initially performed with all the traits, treating the markers as fixed effects. Markers selected in the previous association analysis had their effects estimated adjusting all the allelic effects simultaneously using Random Regression Best Linear Unbiased Predictor. Each population was then divided in an training set comprising 90% of the total number of individuals and a validation set with the other 10%. The estimated effects of the markers were validated using a cross validation approach using random sub-sampling with ten replications so that all individuals had their phenotypes predicted by GS. Details of the overall analytical approach have been described [This study was carried out in two structured populations of Eucalyptus represented by two progeny trials of independent breeding programs. The first was a progeny trial developed by CENIBRA (CEN) with 43 full-sib families generated by an incomplete diallel mating design carried out by intercrossing 11 highly selected Eucalyptus tree breeding practice.To date results have been obtained for height, DBH and wood density while the remaining traits are under analysis. Realized accuracies by Genomic Estimated Breeding Values (GEBV) for H and DBH were 0.67 and 0.69 for CEN and 0.62 and 0.54 for FIB while for WD in FIB it was 0.53. These accuracies match or surpass those obtained by conventional BLUP (Best Linear Unbiased Prediction) based phenotypic selection. Not surprising GEBV accuracies were low (~0.18) across populations implying variable genotype-phenotype associations across backgrounds so that population-specific GS models will be necessary. GS-based reduction in breeding time by 50%, i.e. by reducing a breeding generation time from 12 to 6 years should provide gains \u2265100% in selection efficiencies. If a reduction from 12 to 3 years using flower induction can be achieved, gains in selection efficiency theoretically could surpass 300%. These are among the first experimental results of GS in forest trees and in plants in general. With the technological advances and declining costs of genotyping methods we anticipate that GS will soon be implemented operationally and revolutionize"}
+{"text": "For health professions to evolve in a highly evidence-based world it seems imperative for clinicians to build their research skills. This observational paper aims to report the research skill levels of statewide public-sector podiatrists at two different time points twelve-months apart.The Research Capacity & Culture (RCC) survey was distributed to all Queensland Health podiatrists in January 2011 (n=58) and January 2012 (n=60). The RCC is a validated tool designed to measure indicators of research skill in health professionals. Participants rate skill levels against each individual, team and organisation statement on a 10-point scale . Chi-squared and Mann Whitney U tests were used to determine any differences between survey samples.Thirty-seven (64%) podiatrists responded to the 2011 survey and 33 (55%) the 2012 survey. The 2011 survey respondents reported low skill levels (Median<4) on most individual research aspects. However, most reported their organisations\u2019 skills to perform and support research at higher levels (Median>6). The 2012 survey respondents reported significantly higher skill levels compared to the 2011 survey in individuals\u2019 ability to secure research funding, submit ethics applications and provide research advice (p<0.05).This study reports the research skill levels of the largest podiatry populations to date. The 2011 findings indicated that podiatrists have similarly low research skill levels to those reported in the generic allied health literature. The 2012 findings suggest podiatrists perceived higher skills and support to initiate research than in 2011. This improvement coincided with podiatry research capacity building strategies."}
+{"text": "Mammalian artificial chromosomes are natural chromosome-based vectors that may carry a vast amount of genetic material in terms of both size and number. They are reasonably stable and segregate well in both mitosis and meiosis. A platform artificial chromosome expression system (ACEs) was earlier described with multiple loading sites for a modified lambda-integrase enzyme. It has been shown that this ACEs is suitable for high-level industrial protein production and the treatment of a mouse model for a devastating human disorder, Krabbe\u2019s disease. ACEs-treated mutant mice carrying a therapeutic gene lived more than four times longer than untreated counterparts. This novel gene therapy method is called combined mammalian artificial chromosome-stem cell therapy. At present, this method suffers from the limitation that a new selection marker gene should be present for each therapeutic gene loaded onto the ACEs. Complex diseases require the cooperative action of several genes for treatment, but only a limited number of selection marker genes are available and there is also a risk of serious side-effects caused by the unwanted expression of these marker genes in mammalian cells, organs and organisms. We describe here a novel method to load multiple genes onto the ACEs by using only two selectable marker genes. These markers may be removed from the ACEs before therapeutic application. This novel technology could revolutionize gene therapeutic applications targeting the treatment of complex disorders and cancers. It could also speed up cell therapy by allowing researchers to engineer a chromosome with a predetermined set of genetic factors to differentiate adult stem cells, embryonic stem cells and induced pluripotent stem (iPS) cells into cell types of therapeutic value. It is also a suitable tool for the investigation of complex biochemical pathways in basic science by producing an ACEs with several genes from a signal transduction pathway of interest. Gene therapy may be extremely promising for the treatment of various genetic and acquired disorders in the near future in vivo telomere-associated fragmentation of existing chromosomes Four different strategies have been developed for the construction of artificial chromosomes The incorporation of different integrase recognition sequences and integrase enzyme genes into artificial chromosomes greatly improved the feasibility of integrating a transgene into the artificial chromosome Recently an artificial chromosome expression system (ACEs) was constructed which carry multiple copies (>50) of recombination acceptor sites (attB) for multiple unidirectional loading of expression cassettes by a modified \u03bb integrase The recently developed novel method, in which the ACEs was combined with stem cell therapy for the treatment of a mouse model for a devastating human disorder, Krabbe\u2019s disease www.calyxbio.com). The pATVMin vector was previously used to load transgenes onto Platform ACEs as shown on Herpes simplex virus thymidine kinase (HSVTK) expression cassette, flanked by a LoxP site downstream from the polyA signal. The LoxP site carrying pATVMin plasmid was digested with XbaI. The thymidine kinase expression cassette with the LoxP site was removed from the pmCCKO14 plasmid as an XbaI-SpeI fragment. This fragment was cloned into the LoxP site-containing, XbaI enzyme-digested pATVMin vector. The resulting plasmid was checked by DNA sequencing. The plasmid with the correct sequence was named pST (The pSEV1R (shuttle expression vector-1R) entry vector  and the amed pST .www.calyxbio.com) .The pSTRFP plasmid was constructed by cloning the coding sequence of the mCherry gene into the pST plasmid vector  as follows: the pmR-mCherry plasmid was digested with the BamHI and HindIII. The mCherry CDS  containing DNA fragment was isolated. The pSEV2 (shuttle expression vector-2) entry vector was constructed and kindly donated by Chromos Molecular Systems Inc.  . This vebio.com) . The RFPbio.com) . The pSTbio.com) . The Lacbio.com) . The pCrThe Platform ACEs-carrying Y2913D-SFS Chinese hamster ovary (CHO DG44) cell line from Chromos Molecular Systems Inc. was cultured in MEM alpha , 5% FCS, streptomycin-penicillin  and 10 mg/ml puromycin . The 1D9-16, RFPG18 and RFPG18-12 cell lines were generated in our laboratory and their properties are described in detail in the Results and Discussion section. These cell lines were cultured in the same medium as described above except that the puromycin was omitted. The 1D9-16 and RFPG18-12 cell lines were cultured in the presence of 400 \u00b5g/ml G418 . The RFPG18 cell line was cultured in the presence of 10 \u00b5M ganciclovir .Plasmid transfection experiments were performed with the Superfect reagent  as described by the manufacturer.in situ hybridization (FISH) experiments were performed with a standard protocol. The pPur  plasmid was labeled with FITC fluorescent dye and used as a probe for ACE detection. We used the Roche DIG Nick Translation Mix (1745816) or the Roche Biotin Nick Translation Mix (1745824) for labeling DNA probes.Fluorescence 5\u2032-ACCCCCTTGCGCTAATGCTCTGTTA and NeoR1 5\u2032-TCGATGAATCCAGAAAAGCGGCCA. The expected product size is 784 bp.Genomic DNA samples were isolated with the Zymo Research Quick-gDNA MiniPrep (Cat. No.: D3025). Site-specific integration of transgenes into the ACE chromosome was detected by PCR experiments with the following primers: 193AF: All pictures were photographed under a Zeiss Axiovision Z1 fluorescent microscope by using the Axiovision software purchased with the microscope.therapeutic Artificial Chromosomes (tACs). Although it harbors about 50 to 200 loading sites for gene delivery, the number of useful genes that can be loaded onto the presently available Platform ACEs is limited to the selectable marker genes that are available and that number is very small. In many cases, this can be a problem, as the loading of multiple genes onto the ACE chromosome might be important . Moreover, some of the selectable marker genes may have unwanted side-effects when they are expressed in elevated levels in certain tissues and organs in the body. This restricts the therapeutic and scientific applications of the Platform ACEs.A Platform ACEs chromosome with multiple recombination recognition sites for a special lambda-integrase (ACE integrase) was earlier constructed and a vector system was additionally established to deliver \u201cuseful genes\u201d onto the Platform ACEs We report here the development of a new vector system, which makes use of only one selectable marker gene cassette for the delivery of a transgene . SubsequDiscosoma sp.) as the first gene to load onto the Platform ACEs and constructed the pSTRFP superloading vector . Twenty five cell lines had proper targeting into the ACEs without random integration (36%) and all of these cell lines expressed the RFP protein. Based on strong RFP signal and intact ACEs, we have chosen the 1D9-16 cell line for further experiments.Cre recombinase was transiently expressed in the 1D9-16 cell line to remove the neomycin-thymidine kinase selectable marker gene cassette flanked by direct LoxP sites from the ACEs chromosomes. Forty eight subclones were obtained with 10 \u00b5M ganciclovir selection. Twenty two cell lines (45%) which remained G418 resistant were discarded. The cell lines from which the neomycin-thymidine kinase selectable marker gene cassette was successfully removed were G418 sensitive and ganciclovir resistant. Twenty two cell lines (45%) carried intact ACEs and expressed the RFP protein. Based on strong RFP signal and intact ACEs, we have chosen the RFPG18 cell line for further experiments. The ACEs in the RFPG18 cell line was targeted with the pSTLZ vector (second loading of the ACEs). The LacZ gene was loaded onto the ACEs that already carried the RFP gene from the previous loading experiment. Seventy four G418 resistant cell lines were obtained. Thirty seven cell lines were positive for both RFP signal and LacZ staining (50%). Twenty one cell lines carried the LacZ and RFP genes exclusively on the ACEs (56.7%).We identified cell lines with intact ACE chromosomes carrying and functionally expressing both mCherry and LacZ genes correctly targeted onto the artificial chromosome . In thes"}
+{"text": "Management of liver injury is challenging particularly for the advanced grades. Increased utility of nonoperative management strategies increases the risk of developing massive liver necrosis (MLN). We reported a case of a 19-year-old male who presented with a history of motor vehicle crash. Abdominal computerized tomography (CT) scan revealed large liver laceration (Grade 4) with blush and moderate free hemoperitoneum in 3 quadrants. Patient was managed nonoperatively by angioembolization. Two anomalies in hepatic arteries origin were reported and both vessels were selectively cannulated and bilateral gel foam embolization was achieved successfully. The patient developed MLN which was successfully treated conservatively. The follow-up CT showed progressive resolution of necrotic areas with fluid replacement and showed remarkable regeneration of liver tissues. We assume that patients with high-grade liver injuries could be managed successfully with a carefully designed protocol. Special attention should be given to the potential major associated complications. A tailored multidisciplinary approach to manage the subsequent complications would represent the best recommended strategy for favorable outcomes. Trauma is a major contributor to death in the first four decades of life . AbdomenTransarterial embolization (TAE) has been introduced as a useful and effective tool for the management of hemodynamically stable patients with blunt hepatic trauma in the multimodality approach . The widA 19-year-old male presented with a history of motor vehicle crash. The unrestrained driver sustained mild head and chest injuries (right first rib fracture and occult pneumothorax). Upon physical examination, he was fully conscious with a Glasgow Coma Scale (GCS) of 15 and normotensive but tachycardic. Abdominal examination revealed mild generalized distension and diffuse tenderness mainly at the right upper quadrant with normal bowel sounds, digital rectal examination, and clear urine.Initial laboratory examination showed a white blood cell (WBC) count of 16000 (Ul), Lactic Acid of 2.33 (mmol/L), Alanine transaminase (ALT) of 767 (U/L), and serum glucose of 8.29 (mmol/L). The focused assessment sonography for trauma (FAST) was found positive, whereas the chest and pelvic X-rays and head CT were normal. Chest CT revealed bilateral lung contusion with minimal right sided pneumothorax and fracture of first and fifth ribs. Abdominal CT scan revealed large liver contusion and laceration (Grade 4) with blush and moderate free haemoperitonium (3 quadrants) . PatientA follow-up abdomen CT (48\u2009hrs) revealed left sided pleural effusion and massive liver necrosis (MLN) with significant increase of peritoneal fluid along the left paracolic and pelvic compartments .Another CT after 4 weeks of TAE revealed that both lobes of the liver had diffuse nonenhancing and nonhomogenous areas replacing almost the left lobe and segments V and VIII of the right lobe with fluid loculation but no free fluid . OutpatiThe management of liver injury is challenging particularly for severe grades (Grades III\u2013V) . Though Major liver devascularization (MLN) is a very peculiar entity of great interest. It is related to the disruption of vascular inflow to a liver portion either by the original trauma or following angioembolization . MLN hasTo the best of our knowledge, there are only few reported cases of MLN complicating TAE which are treated nonoperatively. The current report represents a case of severe liver injury (Grade IV with blush) treated with nonoperative management using TAE and complicated by MLN. The patient developed major liver devascularization to some extent related to his vascular anomalies with TAE being less selective. The pattern of liver enzymes, WBC count, clinical presentation, and subsequent scanning confirmed the diagnosis. Nevertheless, the patient managed to tolerate liver devascularization and he showed a smooth recovery without developing severe complications such as hepatic failure, sepsis, abdominal compartment, late bleeding, or multiorgan derangements. Follow-up CT scans demonstrated a great regeneration and full function, recovered liver.In conclusion, we assume that patients with high-grade severe liver injuries could be managed carefully according to a clear protocol. Special attention should be given to the major associated morbidities. A selective or rather tailored multidisciplinary approach to manage the morbid complications would represent the best recommended strategy for success and better outcomes in severe liver injury patients. Further studies are needed to support our assumption."}
+{"text": "Polyglutamine (polyQ) diseases are genetically inherited neurodegenerative disorders. They are caused by mutations that result in polyQ expansions of particular proteins. Mutant proteins form intranuclear aggregates, induce cytotoxicity and cause neuronal cell death. Protein interaction data suggest that polyQ regions modulate interactions between coiled-coil (CC) domains. In the case of the polyQ disease spinocerebellar ataxia type-1 (SCA1), interacting proteins with CC domains further enhance aggregation and toxicity of mutant ataxin-1 (ATXN1). Here, we suggest that CC partners interacting with the polyQ region of a mutant protein, increase its aggregation while partners that interact with a different region reduce the formation of aggregates. Computational analysis of genetic screens revealed that CC-rich proteins are highly enriched among genes that enhance pathogenicity of polyQ proteins, supporting our hypothesis. We therefore suggest that blocking interactions between mutant polyQ proteins and their CC partners might constitute a promising preventive strategy against neurodegeneration. Polyglutamine (polyQ) diseases are fatal neurological disorders that affect the central nervous system. Nine known disorders belong to this family, which includes Huntington's disease (HD) and spinocerebellar ataxia type-1  by expanding a neighboring CC upon interaction with a CC from a partner protein ; 15. SucA very interesting hypothesis follows immediately from the previous model of polyQ action. It has been shown that proteins with expanded polyQ domains can form \u03b2-sheet aggregates We recently performed a cell-based screen for the identification of proteins that influence the aggregation and proteotoxicity of a toxic construct of polyQ ATXN1 , reports a set of aggregation enhancers without enrichment in CC  CC proteins that interact with a wild-type polyQ protein also interact with the corresponding pathogenic polyQ-extended protein, and (ii) these CC protein partners promote the aggregation of the pathogenic polyQ-extended protein. A careful analysis of these interactions should help us to develop therapeutic strategies that might prevent neurodegeneration in humans. We suggest that similar aggregation mechanisms might be relevant for other non-polyQ neurodegenerative diseases involving protein aggregation, such as Alzheimer's or Parkinson's disease."}
+{"text": "The purpose of the study is to evaluate a fully automated motion corrected first pass myocardial perfusion (FPMP) MRI with semi quantitative perfusion parameter maps in patients with suspected ischemic heart disease.Coronary heart disease is the leading cause of death and disability in the US. FPMP MRI is increasingly used to assess ischemic heart disease; however respiratory motion is one of the major problems for myocardial blood flow quantification. An algorithm for motion correction, surface coil correction, temporal denoising and robust pixel-wise parameter map generation model was previously desribed [Xue H et al MICCAI 2009).This work evaluates automated workflow in a clinical setting to diagnose ischemic heart disease comparing free breathing and motion correcteted images and corresponding pixel-wise parameter map.Stress and rest FPMP images were acquired using a 1.5T scanner  in 39 patients with suspected ischemic heart disease. Short axis slices were acquired during infusion of 0.075 mMol/kg of Gadolinium  and adenosine  infusion  was administrated to induce stress. Free breathing, motion-corrected images and corresponding perfusion maps were assessed by 2 radiologists independently using the AHA 16 model and evaluated using a four point Likert scale (poor to excellent) to evaluate image quality and confidence level in presence or absence of hypo-perfusion regions. Upslope index of both free breathing and motion corrected images during stress and rest were manually calculated in non-ischemic and ischemic areas and compared to the corresponding pixel-wise parameter map generated based on motion corrected images. FPMP MRI results were subsequently compared to coronary angiogram, stress echocardiography, or SPECT.Perfusion defects were detected in 25 patients  MRI with semi quantitative perfusion parameter maps showed comparable accuracy for detection of significant coronary artery disease in patients with ischemic disease.Astellas Pharma Global Development, Inc."}
+{"text": "The pre-B\u00f6tzinger complex (pre-B\u00f6tC) is the essential core component of the brainstem respiratory central pattern generator (rCPG) in mammals. Phasic excitatory and inhibitory synaptic inputs during the respiratory cycle are thought to dynamically shape membrane potential trajectories and spiking patterns of pre-B\u00f6tC neurons. These synaptic inputs reflect the functionally interacting neuron populations involved in rhythm and inspiratory-expiratory pattern generation. The dynamic patterns of these synaptic inputs have not been systematically studied and characterized experimentally. Accurate temporal reconstruction of the synaptic input patterns is important for testing current models of the rCPG that incorporate specific excitatory and inhibitory circuit mechanisms for rhythm and pattern generation. A recent computational model of the rCPG generating a normal \u201cthree-phase\u201d respiratory pattern  specifiein situ perfused brainstem-spinal cord preparations of mature rats, which generate a three-phase respiratory pattern and provide mechanically stable conditions for intracellular recordings in functionally intact brainstem circuits.We developed analytical techniques that allow quantitative reconstruction of the patterns of synaptic conductances at high temporal resolution from intracellular recordings of membrane potential trajectories. Our approach extends previously proposed methods for extracting dynamic patterns of synaptic input conductances ,3 and prWe distinguished different types of inspiratory and expiratory pre-B\u00f6tC neurons and analyzed the dynamical changes of excitatory (Ge) and inhibitory (Gi) conductances. Inspiratory neurons exhibited strong excitatory inputs (large dynamic increases in Ge) during their spiking phase followed by a wave(s) of inhibitory inputs during the expiratory period with large increases in Gi and temporal patterns consistent with two populations of inhibitory neurons providing inputs that coordinate inspiratory to expiratory and expiratory to inspiratory phase transitions. Expiratory neurons exhibited strong inhibition during the inspiratory phase, consistent with the rhythmic alternation of inspiration and expiration, and changes in Ge indicating reciprocal interactions between two major populations of inhibitory neurons coordinating the generation of two E1 and E2) phases of expiration. The reconstructed patterns of Ge and Gi are generally consistent with previously proposed circuit architecture [ and E2 p"}
+{"text": "There is no reliable predictor on arrival at hospital for neurological outcome of the patient with out-of-hospital cardiac arrest (OHCA). We hypothesize that ammonia and lactate may predict neurological outcome.We performed a prospective observational study. Non-traumatic OHCA patients who gained sustained return of spontaneous circulation and were admitted to an acute care unit were included. Blood ammonia and lactate levels were measured on arrival at hospital. The patients were classified into two groups: favorable outcome group  1 to 2 at 6-month follow-up), and poor outcome group (CPC 3 to 5). Basal characteristics obtained from the Utstein template and biomarker levels were compared between these two outcome groups. Independent predictors were selected from all candidates using logistic regression analysis.n = 10) were significantly lower than those in the poor outcome group (n = 88) . On receiver operating characteristic analysis, the optimal cut-off value for predicting favorable outcome was determined as 170 \u03bcg/dl ammonia, 12.0 mmol/l lactate . Logistic regression analysis identified ammonia (\u2264170 \u03bcg/dl), therapeutic hypothermia and witnessed by emergency medical service personnel as independent predictors of favorable outcome. When both these biomarker levels were over threshold, the positive predictive value (PPV) for poor outcome was calculated as 100%.Ninety-eight patients were included. Ammonia and lactate levels in the favorable outcome group (Ammonia and lactate blood levels on arrival are independent neurological prognostic factors for OHCA. The PPV with the combination of these biomarkers predicting poor outcome is high enough to be useful in clinical settings."}
+{"text": "The twin-arginine translocation (Tat) protein export system enables the transport of fully folded proteins across a membrane. This system is composed of two integral membrane proteins belonging to TatA and TatC protein families and in some systems a third component, TatB, a homolog of TatA. TatC participates in substrate protein recognition through its interaction with a twin arginine leader peptide sequence.tatC loci and half of these classes possessed only tatC and tatA genes. Phylogenetic analysis of diverse TatC homologues showed that they were primarily inherited but identified a small subset of taxonomically unrelated bacteria that exhibited evidence supporting lateral gene transfer within an ecological niche. Examination of bacilli tatCd/tatCy isoform operons identified a number of known and potentially new Tat substrate genes based on their frequent association to tatC loci. Evolutionary analysis of these Bacilli isoforms determined that TatCy was the progenitor of TatCd. A bacterial TatC consensus sequence was determined and highlighted conserved and variable regions within a three dimensional model of the Escherichia coli TatC protein. Comparative analysis between the TatC consensus sequence and Bacilli TatCd/y isoform consensus sequences revealed unique sites that may contribute to isoform substrate specificity or make TatA specific contacts. Synonymous to non-synonymous nucleotide substitution analyses of bacterial tatC homologues determined that tatC sequence variation differs dramatically between various classes and suggests TatC specialization in these species.The aim of this study was to explore TatC diversity, evolution and sequence conservation in bacteria to identify how TatC is evolving and diversifying in various bacterial phyla. Surveying bacterial genomes revealed that 77% of all species possess one or more TatC proteins appear to be diversifying within particular bacterial classes and its specialization may be driven by the substrates it transports and the environment of its host. As of June 2012, the number of available completed bacterial genome sequences was 4373 (2422 are plasmids and 1951 are chromosomes) and corresponded to a total of 1018 bacterial species. tBLASTn searches resulted in a total of 1415 genomic tatC loci out of a total 782 bacterial species . A list of all TatC sequences identified in this study is provided in tatC sequences, a summary of Tat translocase components  identified in tat operons for each bacterial class surveyed in this study is also provided and listed in Ilyobacter polytropus, from the order Fusobacteriales, which had a plasmid encoded tatC.The TatC protein and nucleotide sequence datasets analyzed in this study were collected from completed sequences bacterial genome collection on the National Center of Biotechnology Information (NCBI) website (Multiple Sequence Comparison by Log-Expectation (MUSCLE), Multiple Alignment using Fast Fourier Transform (MAFFT) and hidden markov model alignment  software of the HMMER3 v3.1 package http://pfam.sanger.ac.uk/) with accession PF00902. The application of the hmmalign software aided in the multiple alignment of distantly related TatC homologue sequences. Non-confidently aligned residue columns were omitted from phylogenetic analyses and synonymous/non-synonymous nucleotide substitution analyses. Poorly aligned residues within amino- and carboxyl- termini and within loop regions were generally removed from multiple alignments due to low conservation in these regions.Multiple sequence alignments of TatC amino acid sequence datasets used for phylogenetic and synonymous/non-synonymous analyses and consensus sequence determinations were performed using three different programs, http://toolkit.tuebingen.mpg.de/blastclust) to aid in the selection of 232 unique, taxonomically diverse TatC sequences that represented all bacterial phyla surveyed. Multiple alignment editing was performed with custom Python scripts and with the multiple alignment editing program Jalview To selectively represent non-redundant taxonomically diverse TatC sequences for phylogenetic and synonymous/non-synonymous analyses the 1415 TatC dataset was analyzed using the web based BLASTClust program (transmembrane hidden markov model (TMHMM) dense alignment surface (DAS) membrane protein structure and topology (MEMSAT) TatC transmembrane domain predictions for TatC sequences were performed using local installations of programs Vulcanisaeta distributa TatC protein sequence (YP_003902595.1) served as the outgroup for phylogenetic analysis (E. coli W strain TatC (YP_006175467.1) was the outgroup for Bacilli TatC analysis  adjacent to the tatC locus/loci from annotated tatC sequence locus tags during genome surveys described above. In some cases, tatA and tatB loci were also sought out within these genomes to confirm legitimate absences from the TatC locus using NCBI tBLASTn searches with E. coli TatA (GenBank: YP_006126698) and TatB (GenBank: YP_006126699) as query sequences. The results of this analysis are presented in Bacterial tatC loci present within Bacilli genomes  was determined by the equation [Freq\u200a=\u200a(ngene/nlocus ) x OtatC] where ngene is the number of times a gene is identified at one of ten loci before or after the tatC locus, nlocus is the number of total loci examined, and OtatC is total number of tatC operons examined. The reading frame of all genes was also considered in the frequency of gene occurrence calculations as well as its proximity to the tatC locus. All of these parameters were used to generate the tatC operon diagrams shown in the right hand panel of Examination of synonymous non-synonymous analysis program (SNAP) package http://hcv.lanl.gov/content/sequence/SNAP/perlsnap.html). Generation of codon aligned tatC nucleotide datasets used for this analysis were performed with the program RevTrans tatC sequences are summarized in tatC sequence included in the analysis, a mean dS/dN value was calculated from all pairwise comparisons to other sequences in the same selected dataset. Pairwise dS/dN values could only be determined for 39% of all pairwise alignments of 232 tatC sequences included in this study since the remaining pairwise dS/dN values had pS values of 0.75 that prevented a reliable Jukes-Cantor transformation calculation of the dS value. Mean dS/dN values are reported in boxplot function as part of the R program version 2.15.2 (http://developer.r-project.org/). The number of observed synonymous nucleotide substitutions (Sd) at each codon was calculated using the Perl script codons-xyplot.pl available within the SNAP software package and the mean Sd values are summarized in tatCd and tatCy were also analyzed using SNAP to determine pairwise dS/dN values for the entire protein in addition to Sd values for each codon in the multiple alignment resulting in mean Sd values.Synonymous to non-synonymous nucleotide substitution analyses were performed with E. coli TatC structure was generated from the recently published X-ray crystal structure of Aquifex aeolicus TatC E. coli TatC (GenBank: YP_006175467.1) and A. aeolicus TatC (Swiss-Prot: O67305) protein sequence. This alignment was used to generate 10 models based on the A. aeolicus TatC crystal structure  of species with tatC homologues were typically facultative anaerobes, obligate anaerobes and facultative aerobes. Very few species possessing Tat systems had an obligate aerobic physiology (\u223c11%) in this survey. This indicates that the Tat system is linked to bacteria that rely upon an anaerobic physiology. However, this finding also supports experiments in E. coli that show a constitutive expression of tat genes under both aerobic and anaerobic conditions Before beginning phylogenetic and sequence-based analyses of bacterial is study . Surprisnt locus . This matatC homologue representing either Gram- negative or Gram- positive bacteria had reduced genome sizes \u22642 Mb and/or were obligate and opportunistic parasites which confirm findings from previous analysis tatC homologues within Gram- negative bacterial genomes appeared to be related to the size of the genome, as genomes \u22642 Mb typically lacked tatC sequences. For example, the obligate parasite phylum Mollicutes  lacked tatC homologues as well as members from the thermophilic Thermotogae phylum . An exception was observed for obligate endosymbiotic \u03b1-proteobacterial members from Rickettsiales, with small average genome sizes of \u22641.3 Mb, yet all possessed a tatC homologue. Since many species within Rickettsiales are also known to be free-living, such as Pelagibacter ubique (SAR11), there may be a greater requirement for the Tat system in this expanding bacterial class. Gram- positive species that lacked recognizable tatC loci were generally opportunistic microflora of plants and animals, typically pathogens, likely due to the genome sequencing bias favouring pathogenic organisms. For instance, Bifidobacteriaceae of the phylum Actinobacteria, was the only Actinobacterial subgroup that lacked tatC homologues with the exception of Bifidobacterium longum.Overall, almost all species that lacked a tatC locus per genome was relatively narrow, where only 39 species from diverse phyla  had at least two tatC loci as listed in tatC homologues was limited to Bacilli species, namely Bacillus subtilis and Bacillus halodurans, that are known to encode for two TatC isoforms, TatCd and TatCy. This tatC survey identified additional species with multiple tatC isoforms in the Bacilli class, Bacillus, in particular within Paenibacillus, Lysinibacillus and Geobacillus genera  and those in possession of more than one tatC locus typically shared a common environmental habitat (in particular those organisms living in soil and/or sea). Like Bacilli, the presence of multiple tatC loci/genome suggests that one or both of these additional Tat systems may support a specialized secretion function or alternatively protein secretion under a restrictive physiology as observed for Bacilli TatC isoforms. Hence, the presence of an additional Tat translocase system may allow a competitive advantage by supporting a specific protein secretion compared to other bacteria that possess a single TatC system in the same ecological niche.The distribution of bacteria in possession of more than one s genera . In facttatC loci and that only 5% have \u22652 tatC loci  was performed to expand upon previous studies involving smaller datasets (\u223c70 sequences) tatC members within bacteria, and to determine the origin of Bacilli TatC isoforms TatCd and TatCy. A chrenarchaeal Vulcanisaeta distributa TatC protein sequence served as the outgroup for this phylogenetic analysis as it represents one of the most ancient microorganisms that possesses a TatC homologue.Phylogenetic analysis of 232 TatC proteins representing diverse taxa from all bacterial classes in possession of one or more tatC and other genes as their genome reduced during evolution tatC genes in the genomes of other obligate intracellular parasites observed in our TatC distribution survey strongly supports this argument. Clades 1\u20133 also demonstrated evidence supporting internal gene duplication events, as many species in possession of more than one TatC in these clades branched together at the same nodes . This indicates that horizontal gene transfer influences clade 4 branching patterns in contradiction to previous findings Branching arrangements within the fourth clade at node 4 demonstrated a different clustering of TatC homologues from diverse taxonomic origins and included species from Actinobacteria, Cyanobacteria, Deinococcus-Thermus, Acidobacteria phyla, and from the class \u03b4-proteobacteria . The lactatC loci in the genomes of eight species dispersed throughout the phylogenetic tree from \u03b3-proteobacteria (Colwellia psychrerythraea), \u03b4-proteobacteria (Geobacter lovleyi), Actinobacteria , Bacteroidetes (Cytophaga hutchinsonii), Acidobacteres (Candidatus Solibacter usitatus) and Nitrospira (Candidatus Nitrospira defluvii). Each homologous TatC pair from these 8 organisms grouped independently with PP\u22650.9 supporting gene duplication events .Internal gene duplication events may explain the presence of multiple n events . NonethePhylogenetic analysis of the TatC protein family demonstrated evidence for combination of linear and environmental-driven inheritance, suggesting that evolutionary pressures acting upon TatC in free-living organisms could account for specialized Tat systems able to confer evolutionary advantages in environmental niches with strong ecological competition. The occurrence of multiple TatC homologues in single species apparently arisen from either intra-genomic events of gene duplication or horizontal gene transfer events further supports this hypothesis, thus potentially expanding the idea of the presence of functionally distinct Tat systems within single organisms, so far narrowed to Bacilli class tatC loci found in Bacilli genomes appeared to be evolving separately from all other multiple TatC homologues,  and integrases (xerC) were identified in a 8 gene radius in either frame from tatC loci as shown during operon conservation analysis  with genes associated with molybdenum cofactor biosynthesis proteins , with chaperones (groE), and 40% frequency of association to various vitamin/cytochrome and cofactor biosynthesis genes  transporters and cofactor biosynthesis, such as high-affinity Fe2+/Pb2+ permease (FTR1/efeU), iron binding lipoprotein/imelysin peptidase M75 (COG2822) and the known Tat substrate ferrous iron dependent DyP-type peroxidase (efeB/ywdH) tatC operons examined in these nodes. Previous experiments have shown that the secretion efeB is effected by the environmental salinity of the growth medium tatCy operon at nodes y5\u2013y7, such as thioredoxin reductases (trx/ydbP) E. coli tatC operons, specifically ubiquinone oxidoreductases and methyltransferases were also found at a frequency of 5% and 18% respectively in Bacilli tatC loci.Examination of the TatCd and TatCy clades in n region . tatCy ois genes . As TatCtatCd operon analysis at branch node d1 in this sub-branch showed high gene associations to the Tat substrate phosphodiesterase D (phoD) gene that confirms previous findings pcp), a periplasmic protein involved in pyroglutamyl signal sequence cleavage B. subtilis TatCd dependent process and its secretion is influenced by phosphate availability phoD gene in the tat operon and in its place had conserved genes with as yet undefined functions . Additionally, genes encoding proteins involving a bound fatty acid like DegV domains (degV) and dihydrofolate reductase (dfrA/DHFR) known to be tightly folded protein in the cytoplasm tatC operons surveyed in nodes d2\u2013d3  in comparison to those classes with higher tatC conservation (dS/dN >1) that indicated sequences that are actively maintained in the host genome. Overall, the mean dS/dN value of all pairwise comparisons of tatC homologues was 2.62, indicating that bacterial tatC sequences are maintained under selective pressure, albeit much lower than initially expected. This result reflected a high proportion of non-synonymous sequence variation occurring in different bacterial classes and dS/dN values for species from various bacterial classes ranged from 0.35 to 5.99 (The ratio of synonymous (dS) to non-synonymous (dN) nucleotide substitution was calculated for all pairwise comparisons of gene sequences coding for 232 taxonomically representative TatC homologues. The purpose was to determine which bacterial classes possessing  to 5.99 .tatC possessing classes showed that five classes including Actinobacteria and Deinococci had the lowest median dS/dN values (1.0\u20132.0) in comparison to \u03b3- proteobacteria, \u03b5- proteobacteria, Bacteroidetes and Bacilli with the highest median dS/dN (3.0\u20134.0) values  values . Low medclade 4; .tatC classes examined (52% of 23 classes) resided within the intermediate median dS/dN value range (2.1\u20133.1) as shown in tatC homologues represented a diverse group largely composed of Gram- negative organisms and a single Gram- positive class (Clostridia). The intermediate median dS/dN values for these bacterial classes indicated that the overall mean dS/dN value of 2.62 accurately reflected the majority of bacterial class tatC sequence variation in bacteria. The broadest ranges of dS/dN values among bacterial classes in this group were found in within Verrucomicrobia (2.74\u20133.76), \u03b2-proteobacteria (1.62\u20135.10) and \u03b4- proteobacteria (2.10\u20133.36), strongly suggesting that tatC homologues in these classes have significantly different selective pressures directing sequence conservation. High tatC dS/dN values observed for \u03b2-proteobacteria and \u03b4-proteobacteria were particularly interesting, since high dS/dN values generally corresponded to species that possessed more than one tatC locus/genome  were related to tatC homologues from Methylobacillus flagellatus and Methylotenera mobilis, suggesting that multiple tatC copies may have greater pressures to maintain synonymous conservation to support conditionally dependent Tat system substrate secretion activity in these methylotrophic organisms.The majority of bacterial s/genome . For exatatC homologues in these classes were maintained under the highest selection pressure. Bacterial classes with high median tatC dS/dN values also tended to possess more than one tatC locus/genome, as observed for multiple tatC sequences found in species from Bacilli and \u03b3- proteobacteria  for Bacilli and \u03b3- proteobacterial species with more than one tatC copy suggesting that multiple tatC copies have greater selective pressures acting upon them. As dS/dN values increased in bacterial classes we surveyed, the frequency of identifying multiple tatC copies also increased  proved to be an exception to this trend and supports a role for lateral gene exchange in common niches influencing high dS/dN values.The highest median dS/dN values (>3.1) were observed for \u03b3- proteobacteria, \u03b5- proteobacteria, Bacteroidetes, and Bacilli and indicated that bacteria . As obsencreased . HowevertatC homologues from various classes, revealed that the selective pressures acting upon tatC sequence variation support our phylogenetic analyses, which demonstrates that TatC evolution is largely directed by the taxonomic origins of its host but also appears to be driven by its environmental pressure. Multiple tatC loci present in bacterial classes also tend to be maintained at higher dS/dN (with the notable exception of Actinobacteria), suggesting that tatC duplicates fulfill important functional purposes for their host.Examination of dS/dN analysis of bacterial Analysis of individual TatC amino acid and nucleotide conservation from multiple alignments was performed to identify any conserved residues within TatC and identify other conserved residues involved in substrate binding regions and/or TatC multimerization contacts. This was carried out by calculating the extent of conservation from aligned amino acids and the extent of synonymous substitutions in each corresponding codon sequence in the nucleotide codon alignment. The most conserved amino acid according to its percentage identity (% identity) and its associated mean synonymous nucleotide substitution (Sd) provide an estimation of the selective pressure acting on particular residues and domains within the protein. The TatC protein alignment used for phylogenetic analyses and its corresponding codon aligned nucleotide sequences were used for these analyses. This resulted in an amino acid sequence where the highest % identity was reported for each residue in alignment (the consensus sequence) in addition to its respective mean Sd value for each codon.A. aeolicus TatC structure E. coli model of TatC  was shown to be important for TatC structure and function based on site-directed mutagenesis experiments (The mean synonymous substitution (Sd) values identified many regions undergoing variable rates of conservation throughout the bacterial TatC protein . Our ana of TatC . Examinaeriments  [29], [3E.coli TatC translocation function when replaced with either Ala Our analysis of TatC residue conservation identified a total of eleven highly conserved (\u226575% identity) amino acid sites from TM3 to the carboxyl terminus of TatC  and poorly conserved (\u226425% identity) residues were mapped onto a model structure of tat operons lack tatB, this analysis was also performed to determine residues that interacted with TatA and TatC specifically, and identify conserved residues specific for only TatA-TatC associations. A comparative TatC-TatCy/Cd conservation (according to % identity) consensus alignment is provided for each amino acid position from amino- to carboxyl- terminus in The final objective of this study was to compare the extent of amino acid conservation within Bacilli TatCd and TatCy isoforms to the bacterial TatC consensus to identify regions or residues in each TatC isoform that may contribute to specialized substrate secretion in Bacilli. Since Bacilli 91GLYK94 motif in both Bacilli TatCd (TP94) and TatCy (YE100) suggest that these residues might contribute to signal sequence specificity since these regions were shown to crosslink to the twin arginine leader peptide in E. coli experiments In general, highly conserved residues identified in the overall bacterial TatC consensus were generally similar to those identified in Bacilli TatCd and TatCy, and the majority of variation from the main consensus was observed sporadically after loop1 throughout the carboxyl terminus of the protein . NotableE. coli TatC photoaffinity crosslinking experiments tatB, our bacterial TatC alignment would be expected to see moderate conservation of TatB-TatC interacting residues  with transposon/integron gene elements compared to TatCd. This suggests that Bacilli TatCd have undergone rapid diversification from their originally duplicated TatCy sources. The combination of Bacilli TatC phylogenetic analysis with tatC operon mapping, also revealed an assortment of interesting gene associations that may be potential substrates/or linked to pathways specific for TatCd/y isoform substrates  followed taxonomic inheritance in agreement with previous findings  out of 4bstrates . This anndidates . It is atatC encoding taxa determined that tatC sequences were more variable sequence in Actinobacteria and Deinococci while \u03b3- proteobacteria, \u03b5- proteobacteria, Bacteroidetes and Bacilli were maintained under the highest rates of conservation  within diverse ervation . This shn system \u20137.Figure S1A protein alignment of all 233 TatC proteins examined in this study. Amino acids for each of the 233 TatC proteins are provided and show all alignable positions examined in this study. Abbreviated TatC sequence tags are provided for clarity and correspond to bacterial genus and species names provided in Additional file 1. Regions highlighted in blue have been predicted to be transmembrane strand regions. The degree of blue highlighting behind each amino acid indicates how many transmembrane prediction programs have assigned that amino acid to a transmembrane segment (three to one according to the shift from the darkest to the lightest blue) Yellow and black bar charts shown at the bottom x-axis of the amino acid alignment indicate the amino acid conservation (top yellow chart) where bar height is proportional to the conservation of physico-chemical properties for each column of the alignment, quality (middle yellow chart) where bar height and shading is proportional to the number of alignable residues and % amino acid identity at each position and the amino acid consensus (bottom black chart) representing the most frequently identified amino acid for each alignable position.(PDF)Click here for additional data file.Figure S2Vulcanisaeta distributa TatC sequence  served as the outgroup for this analysis. Symbols adjacent to taxa indicates multiple TatC copies from the same genomes discussed in the Results and Discussion section and the corresponding species are detailed as follows: Cytophaga hutchinsonii (\u2022); Geobacter lovely (\u2022\u2022); Colwellia psychrerythraea (\u2022\u2022\u2022); Xylanimonas cellulosilytica (x); Streptomyces hygroscopicus (xx); Candidatus Solibacter usitatus (xxx); Nakamurella multipartita (\u00a5); Candidatus Nitrospira defluvii (\u00a5\u00a5); Sulfobacillus acidophilus (Sa); Thermodesulfobium narugense (Tn); Thermodesulfatator indicus (Ti). Numbering in light blue beneath each node represents posterior probability (PP) confidence estimates where 1 represents branching patterns with the highest confidence values and 0 no confidence in relationship at the node. Only PP values equal or greater than 0.6 are shown. Nodes with large black numbers highlight important clade divisions (1\u20134) between branches and Greek delta (d) symbols written beside these clade numbers indicate important delta proteobacterial divisions within that numbered clade. Bacterial classes enriched in major clusters are highlighted on the right hand side of the dendrogram, and in the case of Bacilli TatC sequences, TatCd and TatCy isoforms are also indicated.A rooted phylogenetic tree of bacterial TatC proteins. The rooted dendrogram was generated by Bayesian analysis of 233 TatC sequences from diverse bacterial taxa where the archaeal (PDF)Click here for additional data file.Table S1tatC genome sequences obtained from NCBI for this study.A complete list of all 1415 bacterial (XLS)Click here for additional data file.Table S2tatC sequences from various bacterial classes.The distribution of mean synonymous to non-synonymous (dS/dN) substitutions within (XLS)Click here for additional data file."}
+{"text": "Venturia inaequalis, the pathogenic agent of apple scab, cause severe damage in apple cultivation. In commercial apple production, pesticides are employed frequently and in high quantities. Alternative methods such as the use of mycoparasitic Trichoderma fungi to control fungal plant pathogens have been explored [Trichoderma chitinases has lead to an increase of the trees\u2019 resistance against apple scab [Trichoderma chitinase genes within the plant. At the Julius K\u00fchn-Institute in Dresden, the apple cultivar 'Pinova' was transformed by introducing the construct pBIN (Endo + Nag) into the transgenic lines. With the help of promoter CaMV 35S the transgenic lines constitutively express endochitinase gene ech42 and exochitinase gene nag70 from the biocontrol fungus Trichoderma atroviride. In order to study whether the constitutive expression of ech42 and nag70 has an effect on mycorrhization of plants with transgenic roots  and \u2013 as apple cultivars are propagated vegetatively by grafting\u2013 whether expression of ech42 and nag70 in a transgenic scion grafted on a non-transgenic rootstock has an effect on mycorrhization (systemic effect), a series of greenhouse experiments was conducted. In a first experiment, non-grafted clones of wildtype apple cultivar \u2018Pinova\u2019 and two transgenic lines were cultivated in artificial substrate and inoculated with two AMF species, Glomus intraradices and G. mosseae. After four months of cultivation, root colonization rates were significantly lower in the transgenic lines compared to the non-transformed cultivar 'Pinova' [ech42 and nag70 in a transgenic scion grafted on a non-transgenic rootstock) on mycorrhization, two further experiments were carried out. Grafted sample trees  were cultivated in the greenhouse in pots with artificial substrate and inoculum of Glomus intraradices and G. mosseae. Root samples were taken after four and eight months. A second set of grafted sample trees was cultivated in pots with soil from an intensively managed plantation in the \u2018semi-natural\u2019 environment of a gossamer cage. Root samples were taken after 12 and 24 months. For all experiments, root colonisation rates were determined microscopically. Molecular methods \u2013 PCR with taxa specific primer sets [The project 'Mycorrhizal symbioses of transgenic apple trees with increased resistance against fungal pathogens'  investigates whether the transformation of apple trees with fungal chitinase encoding genes - besides increasing resistance against fungal pathogens - also interferes with mycorrhizal fungi. Pathogenic fungi such as the ascomycete species explored . Geneticple scab . Howeverple scab . Like inple scab . Consequmer sets , cloning"}
+{"text": "A 75-year-old long-term male smoker and poorly controlled hypertensive presented with a 3-month history of intermittent epistaxis refractory to cauterisation with silver nitrate. Nasopharyngeal examination revealed a mass in the post nasal space. An urgent endoscopic biopsy confirmed an extraosseous plasmacytoma. Post operative radiotherapy was scheduled. No evidence of recurrence of disease following completion of treatment has been detected during clinical surveillance.Epistaxis; Nasopharynx; Biopsy; Plasmacytoma; Radiotherapy A 75-year-old long-term male smoker and poorly controlled hypertensive presented with a 3-month history of intermittent epistaxis refractory to cauterisation with silver nitrate. Nasopharyngeal examination revealed a smooth mass extending inferiorly from the right fossa of Rossenmuller and effacing the posterior pharyngeal wall . An urgeSerum and urine assays for Bence Jones protein were negative and there was no evidence of gammopathy. A bone marrow biopsy and Computed Tomography and Magnetic Resonance imaging did not demonstrate any metastasis or skeletal involvement. The Excisional biopsy had been complete and the patient underwent radical radiotherapy with a 45Gy dose in 20 fractions of the nasopharyngeal field.No evidence of recurrence of disease following completion of treatment has been detected during clinical surveillance.A plasmacytoma is a very rare discrete solitary mass of neoplastic monoclonal plasma cells, first described by Schridde in 1905 . They reTissue biopsy, serum electrophoresis (to exclude myeloma) and radiological skeletal survey with bone marrow biopsy to determine skeletal involvement is necessary for diagnosis. Treatment includes a combination of surgical excision and radiotherapy. Follow-up radiological and electrophoresis assessment is required after treatment to detect recurrences and progression to myeloma (10-30% frequency). The overall 10 year survival is 70% ."}
+{"text": "A previous study by our group  showed a significant allergic gastrointestinal inflammation in birch pollen allergic patients with gastrointestinal symptoms during the birch pollen season. The pathophysiological mechanisms of this type of allergic reaction are still poorly studied. However it is not yet explored if all birch pollen patients have signs of gastrointestinal inflammation during the pollen season.To study the immune pathology of the duodenal mucosa in birch pollen allergic patients without gastrointestinal symptoms, outside and during the birch pollen season.All patients were clinically diagnosed as birch pollen allergic. Seven patients allergic to birch pollen without any gastrointestinal symptoms and seven completely healthy individuals were included in the study for comparison. All patients were examined with a standard skin prick test panel and blood samples were analysed for IgE antibodies by component micro-arrays (ISAC). The two groups of patients underwent gastroscopy and duodenal biopsies were taken both during (May-June) and outside the pollen season (November-January) for each patient. Duodenal biopsies were examined with immunostaining for mast cells (IgE and tryptase), eosinophils (eosinophil peroxidase), T-cells (CD3), and dendritic cells (DC) (CD11c).In the pollen allergic group there was a significant increase in eosinophils, mast cells and DC\u2019s but not T cells during the pollen season as compared with values outside the season. Interestingly, in the healthy control group we observed a significant increase in CD3+ cells during the birch pollen season, but no change in the other cell types during the pollen season.Patients allergic to birch pollen have, regardless of subjective gastrointestinal symptoms, clear signs of an ongoing allergic inflammation in their intestinal mucosa during the pollen season."}
+{"text": "This case report describes the use of high-resolution magnetic resonance imaging (HRMRI) to visualize basilar artery atherosclerotic plaque in a patient with a pontine stroke. HRMRI with three-dimensional image acquisition was used to visualize plaque in several planes to localize arterial wall pathology. Fluid attenuated inversion recovery (FLAIR) sequences of the basilar artery showed wall thickening throughout the basilar artery wall and good contrast between the artery wall and cerebrospinal fluid. Intracranial atherosclerosis (ICAD) is a common cause of stroke, but the pathology is not well understood because it cannot be easily studied in living patients. In extracranial carotid arteries, high-resolution magnetic resonance imaging (HRMRI) has shown good correlation with pathology , but carA 55-year-old man with atherosclerotic risk factors presented with acute onset dysarthria and left hemiplegia consistent with the classic clinical syndrome pure motor hemiplegia due to basilar artery branch occlusion . He was In this report, we demonstrate that HRMRI with 3D image acquisition can visualize intracranial plaque in several planes with good spatial resolution. Small improvements in spatial resolution are important when imaging small structures like the basilar artery. We found that an available FLAIR sequence with resolution of 0.4 mm showed good visualization of the atherosclerotic wall, likely due to the suppression of CSF signal. Unlike in T1/PD-weighted VISTA images wherein the vessel wall remained visible in normal volunteers , in our The patient's pontine infarct was proximal to his basilar stenosis A\u2013D and tAt the stenosis , the artHRMRI with 3D image acquisition can visualize basilar artery plaque in multiple planes, allowing identification of plaque features that may contribute to the clinical presentation. The addition of FLAIR sequences helps localize arterial wall pathology by suppressing the surrounding CSF signal."}
+{"text": "Intracardiac blood flow measurements using 4D Phase Contrast CMR (4D PC-CMR) may contain useful information about cardiac pumping. Lagrangian Coherent Structures (LCS) is a new, operator-independent method which can simplify analysis by partitioning the flow into regions with different origins and destinations. Since LCS are operator-independent, they may be used to define quantitative indices of intracardiac blood flow. The partitioning has not previously been validated against particle tracing in 4D PC-CMR blood flow.To investigate whether Lagrangian Coherent Structures computed from 4D Phase Contrast CMR of the human heart partitions diastolic inflow blood from blood already in the left ventricle.Eight healthy volunteers  underwent 4D PC-CMR flow measurements of the whole heart. Three-dimensional LCS surfaces were computed and automatically delineated in the left ventricle during diastole. The only parameter adjustable by the operator was the start of diastole. Particle tracing was performed to study the blood flowing into the ventricle during diastole and the blood already present in the ventricle from the previous heartbeat. LCS and particle traces were compared visually using the software Ensight .In all eight subjects, a distinct LCS was found in the left ventricle during diastole. The LCS separated the inflow blood particle traces and particle traces of blood already in the ventricle in all eight subjects. The Figure shows the typical appearance of the LCS and particle traces in one healthy volunteer.Lagrangian Coherent Structures can separate 4D Phase Contrast CMR data into regions of blood with different origins. Since Lagrangian Coherent Structures are operator-independent, they have the potential to be used to define quantitative indices of intracardiac blood flow."}
+{"text": "This percentage decreases in faster runners, where the incidence of midfoot and forefoot strikers (FFS) increases . It is pet al.  found ru-1 while muscle fibre length change of the medial and lateral gastrocnemius and soleus were recorded using ultrasound and muscle activation via surface electromyography. Individual contribution of the triceps surae muscles to Achilles tendon force was determined using a Hill-type model based on muscle activation, the muscles force-length-velocity relationship , maximum isometric muscle force and pennation angle. Achilles tendon and triceps surae individual muscle forces were recorded while runners performed their natural (fore or rearfoot) and then converted to their unnatural strike.Natural FFS (n=9) and RFS (n=9) distance runners ran on a treadmill at 3msResults from one FFS participant are presented below Figure  &2, addiThis research provides insight into the role of the Achilles tendon during FFS running and sheds light on its\u2019 contribution to reducing energy cost. It also reveals the altered demand on the triceps surae muscles which may have implications for technique recommendations and training requirements."}
+{"text": "Synaptic dysfunction is widely thought to be an important pathogenic event in Alzheimer\u2019s disease (AD). Presenilins, which harbor large numbers of mutations for familial AD and frontotemporal dementia (FTD), are important for neurotransmitter release and synaptic plasticity as well as memory and age-related neuronal survival.2+ imaging coupled with electrophysiological and molecular analyses using both acute hippocampal slices of unique presenilin conditional mutant mice and cultured hippocampal neurons, in which presenilins are acutely inactivated with a lentivirus expressing Cre recombinase.Our recent report showed that presenilins regulate synaptic function by modulating ryanodine receptor-mediated calcium release from the ER. To determine how presenilins regulate intracellular calcium signaling in neurons, we performed Capresenilin-1 knockin mice, in which either an AD- (L435F) or FTD (G183V) -causing mutation is introduced into the respective presenilin-1 endogenous genomic locus, to investigate the mechanisms by which presenilin mutations cause AD or FTD. The analysis of these mutant mice will also be presented.Our results reveal a selective interaction between presenilins and ryanodine receptors in the regulation of calcium homeostasis and synaptic function, and suggest that disruption of calcium homeostasis may be an early pathogenic event leading to synaptic dysfunction in AD. We also generated two"}
+{"text": "A genetic predisposition to cluster headache (CH) has long been debated. Genetic epidemiological studies have reported an increased risk of CH in relatives of CH sufferers. The familial clustering supports a model of autosomal dominant inheritance with reduced penetrance. Some candidate gene studies have been performed, detecting associations with HCRTR2 and ADH4, but these have been limited by small sample size. We have established a large cohort of CH families in which we have previously reported a genome-wide linkage scan, isolating a number of putative linkage loci. DespiteTo further delineate the genetic architecture underlying CH, we have used an exome sequencing strategy in a subset of Northern European families.Exome target enrichment and paired-end sequencing were performed for ten probands. Annotated variants were filtered to exclude known polymorphisms, leaving a total of 1711 novel variants. Exome data from related affected subjects were examined to limit the analysis to variants segregating with the CH phenotype. Segregation analysis by Sanger sequencing in all family members reduced the candidate list to a total of 45 genes (range: 1-13 genes per pedigree). These genes are now being screened in our extended cohort to provide further insight into the role of each gene in CH pathogenesis.Whilst exome sequencing for rare monogenic disorders is now well-established, approaches to detect pathogenic variation with complexities such as locus heterogeneity and incomplete penetrance remain challenging. We have combined exome and Sanger sequencing to isolate novel coding variation segregating across CH families, highlighting the need for large homogeneous cohorts to elucidate the molecular genetic basis of CH. The significance of these variants in CH pathogenesis remains to be determined; however these results provide further evidence for a potential genetic predisposition to this debilitating disorder."}
+{"text": "A single center, cluster randomized controlled effectiveness trial was conducted to compare two novel hand hygiene (HH) promotional strategies. Sixty six wards were randomized to standard HH promotion (control), standard promotion plus HH performance feedback (FB), or FB plus active patient participation (PP). While FB seemed to be well accepted by HCWs, the introduction of PP proved to be more challenging.Here we focus on PP and report the results of a qualitative inquiry, designed to investigate the range of success with its implementation.A ward-level case study was conducted through 3 focus groups with ward staff and 6 interviews with ward head nurses. Participants were selected following an extremes sampling strategy regarding adoption strength. The hospital\u2019s infection control nursing staff participated in additional focus group. All sessions were audiotaped and transcribed verbatim. Analysis was deductive (using a framework of themes that had been previously established) and inductive (grounded theory).Four main and 12 sub-themes (in parenthesis) emerged: Context ; Risk knowledge (nil); Interaction ; Implementation process . The action of confronting another person about a failure became less emotionally menacing through positive experiences, innovative means of communication, and institutionalization of the project. Individual leadership engagement had a major impact on implementation success. Exclusion from intervention arms motivated control wards to improve HH performance independently.This qualitative research permitted to explain the quantitative study findings and to explore the evolutionary and complex implementation process of PP. While PP remains challenging, it is our hope that the findings of this study may facilitate future patient participation projects.None declared"}
+{"text": "Juvenile Fibromyalgia (JFM) is characterized by chronic widespread musculoskeletal pain and approximately 40% of children and adolescents with JFM also suffer from benign joint hypermobility (HM). It is not currently known if the presence of HM affects the pain experience of adolescents with JFM. The objective of this study was to examine whether there were any differences in self-reported pain intensity and physiologic pain sensitivity between JFM patients with and without joint HM.One hundred thirty-one adolescent patients with JFM recruited from four pediatric rheumatology clinics completed a daily visual analogue scale (VAS) pain rating for one week and underwent a standardized 18-count tender point (TP) dolorimeter assessment. Medical records were reviewed for the presence of joint HM. Average pain VAS ratings, tender point count and tender point sensitivity were compared between JFM patients with and without hypermobility (HM+\u2009and HM-).Nearly half (48%) the sample of JFM patients were found to be HM+. HM+\u2009and HM- patients did not differ in their self-reported pain intensity. However, HM\u2009+\u2009patients had significantly greater pain sensitivity, with lower TP thresholds (p\u2009=\u20090.002) and a greater number of painful TPs (p\u2009=\u20090.003) compared to HM- patients.The presence of HM among adolescent patients with JFM appears to be associated with enhanced physiologic pain sensitivity, but not self-report of clinical pain. Further examination of the mechanisms for increased pain sensitivity associated with HM, especially in adolescents with widespread pain conditions such as JFM is warranted. Juvenile fibromyalgia (JFM) is a chronic condition of widespread musculoskeletal pain and fatigue in children and adolescents. Prevalence estimates for JFM range from 1-6% of the pediatric population . While tBenign joint hypermobility (HM) is a relatively more common condition than JFM, with prevalence rates in children and adolescents estimated to be up to 30% . ChildreThe underlying mechanisms for pain hypersensitivity in FM have been extensively studied while the etiology of pain in HM has received little attention. It has been well documented that persons with FM have an overall lower threshold for pain as demonstrated by increased responsiveness and hypersensitivity to pain  in the fAs part of the screening for a larger clinical trial examining the effectiveness of cognitive-behavioral therapy for JFM, we assessed baseline pain intensity and tender point sensitivity (tender point count and tender point threshold) of over 100 adolescents with JFM . For theParticipants were 131 adolescents  with JFM between the ages of 11 and 18\u2009years (mean age\u2009=\u200915.1\u2009years) who were initially screened for the parent clinical trial. Participants were recruited from four pediatric rheumatology clinics  in Ohio and Kentucky, with each site having Institutional Review Board approval. All participants met Yunus and Masi criteria ."}
+{"text": "Purulent mediastinitis is a possible serious complication after mediastinal surgery. We report the case of a localized sternal plasmocytoma treated by sternectomy and prosthetic repair, who needed a second surgery for a fistulizing mediastinitis. Five months earlier, in another Hospital, the patient underwent sternal resection and reconstruction with a \u201csandwich\u201d prosthesis (Methyl-methacrylate and Marlex mesh). Suppurative mediastinitis occurred and septic shock resolution was observed after the spontaneous opening of a mediastinal cutaneous fistula. After referring to our Unit the patient underwent extensive local and systemic preparation and nutritional support; the infected prosthesis was then removed and the gap filled by a laparoscopically-prepared omental flap. Adequate preoperative management, removal of any infected material and minimally invasive omental flap transposition allowed the successful treatment of this life-threatening condition. Purulent mediastinitis secondary to chronic prosthetic infection after sternectomy is a very difficult problem to resolve. The goals of surgical treatment are fast removal of the infected prosthetic material, mediastinal debridement and mediastinal filling with well vascularized tissues. Surgical trauma should be as mild as possible for the usually weak patient\u2019s general conditions ,2.We describe the case of a 73-year-old caucasian male with purulent mediastinitis and prosthetic infection after subtotal sternectomy.Five months earlier, the patient underwent surgery for solitary plasmocytoma in another hospital; chest wall reconstruction was achieved by a Marlex methyl-methacrylate sandwich prosthesis. Two days after surgery, the wound was re-explored to control bleeding from the operative site.At the admittance to our hospital the patient was in a bad clinical condition, with intermittent fever, dyspnea and anterior chest pain. His comorbidities included chronic C virus hepatitis, monoclonal gammopathy and multinodular goiter. Blood sampling revealed an increase in white blood cells, erythrocyte sedimentation rate (ESR) and C-reactive Protein (CRP). Local examination showed an erythematous, swollen, indurated sternal wound with a chronic, purulent fistula opening at the lower third of the surgical incision.A computed tomography (CT) scan showed semi-solid inflammatory tissue with multiple air levels involving the mediastinal surface of the sternal prosthesis and the pericardium Figure\u00a0A-B. MicrUnder general anesthesia with a single lumen oro-tracheal intubation, we laparoscopically prepared an omental flap, transposed at the thoracic level through a minimal diaphragmatic anterior incision Figure\u00a0A. The tePatient was discharged on postoperative day 10 and received intravenous antibiotic therapy for another 2\u00a0weeks. Drains were removed on postoperative day 4; ESR and CRP decreased towards baseline values within 47\u00a0days. The wound healed well without significant flail chest (Figure\u00a0A rigid plaque as methyl-methacrylate in combination with two layers of Marlex mesh has been largely employed to repair large defects after sternectomy. The possible infection of this type of prosthesis is already known  and has Therapeutic alternatives not entailing the removal of the infected prosthesis are to be considered unreliable. In fact sepsis resolution can be achieved only after the thorough removal of all the infected autologous and prosthetic tissues .\u2022Removal of an infected sternal prosthesis is the key for the successful treatment.\u2022Intrathoracic omental flap transposition is preferable to muscle flap but entails an heavier surgical trauma.\u2022Laparoscopically-prepared omental allows to take advantage from the favorable properties of the omentum, without further significant surgical trauma.\u201cWritten informed consent was obtained from the patient for publication of this Case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\u201dESR: Erythrocyte sedimentation rate;CRP: C-reactive protein;CT: Computed tomographyAll authors declare that they have no competing interest.VT, SC and FP wrote the article, JV and SC collected the clinical information, JV selected the images; VT and SC analyzed the English Literature. FP drafted the final manuscript. All authors approved the final manuscript to be published."}
+{"text": "Plasmodium (P.) synthetic lethal (SL) gene pair has antimalarial drug resistance (ADR), a drug targeting the other gene of the SL pair can be used as an effective antimalarial drug for treating drug-resistant strains of malaria diseases. The approach introduced in this study is based on bioinformatic database integration. It employs a promising concept of synthetic lethality and has practical applicability in identifying gene targets to discover potential future drugs.If one gene of the P. genes were searched to find new drugs for clinical malaria treatment from Yeast Fitness DB [Potential antimalarial drug target genes were identified by integrating whole biological information from many databases, including BioGRID , KEGG SStness DB .P. species  was established to identify SL genes that are possible drug targets. Information on SL gene pairs with ADR genes and their first neighbors from the yeast SL gene was inferred to search for pertinent antimalarial drug targets. We suggested that specific antimalarial drug candidates can be inferred by searching drugs that cause a fitness defect in the yeast SL gene.A simple computational tool to analyze inferred SL genes of P. Malaria parasites can be killed by mutating or blocking the SL partner of ADR genes. This concept is useful in selecting candidates as drug targets in antimalarial therapy. The methodology also provides not only drug target gene candidates for further experimental validation, but also information on new usage for already-described drugs. Drug candidates for targeting the suggested genes significantly benefit experimental validation in antimalarial drug discovery.We suggest a new concept of drug-resistant malaria therapy in this study. The alternative antimalarial drug therapy consists of data integration and inference through the homology analysis of yeast-human-"}
+{"text": "Dear SirThis is in reference to our article published before [1]. On 1 year follow up, the patient had local recurrence measuring 8 cm X 5 cm infero-laterally to the previous scar. MRI of the local region showed a large well defined heterogeneously enhancing soft tissue mass in subcutaneous layers involving ilio-tabial tract with areas of deep multiple recurrences . There was no evidence of metastasis. Local excision was done. Histopathology was identical as before- the desmoid tumor. The surgical margins were free; the mass was surrounded with fibrocollagenous tissue. Keeping in view the unresectable deep recurrences, he was administered radiotherapy locally. MRI done after 6 weeks of radiotherapy did not show any residual disease. The child is under close follow up.Even after multiple recurrences, successful salvage is achievable, particularly when high-dose focal radiotherapy is incorporated [2]. It would also be imperative to mention role of intra-operative electron radiotherapy (IOERT), followed by moderate doses of external beam radiotherapy (EBRT) after organ-sparing surgery, in patients with primary or recurrent aggressive fibromatosis. Introduction of IOERT into a multimodal treatment approach in patients with aggressive fibromatosis is feasible with low toxicity and is known to yield good local control rates even in patients with microscopical or gross residual disease [3]. Such facility is however unavailable in our setup.In our case, the hip joint was not involved. A case of aggressive pediatric hip fibromatosis with severe joint destruction has been reported recently [4], and we would like to prepare ourselves for such an eventuality. Source of Support: NilConflict of Interest: None declared"}
+{"text": "The aim of our study was to test the robustness and efficiency of maximum likelihood with respect to different long branch effects on multiple-taxon trees. We simulated data of different alignment lengths under two different 11-taxon trees and a broad range of different branch length conditions. The data were analyzed with the true model parameters as well as with estimated and incorrect assumptions about among-site rate variation. If length differences between connected branches strongly increase, tree inference with the correct likelihood model assumptions can fail. We found that incorporating invariant sites together with  Maximum likelihood (ML) tree inference has been shown to be statistically consistent for binary trees with finite branch lengths under correct model and model parameter assumptions as sequence length increases to infinity The ML method is certainly more robust and more efficient than other methods It is well known that if among-site rate variation (ASRV) is ignored in tree reconstruction, the ML approach underestimates substitution rates, and these estimates become progressively worse with increasing evolutionary distances Early studies argue that combining both models  predominates tree inference even under correct model assumptions (settings . In geneTopology B was designed to test for class I effects (symplesiomorphy effect). The major difference to topology A is that the evolving sequence passes through two long branches, while in topology A the two long branches are parallel. Even if the correct proportion of invariant sites  correct as well as estimated model parameters . This has also been observed in previous studies, e.g. The inclusion of a mixed-distribution model , is not a particular problem of mixed-distribution models. If no invariant sites are estimated in the reconstruction, this model deficiency is partially compensated by a lower estimated value of the Our results show that the risk of obtaining a wrong topology using ML is dependent on the arrangement of the edges (corresponding to which LBA classes the tree is susceptible to). Although our results depend on simulated nucleotid data it can be expected that amino acid sequences are also prone to long branch effects if branch lengths combinations of RB) are kept constant (We designed two sets of data simulations under different topologies  to detecn length . This seranch  . This trTrees were inferred with the Jukes-Cantor (JC) model under different parameter settings using PhyML-3.0-linux64 Wrong topologies were classified into LBA class I, II and III effects . Wrong tFigure S1ML reconstruction success of simulated paramter and branch length settings.(TIFF)Click here for additional data file.Figure S2ML values of reconstructed topologies.(TIFF)Click here for additional data file.Figure S3ML parameter estimates of reconstructed topologies.(TIFF)Click here for additional data file."}
+{"text": "The integrate-and-fire (IAF) neuron model is a Time Encoding Machine (TEM), which maps analog signals into a sequence of strictly increasing time events. There are a number of reconstruction algorithms that ensure perfect recovery of bandlimited input signals from spike trains . For sig"}
+{"text": "The cGMP-dependent protein kinase (PKG) has two tandem cyclic nucleotide binding (CNB) domains which act as the primary intracellular receptor for cGMP ,2. PKG e78-355 structure is free of cGMP and presents the protein in an elongated conformation. A surprising dimeric arrangement between PKG78-355 protomers is orchestrated via hydrophobic contacts between a novel helical element C-terminal to the second cGMP binding site (the switch helix) and the opposite CNB domain B , suggesting the additional importance of the switch helix in mediating cGMP-specific conformational changes inherent to the regulatory domain.We recently solved a crystal structure of the two cGMP binding sites from PKG I\u03b1 in order to highlight the atomic details of the regulatory domain. This PKGB Figure . Small aOverall, these studies provide the first atomic resolution model of tandem cGMP binding domains and expand our understanding of the allosteric mechanisms surrounding PKG activation."}
+{"text": "Interspecific divergence along a benthic to pelagic habitat axis is ubiquitous in freshwater fishes inhabiting lentic environments. In this study, we examined the influence of this habitat axis on the macroevolution of a diverse, lotic radiation using mtDNA and nDNA phylogenies for eastern North America\u2019s most species-rich freshwater fish clade, the open posterior myodome (OPM) cyprinids. We used ancestral state reconstruction to identify the earliest benthic to pelagic transition in this group and generated fossil-calibrated estimates of when this shift occurred. This transition could have represented evolution into a novel adaptive zone, and therefore, we tested for a period of accelerated lineage accumulation after this historical habitat shift.Ancestral state reconstructions inferred a similar and concordant region of our mtDNA and nDNA based gene trees as representing the shift from benthic to pelagic habitats in the OPM clade. Two independent tests conducted on each gene tree suggested an increased diversification rate after this inferred habitat transition. Furthermore, lineage through time analyses indicated rapid early cladogenesis in the clade arising after the benthic to pelagic shift.A burst of diversification followed the earliest benthic to pelagic transition during the radiation of OPM cyprinids in eastern North America. As such, the benthic/pelagic habitat axis has likely influenced the generation of biodiversity across disparate freshwater ecosystems. Freshwater fish are frequently thought to diversify along a benthic (bottom) to pelagic (mid-water) habitat axis-3. HowevClinostomus elongatus and C. funduloides) and five endemic to western North America  form the sister group to a much larger group of species that is primarily confined to eastern North America.All trees are deposited in TreeBASE  Cytb and (B) Rag1 MCC gene trees for the primarily eastern North American OPM cyprinid radiation. Numbers at nodes represent posterior probability values (pp). Asterisks denote 100%\u00a0pp. The \u2018transition nodes\u2019 indicated by black arrows correspond to those in Figure\u00a0Click here for fileDensity plots for lineage accumulation statistics and \u0394AIC values from 1 million simulated pure-birth phylogenies with taxon sampling (black) and 9005 post burn-in trees (red) for Cytb  and Rag1 . Hatched red line indicates values for MCC tree.Click here for fileA list of currently recognized North American OPM cyprinid species, including GenBank accession numbers for previously published and newly sequenced data utilized in this study. Benthic/pelagic designations are based on a number of morphological and ecological characters, and references for these characters are given below the table.Click here for file"}
+{"text": "Respiratory motion compensation is essential for reproducible and robust cardiovascular MRI. Traditionally, breathholds or prospective gating by bellows or navigator signals limit data acquisition to the quiescent phase of respiration . These aFive healthy volunteers were imaged on a 3.0T system  using PC VIPR prescribed over a large chest imaging volume . Interleaving of radial projections that traverse the center of k-space allow for retrospective sorting in a flexible fashion. Our traditional retrospective ECG gating was expanded to incorporate additional sorting of the data into respiratory phases based on the bellows signal Fig.  to proviRepresentative flow waveforms for the DAo during inspiration and expiration are shown in Figure A 3D radial double-gated acquisition and reconstruction that allows for blood flow analysis over the cardiac cycle is presented. Data acquired in healthy volunteers shows significant increased blood flow during expiration compared to inspiration in the Ao. The same effect is marginal in the DAo. Acquisition throughout the respiratory cycle does not prolong scan time while allowing for retrospective selection of arbitrary measurement planes. Further studies are warranted to quantify these respiratory effects in other vessels and to investigate implications for assessing flow.NMSS fund RC1003-A-1, NIH grant 2R01HL072260, and GE Healthcare"}
+{"text": "Achieving tolerance or drug minimization after transplantation and thus preventing permanent immunosuppression with all the known severe side effects is the most important goal in transplantation medicine. In the last 20 years major progress has been made in understanding the tolerance underlying mechanisms and develop therapeutic strategies in small animal models. However, such knowledge could be rarely translated into the development of successful new therapeutic approaches in clinical transplantation. The success is limited by clinical challenges which are not present in our clean animal facilities such as 1) heterologous immunity - pathogen-specific memory T and B cells recognize alloantigens and boost the immune response towards the allograft, 2) pre-sensitization of recipients - presence of allo-specific memory T and B cells which are inert to most known therapeutic regimens. Thus we know now that we need more personalized treatment strategies according to the patient's immune reactivity. Such a strategy should combine three important aspects: i) an improved immune monitoring; ii) treatment which target memory cells and iii) strategies to reinforce regulation.We have established preclinical transplant models with preformed allo-reactive or pathogen-specific memory T cells in which we compare effectiveness of different treatment approaches combining depletional with regulatory approaches.Furthermore, we have performed a DNA microarray screen on samples of transplant patients and identified surface molecules specifically expressed by na\u00efve, central memory, effector memory or terminal differentiated effector memory (TEMRA) T cells. Using this approach we hope to develop antibodies, which specifically deplete effector memory and TEMRA cells but spare na\u00efve and central memory T cells. Such a treatment will be associated with less side effects e.g. infectious complications as compared to global depletion of T and B cells."}
+{"text": "An original total ankle replacement design was developed with the aim of establishing compatibility between the prosthetic articulating surfaces and the retained ligaments. This was achieved with a special shape of a conforming meniscal bearing, free to move forwards/backwards on both metal components during dorsi/plantar flexion. Careful kinematics analyses were carried out in patients after this replacement to assess the functional performance during activity of daily living. A thorough assessment shall include standard gait analysis (GA) and the more accurate motion tracking of the components by 3D fluoroscopic analysis (FA).Eleven patients implanted with the BOX Ankle  were analyzed at 12 months after surgery. GA was performed during stair-climbing/descending using a 8-cameras motion system , electromyography , and an established protocol for lower limb joint kinematics and kinetics [Nearly physiological joint kinematic patterns were observed in both legs Table . A statiNearly normal kinematics and kinetics at the main joints were observed also at the replaced leg. In addition, nearly natural function was restored at the replaced ankle, with large coupled motion in the three anatomical planes. The meniscal-motion was coupled with ankle flexion, supporting the main claims of the designers."}
+{"text": "CaseusJM1, a 936-type phage isolated from an Irish dairy plant.The 936-type lytic bacteriophages are the most frequently encountered species infecting lactococcal dairy starters. Infection by members belonging to this species has a significant negative impact on the cheese production process. Here we report the complete genome sequence of the bacteriophage  Lactococcus lactis represent important starter cultures in the dairy industry, and despite decades of research, such starter strains continue to suffer from phage attacks  FLX titanium sequencer . A 110-fold sequencing coverage was obtained using pyrosequencing technology on a 454 FLX instrument. The files generated by the 454 FLX instrument were assembled with GSassembler  to generate a consensus sequence. Several PCR products covering various sections of the genome were sequenced to ensure correct assembly and the resolution of any remaining base conflicts occurring within homopolymer tracts.The sequencing of the http://www.sanger.ac.uk/resources/software/artemis/). Each of the determined ORFs was functionally annotated using BLASTp (Open reading frames (ORFs) were automatically predicted using Heuristic Approach for Gene Prediction . Proteing BLASTp .CaseusJM1 was found to have a double-stranded linear genome of 30,692\u00a0bp with a G+C content of 34.84%. A total of 51 ORFs were predicted and were divided into a modular organization based on previously published 936-type phages (CaseusJM1 exhibits a high level of homology to genomes of other 936-type phages (>85% identity). Continued analysis of the genomic organization and diversity is essential to help understand why these phages represent such a significant and constant threat to the dairy industry.e phages  with earCaseusJM1 has been deposited in GenBank under accession number KC522412.The complete genome sequence of lactococcal phage"}
+{"text": "Panicum virgatum, and mixed-grass prairie) not currently managed as crops to act as post-breeding and fall migratory stopover habitat for birds. In total, we detected 41 bird species, including grassland specialists and species of state and national conservation concern . Avian species richness was generally comparable in switchgrass and prairie and increased with patch size in both patch types. Grassland specialists were less abundant and less likely to occur in patches within highly forested landscapes and were more common and likely to occur in larger patches, indicating that this group is also area-sensitive outside of the breeding season. Variation in the biomass and richness of arthropod food within patches was generally unrelated to richness and abundance metrics. Total bird abundance and that of grassland specialists was higher in patches with greater vegetation structural heterogeneity. Collectively, we find that perennial biomass feedstocks have potential to provide post-breeding and migratory stopover habitat for birds, but that the placement and management of crops will be critical factors in determining their suitability for species of conservation concern. Industrialization of cellulosic bioenergy production that results in reduced crop structural heterogeneity is likely to dramatically reduce the suitability of perennial biomass crops for birds.Increased production of biomass crops in North America will require new agricultural land, intensify the cultivation of land already under production and introduce new types of biomass crops. Assessing the potential biodiversity impacts of novel agricultural systems is fundamental to the maintenance of biodiversity in agricultural landscapes, yet the consequences of expanded biomass production remain unclear. We evaluate the ability of two candidate second generation biomass feedstocks (switchgrass,  Panicum virgatum) or mixed-grass prairie In North America, land-use changes associated with the expansion of contemporary bioenergy crops are generally expected to reduce biodiversity in affected regions Perennial feedstocks can attract a number grassland bird species during the breeding season Our goal is to directly address this information gap by comparing the bird communities in two important candidate biomass feedstocks with potential to provide post-breeding and migratory stopover habitat: Switchgrass and mixed-grass prairie. We first ask if feedstocks differ in the species richness, species density (species richness per unit area) and abundance of migratory bird communities they support, and then investigate how food availability and habitat structure and composition at multiple spatial scales  shape the distributions of birds during the fall migratory period. Because the post-breeding and en-route habitat requirements of grassland birds are poorly-known, we base our predictions about grassland bird responses to crops on established bird-habitat relationships during the breeding and wintering periods. Grassland bird diversity during the breeding season has been linked to plant species diversity P\u200a=\u200a0.69), species density  or abundance  was evident across study plots.We identified 95.1% of the 979 individuals detected within transects to the species level. In total, we detected 41 bird species, with greater total and obligate species richness in mixed-grass prairie  than switchgrass  and had a lower forb composition than prairie reconstructions . These aWe detected several species of state and continental conservation concern in both feedstock types . Raw speThe high energetic demands of migration predict that food availability should be an important component of habitat quality for migrants and those individuals preparing to migrate The richness of migratory bird communities increases with patch size in forested systems Many grassland specialist birds are \u2018area-sensitive\u2019  during the breeding season Grassland specialist birds commonly avoid selecting breeding habitat within highly forested landscapes Instead, top models of species density and abundance were positively linked with decreasing cover of low, open habitat types and increasing urban land cover. Other studies linking migrant diversity and abundance to surrounding land cover composition are lacking, but this result is surprising given that species richness of breeding bird species decline in relation to increasing urbanization at local and landscape scales Assessing the biodiversity impact of novel production systems is fundamental to reconciling the demands of biodiversity conservation and agricultural production Results of this study suggest that the latter effect is likely to dramatically reduce the suitability of biomass crops as autumn stopover habitat. Switchgrass and prairie are generally expected to be harvested in September, but are somewhat flexible. Harvest strategies that create within-crop structural diversity (e.g. strip harvesting) or that produce a mosaic of harvested and unharvested patches during the migratory period could be a useful management tool Fifteen sites of each of the two biomass crop treatments were selected from established patches throughout southern Michigan . We visiMelospiza melodia) We surveyed the bird community associated with crop patches in the fall of 2008 and 2009, making three visits to each patch: 1) Sep. 7\u2013Sep. 15, 2) Sep. 23\u2013Oct 1, and 3) Oct 7\u201316. While this time period corresponds to the period of peak migratory movement for migrant land birds in this region Ammodramus spp.). Observations of individuals not identified to the species level were used only to estimate community-wide abundance. Bird surveys were conducted during the first four hours after sunrise.Fixed-width transects In order to obtain representative samples of bird communities in patches differing in area without pseudo-replicating To estimate patch-scale species richness, we used area searches to survey portions of each patch not covered by transects. To maintain observer effort proportional to the size of each patch, observers walked at a regular pace though each patch in a systematic pattern such that one observer passed within 75 m of every point in a patch exactly once. Species detected during strip-transect surveys, including those detected at a distance of >50 m, were pooled with detections from area searches to provide an estimate of bird species richness within each patch.During the second site visit we characterized vegetation structure of crops within each 100 m-long transect to determine how microhabitat gradients may affect spatial distributions of birds. We randomly selected five non-overlapping sampling points within each transect at which we recorded vertical density of vegetation and canopy coverage. Vertical density (an index of biomass) Settlement behavior in grassland birds is frequently linked to landscape composition at larger spatial scales (1000\u20131600m) We used principal components analysis to reduce the number of within-patch vegetation structural and landscape-scale variables at the 0.5 km and 1.5 km scales into component variables. We employed an orthogonal rotation method that minimizes the number of variables with high loadings on each axis. Microhabitat variables were moderately correlated  and we eArthropod food availability has been linked to the distributions of post-breeding and migratory birds We tested for spatial autocorrelation among sites by comparing residuals of bird community models by using the Moran's index (I) as a function of spatial distance We took a model selection approach to determine the relative importance and effect size of 11 environmental variables and feedstock type  in explaWe modeled the richness of the avian community using generalized linear models with a Poisson distribution and log-link function using SPSS version 15 a priori candidate models that reflected our assessment of likely causes of variation in richness, species density, occurrence and abundance. Our analyses included models of each explanatory variable alone, and two- and three-variable models that we determined to be ecologically relevant. Because species-area relationships may differ by feedstock, we also included models with interactions between patch size and feedstock type. We evaluated the degree of support for logistic models using Akaike's second-order information criterion with a small sample size adjustment (AICc) c (quasi-AICc) which accounts for potential overdispersion of generalized linear models c or \u25b5QAICc values and normalized Akaike weights (iw). We considered models with \u25b5AICc or QAICcc or QAICc>2 and We developed a set of Table S1Fit of global models for avian community metrics in model selection analyses. The fit of generalized linear models is assessed as c-hat. A c-hat approximating 1 indicates good fit, while a value greater than 1, but less than 4 indicates moderate to severe overdispersion (DOCX)Click here for additional data file.Table S2Correlation matrix of microhabitat vegetation structural and composition variables. Microhabitat variables describing the structure and composition of biofuel crop stands were moderately-correlated.(DOCX)Click here for additional data file.Table S3Eigenvalues of the first three orthogonal microhabitat principal components extracted.(DOCX)Click here for additional data file.Table S4Loading matrix for the first microhabitat principal component. The principal component was positively related to vertical density and percent grass cover, and negatively related to forb cover.(DOCX)Click here for additional data file.Table S5Correlation matrix of land-use categories in landscapes surrounding focal patches at the 0.5 km scale. The percent cover of forest in landscapes surrounding biofuel crops was negatively correlated with crop cover, urbanization and open habitat types at the 0.5 km scale.(DOCX)Click here for additional data file.Table S6Eigenvalues of the first four orthogonal landscape principal components extracted at the 0.5 km scale.(DOCX)Click here for additional data file.Table S7Loading matrix for the first two landscape principal components at the 0.5 km scale. Landscape principal component 1 exhibited a strong positive relationship with the cover of cropland and open habitats, while landscape principal component 2 was most strongly characterized by a strong positive relationship with urbanization.(DOCX)Click here for additional data file.Table S8Correlation matrix of land-use categories in landscapes surrounding focal patches at the 1.5 km scale. The percent cover of forest in landscapes surrounding biofuel crops was negatively correlated with crop cover while urban cover and open habitat types were also negatively correlated at the 1.5 km scale.(DOCX)Click here for additional data file.Table S9Eigenvalues of the first four orthogonal landscape principal components extracted at the 1.5 km scale.(DOCX)Click here for additional data file.Table S10Loading matrix for the first two landscape principal components at the 1.5 km scale. Landscape principal component 1 exhibited a strong positive relationship with forest cover and a strong negative relationship with crop cover, while landscape principal component 2 exhibited a strong negative relationship with urbanization and a positive relationship with open habitats including old fields, prairie, switchgrass and pasture.(DOCX)Click here for additional data file."}
+{"text": "Congenital bicuspid aortic valve (BAV) is the commonest inherited cardiac defect that is often associated with a medley of other cardiovascular anomaly, the most frequent being aortic dilatation which may be a consequent of an interplay between genetic and hemodynamic factors. This retrospective study aims to find a correlation between BAV valve morphology with thoracic aortic dimension with cardiovascular magenetic resonance imaging (CMR).A retrospective analysis of the aortic valve and aortic (Ao) dimension was made of 149 patients aged between 6 and 77 years  with BAV who underwent CMR study. BAV patients with associated coarctation or valvular dysfunction were excluded. Images were acquired with either a Siemens Avanto or Sonata 1.5T scanner in orthogonal planes. Aortic maximal intraluminal dimensions in end diastole were measured at the annulus, sinuses, sino-tubular junction, mid ascending aorta, arch and proximal descending aorta. These measurements were indexed according to body surface area (BSA). BAV valve morphology were characterised in cross-sectional steady-state free precession (SSFP) cine images and grouped according to the presence or absence of a raphe.Of the valve morphology, majority of patients (59.7%) had a raphe, almost always seen between the fused right and left cusps (89%). The indexed aortic root and ascending aortic dimensions were found to be smaller in patients with remnant raphe BAV as compared with those without a raphe (\u2018pure' BAV). There was a trend towards smaller indexed proximal aortic arch dimensions in BAV patients with valvular raphe although this did not reach statistical significance (p=0.07). There were no difference in indexed aortic arch and proximal descending aortic dimension between the 2 groups as shown in the table below:Majority of BAV patients have a remnant raphe, commonly between the fused right and left cusps. These patients were also found to have smaller indexed aortic root and ascending aortic dimensions compared with those with \u2018pure' BAV which may indicate an inherent difference in biologic aortic structure.No funding"}
+{"text": "In order to differentiate Epstein-Barr virus (EBV) virion DNA versus viral DNA released from tumor cells, we have taken advantage of the observation that viral episomal genomes of herpesviruses are methylated in latently infected cells whereas un-methylated genomes are synthesized and packaged into virions during the lytic phase. We used paramagnetic beads linked to methylCpG binding protein to separate virion and cell-derived viral DNA.DNA isolated from EBV Figure  virions Tumor derived viral DNA can be distinguished from virion associated viral DNA based on preferential binding to methylCpG binding protein. Tumor derived viral DNA was predominantly present in the blood from patients with Hodgkin-Lymphoma, but not in patients without EBV associated malignancy. This technique may be applied to detect tumor derived viral DNA in the blood of patients with EBV associated malignancies."}
+{"text": "The literature data demonstrate that the initial stage of abdominal sepsis (AS) is characterized with typical immune shifts as white blood cell (WBC) activation, decrease of T-lymphocyte and B-lymphocyte function followed by dysimmunoglobulinemia. As AS progresses immunity deficiency acquires severe combined character. Impact of immunity deficiency on a course is not described.Escherichia coli K30 LPS was used as antigen for AE antibody detection. All data were compared with healthy donors (99 patients). As a method of immunity correction we selected Sandoglobulin , introduced as 3 ml once intravenously.We investigated 33 patients  with abdominal sepsis . Anti-endotoxin (AE) antibodies  were determined by original modification of hard-phase immunoenzyme analysis. n = 6, no evidence from normal parameters) and low initial immunity . All patients needed comprehensive medication support. The patients with high immunity did not need any immunotherapy. But the patients with low initial immunity required immune therapy to avoid severe course of peritonitis and unfavorable outcomes. Single introduction of Sandoglobulin on the fifth day after surgery was accompanied with increase of immunity indices . Successful surgical treatment and immunotherapy of abdominal sepsis are accompanied by activation of AE immunity, all-class anti-LPS-immunoglobulin concentration growth that blocks mechanisms of further inflammation progress and result in rapid patients' recovery.According to results of immunity parameter investigation on the day of admission we shared all patients into two groups: with high initial immunity (es Table . SimultaPeritonitis patients with initial low immunity need passive nonspecific immunotherapy that stimulates organism protective functions and promotes rapid recovery."}
+{"text": "Ferrets are widely used as animal models for studying influenza A viral pathogenesis and transmissibility. Human-adapted influenza A viruses primarily target the upper respiratory tract in humans (infection of the lower respiratory tract is observed less frequently), while in ferrets, upon intranasal inoculation both upper and lower respiratory tract are targeted. Viral tropism is governed by distribution of complex sialylated glycan receptors in various cells/tissues of the host that are specifically recognized by influenza A virus hemagglutinin (HA), a glycoprotein on viral surface. It is generally known that upper respiratory tract of humans and ferrets predominantly express \u03b12\u21926 sialylated glycan receptors. However much less is known about the fine structure of these glycan receptors and their distribution in different regions of the ferret respiratory tract. In this study, we characterize distribution of glycan receptors going beyond terminal sialic acid linkage in the cranial and caudal regions of the ferret trachea (upper respiratory tract) and lung hilar region (lower respiratory tract) by multiplexing use of various plant lectins and human-adapted HAs to stain these tissue sections. Our findings show that the sialylated glycan receptors recognized by human-adapted HAs are predominantly distributed in submucosal gland of lung hilar region as a part of O-linked glycans. Our study has implications in understanding influenza A viral pathogenesis in ferrets and also in employing ferrets as animal models for developing therapeutic strategies against influenza. The host tissue or cell tropism of the viruses have been investigated previously using Ferrets are widely used as an animal model for understanding influenza A viral pathogenesis and transmission Sambucus nigra agglutinin (SNA-I) and Maackia amurensis lectin (MAL-II) One of the important factors governing the tissue or cellular tropism of the virus is the specific binding of its surface glycoprotein hemagglutinin (or HA) to sialylated glycan receptors  on the host cell surface The advancements in the chemical and chemoenzymatic synthesis of glycans have led to development of microarray platforms comprising of hundreds of diverse glycan structures and structural motifs displayed on various surfaces Given the importance of ferrets as widely used animal models for influenza infection, in this study, we have systematically characterized the glycan structural motifs distributed in the tracheal and hilar regions (primary sites of influenza A virus infection) of the ferret respiratory tract - on any N-linked or O-linked glycan, thereby displaying the broadest specificity to \u03b12\u21926 sialylated glycans. Therefore staining pattern of SNA broadly indicates distribution of \u03b12\u21926 sialylated glycans. In order to understand more specifically the distribution of receptors for human-adapted influenza A viruses, recombinantly expressed HAs of two prototypic human-adapted pandemic virus strains from the 1918 H1N1 pandemic, A/South Carolina/1/1918 (or SC18), and from 1957\u201358 H2N2 pandemic, A/Albany/6/58 (or Alb58) were used. While SC18 has been shown to specifically bind to at least tetrasaccharide glycan motifs terminated by \u03b12\u21926-linked sialic acid, Alb58 shows a broader specificity by recognizing a minimum trisaccharide motif . MAL-II was used to characterize distribution of avian receptors. As observed earlier, human-adapted viruses showed predominant binding to non-ciliated (including goblet cells) cells in the upper respiratory tract The lectins and recombinant HAs were used individually or in a multiplexed fashion (co-staining) to delineate glycan structures in regions of the ferret respiratory tract including cranial and caudal parts of the tracheal tissue section and lung hilar section. These regions are known to be infected by human-adapted influenza A viruses. Based on the staining patterns, a detailed picture of the distribution of sialylated glycan structural motifs was obtained that goes beyond terminal sialic acid linkage. The extent of lectin staining of various cell types in the different tissue sections was visually scored and is summarized in Paraffinized tissue sections (5 \u00b5m thickness) were stained with hematoxylin and eosin to identify distinct cell types and compare it with that of human respiratory tract. Tracheal tissue sections from the cranial and caudal regions and lung hilar region were analyzed . HoweverMaackia amurensis agglutinin (MAL-II) was used to probe \u03b12\u21923 sialylated glycan receptor distribution in ferret respiratory tract  and from the 1958 pandemic (Alb58) show efficient aerosol transmission in ferrets SC18 HA showed predominant staining of submucosal glands in both ferret tracheal and lung hilar section  and lung hilar sections . All the plant lectins and HAs used in this study showed a substantial loss of staining upon Sialidase A treatment, thereby confirming that staining of tissues by lectins is due to their specific binding to sialylated glycans on the tissue sections .In order to verify the sialic acid binding specificity of lectins used in this study, the tissue sections were treated with Ferrets have been used extensively as a model to study influenza A virus transmission and pathogenesis. Upon intranasal inoculation of the virus, ferrets exhibit similar clinical manifestation as that of humans although there seems to be a difference in viral tropism between ferrets and humans. Upper respiratory tract is the primary site of influenza A infection in humans. Apart from upper respiratory tract, involvement of lower respiratory tract (lung hilar region) is also reported in ferrets. Viral tropism is determined by distribution of influenza A glycan receptors, which are recognized by the viral hemagglutinin (HA) during infection.in vitro binding assay to determine the pattern of viral attachment (PVA) of fluorescein labeled human and avian influenza A viral strains to tissues  has been performed Plant lectins such as SNA-I have been used to stain ferret tracheal tissues in the past and it is generally known that these tissues predominantly express \u03b12\u21926 sialylated glycan receptors similar to human tracheal tissues Recently, with the emergence of glycan array technology, the glycan binding specificities of several plant lectins and influenza A virus hemagglutinins have been extensively characterized. In this study we used a combination of both lectins and recombinant human-adapted HA to systematically stain both the upper and lower respiratory tissues  in ferrets. The use of recombinant human-adapted HAs and co-staining with multiple lectins permitted us to define glycan receptors for human-adapted influenza A viruses going beyond terminal sialic acid linkage and map their distribution parts of the ferret respiratory tract Figure 6Sialidase A treatment, our results suggest that goblet cell region in human tracheal tissue might have a more predominant expression of the sialyl-Tn-antigen motif than the submucosal region in the ferret lung hilum although both these regions appear to be target sites for binding by human-adapted influenza viruses. This result is also supported by recent findings that show increased expression of sialyl-Tn antigen after virus infection due to goblet cell and/or acinar gland neoplasia in ferrets Our observations support the notion that the receptors for human-adapted influenza A viruses in ferrets are O-linked \u03b12\u21926 sialylated glycans  that are predominantly distributed in the submucosal glands of the lower respiratory tract (lung hilar region). This notion is also consistent with earlier reports of viral antigens being predominantly found in the submucosal glands in ferret trachea and lung hilar region upon infection with human influenza A virus It is interesting to note that though glycan receptors for human influenza A viruses are differentially distributed in humans and ferrets, they are predominantly expressed in the context of O-linked glycans in either goblet cells (in humans) or in submucosal glands (in ferrets). Given that these O-linked glycans are predominantly expressed in the context of mucins, our study provides a basis to further investigate the role of mucins in influenza A infection. We speculate that by infecting the mucin secreting cells such as goblet cells and submucosal glands, human-adapted influenza A viruses can be easily encapsulated into respiratory droplets formed during sneezing that can in turn facilitate efficient airborne transmission of the virus. In fact, the efficient transmission via respiratory droplets is a hallmark property of human-adapted viruses in the ferret animal models In summary, using a panel of lectins, we have systematically characterized the glycan receptor distribution for influenza A HA in ferret upper and lower respiratory tract, especially receptors relevant to human adapted viruses Figure 6WT HA gene, was used to infect (MOI\u200a=\u200a1) suspension cultures of Sf9 cells  cultured in BD Baculogold Max-XP SFM . The infection was monitored and the conditioned media was harvested 3\u20134 days post-infection. The soluble HA from the harvested conditioned media was purified using Nickel affinity chromatography . Eluting fractions containing HA were pooled, concentrated and buffer exchanged into 1\u00d7 PBS pH 8.0 (Gibco) using 100K MWCO spin columns . The purified protein was quantified using BCA method (Pierce).Briefly, recombinant baculoviruses with Sialidase A pretreatment, tissue sections were incubated with 0.2 units of Sialidase A  for 3 hours at 37\u00b0C prior to incubation with the proteins. Sections were then washed and viewed under a Zeiss LSM510 laser scanning confocal microscope.Formalin fixed and paraffin embedded ferret tracheal and lung hilar tissue sections were obtained from Lovelace Respiratory Research Institute and Division of Comparative Medicine (Massachusetts Institute of Technology) respectively. The lung hilar tissue sections were obtained from 4 year old male normal ferrets that were not exposed to prior influenza A virus infection. The tracheal sections were also obtained from normal ferrets that were not exposed to prior influenza A virus infection. Tissue sections were deparaffinized, rehydrated and pre-blocked with 1% BSA in PBS for 30 minutes at room temperature (RT). HA-antibody pre-complexes were generated by incubating 20 \u00b5g/ml of recombinant HA protein with primary  and secondary  antibodies in a ratio of 4\u22362\u22361 respectively for 20 minutes on ice. Tissue binding studies were performed by incubating tissue sections with the diluted HA-antibody complexes for 3 hours at RT. To visualize the cell nuclei, sections were counterstained with propidium iodide  for 20 minutes at RT. In the case of Formalin fixed and paraffin embedded ferret tracheal and lung hilar tissue sections were obtained from Lovelace Respiratory Research Institute and Division of Comparative Medicine (Massachusetts Institute of Technology) respectively. Tissue sections were deparaffinized and rehydrated. The tissue sections were incubated with 10 \u00b5g/ml of lectins  respectively for 3 hours in dark at RT. Lectins were obtained from Vector Labs. To visualize the cell nuclei, sections were counterstained with propidium iodide  for 20 minutes at RT. Sections were then washed, mounted and viewed under a Zeiss LSM510 laser scanning confocal microscope. For MAL-II, since the lectin was biotinylated, prior to adding the lectin, the tissue sections were incubated with streptavidin/biotin kit (Vector Labs) to block endogenous biotin for preventing non-specific staining of the tissues. For lectin co-staining experiments, Jacalin and SNA-I (10 \u00b5g/ml each) was added simultaneously to the tissue sections.Table S1Glycan binding specificities of lectins used in this study. Shown in the table is the panel of lectins used in this study and the cartoon representation of glycan motifs recognized by these lectins. The \u201c{\u201c used to indicate that the glycan motif on the left of \u201c{\u201c can be linked to either one or more branching positions on the N-linked core glycan structure or different O-linked core glycan structures. Glycan cartoon representation key: N-acetyl-D-neuraminic acid (purple diamond), D-galactose (yellow circle), D-mannose (green circle), N-acetyl-D-glucosamine (blue rectangle), N-acetyl-D-galactosamine (yellow rectangle).(PDF)Click here for additional data file.Figure S1Submucosal gland co-staining with Jacalin and Alb58 HA. Submucosal glands in the ferret trachea showed extensive co-staining with Jacalin and Alb58 HA. The co-staining is indicated by a yellow staining pattern. The submucosal glands are marked by white dotted circle. The apical surface is marked with a white arrow.(PDF)Click here for additional data file.Figure S2Sialic acid-binding specificity of lectins.Sialidase A from Arthrobacter ureafaciens was used to cleave all the sialic acids from the ferret lung hilar tissue sections prior to staining with SNA-I, Alb58 HA and SC18 HA (green). A substantial reduction in staining was observed upon Sialidase A treatment which indicated sialic acid specific binding of HA and lectins in these tissue sections. The apical surface is marked with a white arrow.(PDF)Click here for additional data file."}
+{"text": "Mutagenic DNA repair (MDR) transiently increases mutation rate through the activation of low-fidelity repair polymerases in response to specific, DNA-damaging environmental stress conditions such as ultraviolet radiation (UVR) exposure. These repair polymerases also confer UVR tolerance, intimately linking mutability and survival in bacteria that colone habitats subject to regular UVR exposure.Pseudomonas cichorii 302959. Relative fitness measurements of isolates and population samples from replicate lineages indicated that adaptive improvements emerged early in all lineages of our evolution experiment and specific increases in relative fitness correlated with distinct improvements in doubling and lag times. Adaptive improvements gained under UVR and non-UVR conditions were acquired preferentially, and differentially contributed to relative fitness under varied growth conditions.Here, we investigate adaptive specificity in experimental lineages of the highly UVR-mutable epiphytic plant pathogen P. cichorii 302959.These results support our earlier observations that MDR activation may contribute to gains in relative fitness without impeding normal patterns of adaptive specificity in  Mutation is the most fundamental source of variation on which natural selection may drive evolution. However, the predominantly deleterious nature of mutation maintains selection pressure in favor of lower mutation rates as evidenced by the conservation of multiple DNA error-avoidance and error-repair processes Escherichia coli DinB) and polV (E. coli UmuDC) rescue stalled replication forks and permit DNA synthesis across damaged regions of DNA in a template-independent manner by nature of their high processivity and low fidelity Inducible mutability in the form of mutagenic DNA repair (MDR) transiently increases mutation rate through the activation of low-fidelity repair polymerases in response to specific environmental stress conditions such as ultraviolet radiation (UVR) exposure. UVR directly damages DNA causing lesions, including cyclobutane pyrimidine dimers and 6-4 photoproducts, that distort the helical structure, interrupting replication fork progression and inducing the SOS response. The SOS regulon coordinates the control of more than 40 unlinked genes involved in DNA repair, recombination, and cell cycle control Pseudomonas cichorii 302959 rulAB, a homolog of umuDC found in various plant-associated Pseudomonas species P. cichorii 302959 were maintained in a serial transfer regime for 500 generations during which half received daily MDR activation in the form of UVR exposure MDR-mediated UVR tolerance provides a critical ecological advantage to epiphytic plant pathogens harboring Y family polymerases that reside in habitats optimized for solar UVR exposure The results of our initial study suggested that regular activation of inducible mutability in the form of MDR was not detrimental to fitness, but rather could contribute to adaptation and genetic diversity P. cichorii 302959 by examining physiological components of relative fitness improvements. Relative fitness measurements indicate an overall growth advantage that we hypothesized could be subdivided into discrete improvements in bacterial physiology to reveal a more detailed understanding of the adaptation of P. cichorii 302959 to specific laboratory environments. Our results suggest that improvements in doubling and lag times contributed to specific relative fitness gains by both UVR and non-UVR lineages in their respective environments. Surprisingly, specific fitness improvements appeared relatively early in all experimental lineages, independent of regular MDR activation.In the present study, we investigated adaptive specificity in experimental lineages of P. cichorii 302959 was originally isolated in Japan P. cichorii 302959 were derived from a single ancestral colony and propagated by serial transfer for 500 generations in minimal liquid media \u22122 of UVC (254 nm) radiation from an XX-15 UV lamp  that resulted in \u223c10% survival by each lineage population. The energy output of the lamp was monitored with a UV-X radiometer fitted with a UV-25 sensor  and determined to be 1.5 J m\u22122 s\u22121. Following UVR irradiation, cultures were diluted 1\u2236100 into fresh medium and incubated under dark conditions to minimize photoreactivation. These lineages diversified into a fluctuating coexistence of \u2018round\u2019 (R) and \u2018fuzzy\u2019 (F) colony morphotypes. Eight non-UVR lineages (numbered 33\u201340) were diluted daily into fresh medium without MDR activation by UVR exposure and contained only the R morphotype. The culture transfer strategies for both UVR and non-UVR lineages resulted in a 1000-fold daily increase in the growth of each population, representing \u223c10 generations of binary fission.The ancestral \u2018round\u2019 strain of e.g., 25R refers to an isolate from lineage 25 that exhibits the round colony morphotype). Each lineage contained \u223c1010 total P. cichorii 302959 cells at stationary phase, and the relative fitness of these communities has been shown to rely on the ecological interactions of sympatric genotypes 8 cells thawed from preserved UVR lineages to maintain the assemblage of diverse genotypes. Isolates and population samples from generation 500 characterized here are identical to those reported previously Samples from each lineage were periodically preserved in a nonevolving state in 10% glycerol at \u221280\u00b0C. All evolved isolates in this study were derived from the ancestral genotype following either 250 or 500 generations of selection in the lineage experiment . We defiP. cichorii were cultured at 28\u00b0C in Luria\u2013Burtani (LB) broth , in Davis Minimal broth supplemented with 25 mg l\u22121 glucose (DM25) (Difco), or on King's medium B (KB) agar \u22121, gentamicin 10 \u00b5g ml\u22121. Competent cell preparation was performed according to Choi et al.et al.Strains of xylE) which causes expressing colonies on agar media to turn yellow when sprayed with 0.1 M catechol. The relative fitness (W) of the two competitors was calculated as the ratio of their realized growth rate as described previously W\u200a=\u200a1.The relative fitness of all isolates and population samples was determined by direct competition with the ancestor under both UVR and non-UVR conditions to identify patterns of specific or general adaptation as described previously t-tests against the hypothesis of mean equal fitness (W\u200a=\u200a1). Fitness measurements were compared using two-tailed paired t-tests to determine any significant differences in adaptation between growth intervals (generations 250 vs. 500) or growth environments (UVR vs. non-UVR conditions).The six replicates of each relative fitness measurement were analyzed by two-tailed, independent Before optical density (OD) measurement, lineage isolates and population samples were grown overnight in LB broth and subcultured into 10 ml DM25 at 28\u00b0C for 24 hr acclimation. Cultures were diluted 1000-fold into fresh DM25, and 100 \u00b5l samples were removed for OD measurement at 600-nm in 96-well microtiter plates using a Tecan Safire . Samples were removed for measurement at 0 hr and at 1 hr intervals from 4 hr to 15 hr. Growth curves for each lineage isolate and population sample were repeated in triplicate under both UVR and non-UVR conditions.600 values from growth curves were standardized by dividing by the initial OD600 (0 hr) and then log2 transformed. The transformed values were plotted, and the window of exponential growth was identified by linear regression ODN1 and N2 are raw, untransformed OD values corresponding to the window of exponential growth observed in the log2 transformation plot and t is the time interval between them where \u22122 UVC as described above. Cell suspensions were mixed continuously while receiving UVR doses to eliminate survival as a result of shading. Following irradiation, surviving cells were enumerated by dilution plating conducted under dark conditions.Lineage isolates and population samples were grown overnight in LB broth and 2 ml of culture were pelleted, washed with 1 ml saline, resuspended in 1 ml saline, and held on ice. The cell suspensions were mixed with 9 ml saline in a glass petri dish and exposed to a single dose of approximately 140 J mP. cichorii 302959 ancestor under both UVR and non-UVR conditions to examine adaptation during experimental evolution. We evaluated the relative fitness of each lineage by competing both population samples (a subset of the entire lineage maintaining the assemblage of diverse genotypes) and single-colony isolates. In our previous study, we analyzed changes in relative fitness in replicate lineages after 500 generations The relative fitness of all lineages was determined by competition with the P>0.320). Therefore, measurements of the two groups have been combined when comparing isolates from UVR and non-UVR lineages but are also presented individually to provide additional sampling of the genetic diversity present in UVR lineages. Relative fitness measurements were also conducted using population samples to observe any influence of genotype community structure in UVR lineages. We have combined the relative fitness values determined at generation 250 in this study with previously published measurements at generation 500 t-test against the hypothesis of mean fitness equal to that of the ancestral P. cichorii 302959 (W\u200a=\u200a1) and is significant where indicated in the figures. Paired t-tests were also used to determine significant differences in relative fitness between growth environments (UVR vs. non-UVR conditions) or growth intervals (generations 250 vs. 500) and these P values are listed at the bottom of each figure.Isolates from UVR lineages expressed two different morphologies, R and F, and single-colony representatives of each from generations 250 and 500 were characterized. Neither morphotype group exhibited a significant fitness advantage under either UVR or non-UVR conditions  with the exception of the isolate from lineage 37 . When compared to isolates from generation 500, there was no significant difference in relative fitness under non-UVR conditions  were also observed. The ancestral tion 500 . Lag timtion 500 . The lagtion 500 . Converstion 500 . A compl\u22122 s\u22121 was used to resolve subtle differences in UVR tolerance that could not be distinguished at the lower dosage used during lineage propagation. The ancestral P. cichorii 302959 strain exhibited a 0.7% survival rate at the elevated dose. Population samples from UVR lineages displayed the most consistent improvements in UVR tolerance with average survival rates of 4.3% and 4.0% at generations 250 and 500, respectively. R and F morphotype isolates exhibited a mixture of UVR tolerance phenotypes that were higher, lower, or comparable to that of the ancestor. A complete list of UVR tolerance measures for each population sample and isolate is available in Changes in UVR tolerance could lead to changes in relative fitness under UVR conditions. Therefore, the UVR tolerance of population samples and isolates from each UVR and non-UVR lineages taken at generations 250 and 500 was determined following a single dose of UVC. An elevated dose of \u223c140 J mP. cichorii 302959 ancestor under both non-UVR and UVR conditions. The resulting fitness trajectories are plotted in To track changes in relative fitness during lineage growth over the course of 500 generations, preserved population samples from four randomly selected lineages were obtained at different intervals and competed against the Similarly, non-UVR lineages 36 and 39 exhibited fitness gains under their native, non-UVR conditions first . NeitherP. cichorii 302959 emerged early and correlated with discrete growth improvements but was not dependent upon MDR activation. In a previous study, we maintained parallel cultures of P. cichorii 302959 for 500 generations with daily MDR activation in the form of UVR exposure and observed higher relative fitness particularly under UVR conditions P. cichorii 302959 to evaluate this observed adaptive specificity.Our results suggest that adaptive specificity in laboratory evolved populations of the highly UVR-mutable P. cichorii 302959 lineages emerged within the first 250 generations of growth. Additional fitness gains attained between generations 250 and 500 were primarily achieved under UVR conditions, even in non-UVR lineages. The dramatic changes in fitness exhibited by F isolates from lineages 27 and 28 demonstrate that UVR lineage populations contained a dynamic balance of genotypes, and that isolates sampled at generation 500 were not necessarily derived from those sampled at generation 250. Together, these results emphasize the complexity of adaptation in the UVR lineage populations due to the high adaptive potential and plasticity of the ancestral P. cichorii 302959 inducible mutator genotype. Additionally, the increase in relative fitness observed only under UVR conditions between generations 250 and 500 in some non-UVR lineages offers the first indication that beneficial mutations differentially contribute to fitness under the two growth conditions.The relative fitness of all 16 lineages was determined at the generation 250 midpoint of our evolution experiment with the intent to gain further information on the acquisition of fitness observed previously at the generation 500 endpoint. Fitness measurements at the midpoint can offer some indication of the timing, number, magnitude, and parallel nature of adaptive improvements achieved by each lineage. Measurements of relative fitness at generation 250 reflected the same patterns of adaptive specificity observed previously at generation 500 P. cichorii 302959 obtained at generations 250 and 500 under both UVR and non-UVR conditions. Growth dynamic improvements correlated well with changes in relative fitness such that nearly all evolved lineages with increased fitness displayed corresponding reductions in both doubling and lag times compared to the ancestor. The average reductions in both lag and doubling times exhibited by UVR lineages were greatest under UVR conditions while non-UVR lineages displayed comparable reductions under both conditions. These results are consistent with the observed patterns of adaptive specificity in relative fitness measurements suggesting that specific growth improvements are responsible for the characteristic gains in relative fitness displayed by UVR lineages under UVR conditions.Measures of relative fitness indicate the overall advantage of one bacterial strain or population over another but provide no information about the underlying physiological differences responsible for the advantage. Changes in growth dynamics have been identified as distinct components of relative fitness improvements in similar studies conducted previously Improvements in lag time could be indicative of a faster metabolic transition from stationary phase to exponential growth due to adaptation to the culture media or to the cyclic nature of the serial transfer regime. Improvements in lag time under UVR conditions specifically could result from increased UVR tolerance or more efficient DNA repair in the form of improved SOS induction or polymerase processivity. The complex SOS regulatory network is comprised of both transcriptional and post-transcriptional regulators that tightly control the temporal activity of its gene products E. coli, adaptive mutations that contribute to survival through catabolism of cellular detritus P. cichorii 302959 or any evolved lineages in glucose-free Davis Minimal medium amended with a bacterial suspension killed either by prolonged heat or UVR exposure (data not shown). Therefore, increased relative fitness under UVR conditions and the adaptive specificity of UVR lineages that is reflected in improved growth likely did not result from either increased UVR tolerance or a heightened ability to scavenge nutrients as a carbon source.We explored changes in UVR tolerance as an obvious candidate for improved fitness and lag time under UVR conditions but only observed increased UVR tolerance concurrently with fitness gains in a limited number of instances. In general, there was no pattern to suggest that greater UVR tolerance was primarily responsible for increased relative fitness observed under UVR conditions. Alternatively, improved fitness under UVR conditions could result from enhanced nutrient scavenging. Approximately 90% of the population died as a result of UVR exposure during each cycle of the UVR lineage regime. The death of these individuals could release additional nutrients in the form of cell lysate that is transferred with surviving cells to fresh medium for the next cycle of growth. Any mutation that would enhance the utilization of these nutrients could lead to greater fitness exclusively under UVR conditions. In evolution experiments with We previously observed the reproducible emergence of an F morphotype that coexisted with the ancestral, R morphotype in all UVR lineages but never in non-UVR lineages P. cichorii 302959 genotype. Furthermore, the early fitness improvements by UVR lineages are consistent with the emergence of F morphotypes and spontaneous rifampicin-resistant colonies reported previously It is clear from our relative fitness measurements that adaptive changes in both non-UVR and UVR lineages were concentrated in the first 250 generations, confirming both the strong selection pressure of the experimental environments and the high adaptive potential of the ancestral P. cichorii 302959 exhibited by both UVR and non-UVR lineages. Such adaptive specialization can result in fitness trade-offs due to either antagonistic pleiotropy or mutation accumulation resulting in lower fitness under different environmental conditions The fitness trajectories in this study also suggest that adaptive improvements differentially contributed to relative fitness gains under UVR and non-UVR conditions. The ordered acquisition of improvements in the two environments favored the respective conditions under which each lineage was propagated such that UVR lineages first exhibited specific fitness gains under UVR conditions and non-UVR lineages under non-UVR conditions. Based on our previous observations of relative fitness at generation 500, we concluded that non-UVR lineages exhibited comparable fitness gains under UVR and non-UVR conditions due to their adaptation to the shared culture medium P. cichorii 302959 genotype is more poorly adapted to the UVR conditions and therefore more adaptive opportunities exist than under non-UVR conditions. Although the first two possibilities lend support to the proposed positive influence of inducible mutability on adaptive evolution, we do not have sufficient information to distinguish them from each other or from the third possibility.Interestingly, when fitness did increase in the alternate environment, corresponding improvements in fitness were not observed in the native environment. It is unlikely that fitness improvements under UVR and non-UVR conditions are independent. Rather, mutations that contribute to fitness observable only in the alternate environment may represent general improvements of smaller effect in the native environment. After gaining fitness in the alternate environment, UVR lineages continued to gain fitness specifically under their native conditions while non-UVR lineages did not, producing the illusion of adaptive specificity exclusively in UVR lineages. We can propose three possible explanations for this discrepancy: (1) MDR activation provides access to more beneficial mutations by altering the mutation spectrum of UVR lineages; (2) by increasing the overall mutation rate, MDR activation increases the rate at which beneficial mutations appear in the population and non-UVR lineages would gain additional relative fitness if propagated for a longer time; or (3) the ancestral P. cichorii 302959 during experimental evolution by measuring relative fitness and corresponding changes in physiology. Our results suggest that adaptive specificity in this organism correlates with discrete growth improvements but does not depend on MDR activation. Adaptive improvements in all lineages were concentrated in the first 250 generations of experimental evolution and specific increases in relative fitness correlated with distinct improvements in doubling and lag times. Furthermore, UVR lineages exhibited additional gains in fitness after generation 250 exclusively under UVR conditions that were reflected in further doubling and lag time improvements but likely not greater UVR tolerance or scavenging of nutrients to support the growth of new biomass. Fitness trajectories of select lineages clearly indicate that adaptive improvements under UVR and non-UVR conditions were acquired preferentially and differentially contributed to relative fitness under varied growth conditions.In summary, we have investigated the adaptive specificity of The results of this study lend support to our earlier observations that suggest increased mutation rate in the form of inducible mutability does not impede adaptation by mutation accumulation. Rather, UVR and non-UVR lineages preferentially acquired adaptive growth improvements in a similar manner and additional fitness gains by UVR lineages may have been due to greater access to beneficial mutations. Our future work will compare the influence of different mechanisms of mutability on adaptation in an advanced genetic system equipped with genomic tools for analysis.Table S1P. cichorii 302959 during growth under non-UVR and UVR conditions.Doubling time of population samples and isolates from lineages of (DOCX)Click here for additional data file.Table S2P. cichorii 302959 during growth under non-UVR and UVR conditions.Lag time of population samples and isolates from lineages of (DOCX)Click here for additional data file.Table S3P. cichorii 302959 following \u223c140 J m\u22122 UVC.Percent survival of population samples and isolates from lineages of (DOCX)Click here for additional data file."}
+{"text": "Phocarctos hookeri), a nationally critical, declining species impacted by trawl fisheries. We used satellite telemetry and linear mixed effects models to investigate sex differences in the foraging ranges of juvenile NZ sea lions. Male trip distances and durations were almost twice as long as female trips, with males foraging over the Auckland Island shelf and in further locations than females. Sex was the most important variable in trip distance, maximum distance travelled from study site, foraging cycle duration and percent time at sea whereas mass and age had small effects on these characteristics. Our findings support the predictions of the niche divergence hypothesis, which suggests that sexual segregation acts to decrease intraspecific resource competition. As a consequence of sexual segregation in foraging ranges, female foraging grounds had proportionally double the overlap with fisheries operations than males. This distribution exposes female juvenile NZ sea lions to a greater risk of resource competition and bycatch from fisheries than males, which can result in higher female mortality. Such sex-biased mortality could impact population dynamics, because female population decline can lead to decreased population fecundity. Thus, effective conservation and management strategies must take into account sex differences in foraging behaviour, as well as differential threat-risk to external impacts such as fisheries bycatch.Sexual segregation  is observed in a large range of taxa. Investigating causes for sexual segregation is vital for understanding population dynamics and has important conservation implications, as sex differences in foraging ecology may affect vulnerability to area-specific human activities. Although behavioural ecologists have proposed numerous hypotheses for this phenomenon, the underlying causes of sexual segregation are poorly understood. We examined the size-dimorphism and niche divergence hypotheses as potential explanations for sexual segregation in the New Zealand (NZ) sea lion ( Diomedea exulans) have larger overlap with fisheries activities than males, resulting in higher bycatch mortality of females Sexual segregation, defined here as differential space and resource use by males and females Cervus elaphusLoxodonta africanaPicoides pubescensParus atricapillusNumerous hypotheses have been advanced to explain sexual segregation Anguilla rostrataArctocephalus forsteriThe causes of sexual segregation have been predominantly studied in terrestrial vertebrates Phocarctos hookeri) provides an ideal study system to examine two of the main competing hypotheses for sexual segregation: the size-dimorphism (sex-related size differences) or niche divergence (decreasing intraspecific resource competition) hypotheses. Adult male and female NZ sea lions are thought to forage in different areas Notodarus sloanii) around the subantarctic Auckland Islands, both through mortality in bycatch and potential resource competition The New Zealand (NZ) sea lion (Our study aimed to answer three main questions: (1) What are the foraging ranges and at sea movements of juvenile NZ sea lions at the Auckland Islands? (2) Are the size-dimorphism and niche divergence hypotheses potential explanations for sexual segregation in the foraging ranges of NZ sea lions? Under the size-dimorphism hypothesis, although males are larger and would require more energy per unit time to meet energy requirements, females require higher quality (i.e. higher energy) prey due to the allometric relationship between metabolic requirements and body size/gut capacity This study was conducted with approval from the Department of Conservation (DOC) and University of Otago Animal Ethics Committees . Instrument deployments were performed under full inhalant gas anaesthesia, and all efforts were made to minimize pain and suffering.We collected data over four austral summers from January-February, 2007\u20132010 at Sandy Bay, Enderby Island in the NZ subantarctic Auckland Islands  and also vehicle-borne high frequency  transmitters to facilitate recaptures. We attached the instruments to the dorsal pelage of the animal below the shoulder blades on the back midline using two-part epoxy resin. Once the instruments were securely attached, we stopped the flow of anaesthetic and the sea lion was allowed to recover. We observed each animal until it was fully conscious and had returned to the location of capture. Where possible, we recaptured the animals before the end of the field season (February 18) to retrieve instruments.Animal positions at sea were calculated by the Argos satellite system and detailed information on the satellite location classes and number of locations received is provided in . We filtAfter filtering satellite data with the state-space model, we defined complete foraging trips as trips with the start and end locations at Sandy Bay or within 10 km of Enderby Island following Chilvers 2008a. We restricted calculations of mean distance travelled per trip to complete foraging trips. Maximum distance travelled from Enderby Island per foraging trip was measured in ArcGIS 9.3.1 The squid fisheries operate between January-May on the Auckland Island shelf, utilising mid-water column and bottom trawls. To assess the potential sex differences in the overlap of juvenile NZ sea lion foraging grounds with the squid trawl fisheries, we mapped the 50% and 95% kernel UDs of combined fishing effort from 2007\u20132010 (NZ Ministry of Fisheries), along with the kernel UDs of the male and female satellite locations from 2007\u20132010. To quantify individual sea lion overlap with fisheries, we mapped the 50% and 95% kernel UDs of combined fishing effort from 2007\u20132010 (NZ Ministry of Fisheries) along with UDs of individual female and male juvenile NZ sea lions.C) scores. Where necessary, the response variables were power or square root transformed to improve the normality of the model residuals. To improve the interpretability of regression coefficients, we centred and standardized the age and mass predictor variables Although inter-annual variation may influence the foraging behaviour observed, small sample sizes per year precluded the differentiation of annual and individual differences. Furthermore, foraging studies on individual adult female NZ sea lions followed across several years indicate no annual variation in foraging behaviour C) scores To identify the relative importance of the predictor variables  across the different foraging trip characteristics and to generate weighted coefficient estimates, we used a model averaging approach based on the Akaike Information Criterion correction for small sample size .From January\u2013February, 2007\u20132010, we deployed a total of 33 satellite tags on 19 female (2\u20133 years-old) and 14 male (2\u20135 years-old) juvenile NZ sea lions . Two malP<0.001). Male trip distances and maximum distance travelled from the study site were almost twice as long as female distances (2 vs. 523 km2), while the 95% kernel UDs of males were over two times larger than females , maximum distance from study site  and foraging cycle duration . Significant repeatability estimates indicate male juvenile NZ sea lions consistently travelled further distances for longer periods than females.Sex had the most important effect on trip distance, maximum distance from study site, foraging cycle duration and percent time at sea  and S3. 2 vs. 3844 km2). As a percentage of the 95% kernel UD area, female foraging grounds had proportionally almost double the amount of overlap with squid trawl fisheries operations than males  with squid trawl fisheries. From 2007\u20132010, the squid fisheries operated at depths 98\u2013338 m (NZ Ministry of Fisheries). Sixty-one percent of tagged female and 47% of male juvenile NZ sea lions dives were within the depth range targeted by squid trawl fisheries . Based on the assumption that male and female NZ sea lions behave similarly in fishing areas (e.g. one sex does not avoid trawl nets more than the other sex), a consequence of the sexual segregation in the foraging ranges of juvenile NZ sea lions is the higher risk of resource competition and bycatch of females in the squid fishery. Juvenile female NZ sea lion foraging grounds had proportionally double the overlap with fisheries operations than males . Of the Sex-biased mortality of females in fishery operations have been reported for several species  from 2007\u20132010. The Auckland Islands are represented in light grey. Bathymetric contours are shown as black lines. The Auckland Island shelf is represented by the 500 m bathymetric boundary.(TIF)Click here for additional data file.Figure S2Utilisation distributions (UD) of individual female juvenile New Zealand sea lions (Phocarctos hookeri) and squid trawl fisheries. Individuals with: A) 0\u201325%, B) 26\u201350% and C) 51\u201375% of their 95% UD overlapping with fisheries. Note panel C is represented by two figures of five individual females per map.(TIF)Click here for additional data file.Figure S3Utilisation distributions (UD) of individual male juvenile New Zealand sea lions (Phocarctos hookeri) and squid trawl fisheries. Individuals with: A) 0\u201325%, B) 26\u201350% and C) 51\u201375% of their 95% UD overlapping with fisheries.(TIF)Click here for additional data file.Table S1Satellite location data for female and male juvenile New Zealand sea lions (Phocarctos hookeri).(DOC)Click here for additional data file.Table S2Results of linear mixed effects models run on juvenile New Zealand sea lion (Phocarctos hookeri) foraging trip characteristics: trip distance and maximum distance from study site.(DOC)Click here for additional data file.Table S3Results of linear mixed effects models run on juvenile New Zealand sea lion (Phocarctos hookeri) foraging trip characteristics: foraging cycle duration and percent time spent at sea.(DOC)Click here for additional data file."}
+{"text": "To the Editor: Birge and Sonnesyn report the first death of a Minnesota resident caused by Powassan virus (POWV) (1]) .The 17 POWV infections detected in Minnesota residents from 2008 through 2011   were found through enhanced surveillance. Health alerts to Minnesota medical providers described POWV as a possible etiologic agent for viral meningitis and encephalitis. Providers consulted with MDH on suspected cases and submitted serum and cerebrospinal fluid specimens to MDH. MDH conducted serologic testing for endemic arboviruses (including POWV) and reverse transcription PCR (RT-PCR) for flaviviruses and POWV. MDH would not have detected any POWV infections without enhanced surveillance. Limited field studies also identified POWV-infected ticks in 4 Minnesota counties  is preferred (Ixodes scapularis ticks (blacklegged ticks), the tick species associated with deer tick virus transmission, and viruses from all POWV-positive tick pools were confirmed as deer tick virus by sequencing. The distribution of the 2 lineages in North America is poorly understood, and most cases likely go undetected without specific POWV surveillance efforts.Few POWV infections are identified by lineage (prototype vs. deer tick virus); Minnesota\u2019s first case in 2008 was identified as a deer tick virus infection, but the lineage was unknown for the other 16 cases. However, many case-patients had likely exposure to"}
+{"text": "Fibrotic burden of LV myocardium quantified by CMR provides additional information about LA size and mechanics than morphological severity of LV hypertrophy measured by LV mass index alone.Progressive myocardial stiffness of the LV in patients with hypertrophic cardiomyopathy (HCM) impedes early diastolic filling and left atrial (LA) emptying functions. Over time, LA of patients with HCM progressively dilates and undergoes structural and functional remodeling with serious cardiac events such as development of atrial fibrillation and diastolic heart failure despite optimal medical therapy.We studied 65 HCM patients  with CMR. The fibrotic content of the LV myocardium  was obtained using serial R1 mapping by cine-IR method before and up to 30 minutes after contrast injection. LA volumes and LA emptying function across 3 phases of the cardiac cycles, and LV function were also quantified. We sought to determine the strongest variables that predispose the patients to have LA dilatation and impaired LA emptying function.FIMeanSeg demonstrated strong positive correlation with LA volumes across all 3 phases of the cardiac cycle, with the strongest correlation with LAMax volume at end-ventricular systole (r=0.41, P = 0.0005, Figure FIMeanSeg provides independent association with LV volume beyond knowledge of ventricular functional parameters and severity of ventricular hypertrophy by LV mass. This novel method may add to the current characterization of impaired diastolic function in HCM patients and may have prognostic implications.Yucheng Chen got the salary from China Scholarship Council."}
+{"text": "Patients with transposition of the great arteries (TGA) after atrial baffle switch operation show differences in ventricular torsion and outflow tract geometry compared to healthy volunteers. We sought to investigate if these differences in cardio-mechanics translate into abnormal blood flow patterns in the pulmonary trunk and the aorta.Blood flow patterns were assessed with flow-sensitive four-dimensional velocity-encoded magnetic resonance imaging (4D VEC MRI), using a 1,5T Phillips MRI system. Measurements were made in the pulmonary trunk and the aorta in healthy volunteers (n=7) and TGA patients after atrial baffle switch operation (n=10). Blood flow was analyzed for vortex formation using custom-made software.There were clear differences in blood flow patterns between healthy volunteers and TGA patients in both the pulmonary trunk and the aorta. In healthy volunteers, flow was laminar, parabolic in the pulmonary trunk and showed left helical flow pattern in the aorta. In TGA patients we observed opposite flow patterns with predominant parabolic flow in the aorta but helical flow and vortex formation in the pulmonary trunk.There are abnormal flow profiles in the aorta and pulmonary trunk in TGA patients. The data of this study provides evidence that differences in left and right ventricular cardio-mechanics directly translate into different flow patterns."}
+{"text": "Studies performed three decades ago in our laboratory supported the hypothesis that radiation efficacy may be augmented by bacterial extracts that stimulate non-specific systemic antitumor immune responses. Application to the clinic was halted by unacceptable side effects and toxicities resulting from exposure to whole bacterial pathogens. Later scientific advances demonstrated that DNA isolated from bacteria was immunostimulatory and could be reproduced with synthetic oligodeoxynucleotides (ODNs), thus fueling the transition from bugs to drugs. Unmethylated CpG motifs within bacterial DNA induce activation of Toll-like receptor 9 and subsequently activate antigen-specific cellular immune responses. CpG ODNs have demonstrated favorable toxicity profiles in phase I clinical trials. We showed that this potent immunoadjuvant can be used in combination with radiation therapy to enhance local and systemic responses of several murine tumors. Studies demonstrated that enhanced tumor response is mediated in part by the host immune system. Antitumor efficacy was diminished in immunocompromised mice. Animals cured by combination of radiation and CpG ODN were resistant to subsequent tumor rechallenge. This body of work contributes to our understanding of the dynamic interplay between tumor irradiation and the host immune system and may facilitate translation to clinical trials. Bacillus Calmette\u2013Gu\u00e9rin and Corynebacterium parvum were used to stimulate antitumor immunity  of sarcomas ,b. The r disease .C. parvum was an effective adjunct to radiotherapy, since treatment response depends not only on radiobiological factors but also on the immune response of the tumor-bearing host (C. parvum increased radiosensitivity of well-established (8 mm diameter) immunogenic murine fibrosarcomas when local irradiation was given as a single-dose or in multiple fractions . In normal mice, 100% tumor take was achieved with inoculations as low as 2.5 \u00d7 105 tumor cells. At 100\u2013120 days after treatment, mice cured by radiation alone required 2 \u00d7 105 tumor cells to produce 50% tumor take, whereas mice treated with CpG ODN 1826 plus irradiation were totally resistant to tumor rechallenge with cell numbers as high as 8 \u00d7 105. Like the animals rechallenged by the s.c. route, mice locally cured by CpG ODN 1826 plus irradiation were much more resistant to development of artificial metastases in the lung than were those cured by radiation alone. These results showed that the systemic antitumor rejection response generated by CpG ODN 1826 plus radiotherapy exerted antitumor effects long after exposure to the agents. Secondary tumor rejection was most likely due to development of a memory response and possibly specific T cell-mediated immunity  radiotherapy induced an immune-mediated abscopal effect when combined with anti-CTLA-4 antibody in two preclinical rodent tumor models  was well-tolerated and induced systemic antitumor responses even in patients with significant tumor burden (in situ vaccination strategy combined with radiation in patients with T cell lymphoma mycosis fungoides skin lesions (Early clinical reports showed CpG 7909 was an effective and well-tolerated adjuvant for improving vaccine responses ,b. Minorr burden . Encoura lesions .Treatment of mice bearing established immunogenic or non-immunogenic tumors with CpG ODN 1826 markedly enhanced response to single-dose and fractionated radiotherapy, likely through immune-mediated mechanisms. CpG ODN also induced a durable systemic immune memory response against subsequent rechallenge with tumor cells. These observations suggest CpG ODN could be used not only as an \u201cimmunosensitizer\u201d in combination with radiotherapy but also as an adjuvant to prevent or reduce metastatic disease at sites distant from the primary irradiated tumor. These findings and others have demonstrated that CpG ODNs can be given in combination with conventional radiotherapy to improve therapeutic efficacy. Further studies are warranted to elucidate the dynamic interplay between tumor irradiation and the host immune system to facilitate translation to clinical trials. Our studies using CpG ODNs as radiation enhancing agents are being supplemented by new integrated approaches proposing a partnership between radiotherapy and immunotherapy designed to capitalize on radiation\u2019s ability to enhance immunogenicity of the primary tumor and its microenvironment .The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Helicobacter pylori (H. pylori) and the actual H. pylori treatments fail with increased regularity because of continuously rising antibiotic resistances. To meet this challenge, we focus on the development of a new anti-infective therapy against H. pylori by targeting a secreted enzyme, high temperature requirement A (HtrA). Release of the serine protease HtrA near the host\u2019s gastric epithelial cells leads to loss of cellular adhesion due to E- cadherin cleavage [In vitro substrate cleavage assays as well as cellular infection assays fully support the biophysical data.More than 50% of the world population is infected with cleavage . We inve"}
+{"text": "Every day health care workers are exposed to dangerous and deadly blood borne pathogen like HBV. HBV is 100 times more likely to be transmitted after a percutaneous exposure through infected blood than HIV. Hepatitis B infection can be prevented by vaccination.To study the effect of vaccination program among the health care workers of Sri Ramachandra University (SRU), Porur, Chennai. It is mandatory for all health care workers of SRU to be vaccinated against HBV at the time of appointment, producing anti-HBs titer is mandatory. They are advised for re-vaccination according to their anti-HBs titer.This study was conducted among the health care workers of SRU who had needle stick injury for a period of 1 year (1st November 2010 to 31st October 2011).The blood samples were processed for serology screening by Micro Particle Enzyme Immuno assay (MEIA) followed by ELISA. The results were studied.85 samples from health care workers who had needle stick injury were processed .The samples were from doctors (38%), nurses (20%), technicians (7%), housekeeping staff (23 %), and students (10%). All the samples of injured persons were found seronegative by both methods, anti-HBs titer was found to be protective.Strict HBV vaccination program and monitoring the anti-HBs titer were effective in prevention of HBV transmission by needle stick injury to health care workers of SRU. This can be implemented in all health care organizations for the benefit of health care providers."}
+{"text": "Genetically manipulated animals like mice or rabbits play an important role in the exploration of human cardiovascular diseases. It is therefore crucial to identify animal models that closely represent the human cardiac phenotype.Phase contrast MRI  was usedSimilar behavior in the global LV myocardial motion pattern was observed in all species, particularly for the radial and long-axis motion as can be seen in Figure The results revealed a significantly different myocardial motion pattern in mice and rabbits compared to humans. Especially systolic rotation of rabbits more closely resembled human left ventricular performance, a finding that should be considered when investigating myocardial performance using mouse models. These findings underline that in the assessment of myocardial motion animal models cannot be conferred one-to-one to human beings. This deeper knowledge of mammalian-related differences in myocardial motion can help to select animal models that best mimic the human phenotype when investigating myocardial diseases.DFG FO 507/3-1."}
+{"text": "Brain tissue changes in autism spectrum disorders seem to be rather subtle and widespread than anatomically distinct. Therefore a multimodal, whole brain imaging technique appears to be an appropriate approach to investigate whether alterations in white and gray matter integrity relate to consistent changes in functional resting state connectivity in individuals with high functioning autism (HFA). We applied diffusion tensor imaging (DTI), voxel-based morphometry (VBM) and resting state functional connectivity magnetic resonance imaging (fcMRI) to assess differences in brain structure and function between 12 individuals with HFA  and 12 healthy controls . Psychological measures of empathy and emotionality were obtained and correlated with the most significant DTI, VBM and fcMRI findings. We found three regions of convergent structural and functional differences between HFA participants and controls. The right temporo-parietal junction area and the left frontal lobe showed decreased fractional anisotropy (FA) values along with decreased functional connectivity and a trend towards decreased gray matter volume. The bilateral superior temporal gyrus displayed significantly decreased functional connectivity that was accompanied by the strongest trend of gray matter volume decrease in the temporal lobe of HFA individuals. FA decrease in the right temporo-parietal region was correlated with psychological measurements of decreased emotionality. In conclusion, our results indicate common sites of structural and functional alterations in higher order association cortex areas and may therefore provide multimodal imaging support to the long-standing hypothesis of autism as a disorder of impaired higher-order multisensory integration. Autism spectrum disorders (ASD) are neurodevelopmental and behaviorally defined disorders characterized by deficits in social reciprocity, impaired communication and repetitive patterns of behavior and interests The precise pathophysiology of ASD remains unclear apart from ASD that occur secondary to clearly defined neurological or genetic disorders like tuberous sclerosis or Rett syndrome. So far, genetic These altered neural tissue properties have been proposed to be exponentially distributed meaning that early brain abnormalities in ASD increasingly affect additional regions and functional systems throughout development A data-driven, multimodal structural  and functional (fcMRI) imaging approach might be able to detect superregional, system-level alterations in HFA as it does not limit the analysis to predefined regions, tissue types or functional systems.Diffusion tensor imaging (DTI) is based on the measurement of diffusion properties of water molecules Voxel based morphometry (VBM) is a complementary approach to investigate structural brain abnormalities by assessing macroscopic volumetric changes of gray and white matter brain tissue. Structural neuroimaging studies in HFA have reported decreased white matter Task dependent functional magnetic resonance imaging (fMRI) studies in HFA have shown various alterations Functional connectivity magnetic resonance imaging (FcMRI) is an approach that allows for the detection of functional brain networks without task constraints. Functional connectivity has been defined as the temporal correlation of a neurophysiologic index measured in different brain areas In summary the reported VBM, DTI and fcMRI findings indicate that individuals with HFA display alterations of gray matter volume, fractional anisotropy and functional connection strength, and that these alterations predominantly affect frontal and temporal association cortices.We hypothesized that structural and functional alterations in HFA, although complex and widely distributed, affect similar or overlapping brain regions. We furthermore expected that these convergent structural and functional alterations are more likely to be located in multimodal association cortex areas rather than in unimodal primary sensory or motor cortex regions. To test these hypotheses, this study combined structural  and functional (fcMRI) data-driven imaging approaches.All participants gave written consent before participating. The study was approved by the institutional review board of Ludwig-Maximilians University Munich and complies with the declaration of Helsinki. HFA participants were recruited from the outpatient clinic of the Department of Psychiatry and Psychotherapy, Ludwig-Maximilians University Munich. Healthy controls were recruited by advertisement and word of mouth. For subject characteristics see All participants had a full scale IQ >85. The language-based IQ of HFA and HC individuals did not differ significantly (p\u200a=\u200a0.70). The language based IQ was estimated using a vocabulary test Two additional psychological tests were applied to the HFA group exclusively. The first one was the Freiburg Personality Inventory (FPI) which is a psychological test to assess personality traits http://fcon_1000.projects.nitrc.org/indi/abide/.Data acquisition was performed at a magnetic field strength of 3.0 Tesla . DTI was performed using a singleshot spin-echo sequence and SENSE parallel imaging (undersampling factor of 3). Diffusion-weighted images were acquired in 20 non-collinear diffusion-encoding directions with multiple diffusion weighting b-values (b\u200a=\u200a1000 s/mm2 and b\u200a=\u200a0). Data acquisition parameters included the following: 25 contiguous (no-gap) 4.0 mm-thick axial slices with an acquisition matrix of 128\u00d7128 over a FOV of 230 mm, repetition time (TR) \u200a=\u200a 9300 ms, echo time (TE) \u200a=\u200a 102 ms, and spatial resolution \u200a=\u200a 1.8\u00d71.8\u00d74.0 mm. The DTI sequence was repeated three times and averaged to obtain stable diffusion parameters. For an anatomical reference and the VBM analysis a high-resolution isotropic Magnetization Prepared Rapid Gradient Echo (MPRAGE) sequence was acquired . During the 6-minute resting state functional experiment participants were instructed to minimize head movement and stay awake with their eyes closed. Data was acquired using T2*-weighted echo planar imaging . All high-resolution T1 MPRAGE images were quality controlled by a board certified radiologist to detect potential artifacts such as ringing due to motion, spiking or signal loss. The imaging raw data illustrated in this study has been made publically available through the ABIDE (Autism Brain Imaging Data Exchange) consortium and can be downloaded here: To investigate between group differences in FA values, we analyzed DTI data using the tract-based spatial statistics (TBSS) approach implemented in FSL 4.16  Software Library, Oxford, UK). Images were corrected for eddy currents due to changing gradient fields and head motions Structural data analysis was performed using the VBM tool implemented in FSL 4.16. Structural images were brain-extracted using BET http://afni.nimh.nih.gov/afni). The first 5 functional scans of each session were discarded. We used the FMRI Expert Analysis Tool (FEAT) All data analysis steps were performed using FSL 4.16 and Analyses of Functional Images . Previously preprocessed DTI and VBM files of HFA participants and controls served as the input. The algorithm was set to decompose the multimodal input into eight co-varying components. The resulting pseudo-z-scored component maps were normalized to values between -8 and 8, analogous to Groves and colleagues To test the relationship between measures of different imaging modalities an additional analysis called \u201elinked independent component analysis for multimodal data fusion\u201c was performed. Linked ICA is a robust data fusion model that takes multi-modal data and characterizes inter-subject variability in terms of a set of multimodal components Psychological test results were correlated with FA, VBM and functional connectivity values within regions showing the most significant differences between HFA and HC. In order to maintain statistical power, we limited the correlation analysis to two out of twelve subscales of the FPI , namely emotionality and social interaction. These test items were chosen because alterations in these domains represent core features of HFA, rather than other subscales like aggressive behavior or health sorrows. The QEAS (questionnaire to estimate autistic symptoms) only consisted of 2 subscales, namely empathy and adequate social behavior, both of which were tested for correlation with imaging measures. In addition, we tested all subscales  and the sum of the Autism Quotient Questionnaire. Within each modality the significance of the Pearson product moment correlation results was Bonferroni-corrected for multiple testing . To correlate functional connectivity results we defined one region of interest (ROI) in the left STG based on the statistical group difference map obtained during fcMRI analysis and calculated the connection strength to the DMN. To correlate VBM measures, individual gray matter volume was summed up in a ROI in the left MTG, based on the VBM group difference map obtained previously. To correlate DTI measures we defined two regions of interest (ROI) based on the statistical group difference map obtained during DTI analysis. ROIs had a diameter of 16 mm around the peak voxel on the FA skeleton. FA values for each HFA subject were averaged within each of these two ROIs and correlated to psychological test results.corr\u22640.01, DTI analysis revealed three main clusters of significantly reduced FA values in HFA when compared to HC: HFA individuals displayed lower FA values in a right-sided cluster reaching from the splenium of the corpus callosum into the superior longitudinal fasciculus within the parietal and temporal lobe and into the lateral occipital cortex (At pcorr\u22640.1). At an uncorrected p-value (puncorr\u22640.001) clusters of reduced gray matter volume of HFA were detected within the bilateral temporo-parietal junction area  and functional (fcMRI) data-driven imaging approaches to detect subtle, complex and widely distributed brain alterations in individuals with HFA and to investigate whether these alterations affect similar brain regions across modalities. We found three regions of convergent structural and functional alterations in HFA, all of which were located in higher order association cortex. The two regions displaying the most prominent FA value decrease, namely the right temporo-parietal junction area and the left frontal lobe showed concomitant functional connectivity decrease to the DAN and the LFPN respectively and a trend towards decreased gray matter volume. Interestingly, DTI alterations in these two main clusters seemed to be located down the neuronal stream to VBM changes. A formal testing of the relation between these structural properties revealed that DTI and VBM measures in these two clusters co-varied across participants, meaning that high FA values coincided with high gray matter volume and vice versa. In a third cluster of convergent structural and functional alterations decreased functional DMN connectivity in the bilateral superior temporal gyrus was accompanied by a trend towards gray matter volume decrease in the temporal lobe of individuals with HFA.The functional and structural differences between HFA and HC individuals in the right temporo-parietal cortex found in this study are in line with previously reported abnormalities of parietal lobe anatomy in terms of alterations in FA-properties The temporal lobe is another region known to be affected by autism pathology Convergent structural and functional alterations in HFA were also revealed in a mainly left-sided cluster including the prefrontal cortex, the ACC and the anterior corpus callosum. Differences in frontal lobe anatomy and function have previously been described in Asperger\u2019s syndrome The main sites of functional and structural pathology reported in the present study can be attributed to higher order association cortex while primary sensory and motor cortices show almost no significant differences in functional connectivity strength or structural integrity. Higher order association areas are located in the prefrontal, the superior temporal and in the inferior parietal cortex and are known to display similar cytoarchitectonic properties One limitation to our study is that no formal analysis of the relationship between functional connectivity and structural changes was performed. While the relation between DTI and VBM measurements had been successfully explored before In conclusion, the results of the present study indicate that brain alterations in HFA, although subtle and widely distributed, converge into common sites of structural and functional differences in higher order association cortex areas such as the temporo-parietal junction and the prefrontal cortex in individuals with high functioning autism. These findings support the long-standing hypothesis of autism as a disorder of impaired higher-order multisensory integration.Figure S1Relation between DTI and VBM parameters. To investigate the relationship between DTI and VBM variance, \u201clinked independent component analysis for multimodal data fusion\u201d, a data fusion model that characterizes inter-subject variability of multi-modal data in terms of a set of multi-modal components, was performed. Here we show one component where DTI and VBM parameters co-varied across participants. This component comprised multiple brain regions, including the left frontal cortex and right temporo-parietal cortex. The images are color-coded according to significance (z-statistic), with red-yellow showing larger values for subjects with positive weights . To show the effects within regions that show a disease effect in HFA, DTI and VBM results shown in (TIFF)Click here for additional data file."}
+{"text": "Gene silencing of O6-methylguanine\u2013DNA methyltransferase (MGMT) by promoter methylation improves the outcome of glioblastoma patients after combined therapy of alkylating chemotherapeutic agents and radiation. The purpose of this study was to assess the frequency of MGMT promoter methylation in soft tissue sarcoma to identify patients eligible for alkylating agent chemotherapy such as temozolomide.Paraffin tumor blocks of 75 patients with representative STS subtypes were evaluated. The methylation status of the MGMT promoter was assessed by methylation-specific polymerase-chain-reaction analysis (PCR). Furthermore, immunohistochemistry was applied to verify expression of MGMT. MGMT gene silencing was assumed if MGMT promoter methylation was present and the fraction of tumor cells expressing MGMT was 20% or less. Methylation specific PCR detected methylated MGMT promoter in 10/75 cases. Immunohistochemical staining of nuclear MGMT was negative in 15/75 cases. 6/75 tumor samples showed MGMT promoter methylation and negative immunohistochemical nuclear staining of MGMT. In none of the tested STS subtypes we found a fraction of tumors with MGMT silencing exceeding 22%.MGMT gene silencing is a rare event in soft tissue sarcoma and cannot be recommended as a selection criterion for the therapy of STS patients with alkylating agents such as temozolomide. Soft tissue sarcoma (STS) form a heterogeneous group of malignant tumors arising in the mesenchymal tissues. A considerable fraction of patients presents with locally advanced disease and requires multimodal therapy including chemotherapy or chemoradiation. DoxorubParaffin blocks of tumor biopsie or resections of 75 patients with representative histological sarcoma subtypes were obtained from the local tumor tissue bank Table\u2009. These tFor methylation specific PCR, genomic DNA was isolated from paraffin sections of the selected tissue blocks and bisulfite converted with a commercial kit  according to the manufacturer\u2019s instructions. The bisulfite treated DNAs were amplified by a two-step PCR approach to improve the sensitivity of detecting methylated alleles. For theImmunohistochemical analysis of formalin-fixed, paraffin-embedded sections of the selected tumor samples was performed according to standard protocols. The primary antibody used was MGMT Monoclonal Antibody MT 23.2  after heat antigen retrieval in pH 9 buffer . Only nuclear staining was considered positive. MGMT expression was considered lost when there were 20% or less stained tumor cell nuclei.MGMT gene silencing was assumed if methylation specific PCR detected MGMT promoter methylation AND immunohistochemistry demonstrated MGMT expression in less or equal than 20% of tumor cells. Results of these analyses are presented descriptively. Median and range are given if appropriate.Methylation specific PCR detected unmethylated MGMT promoter in 65/75 cases. In 10/75 tumor samples we found MGMT promoter methylation. Yet, in each of these cases also unmethylated MGMT promoter was detected. An example of the methylation specific PCR is given in Figure\u2009Immunohistochemical staining showed inhomogeneous expression of MGMT in most patients. Immunohistochemistry was regarded negative in 15/75 cases. An example of negative and positive staining for MGMT is depicted in Figure\u2009In 6/75 tumor samples we detected both MGMT promoter methylation and negative staining of MGMT. In none of the tested STS subtypes we found a fraction of tumors with MGMT silencing (MGMT promoter methylation and negative immunohistochemistry for MGMT) that exceeded 22% , malignant fibrous histiocytoma (MFH) and synovial sarcoma and reported MGMT promoter methylation in 21/62 cases. KawagucA selection criterion for a personalized therapy in soft tissue sarcoma should be easy and reliable to assess, discriminate between tumors that are targeted well and positive in a relevant number of patients. AlthougAll authors declared that they have no competing interest.JJ, FW, PS and PH participated in the design of the study. PH took responsibility for the funding. MH, CS and PS carried out the methylation specific PCR and immunohistochemistry. JJ and MH performed the statistical analysis. JJ drafted the manuscript. All authors read and approved the final manuscript."}
+{"text": "While optimal cytoreduction is the standard of care for advanced ovarian cancer, the related post-operative morbidity has not been clearly documented outside pioneering centers. Indeed most of the studies are monocentric with inclusions over several years inducing heterogeneity in techniques and goals of surgery. We assessed the morbidity of optimal cytoreduction surgery for advanced ovarian cancer within a short inclusion period in 6 referral centers dedicated to achieve complete cytoreduction.The 30 last optimal debulking surgeries of 6 cancer centers were included. Inclusion criteria included: stage IIIc- IV ovarian cancer and optimal surgery performed at the site of inclusion. All post-operative complications within 30 days of surgery were recorded and graded using the Memorial secondary events grading system. Student-t, Chi2 and non-parametric statistical tests were performed.180 patients were included. There was no demographic differences between the centers. 63 patients underwent surgery including intestinal resections (58 recto-sigmoid resection), 24 diaphragmatic resections, 17 splenectomies. 61 patients presented complications; One patient died post-operatively. Major (grade 3\u20135) complications requiring subsequent surgeries occurred in 21 patients (11.5%). 76% of patients with a major complication had undergone an ultraradical surgery (P\u200a=\u200a0.004).While ultraradical surgery may result in complete resection of peritoneal disease in advanced ovarian cancer, the associated complication rate is not negligible. Patients should be carefully evaluated and the timing of their surgery optimized in order to avoid major complications. Residual disease after surgery is the main prognostic factor in advanced ovarian cancer Extensive debulking surgery may increase morbidity and delay initiation of chemotherapy The following specialized and high-volume care centers were included in this longitudinal retrospective study.Institut Claudius Regaud, Toulouse; Institut Gustave Roussy, Villejuif; Institut Paoli Calmettes, Marseille; H\u00f4pital Europ\u00e9en Georges Pompidou, Paris; Centre Oscar Lambret, Lille; Institut Bergoni\u00e9, Bordeaux.In order to avoid any bias due to case selection we included the last 30 patients who underwent complete cytoreductive surgery for an advanced ovarian cancer in each center.All surgeries were performed by/or under the supervision of a senior surgeon (more than 5 years of experience in the management of advanced ovarian cancers).Inclusion criteria: we considered patients with primary epithelial ovarian carcinoma stages IIIC and IV operated in the participating centers. Stage IIIC disease included patients with bulky peritoneal disease, but not those with lymph node involvement only. All surgical procedures had to be performed in the inclusion center, achieving complete  cytoreductive surgery. In case of neo-adjuvant chemotherapy, diagnosis and tumor extent was assessed by an initial laparoscopy.Primary debulking surgery (PDS) was defined as patients undergoing a debulking surgery before any chemotherapeutic treatment. Interval debulking surgeries (IDS) was defined as patient undergoing a debulking surgery after cycles of neo-adjuvant treatment. The numbers of cycles were at the discretion of the treating physician.All data were recorded without identifiers therefore our study did not require informed consent from patients. The need for written informed consent from the participants was waived as this was an audit with no identifiers accessible to the external observers.2, liver resection.All patients\u2019 charts were collected and analyzed by external observers  according to a predefined checklist. Demographic, per and postoperative data were recorded. Sugarbaker scoring system The Memorial Sloan-Kettering Cancer Center surgical secondary events grading system We considered all events occurring within 30 days after debulking surgery.All patients were staged according to the International Federation of Gynecology and Obstetrics (FIGO) system Categorical variables were compared using Fisher exact test and continuous variables were compared using the Student t-test. All statistical tests were two-sided and differences were considered significant at a level of p<0.05.180 patients operated between 2005 and 2008 were included. Demographic characteristics of the population are presented in The mean Sugarbaker score was 14.8, ranging from 10 to 33. Sixty (33.3%) patients had an extensive disease with Sugarbaker score above 10. 128 (71%) patients underwent a laparoscopy before the cytoreductive surgery. Seventy one patients (40%) underwent PDS followed by adjuvant chemotherapy. One hundred and nine patients (60%) received neo-adjuvant chemotherapy and underwent IDS after a mean of 3.2 cycles of neoadjuvant chemotherapy. There were no demographic differences between these two groups. The procedures performed are depicted in There were 61 (33%) complications comprising 40 (22%) minor and 21 (11%) major complications . One hunWe analyzed the different factors involved in the occurrence of complications. ASA score, presence of ascitis and previous surgeries were not associated to the occurrence of complications  in univariate analysis.As demonstrated in Diaphragmatic and small bowel resections were not associated with increased complications. Operative parameters such as duration of surgery, results of the surgery  and use of drains were not associated with post-operative complications on univariate analysis.In this multicentric analysis of surgical morbidity during cytoreductive surgery for advanced ovarian cancer we identified the following variables being predictive for complications: timing of surgery (PDS vs. IDS), the extent of surgery  and realization of a colic or rectal resections. This is concordant with a recent study published by Aletti et al. We used the MSKCC scoring system to classify complications occurring in our patients. Our overall rate of complications was 33% (61 patients/180 patients), with 11% (22 patients/180 patients) having severe complications. The complication rate in a meta-analysis using population-based reports varied between 2.5% to 4.8% We chose a different approach and established an independent audit. We selected 6 different reference centers for the treatment of advanced ovarian carcinomas. In order to avoid selection bias we performed a longitudinal study including the 30 last patients who underwent optimal debulking surgery for ovarian cancer. Two external reviewers independently reviewed the records. The patients were homogenous with no significant demographic differences across the six centers. We included only the last 30 patients per center to reduce as much as possible the bias induced by heterogeneity of care induced by long inclusion periods. Therefore we have limited most of the bias induced by retrospective studies. Several studies have documented that gynecologist-oncologist usually gives optimal level of care in advanced ovarian cancers The inclusion criteria of this study was complete surgery achieved we did not record the number of patients in which complete surgery was attempted. However in multicentric studies performed in France including many of the centers which participated in this study, the rate of complete surgery was around 70%\u201385% As demonstrated by the univariate and multivariate analysis, most of the major complications were related to bowel resections (14/22).Other radical procedures such as extensive peritoneal resections or diaphragmatic resections were not associated to significant increase of major complications. This is in accordance with Chereau et al., who found an acceptable complication rate of diaphragmatic surgery for stage III/IV ovarian cancer surgeries All patients in our study had immediate re-anastomosis. 13 patients (7.2%) had diverting protective stomas, two were performed for the management of a complication during reoperation.. Most of the anastomosis were performed mechanically (49/61).Mourton et al. published their experience of 70 patients with recto-sigmoid resection and primary anastomosis Our overall leakage related complications were slightly above the range of the literature with 14/180 patients (7.7%) with a lower rate of protective stomas. The rate of complications due to anastomotic leak was 22% (14/61) if we only consider patients with bowel resection. Several factors can explain higher complication rate related to bowel resection in our study: (i) most of the patients had advanced disease with important tumor burden (ii) we only included patients with optimal surgeries and maximal surgical efforts. (iii) there is no reporting bias as external auditors longitudinally included all cases. (iv) finally the low rate of protective stoma might explain why a significant number of the anastomotic leaks directly lead to complications requiring radiological or surgical intervention. Whether we should perform diverting protective stoma in case of bowel (recto-sigmoid) resection in advanced ovarian cancer surgery cannot be answered by our study.We were able to identify some risk factors of anastomotic leak. First Sugarbaker scores of patients with bowel resections who presented major complications were significantly higher than peritoneal carcinosis index of patients with bowel resection without major complications (19+/\u22125.03 versus 10+/\u22126.32). It seems that increased morbidity is not due to a unique surgical procedure but to accumulation of multiple bowel resections associated to extensive peritoneal resections that might act as a protective barrier. We also observed a trend for patients who had neo-adjuvant chemotherapy to develop less major complications following bowel resections (13% for patient with neo-adjuvant chemotherapy versus 32% for patients without neo-adjuvant chemotherapy). We had recorded characteristics for bowel anastomosis. While most of them were made automatically with few protective stomas the numbers of complications did not allow us to carry an insightful statistical analysis. In the participating centers the bowel resection and anastomosis was directly made by the gynecologist-oncologists .A meta-analysis by Bristow et al. demonstrated that each cycle of neo-adjuvant chemotherapy will have a negative incidence on the overall survival. However a recent meta-analysis demonstrated than neoadjuvant chemotherapy helped the gynecologic oncologist achieve an increased rate of optimal cytoreduction Our study demonstrates a lower number of complications in patients with neoadjuvant chemotherapy, in relation to the reduction of the need for radical surgery. The recently EORTC randomized trial has demonstrated that neo-adjuvant chemotherapy might be as good as upfront surgery in advanced ovarian cancer This is a multicentric study of post-operative complications in optimal surgery of advanced ovarian carcinomas performed as an independent audit. While the overall complication rate is acceptable and justifies active surgical approach we have been able to point out bowel resection as the main cause of major complications and therefore suggest that patients requiring such procedure to be clearly identified and optimal preventive procedures applied to prevent occurrence of major complications."}
+{"text": "Gene regulatory networks play essential roles in living organisms to control growth, keep internal metabolism running and respond to external environmental changes. Understanding the connections and the activity levels of regulators is important for the research of gene regulatory networks. While relevance score based algorithms that reconstruct gene regulatory networks from transcriptome data can infer genome-wide gene regulatory networks, they are unfortunately prone to false positive results. Transcription factor activities (TFAs) quantitatively reflect the ability of the transcription factor to regulate target genes. However, classic relevance score based gene regulatory network reconstruction algorithms use models do not include the TFA layer, thus missing a key regulatory element.Gene expression and Transcription factor activity based Relevance Network (GTRNetwork). Different combinations of TFA prediction algorithms and relevance score functions have been applied to find the most efficient combination. When the integrated GTRNetwork method was applied to E. coli data, the reconstructed genome-wide gene regulatory network predicted 381 new regulatory links. This reconstructed gene regulatory network including the predicted new regulatory links show promising biological significances. Many of the new links are verified by known TF binding site information, and many other links can be verified from the literature and databases such as EcoCyc. The reconstructed gene regulatory network is applied to a recent transcriptome analysis of E. coli during isobutanol stress. In addition to the 16 significantly changed TFAs detected in the original paper, another 7 significantly changed TFAs have been detected by using our reconstructed network.This work integrates TFA prediction algorithms with relevance score based network reconstruction algorithms to reconstruct gene regulatory networks with improved accuracy over classic relevance score based algorithms. This method is called E. coli gene transcriptome data gives a set of potential regulatory links with promising biological significance for isobutanol stress and other conditions.The GTRNetwork algorithm introduces the hidden layer TFA into classic relevance score-based gene regulatory network reconstruction processes. Integrating the TFA biological information with regulatory network reconstruction algorithms significantly improves both detection of new links and reduces that rate of false positives. The application of GTRNetwork on  Gene regulatory networks play an essential role in controlling gene expression and ensuring that the right genes are expressed or silenced at the right time in the right place to make the organism function appropriately. Better understanding of gene regulatory structure aids biological researchers and biochemical engineers in obtaining more complete views of the complex gene expression and regulatory mechanisms in organisms.In the gene regulation process, an active transcription factor (TF) can bind DNA and control gene expression. However, many TFs are not inherently active. Complex mechanisms, such as forming dimers, interacting with signal metabolites or binding specific micro-RNAs, are needed in order to control the activities of these TFs . The actSince TFA is governed by various complex molecular interactions, it is difficult to determine directly from experiments, especially if the activation mechanism is unknown. However, it is possible to computationally predict the change of TFAs relative to a reference state using transcriptome data and a known TF-gene network architecture ,2. Netwoin vivo  is the relative gene expression level matrix and L \u00d7 M matrix [TFAr] is the relative transcription factor activities, the elements ijEr(t) = ijE(t)/ijE(0) and kjTFAr(t)/kjTFAr(0), N \u00d7 L matrix [CS] is the control strength matrix of transcription factors and genes. The gene expression model in Eq. (4) can be decomposed into matrix [CS] and matrix log([TFAr]) using different algorithms.where Er] can be obtained from transcriptome experiments such as DNA microarrays or RNAseq, and the control strength information must be initialized from the literature e.g. RegulonDB  and [CS], transcription factor activities log([TFAr]) can be estimated. There are three major approaches to estimate log ([TFAr]) expectation maximization (EM) approach (e.g. gNCA-r) ) matrix, log ( and log ([TFAr]) need to fit three criteria given below to ensure the uniqueness of the decomposition  must have full-column rank.(i) The connectivity matrix  must have at least L-1 zeros.(ii) When a node in the regulatory layer is removed along with all of the output nodes TFAr], must have full row rank. In other words, each regulatory signal cannot be expressed as a linear combination of the other regulatory signals.(iii) The matrix, log  with elements ij Zgene regulatory networks with different sensitivities can be reconstructed by searching for gene regulatory links containing TF genes with the Z score larger than the threshold. The information of TF genes (which genes encode TFs) can be found from database such as RegulonDB Inputs: a) Log 2 ratio transcriptome data in matrix [C]b) Initial TF-gene network topology in adjacency matrix  and matrix [C]. 1. Match the genes between the matrix [Er] and store the reduce matrix as [Er0]. Remove unmatched genes in [C] and store the reduced matrix in [C0].Remove unmatched TFs and genes in [Er0] and [C0] to fit the criteria.2. If the TFA prediction algorithm is gNCA-r or FastNCA, check the three criteria described in TFA prediction section and reduce the matrix [2 ratio TFA matrix [TFA] from matrix [Er0] and [C0].3. Apply TFA prediction algorithm to predict the logM] between TFAs and all expression levels of all genes from matrix [TFA] and [Er].4. Calculate the relevance score matrix [Z] of relevance score matrix [M] using CLR algorithm.5. Calculate the joint statistical likelihood matrix [Z] so that there are S elements in [Z] greater than T. For all the TF-gene pairs having a Z score greater than T, construct a regulatory link.6. Set a threshold T for matrix [7. If the operon list is available, check and add all genes in the same operon of TF target genes to the regulatory target set of the TF.YF developed and implemented the GTRNetwork algorithm and drafted this manuscript. LRJ and JD developed the initial concept and suggested ways to improve the algorithm and testing methods. All authors read and approved the final version of the manuscript.Test results of GTRNetwork Algorithm combinations, GTRNetwork algorithm using TF-gene network topologies providing different level of information as input, the input initial TF-gene network topologies are obtained by randomly deleting 70%, 50%, 30% or 10% links of the TF-gene links data from RegulonDB 7.0 [onDB 7.0 .Click here for fileE. coli predicted using GTRNetworkPotential new regulatory links of . Gene expression data is obtained from M3D database [database  and contdatabase  is used database Click here for file"}
+{"text": "Campylobacter jejuni transcriptional response under iron replete and iron limited conditions was characterized using RNA-seq. We have identified 111 novel C. jejuni 5\u2019UTRs and mapped 377 co-transcribed genes into 230 transcriptional operons. In contrast to previous microarray results, the C. jejuni iron stimulon is less extensive than previously believed and consists of 77 iron activated genes and 50 iron repressed genes. As anticipated, the iron repressed genes are primarily those involved in iron acquisition or oxidative stress defense. Interestingly, these experiments have revealed that iron is an important modulator of flagellar biogenesis with almost all the components of the flagella found to be iron activated. Given that motility is a well-known C. jejuni colonization factor, this suggests that there is an important regulatory coupling of flagellar biogenesis and iron level in C. jejuni. In addition we have identified several consensus mutations in the C. jejuni NCTC11168 strain that are widespread in the Campylobacter research community and which may explain conflicting phenotypic reports for this strain. Comparative analysis of iron responsive genes with the known Fur regulon indicates that many iron responsive genes are not Fur responsive; suggesting that additional iron regulatory factors remain to be characterized in C. jejuni. Further analysis of the RNA-seq data identified multiple novel transcripts including 19 potential ncRNAs. The expression of selected ncRNAs was confirmed and quantified with qRT-PCR. The qRT-PCR results indicate that several of these novel transcripts are either Fur and/or iron responsive. The fact that several of these ncRNAs are iron responsive or Fur regulated suggests that they may perform regulatory roles in iron homeostasis.The genome-wide  Campylobacter jejuni face additional challenges in acquiring sufficient iron as their hosts typically restrict free iron to prevent unwanted microbial growth  were plotted according to Log2(fold change). Genes identified as being iron repressed by both techniques are either dark purple (iron repressed) or dark green (iron activated). Genes only identified in the iron seq analysis are shown as light purple or green squares (repressed and activated respectively). Genes in blue were iron activated in the RNA-seq and iron repressed in the microarray. Genes in grey were not significantly differentially expressed in the RNA-seq analysis. See Table S2 for specific gene details.(TIF)Click here for additional data file.Figure S3Comparison between Fur regulation and iron responsive genes.The RNA-seq iron regulon was compared to the direct and indirect Fur regulons determined using ChIP-chip and microarrays respectively . While the majority of the iron repressed genes were regulated by Fur, most iron activated genes were not Fur responsive. This suggests the presence of additional iron responsive regulatory elements in C. jejuni. The length of the bars/ribbons is proportional to the number of genes in each group. Figure made using Circos v0.54 [52].(TIF)Click here for additional data file.Figure S4Average insert size of Illumina sequencing libraries.The average insert size for each of the Illumina sequencing libraries constructed was calculated based on the paired-read alignment to the C. jejuni NCTC 11168 genome.(TIF)Click here for additional data file.Figure S5Additional ncRNA validation experiments.Panel A: Northern blot showing expression of ncRNA_Z across different conditions. The 5S RNA is also shown as a loading control. Densitometry analysis did not reveal differential expression of ncRNA_Z when normalized to the loading control. Panels BCD: qRT-PCR experiments of ncRNAs AA, Z and P with varying levels of template RNA for each RT reaction. Differentially expressed conditions  are indicated with an asterisk. (TIF)Click here for additional data file.Table S1Statistics for high throughput sequencing runs.Listed are the read statistics for the high throughput sequencing runs performed in this study as well as runs that were reanalyzed from other studies .(XLSX)Click here for additional data file.Table S2Genes differentially expressed between iron limited and iron replete conditions.Listed are the genes that were found to be significantly differentially expressed under iron limitation .(XLSX)Click here for additional data file.Table S3Fold changes in gene expression as determined by RNA-seq and microarray analysis.Listed are the fold changes in gene expression as determined by either RNA-seq or previous microarray analysis [4].(XLSX)Click here for additional data file.Table S4RPKM values for each gene and sequencing run.Listed are the RPKM values for each C. jejuni gene in each sequencing reaction.(XLSX)Click here for additional data file.Table S5C. jejuni.Percent contribution of COG categories to the total transcriptome of Listed are the overall contributions of each COG category to the total transcriptome.(XLSX)Click here for additional data file.Table S6C. jejuni as determined by RNA-seq.5'UTRs in Listed are the locations and lengths of the 5\u2019UTR regions that were identified by manually inspecting reads that extended beyond the C. jejuni NCTC11168 predicted start codon. Included are those identified using previous a previous RNA-seq study [16] and those identified using dRNA-seq [17].(XLSX)Click here for additional data file.Table S7C. jejuni as determined by RNA-seq.Novel transcripts identified in Listed are the locations and strand origin of the novel C. jejuni NCTC11168 transcripts identified in this study.(XLSX)Click here for additional data file.Table S8Genes Identified in Operonic Structure.Listed are the genes identified as being in operonic structure by using the aligned RNA-seq paired-end reads to infer co-transcription. (XLSX)Click here for additional data file.Table S9C.Operonic Transcripts in jejuni. Listed are genes present in operonic structure that may form potential operonic transcripts.(XLSX)Click here for additional data file."}
+{"text": "A 58 year-old male was referred to our institute for recurrent palpitations followed by ICD shocks. The patient had a history of ischemic cardiomyopathy (EF 25%) and had received a dual-chamber ICD two years earlier for primary prevention of sudden cardiac death. The device interrogation showed multiple episodes of tachycardia and anti-tachycardia pacing (ATP), which frequently terminated the tachycardia. However, occasional failure to terminate the tachycardia or immediate re-initiation within the redetection window led to ICD shocks. A typical episode of tachycardia with its initiation is shown in Device interrogation showed the onset of tachycardia with a near-simultaneous atrial and ventricular activity (fourth beats). Such an onset of tachycardia with less atrial beats than ventricular beats rules out atrial tachycardia. Device interrogation also revealed multiple sequences of ATP that entrained the tachycardia with a VAV response further ruling out atrial tachycardia. The ventricular electrogram morphology during sinus rhythm was similar to that during tachycardia, and the 12-lead EKG demonstrated identical wide QRS morphology during sinus rhythm and during tachycardia . The similarity in QRS morphology (and ventricular electrogram) during sinus rhythm and tachycardia could be consistent with bundle branche reentry VT as those arrhythmias are typically seen in patients with severe cardiomyopathy (like our patient). However, the tachycardia initiation with simultaneous V and A makes this diagnosis unlikely.  Based on these observations, the two differential diagnoses are:-junctional ectopic tachycardia (JET) that starts with V (4th beat) and conducts retrogradely to A (4th beat).-typical slow fast atrioventricular nodal reentrant tachycardia (AVNRT) that initiates with A (3rd beat) leads to V (3rd beat) through the fast pathway and gives a second V (4th beat) through the slow pathway (1:2 response).The patient underwent an electrophysiology study after discontinuing the beta blockers for 5 days. The baseline intracardiac intervals were unremarkable. The mode of tachycardia initiation   was either spontaneous see  or afterFurther EP maneuvers were performed to differentiate JET and AVNRT as recently reported . APD delBased on these findings, the tachycardia was thus diagnosed as AVNRT. The slow pathway area was successfully targeted with one RF application to render the tachycardia non-inducible.  No arrhythmia has been observed on the ICD telemetry for more than a year.In the case presented here, a sinus beat led to 1:2 response with conduction via the fast pathway generating the first QRS* followed by conduction over the slow pathway leading to the second QRS** and induction of AVNRT .An atrial extrasystole causing 1:2 response is an uncommon phenomenon that has been previously described . However"}
+{"text": "CRT is an effective treatment for patients with heart failure and intraventricular conduction delay. However, clinical non-response rates remain unacceptably high; emphasizing the need for improved selection criteria. Central to the underlying mechanism of resynchronization is the relationship between mechanical and electrical activation. The purpose of this study was to demonstrate that mechanical and electrical activation can be quantified in patients with CRT devices combining cardiovascular magnetic resonance (CMR) and electrical myocardial imaging (EMI).Non-invasively characterize mechanical and electrical activation patterns in patients undergoing cardiac resynchronization therapy (CRT)Patients implanted with biventricular CRT for greater than 9 months (N=10) were mapped with 120 body surface electrodes during both intrinsic activation (device off) and CRT pacing. CMR tagging was also acquired with pacing on/off to perform strain analysis. The circumferential uniformity ratio (CURE) was computed to characterize temporal-spatial mechanical dyssynchrony . CMR images of the torso and heart were then used to reconstruct electrical epicardial activation maps using a novel EMI technique. Electrical synchrony was indexed by the mean total activation difference time . Only 2 patients underwent full analysis.CURE decreased from 0.73 to 0.51 when the device was turned off, indicating an increase in mechanical dyssynchrony. The corresponding LVEF decreased as well in on/off modes from 42% to 29%. Figure CMR and non-invasive EMI are feasible in patients with CRT devices. This ability to quantify mechanical and electrical synchrony before and after CRT may provide insights into mechanisms of resynchronization and lead to robust dyssynchrony metrics that will identify appropriate candidates for CRT."}
+{"text": "Radioembolization offers a novel way to treat the nonresectable, liver predominant hepatic malignancies with better tumor response and overall progression-free survival rates. Transarterial catheter-based radioembolization procedure involves the hepatic arterial administration of glass- or resin-based beta emitting Yttirum-90 microspheres. Safe delivery of the tumoricidal radiation dose requires careful angiogram planning and coil embolization to quantify lung shunting and prevent systemic toxicity, respectively. Diagnostic pretreatment angiogram also serves to identify the hepatic arterial variant anatomy and other coexisting pathologies that might require a different or alternative approach. We describe a complex case of celiac artery stenosis with tortuous pancreaticoduodenal arterial arcade precluding access to the right hepatic artery for performing radioembolization. Celiac artery stenting of the stenosis was performed to facilitate subsequent safe and successful Yttrium-90 microsphere radioembolization. She was referred for Yttrium-90 (90Y) radioembolization procedure for treatment of unresectable stable right hepatic lobe metastatic lesions  within the right hepatic artery (A planning or mapping angiogram was performed. The aortogram demonstrated a tight (approximately >90%) stenosis of the proximal celiac axis with mild poststenotic dilatation . A superstenosis . Subsequstenosis . Absencec artery . 90Y microspheres  was administered within the right hepatic artery through the stented celiac artery approach during the treatment phase utilizing the standard protocol till the end point. Bremsstrahlung images obtained after the 90Y radioembolization confirm proper delivery of microspheres to the targeted region without any abnormal extratumoral distribution (Approximately 27.8\u2009mCi (1029\u2009MBq) of ribution . Patient90Y microspheres are permanent biocompatible and non-biodegradable medical devices with a 90Y beta emitter within glass spheres or adsorbed onto resin spheres. Tumor cells receive the blood supply predominantly through the arterial system compared to the normal liver tissue which receives supply from the portal venous system. This preferential flow facilitates selective delivery of the radioactive microspheres to the tumor during transcatheter arterial therapies [90Y microsphere treatment, multiple studies reported improved tumor response and delayed time to progression compared to other treatment modalities [Microsphere radioembolization therapy is currently approved for unresectable hepatic metastatic disease from colorectal cancer  and unresectable hepatocellular carcinoma as a humanitarian device exemption  within the United States. herapies . The selherapies . Given tdalities \u20137. 90Y microspheres are administered selectively up to the calculated dose or until flow stasis is achieved. A posttreatment Bremsstrahlung scan confirms dose delivery to tumor and absence of extrahepatic activity. These technical details and guidelines have been meticulously described previously [The first step in the multidisciplinary approach is the planning or mapping angiogram phase that serves to confirm the normal or variant hepatic arterial anatomy and to coil embolize the GDA. Subsequently, Tc-99m MAA is injected to confirm lack of extrahepatic distribution and quantify the intrinsic tumoral lung shunting, which is used in conjunction with anatomical imaging volume and laboratory data for dose calculation. The treatment phase angiogram serves to reconfirm the arterial anatomy of the tumor, after which the eviously \u201310. Posteviously , 12. Arterial variants and abnormalities in the mesenteric and hepatic circulations might require alternate techniques for safe and effective radioembolization . Celiac 90Y microsphere therapy in cases of celiac artery stenosis [90Y radioembolization treatment in English literature.Up to date, there have been a few case reports demonstrating the utilization of the SMA-inferior PDA approach for stenosis , 13. The90Y microspheres radioembolization offers a unique opportunity to treat nonresectable, liver predominant hepatic malignancies with good tumor response, and overall progression free survival rates. Hepatic arterial variants and abnormalities such as arterial stenosis might limit access to the hepatic arterial branches supplying the tumor, and therefore, require alternate approaches or additional minimally invasive endovascular interventions. We report the use of stenting procedure in a case of celiac artery stenosis to facilitate hepatic 90Y microsphere radioembolization. This technique can be performed as a first line approach or in cases where the hepatic branches are not technically accessible through the conventional SMA-PDA arcade approach. Although the use of celiac axis stenting for 90Y microspheres radioembolization has been successful in our case, this approach should be evaluated further in a larger study population."}
+{"text": "Chronic myelogenous leukemia (CML) is a leukemic stem cell (LSC)-driven myeloproliferative disorder and is associated with a characteristic chromosomal translocation which generates a constitutively active tyrosine kinase, the BCR-ABL oncoprotein. The standard treatment therapy for CML patients is the BCR-ABL tyrosine kinase inhibitor (TKI) imatinib. It is a life-long treatment due to the fact that LSCs are resistant to TKIs. Since its introduction, imatinib has improved the 5-year survival rate up to 90%. An emerging problem is resistance to imatinib, which is mainly caused by mutations inside the BCR-ABL kinase domain, and its increasing incidence during disease progression. It has been reported that BCR-ABL drives its own mutation via upregulation of reactive oxygen species (ROS) causing oxidative DNA damage. Among the several dozens of intensively characterized mediators of BCR-ABL action, the transcription factor STAT5 is among the few ones that is critical for leukemia initiation and maintenance and it has been shown that STAT5 becomes upregulated during disease progression.qPCR analysis of primary CML patient samples reveal a positive correlation of STAT5 mRNA levels and BCR-ABL mutations. Using BCR-ABL transformed murine cell lines retrovirally overexpressing STAT5A or STAT5B, we can show that STAT5 triggers ROS production leading to an increase in DNA double-strand breaks.We hypothesize that STAT5 is an important mediator of imatinib resistance in CML due to its ability to drive ROS production consequently leading to BCR-ABL mutations."}
+{"text": "Neurons co-express a multitude of different ion channels that determine the electrophysiological behaviour of the cell. Recent experimental observations have revealed that the expression of different ion channels varies dramatically within neurons of a defined type, even when these neurons exhibit stereotyped electrical properties -5. This"}
+{"text": "Approved drugs serve as functional probes for analyzing disease-relevant biochemical pathways or are screened against proteins to identify novel medical applications resulting in a repurposing of known drugs. Despite these benefits of approved drugs, it is almost impossible to physically obtain a complete collection. Commercial vendors cover about 50-65% of drugs. Academic efforts such as the Johns Hopkins Clinical Compound Library (JHCCL)  and the"}
+{"text": "Random or stochastic monoallelic expressed genes (StMA genes) represent a unique form of monoallelic expression where allelic choice is made at random early in development. The consequential clonal diversity provides opportunity for functional heterozygosity in tissues such as the brain, and can impact on both development and disease. We investigate the relationship of StMA expressed genes previously identified in clonal neural stem cells with the neurodevelopmental disorders autism and schizophrenia. We found that StMA genes show an overrepresentation of schizophrenia risk candidates identified by genome wide association studies from the genetic association database. Similar suggestive enrichment was also found for genes from the NHGRI genome-wide association study catalog and a psychiatric genetics consortium schizophrenia dataset although these latter more robust gene lists did not achieve statistical significance. We also examined multiple sources of copy number variation (CNV) datasets from autism and schizophrenia cohorts. After taking into account total gene numbers and CNV size, both autism and schizophrenia associated CNVs appeared to show an enrichment of StMA genes relative to the control CNV datasets. Since the StMA genes were originally identified in neural stem cells, bias due to the neural transcriptome is possible. To address this, we randomly sampled neural stem cell expressed genes and repeated the tests. After a significant number of iterations, neural stem cell expressed genes did not show an overrepresentation in autism or schizophrenia CNV datasets. Therefore, irrespective of the neural derived transcriptome, StMA genes originally identified in neural stem cells show an overrepresentation in CNVs associated with autism and schizophrenia. If this association is functional, then the regulation (or dysregulation) of this form of allelic expression status within tissues such as the brain may be a contributory risk factor for neurodevelopmental disorders and may also influence disease discordance sometimes observed in monozygotic twins.  Several forms of monoallelic gene expression have been identified. Imprinting, a form of monoallelic gene expression based on parent-of-origin effects, is highly represented in the brain transcriptome , and sevWe utilized allelic expression measures from a previous study of clonal neural stem cells to construct a list of stochastic monoallelic (StMA) expressed genes . A clonehttp://geneticassociationdb.nih.gov), NHGRI GWAS catalog (http://www.genome.gov/gwastudies) and 81 associated SNPs from the psychiatric genetics consortium [P\u00a0< 2 \u00d7 10\u22125 . Genes mapping close to or containing the risk SNPs in the latter study were identified with Galaxy analysis server [Enrichment analysis was carried out on both association studies  and CNV datasets (using StMA gene lists only). Candidate genes from association studies were taken from the Genetic Association Database (s server . Associahttp://bbgre-dev.iop.kcl.ac.uk), 120 autism patients with de novo CNVs from the DECIPHER consortium repository (http://decipher.sanger.ac.uk), 843 autism spectrum disorder patients from a developmental disability CNV study [http://www.ncbi.nlm.nih.gov/dbvar ) [Disease associated CNV locations were obtained from a number of sources: 75 autism patients from the Brain Body and Genetic Resource Exchange (BBGRE) CNV database  \u201317. For We used publically available neuropsychiatric datasets to look for enrichment of StMA genes relative to control data. First, occurrence of StMA genes and BA genes within datasets from the genetic association database  were exaSince allelic status of StMA genes correlates with overall transcript levels ,6,19, suDisease datasets were obtained from CNV databases and publications. Autism CNVs from BBGRE and DECIPHER databases show high enrichment of StMA gene occurrence relative to the total number of genes (3.2-5.0 fold). The number of CNV regions containing StMA genes also showed a higher proportion of autism and schizophrenia CNV regions containing StMA genes (14 to 25%) compared with dbVAR control CNVs (2%). When the CNV size is taken into account to calculate gene density, the frequency of StMA genes per megabase of CNV was 2 to 4 fold higher than the dbVAR control CNV regions. The remaining two autism publication derived datasets represent a comprehensive CNV morbidity map of neurodevelopmental delay, with some of the patients having an autism spectrum disorder diagnosis  and 5 geThe schizophrenia datasets were obtained from two publications. We used 12 replicated schizophrenia CNVs documented in a recent meta-analysis review by Since our identified StMA genes were originally identified in neural stem cells , it is cWe have demonstrated an associative link of neural stem cell identified StMA genes with autism and schizophrenia GWAS and CNV identified genes. Pathological neuropsychiatric-associated CNVs are likely to alter the transcript levels of specific risk genes . SimilarConsistent with our disease enrichment findings, allelic imbalances identified within induced pluripotent stem cell derived differentiated human neurons also show a modest association for schizophrenia and autism candidate genes . Allele In summary, we have previously identified genes showing stochastic monoallelic expression patterns in clonal neural stem cells, together with a number of genetic and epigenomic associations . Here weTable S1Control CNV datasets used to construct the dbVAR control dataset.Total gene content and StMA gene occurrence are shown for each data set. The Conrad et al (2010) control study consisted of two CNV lists \u2013 a CNV discovery dataset and HapMap based dataset as shown in the table.(DOCX)Click here for additional data file.Table S2Summary of CNV data sets based on genes mapped to minimal overlap CNV coordinates.Total gene content and StMA gene occurrence are shown for autism (BBGRE and DECIPHER) and schizophrenia  CNV datasets based on genes mapped to minimal overlap CNV coordinates. Enrichment tests were carried out relative to dbVAR controls, a merger of CNV loci as shown in table S2. (DOCX)Click here for additional data file.File S1Allelic expression gene lists and CNV coordinates and their associated genes used in the study.(XLSX)Click here for additional data file.File S2R code used for CNV enrichment analysis and permutation test.(TXT)Click here for additional data file."}
+{"text": "Urosepsis associated with urinary tract calculi is a critical disease. Patients with this condition occasionally require drainage, mostly ureteric stent placement and these patients need longer hospitalization. However, indications for timely ureteric stenting for urosepsis associated with urinary tract calculi have not been clearly determined. The objective of the study was to evaluate whether earlier stent placement might lead to shorter length of stay (LOS) in hospitals.For patients who required ureteric stent procedures for urosepsis associated with urinary tract calculi in our hospital from July 2008 to July 2012, we compared the LOS in our hospital between patients with earlier stenting and those without it. A linear regression model was used for multivariable-adjusted comparison.In a total of 30 patients , the mean days from emergency room admission to ureteric stenting was 3.53days  and the overall mean LOS was 36 days . The early-stenting group  had significantly shorter LOS than the delayed-stenting group  with adjusted \u03b2 coefficient of -26 days .In patients with urosepsis associated with urinary tract calculi, earlier stenting within 2 days of admission may reduce the hospital LOS."}
+{"text": "C), which acquires altered conformation, form aggregates and is resistant to proteolysis. PrPC is a cell surface glycosyphosphatidylinositol (GPI)-anchored protein of 208-209 aminoacids which is codified by a single exon and whose expression is developmentally regulated. In adult animals PrPC is highly expressed in the central nervous system but peripheral nervous system and other organs or tissues also express this protein.Prions are proteinaceus infectious agents associated to invariable fatal neurodegenerative disorders named transmissible spongiform encephalopathies or prion diseases. The mechanism associated with disease propagation lays on post-translation modifications of the cellular prion protein  or Hop (its human homologue). Comparative experiments using neurons derived from wild type and PrPC-null mice demonstrated that PrPC binding to vitronectin promoted axonal growth in dorsal root ganglion neurons (DRG). In addition, PrPC interaction with laminin activated metabotropic glutamate receptors, Ca2+ mobilization and PKC activation promoting neuronal plasticity and memory formation in rats. STI1 was the most explored PrPC ligand. The PrPC-STI1 engagement induces PKA an ERK1/2 activation, which increase neuronal survival and differentiation. The signaling pathways modulated by PrPC-STI1 also included Ca2+ influx by activation of \u03b1-7 nicotinic acetylcholine receptor, induction of PI3K and mTOR. These last two pathways were associated to increased protein synthesis. An increment on the self-renewed of neuronal progenitors is also modulated by PrPC-STI1 engagement.The use of cellular models led to the characterization of PrPC at the neuronal membrane and recently we demonstrated that this protein is abundantly secreted by astrocytes. Secreted STI1 plays an autocrine activity upon astrocytes modulating their proliferation and differentiation. The mechanism associated with STI1 secretion is under evaluation but preliminary results indicated that this protein is secreted by microvesicles derived from multivesicular bodies.The co-chaperone STI1 is known to interact with PrPC and STI1/Hop in cellular survival and differentiation raised questions regarding their involvement in tumoral processes. In fact, the literature has been pointed that PrPC expression contributes to cancer progression and resistance to various cancer therapies. STI1/Hop expression was also associated with the proliferation of tumor cells. Our data pointed that STI1 secreted by glioblastoma cells has an autocrine function mediating proliferation of these cells by binding to PrPC. We are presently evaluating how to interfere with the PrPC-STI1 binding in order to modulate tumor growth.The involvement of PrPC-STI1 engagement is an interesting therapeutic target for both neurodegeneration and cancer and investments should be done to address these issues.Together our results point that PrPThere are no competing interests in this presentation."}
+{"text": "Dear Editor,I was interested to read the paper entitled \"Effects of clonidine premedication upon postoperative shivering and recovery time in opium addicted and non-addicted patients by elective leg fracture surgeries\" . I note"}
+{"text": "\u0394Mye mice, which lack IKK\u03b2 in myeloid cells. In summary, the oral or systemic route of allergic sensitization and IKK\u03b2 signaling in myeloid cells regulate how the gender influences allergen-specific responses and lung allergic inflammation.Gender influences the incidence and/or the severity of several diseases and evidence suggests a higher rate of allergy and asthma among women. Most experimental models of allergy use mice sensitized via the parenteral route despite the fact that the mucosal tissues of the gastrointestinal and respiratory tracts are major sites of allergic sensitization and/or allergic responses. We analyzed allergen-specific Ab responses in mice sensitized either by gavage or intraperitoneal injection of ovalbumin together with cholera toxin as adjuvant, as well as allergic inflammation and lung functions following subsequent nasal challenge with the allergen. Female mice sensitized intraperitoneally exhibited higher levels of serum IgE than their male counterparts. After nasal allergen challenge, these female mice expressed higher Th2 responses and associated inflammation in the lung than males. On the other hand, male and female mice sensitized orally developed the same levels of allergen-specific Ab responses and similar levels of lung inflammation after allergen challenge. Interestingly, the difference in allergen-specific Ab responses between male and female mice sensitized by the intraperitoneal route was abolished in IKK\u03b2 Thus, the magnitude and quality of the allergen-specific immune response are controlled by the dose and frequency of exposure to allergen, the type of adjuvant, the genetic background, the route of sensitization and the gender. Previous studies showed that the subcutaneous route was more effective than the intraperitoneal (ip) route at inducing IgE antibodies Cytokines produced by myeloid cell subsets, including macrophages and dendritic cells, influence differentiation of naive T lymphocytes into Th2 cells capable of supporting induction of IgE Abs and effector cells involved in allergic responses. The nuclear factor \u03baB (NF-\u03baB) pathway plays an important role in cytokine responses to a variety of stimuli Experimental murine models of allergy and asthma use mostly female mice and the possible influence of gender on allergen-induced lung inflammation has not been thoroughly investigated. To address this question, we compared allergen-specific Ab responses and subsequent responses to nasal allergen challenge in male and female mice sensitized either orally or via ip injection with the model food antigen ovalbumin (OVA) and cholera toxin as adjuvant. We show that ip sensitization of adult mice results in a significant gender-disparity with female mice developing higher IgE and Th2-associated response and allergic airway inflammatory responses upon allergen challenge. Such differences were not seen in male and female mice sensitized via the gastrointestinal tract, suggesting that gender differentially influences allergic sensitization depending on the route of exposure.\u0394Mye mice, in which IKK\u03b2-dependent NF\u03baB signaling was eliminated in myeloid cells Wild-type C57BL/6 mice were obtained from the Jackson Laboratories  or NCI  and acclimated in our facility before use. The IKK\u03b2Immunohistochemistry was performed on 5 \u03bcm sections of formalin-fixed and paraffin-embedded tissues. Lung tissues were inflated before fixation and tissue sections were stained with hematoxylin and eosin according to standard protocols. Quantification of lung inflammation was performed in a blinded fashion by two independent investigators as previously described Oral sensitization to the food antigen was performed on days 0 and 7 by intragastric administration of 250 \u03bcl of PBS containing 1 mg of ovalbumin (OVA) and 10 \u03bcg of cholera toxin as adjuvant. Parenteral sensitization was performed on days 0 and 7 by intraperitoneal injection of 100 \u03bcl of PBS containing 100 \u03bcg of OVA and 1 \u03bcg of cholera toxin. Nasal antigen challenges were performed on days 15, 16 and 19 with 100 \u03bcg of OVA as previously described Plasma samples were collected one week after each sensitization, on days 7 and 14, and plasma levels of OVA-specific antibodies were measured by enzyme-linked immunosorbent assay (ELISA) as previously described Mechanical properties of the mouse lung were assessed on anesthetized mice using the forced-oscillation technique as previously described Cytokine mRNA responses antibodies were analyzed by Real-Time RT-PCR as previously described 2 below the detection limit. All tests were considered significant at a probability of p<0.05.Results are expressed as the mean \u00b11 SD. Unless otherwise indicated, statistical significance was determined by Student\u2019s T test or by ANOVA followed by the Fisher Least Significant Difference Test . For statistical analysis, antibody levels below the detection limit were recorded as two logWe first examined the antibody responses after oral or parenteral  sensitization. In mice sensitized by the ip route, the IgE, IgG2a/c levels were higher in females . In contWe next examined whether the gender-induced difference in allergen-specific Ab responses would affect responses to nasal antigen challenge . HistoloAllergen-induced airway hyper-responsiveness (AHR) is an important outcome of inflammation and airway remodeling in asthma. Twenty-four hours after the last challenge with OVA , there wAirway hyper-responsiveness also is controlled by cytokines secreted in response to antigen challenge; we and others have previously shown that differences in cytokine responses can lead to discrepancies between lung inflammation and AHR \u0394Mye mice). Interestingly, no difference was found in the level of serum IgG and IgE antibodies between male and female IKK\u03b2\u0394Mye mice sensitized by the parenteral route, except for IgA, which was higher in females (\u0394Mye mice sensitized by the oral route exhibited no difference in antibody responses (Myeloid cells are major contributors of pro-inflammatory cytokines. As mentioned above, it has been suggested that an increased expression of interleukin-6 by monocytes in women could contribute to the higher risks of inflammatory disorders in this population when compared to men  females . As with females , male anesponses .\u0394Mye mice sensitized orally failed to develop airway reactivity to methacholine (\u0394Mye mice sensitized via the parenteral route also failed to show increased lung resistance to methacholine challenge. Surprisingly, male IKK\u03b2\u0394Mye mice sensitized via the parenteral route retained the ability to develop allergen-induced airway hyper-responsiveness, suggesting that the IKK\u03b2 pathway plays a major role in allergen-induced airway hyper-responsiveness in female mice. This discrepancy in lung responses between male and female IKK\u03b2\u0394Mye mice sensitized via the parenteral route was further confirmed by the analysis of lung inflammation (\u0394Mye mice showed higher levels of inflammation than those of female IKK\u03b2\u0394Mye mice sensitized via the same parenteral route (We next examined whether the changes in allergen-specific responses induced by IKK\u03b2 deficiency in mice sensitized by the parental route also affect allergen-induced airway hyper-responsiveness. Twenty-four hours after the last antigen challenge, both male and female IKK\u03b2acholine . Female ammation . Thus, lal route .Experimental and clinical data indicate a difference in gender susceptibility to airway hyper-responsiveness and allergic inflammation. However, these differences appear to vary with the experimental system used and the end point analyzed. There are known differences in lung airway size, alveolar number and volume between males and females Several mouse strains have been studied to characterize pulmonary functions Airway hyper-responsiveness to cholinergic agents like methacholine is a defining feature in experimental asthma. Furthermore, airway hyper-responsiveness in the context of allergic asthma generally is associated with allergic inflammation characterized by eosinophilia and mucus production Most murine models of asthma evaluate responses after intraperitoneal sensitization followed by several nasal challenges. The oral route of sensitization we used in this study more likely recapitulates events that occur during common sensitization to food allergens. The importance of the route of sensitization has been already demonstrated by Hansen et al. who compared ip versus nasal sensitization \u0394Mye mice further supports the notion that myeloid cells and other innate cells at the site of allergic sensitization control the profile of allergen-specific B and T cell responses and subsequent pathologic responses to allergen challenge.The immune system in mucosal tissues of the GI tract has evolved alongside, but separate from the general bloodstream to adapt to the unique environment in this site. Mine et al. In summary, we have shown than allergic sensitization via the gastrointestinal tract leads to similar patterns of allergen-specific immune responses in male and female mice. We also showed that IKK\u03b2 in myeloid cells plays a key role in the gender disparity with regard to responses to intraperitoneal sensitization and further studies are warranted to better understand underlying mechanisms. Finally, our findings add support to the notion that airway hyper-responsiveness to methacholine challenge do not always reflect differences in airway inflammation. Thus, careful selection of experimental models and assays are crucial to study mechanisms of gender disparity for allergic diseases."}
+{"text": "L-Gulonolactone oxidase-deficient mice (Gulo(\u2212/\u2212)) were used to study the effects of ascorbate deficiency on aortic relaxation and lowering of blood pressure by nitroglycerin (GTN). Special emphasis was given to changes in expression and activity of vascular aldehyde dehydrogenase-2 (ALDH2), which has been recently characterized as key enzyme of vascular GTN bioactivation.Ascorbate deficiency was induced in Gulo(\u2212/\u2212) mice by ascorbate deprivation for 4 weeks. Some of the animals were concomitantly treated with the proteasome inhibitor bortezomib and effects were compared with ascorbate-supplemented Gulo(\u2212/\u2212), untreated or nitrate-tolerant wild-type mice. Aortic relaxation of the experimental groups to GTN, acetylcholine and the NO donor diethylamine NONOate was studied. Changes in mRNA and protein expression of vascular ALDH2 were quantified by real-time PCR and immunoblotting, respectively, and aortic GTN denitration rates were determined by thin layer chromatography. Ubiquitination of proteins was analyzed by immunoblotting.Like GTN treatment, ascorbate deprivation induced vascular tolerance to GTN that was associated with markedly decreased rates of GTN denitration. Ascorbate deficiency did not affect ALDH2 mRNA levels, but reduced ALDH2 protein expression and the total amount of ubiquitinated proteins to about 40% of wild-type controls. These effects were largely prevented by ascorbate supplementation or treating Gulo(\u2212/\u2212) mice with the 26S proteasome inhibitor bortezomib.Our data indicate that ascorbate deficiency results in vascular tolerance to GTN via proteasomal degradation of ALDH2. The results support the view that impaired ALDH2-catalyzed metabolism of GTN contributes significantly to the development of vascular nitrate tolerance and reveal a hitherto unrecognized protective effect of ascorbate in the vasculature."}
+{"text": "Buthus scorpions using mtDNA sequences. We sampled 91 individuals of the genus Buthus from 51 locations scattered around the Atlas Mountains . We sequenced 452 bp of the Cytochrome Oxidase I gene which proved to be highly variable within and among Buthus species. Our phylogenetic analysis yielded 12 distinct genetic groups one of which comprised three subgroups mostly in accordance with the orographic structure of the mountain systems. Main clades overlap with each other, while subclades are distributed parapatrically. Geographic structures likely acted as long-term barriers among populations causing restriction of gene flow and allowing for strong genetic differentiation. Thus, genetic structure and geographical distribution of genetic (sub)clusters follow the classical theory of allopatric differentiation where distinct groups evolve without range overlap until reproductive isolation and ecological differentiation has built up. Philopatry and low dispersal ability of Buthus scorpions are the likely causes for the observed strong genetic differentiation at this small geographic scale.The immense biodiversity of the Atlas Mountains in North Africa might be the result of high rates of microallopatry caused by mountain barriers surpassing 4000 meters leading to patchy habitat distributions. We test the influence of geographic structures on the phylogenetic patterns among  The Mediterranean region comprises a highly diverse geographic area characterized by a variety of peninsulas and islands. This underlying geographic structure is reflected in biogeographical patterns of the region already described by de Lattin (1949) De Lattin (1949) Buthus, which has undergone extensive speciation within NW Africa Buthus scorpions are widely distributed over large parts of Africa and show a circum-Mediterranean stronghold including the Mediterranean islands, with extraordinarily high diversity in North Africa In order to test for the influence of orographic structures on differentiation and speciation processes, we selected the scorpion genus Buthus species from 51 locations over major parts of the Antiatlas, High Atlas, Middle Atlas and Jebel Sahro during spring 2008 and 2009. Three specimens of the related genus Androctonus from two locations served as outgroup. We analysed a fragment of the mitochondrial Cytochrome Oxidase I (COI) gene, which has been shown to be highly informative at species level and consequently is one of the most commonly used markers for phylogenetic and phylogeographic studies. Due to its high potential for species identification it is often chosen as the barcoding gene in zoological studies. Here we use its properties to address the following questions:For this study we collected a total of 91 individuals belonging to 4 described Buthus exhibit geographic structuring?Does genetic variation within Do genetic structures follow any geographical and/or evolutionary pattern?Are genetic lineages in accordance with current taxonomy?Androctonus mauritanicus (JF820097) was obtained from genbank as an additional outgroup. Details about analyzed individuals, including genbank accession numbers, are given in We generated 94 sequences (including three outgroup specimens) with a total length of 452 base pairs. One sequence from The second dataset included 84 additional sequences obtained from genbank . In totaButhus lineages, which were recovered in all analyses  Several lineages are composed of different species: four of the five lineages with ten or more individuals analysed contain two to three species; even lineage H  includes two different morpho-types.The 12 lineages A through L do not match with current taxonomy (as reflected by morphology based identification keys): (i) The two tree hypotheses (ML and BI) constructed from our original dataset distinguish 12 genetic lineages. One of these clusters (lineage K) is further structured into three sub-clades. The genetic clusters exhibit a clear geographic pattern with all the lineages being confined to relatively restricted areas. None of the lineages is widely distributed. Most lineages are separated from each other by geographic barriers such as high mountain ranges or steep valleys. Only some basal lineages show range overlap (e.g. K) while all younger groups are strictly allopatric or parapatric (e.g. the three sub-groups of K). Four groups (A\u2013D) are situated around the western and north-western parts of the High Atlas. One group is located in the westernmost Antiatlas (E), three others at the northern foothills of these mountains (F\u2013H) and one at the southern foothills of the Antiatlas (J). The largest cluster (K) is distributed south of the High Atlas, east of the Draa valley, and splits further into three subclades, which form distinct strictly parapatric groups following the orographic structures of this region . Another cluster (I) extends from the Draa valley to the south western edge of the Antiatlas, probably including parts of the distribution ranges of clade G and H.Buthus scorpions mostly does not exceed elevations higher than 2500 m asl Buthus individuals. A similar pattern was observed for the same taxonomic group using various molecular markers such as allozymes, nuclear and mitochondrial DNA all of which showed significant genetic differentiation patterns even among local populations Buthus lineages also include their last centre of differentiation. Thus, our study area may comprise 12 allopatric refugia during the last ice age revealing a much more fine grained biogeographical sub-structure than previously observed in the Maghreb e.g. Buthus in Morocco is much more complex than the structures observed in other Mediterranean sub-centres Buthus individuals  gene was amplified using standard PCR procedures with the following primers: forward 5\u2032 GGT CAA CAA ATC ATA AAG ATA TTG G 3\u2032, reverse 5\u2032 TAA ACT TCA GGG TGA CCA AAA AAT CA 3\u2032For all individuals, DNA was isolated from leg, caudal segment or telson muscle tissue using the Qiagen DNeasy kit with standard protocols for tissue samples. A 452 bp fragment of the mitochondrial Cytochrome Oxidase I ). Sequences were inspected and aligned using Geneious 5.0.3 We included 91 sequences of General alignment statistics  were calculated using DNAsp v. 5.10 The best fitting model of sequence evolution for phylogenetic tree reconstruction was chosen using MrModeltest 2.3 Buthus scorpions obtained from genbank  In a second analysis, we included 84 sequences from bank see  resultinbank see . When thAppendix SIDNA sequences obtained from NCBI genbank.(DOC)Click here for additional data file."}
+{"text": "The mechanisms mediating this effect are still unclear. The activity of several ion channels is sensitive to changes in temperature, leading to cytosolic calcium influx. Calcium is universally involved in cellular processes, its effects depending on the cellular context. Although not much is known about the role of calcium in immune cells, it has been shown that calcium is necessary for inflammasome assembly. Conventional methods of measuring calcium are not ideal to study the relation between temperature and intracellular calcium concentrations  is highly dependent on temperature. This is not established in detail because the indicator is mostly used in temperature independent assays. Here, we determined KdFluo-4 for temperatures in a range of 5-55oC, enabling calculation of exact intracellular calcium concentrations. We applied the assay in different cell lines and primary human innate immune cell populations.[Ca2+]i to basal levels. This [Ca2+]i increase can be blocked by the aspecific ion channel antagonist Ruthenium Red.Exposing cells to decreasing temperature induces elevated intracellular calcium concentrations. Subsequently rising temperature restores [Ca2+]i measurements in innate immune cell populations under tight temperature control.We show that the intracellular calcium concentration in immune cells increases significantly upon decreasing temperature. Blockade by Ruthenium Red indicates that this effect is mediated by thermosensitive ion channels. We successfully optimized a 96-well format fluorescense-based assay using a qPCR machine, enabling [CaNone declared"}
+{"text": "Poribacteria is one of the most dominant and widespread members of the microbial communities residing within marine sponges. Cell compartmentalization had been postulated along with their discovery about a decade ago and their phylogenetic association to the Planctomycetes, Verrucomicrobia, Chlamydiae superphylum was proposed soon thereafter. In the present study we revised these features based on genomic data obtained from six poribacterial single cells. We propose that Poribacteria form a distinct monophyletic phylum contiguous to the PVC superphylum together with other candidate phyla. Our genomic analyses supported the possibility of cell compartmentalization in form of bacterial microcompartments. Further analyses of eukaryote-like protein domains stressed the importance of such proteins with features including tetratricopeptide repeats, leucin rich repeats as well as low density lipoproteins receptor repeats, the latter of which are reported here for the first time from a sponge symbiont. Finally, examining the most abundant protein domain family on poribacterial genomes revealed diverse phyH family proteins, some of which may be related to dissolved organic posphorus uptake.The candidate phylum  Poribacteria, symbionts of marine sponges, based on six single-amplified genome (SAG) sequences Poribacteria. Poribacteria were first discovered as highly abundant symbionts of marine sponges Poribacteria are one of the most predominant taxa inhabiting the extracellular matrix (mesohyl) of sponge species around the world Poribacteria showed a moderate phylogenetic relationship to Planctomycetes, Verrucomicrobia, and Chlamydiae (PVC superphylum) based on monophyletic clustering in 16S rRNA gene analysis Poribacteria were classified as members of the PVC superphylum although the exact position within the superphylum could not be completely resolved Poribacteria were also suspected to have a compartmentalized cell plan Poribacteria. We further reveal a large abundance and diversity of eukaryote-like domain containing proteins as well as phyH-like proteins in Poribacteria.Single-cell genomics is a powerful tool to describe genomes of as yet uncultivated organisms from diverse environments Candidatus Poribacteria WGA 3A, 3G, 4C, 4CII, 4E and 4G with Genbank accession numbers ADFK02000000, ASZN01000000, APGO01000000, ASZM01000000, AQTV01000000, AQPC01000000, respectively. These genomes were previously obtained by our group from uncultivated bacteria inhabiting the marine sponge Aplysina aerophoba by fluorescence activated cell sorting (FACS), multiple displacement amplification (MDA), and next generation sequencing Six poribacterial single-cell genome sequences were included in this study, these being Please also note that the initial version of genome WGA 3A (first published as WGA A3 with accession number ADFK00000000 version ADFK01000000) For clustering of pfam 05721-PhyH family proteins we used the fastclust algorithm in usearch Aerophobetes (CD12) and Hydrogenedentes (NKB19) were obtained by blast searches Sequences for 16S rRNA gene based phylogenetic analysis were selected from the SILVA 16S rRNA database version 108 Poribacteria were translated into all six reading frames and marker genes were detected and aligned with hmmsearch and hmmalign included in the HMMER3 package http://phylosift.wordpress.com/). Extracted marker protein sequences were used to build concatenated alignments of up 83 markers per genome. Alignments were included into the database constructed by Rinke and coworkers For the calculation of the bacterial phylogenetic tree we followed the procedure described by Rinke et al. Poribacteria SAGs clustered with the recently proposed phyla Aerophobetes (CD12) and/or Hydrogenedentes (NKB19) Elusimicrobia, formed in some tree calculations a sister clade to the PVC superphylum (Poribacteria with strong bootstrap support (Aerophobetes (CD12) and/or Hydrogenedentes (NKB19) (Poribacteria were placed (bootstrap support 91%) separately within a larger cluster of other phyla including the PVC superphylum as well as the candidate phylum WS3, recently renamed as LatescibacteriaAnalysis of phylogenetic interferences of up to 83 marker genes  showed that all poribacterial SAGs clustered, with 100% bootstrap support in all our tree calculations, in a monophyletic group distinct to the PVC superphylum , Fig. 1. support . However (NKB19) . InsteadPoribacteria in the tree of life will be further refined as more genome sequences of Poribacteria and of other candidate phyla become available. Importantly, the phylogenetic analyses performed in this study (whether 16S rRNA gene or marker genes based) did not support a clustering of Poribacteria with the PVC superphylum, which is in contrast to what was suggested earlier The inconsistency between phylogenomic and the 16S rRNA gene-based phylogeny might be due to the relatively low resolution provided by the single marker gene (16S rRNA) analysis compared to multiple genes analysis as has been suggested previously Poribacteria outside the PVC superphylum. However, these studies included only one poribacterial genome sequence available at that time, Candidatus Poribacteria sp. WGA A3 in its initial version (ADFK01000000). This version was later shown to be flawed by contaminating DNA and was replaced in Genbank (ADFK02000000) Poribacteria. Besides phylogenetic analysis, two marker proteins were described for members of the PVC superphylum Poribacteria.Previous studies based on concatenated alignments of protein data Poribacteria based on ring shaped fluorescence in situ hybridization (FISH) signals and the electron microscopic observations of compartmentalized prokaryotic cells in the mesohyl of the sponge Aplysina aerophobaPlanctomycetesGemmata obscuriglobus where the compartment was proposed to be a nucleus-like structure Poribacteria, we searched poribacterial SAGs for possible genomic evidence of such features. We were not able to find membrane coat like proteins or any genomic indication of large cell compartments. This is in accordance with a recent study which challenged the concept of the existence of these compartments even in other bacteria and confutes the existence of a nucleus-like structure in G. obscuriglobusCell compartmentalization is one characteristic that has been proposed for Poribacteria. Four of six poribacterial SAGs encoded for genes with hits to either one of two pfam domains namely, pfam00936 BMC or pfam03319 EutN CcmL , and some additional phyla  in utN CcmL . These dutN CcmL  that encutN CcmL . A detaiutN CcmL . This isutN CcmL . Poribacal phyla , appear The so far best described BMC functions are the carboxysome and BMCs containing enzymes for ethanolamine or propanediol utilization. Bioinformatic analysis of all available BMC shell protein encoding genomic regions at the time by Yeates et al. Poribacteria where the identified genomic regions with BMC shell protein genes (group A-C) appear scattered across the genome. For example, the different BMC shell protein genes (with pfam00936 and pfam03319) are generally in different genomic regions on poribacterial genomes and not encoded together within one region, as it is the case for many so far functionally characterized BMC types Poribacteria.It is suspected that novel BMC functions will be revealed in the future Eukaryote-like repeat domain containing proteins have received much recent attention in sponge microbiology and their involvement in mediating host-microbe interactions has been postulated. Especially ankyrin (ANK) and tetratricopeptide repeats (TPR) have been in focus of such investigations Vibrio, Colwellia, Bradyrhizobium and Shewanella. Pfam domain 07593- ASPIC and UNbV was also present on several poribacterial SAGs in multiple copies. ANK repeat domains were detected  in lower numbers on a total of 14 genes on SAGs 3G, 4C and 4E  but in lower abundances. We were also able to find Sel1 repeat like proteins domains encoded on poribacterial SAGs 3G and 4E  which have a similar structure to TPRs C and 4E . The freC and 4E .Poribacteria this domain has only been found in proteins of 14 bacterial genomes but not in archaeal genomes publically available at the IMG/MER database in July 2013. Most of these bacterial hits however do not show the tandem repeats that are characteristic for this domain in eukaryotes. Such tandem repeats were only detected in the poribacterial proteins and proteins of four other bacterial genomes. Amongst these were free-living marine cyanobacteria , the marine deep sea piezophile Mortiella sp. PE36, and the strictly anaerobic bacterium Paludibacter propionicigenes WB4, DSM 17365. The LDL receptor is best described in mammals where they transport ligands into the cell for degradation by lysosomes and plays a role in cholesterol homeostasis The occurrence of low-density lipoprotein (LDL) receptor repeat class B domains (pfam00058) on poribacterial genomes seemed noteworthy. We found these domains on one gene in each SAG 4C and 4E as well as on five genes in SAG 3G. Outside of Poribacteria since all of the discovered genes with these domains had predicted transmembrane helices (TMHs) (\u223c86%) with the majority of the protein located outside of the cell or signal peptides (SPs) (\u223c14%). TMHs and SPs were also frequently predicted on genes representing other eukaryote-like proteins of Poribacteria . These proteins are Fe(II) and 2-oxoglutarate dependent oxygenases that catalyze a wide range of oxidative reactions Among bacterial phyH genes are some potentially involved in quorum sensing Poribacteria.Among poribacterial genomes we found a remarkably high occurrence of genes encoding for proteins with pfam domain pfam05721-phyH . This pfPoribacteria-specific functions within the phyH family.A clustering analysis of poribacterial sequences showed that there was large diversity amongst poribacterial phyH family genes with 305 sequences clustering in 193 clusters with 60% aa id threshold . For thePoribacteria and elucidated one possible function of phyH superfamily genes in this candidate phylum.Although the majority of poribacterial phyH genes remained without further functional characterization, we were still able to make functional predictions in some cases. Poribacterial SAGs 3G and 4E encoded for phyH genes  with homologies (40% aa id each) to a 2-aminoethylphosphonate (2-AEPn) utilization gene (phnY) for which function was experimentally proven Poribacteria which are almost exclusively found in association with marine sponges. Here we show by use of phylogenetic and phylogenomic analyses that Poribacteria are not members of the PVC superphylum, but rather form a distinct monophyletic phylum in close proximity. We provide genomic evidence for bacterial microcompartments in Poribacteria that show no similarity to any previously described BMCs. Further novel functions might be hidden in the various eukaryote-like protein domains, which may be involved in mediating host-microbe interactions within the sponge holobiont. The high abundance of diverse phyH-domain containing proteins points to important and potentially specific functions in Poribacteria. Most of these functions remain to be revealed in future studies but some show the genomic potential for organic phosphorous utilization. Our analyses show how genome sequences can help to revisit past hypotheses and at the same time open the way for new investigations by revealing novel functional features. Challenges for the future will be to experimentally demonstrate function and to ultimately understand the implications for symbiosis.Our study demonstrates the power of single-cell genomics to reveal novel features of the candidate phylum Table S183 marker genes used for phylogenetic analysis.(PDF)Click here for additional data file.Table S2BMC group A genes with annotation.(PDF)Click here for additional data file.Table S3BMC group B genes with annotation.(PDF)Click here for additional data file.Table S4BMC group C genes with annotations.(PDF)Click here for additional data file.Table S5BMC group D genes with annotation.(PDF)Click here for additional data file.Table S6BMC shell protein pfam domain distribution on all genomes with either domain in IMG in July 2013.(PDF)Click here for additional data file.Table S7Overview of gene copy numbers (no) and percentage of genes per total genes on genome (%) of repeat proteins and eukaryote like protein domain genes on poribacterial SAGs and the maximum and average number of gene copies found on X finished genomes of marine free-living bacteria (n\u200a=\u200a101).(PDF)Click here for additional data file.Table S8List of all repeat and eukaryote like domain protein encoding genes on poribacterial SAGs. Information is shown as available in IMG/MER system. THM: number of predicted transmembrane helicies. SP: signal peptide predicted yes (Y) or no (N).(PDF)Click here for additional data file.Table S9List of total repeat and eukaryote like protein domain encoding genes of poribacterial SAGs showing the number of genes (# genes), the number of genes with transmemebrane helicies (# TMH), percentage of genes with transmembrane helicies (% TMH), number of genes with signal peptide (# SP), and percentage of genes with signal peptide (% SP) for each domain.(PDF)Click here for additional data file.Table S10phyH domain distribution on publically available genomes.(PDF)Click here for additional data file.Table S11Poribacterial phyH gene clusters based on 60% amino acid identity.(PDF)Click here for additional data file.Text S1Genomic evidence for microcompartments in Poribacteria. (extended description of genomic architecture)(PDF)Click here for additional data file."}
+{"text": "We are able to detect subclinical post-irradiation changes to the heart with left atrial late gadolinium enhanced magnetic resonance imaging (LGE-MRI).There are over 11 million cancer survivors, yet many long-term cancer survivors experience lasting changes including cardiac functional and anatomical abnormalities following external beam radiation and chemotherapy. One of the well-established pathological and histological sequelae of radiation exposure to the heart is intense post-irradiation injury with fibrotic changes. Here, we have explored the ability to apply LGE to identify the extent of left atrial uptake after radiation therapy.A total of 20 patients were enrolled in this study; 10 patients (ages 29 to 64 years) who had survived 9.2 \u00b1 25 years after thoracic external beam radiation for lymphoma and 10 control patients (ages 55 to 66 years) recruited from the University colonoscopy center. All patients underwent a MRI study including cine imaging, left ventricular LGE, and high-resolution LGE imaging of the left atrium. The extent of late gadolinium enhancement was calculated as a relative percent of total left atrial wall using a threshold-based algorithm based on pixel intensity distribution.As seen in Figures Patients with thoracic radiation for lymphoma have greater LGE reflecting radiation-induced injury than in an older group of controls without thoracic radiation therapy. LGE-MRI shows promise for finding and screening for prevalent myocardial tissue changes in this group of patients. Further studies with larger patient populations post thoracic radiation therapy with and without chemotherapy  and with longitudinal follow up would be useful for correlation with external beam radiation dosimetry and the development of future cardiovascular events in long-term cancer survivors.University of Utah Seed Grant."}
+{"text": "One third of all spinal injuries involve cervical vertebrae, and the impact of injury to the cervical spinal cord is profound and requires systemic treatment. The role and timing of surgical decompression after an acute spinal cord injury (SCI) remains one of the most controversial topics pertaining to spinal surgery. Lack of controlled, prospective, multicenter clinical studies has contributed to confusion in optimal treatment methods for patients with injuries of the cervical spinal cord. Clinically, the question of whether surgical decompression improves motor recovery following SCI remains surrounded by controversy.Two cases with a 32-year-old man who developed right -sided Brown-S\u00e9quard Syndrome Following a motor to car accident with the large right paramedian C3\u2013C4 disc herniation, and ipsilateral spinal cord compression and a 30-year-old man with the syndrome of acute central cervical spinal cord injury with motor impairment involving only upper extremities due to central C2\u2013C3 disc herniation following a pedestrian accident are reported. Discectomy and anterior cervical fusion with the polyetheretherketone (PEEK) cage were performed. A complete motor deficit recovery and a marked sensitive deficit improvement were obtained.The need for and timing of surgical decompression in post traumatic spinal cord injury is controversial. Surgery may expedite neurological recovery in some patients and may provide additional neurological recovery when clinical improvement has plateaued or worsened. In our patient a complete motor deficit recovery was observed. Cervical, Disc herniation, Spinal cord injury"}
+{"text": "Arterial stiffness had been proposed as the cause of sub-clinical left ventricular dysfunction in patients with COPD. Vascular studies in COPD patients were mainly assessed by carotid-femoral (aortic) pulse wave velocity using micromanometer applanation tonometry. The evaluation of pulmonary artery (PA) elasticity in COPD has not been assessed. This study seeks to evaluate indices of PA stiffness in patients with COPD. We hypothesized that patients with COPD would have increased pulmonary artery stiffness compared to healthy individuals. To test this we determine the pulmonary artery area change (distensibility or pulsatility in %) by cardiac magnetic resonance imaging (MRI) and related PA distensibility to the severity of COPD.100%x(maximum area-minimum area)/minimum area.MRI studies were performed using a 1.5T scanner  on 71 participants recruited to date into an ongoing nested case-control study of current and former smokers, age 58-79 years, free of clinical cardiovascular disease. COPD presence and severity was defined on post-bronchodilator spirometry by GOLD criteria . To measure left ventricular function, the heart was imaged with MRI in short-axis orientation using a retrospectively gated steady-state free precession sequence. Phase-contrast images perpendicular to the pulmonary trunk were obtained using a segmented fast gradient echo sequence  without breath hold. Pulsatility of the pulmonary vessels (in %) was measured from the largest systolic and the smallest diastolic areas derived from the magnitude images as: Participants with COPD had increased PA stiffness compared to normals as shown in Table Patients with COPD may have increased pulmonary artery stiffness measured by MRI PC imaging. Ongoing recruitment into this study is may confirm these preliminary findings."}
+{"text": "A discrete transition of wall stiffness at the interface of a compliant aorta and stiffer carotid arteries creates a reflection site for the aortic pulse wave and consequently limits excessive pulsatile energy transmission towards the brain. Arterial wall stiffness can be expressed by the pulse wave velocity (PWV) and dual-slice one-directional through-plane velocity-encoded (VE) MRI is well-validated for accurate PWV-assessment. The hypothesis is that with aging, leveling of PWV across the aortic arch and carotid artery will occur with negative effect on the flow towards the brain. The purpose of this study was to evaluate PWV and volume flow in aorta and carotid artery in younger and older volunteers using 3T VE MRI.Sixteen younger volunteers with age<30 years (mean 25\u00b13years) and sixteen older volunteers with age>45 years (mean 56\u00b16years) underwent 3T MRI (Philips) to assess PWV in the aortic arch and the left carotid artery based on the transit-time method. PWV in the aortic arch was acquired from a single VE MRI acquisition Figure  and fromAll measurements are presented in Table PWV leveling between the aortic arch and the left carotid artery at older age represents increased stiffening of the aortic arch and is associated with a reduction in volume flow towards the brain. High-field velocity-encoded MRI is well-suited for PWV evaluation across vascular trajectories.This study is supported by an unconditional grant provided by Dr. Rainer Bluemm ."}
+{"text": "Silene latifolia with the aim of studying gene expression differences between the two sexes in both reproductive and vegetative tissues. The catalogue contains more than 15 reference genes with both stable expression intensities and a range of expression intensities in flower buds and leaf tissues. These reference genes were used to normalize expression differences between reproductive and vegetative tissues in eight candidate genes with sex-biased expression. Our results suggest a trend towards a reduced sex-bias in sex-linked gene expression in vegetative tissues. In this study, we report on the systematic identification and validation of internal reference genes for adequate normalization of qRT-PCR-based analyses of gene expression differences between the two sexes in S. latifolia. We also show how RNA-seq data can be used efficiently to identify suitable reference genes in a wide diversity of species.Quantitative real time (qRT)-PCR is a precise and efficient method for studying gene expression changes between two states of interest, and is frequently used for validating interesting gene expression patterns in candidate genes initially identified in genome-wide expression analyses, such as RNA-seq experiments. For an adequate normalisation of qRT-PCR data, it is essential to have reference genes available whose expression intensities are constant among the different states of interest. In this study we present and validate a catalogue of traditional and newly identified reference genes that were selected from RNA-seq data from multiple individuals from the dioecious plant  RNA-seq, a transcriptome-based next-generation sequencing technique, has revolutionised genome-wide gene expression analysis and has massively increased the number of studied genes and species. In comparison to microarrays for example, RNA-seq has two major strengths For accurate expression estimation of target genes, expression estimates are normalised relative to internally expressed reference genes. These must be equally expressed among the states of interest for normalization to reduce non-specific variation. Such variation may be the result of different amounts of template RNA or different efficiencies in cDNA synthesis, for example. In addition, suitable reference genes should be expressed at intensities similar to those of the target genes. Typically, two to four references genes are recommended for adequate qRT-PCR data normalization de novo reference transcriptomes Reference genes in species with uncharacterized genomes have been identified using microarray data www.leonxie.com/referencegene.php?type=reference) takes into consideration results from all algorithms to arrive at a robust stability estimate and thus further facilitates the identification of suitable reference genes.Several different algorithms are available for assessing the stability of reference genes using qRT-PCR, such as geNorm Silene latifolia Poiret), a dioecious plant with evolutionarily young sex chromosomes, has become a model system for studies of plant sex chromosomes and the evolution of separate sexes S. latifolia plants.Novel reference genes have recently been characterized in several plant species including model de novo reference transcriptome) in male and female flower buds of S. latifolia. The qRT-PCR expression stability of these newly developed reference genes was then compared to traditional reference genes in flower buds and leaf tissues. Finally, we used the best reference genes to estimate the percentages of sex-biased genes in reproductive and vegetative tissues of S. latifolia by comparing a set of eight randomly chosen sex-linked genes with sex-biased expression patterns In the present study, we used RNA-seq data from multiple male and female individuals to identify the most stably expressed genes  Arabidopsis thaliana entries of the Uniprot database actin 11 (SL_ACTIN), putative ubiquitin-conjugating enzyme E2 21 (SL_UBCE), tubulin beta-5 chain (SL_TUB), eukaryotic translation initiation factor (SL_EF1), ubiquitin 11 (SL_UBQ), and glyceraldehyde-3-phosphate dehydrogenase (SL_GAPDH).Candidate reference gene sequences were annotated using the t) values exceeded 35. In cases of signals in NTC, the difference between the Ct of NTC and that of the template had to be \u22658 Ct values. Primer assays that produced \u226510% missing data were excluded. The remaining gene assays were ranked according to their expression stability between males and females in flower buds and leaves . We used the web tool RefFinder to assign robust ranks based on the results from the four widely used stability estimators geNorm, \u0394ct, NormFinder, and BestKeeper. We used all data, including the technical replica, to calculate stabilities. Results from one leaf sample were consistently identified as outliers and were therefore removed. Consequently, we randomly removed one leaf sample of the other sex to maintain a balanced design. qRT-PCR efficiencies were calculated across all samples and tissues using LinReg Four flower buds (5\u20136 mm) without the calyx and one disc (1 cm diameter) of a young, fully developed rosette leaf were collected from three males and three females of an 11-generation inbred line (U11); similarly, four males and four females were collected from the C1 cross. All samples were snap-frozen in liquid nitrogen directly after sampling. Total RNA was extracted from both tissue types separately using the RNeasy Plant extraction kit  with a BeadRuptor . RNA was treated in tube (see manufactory's instruction) with a RNase-Free DNase Set  and purified over a second column because we observed that on-column digestions were not sufficient to eliminate genomic DNA contaminations. RNA was checked for genomic DNA contamination by amplifying an intron-spanning PCR product whose fragment size was checked on agarose gels. The integrity of the RNA was assessed on an Agilent 2100 Bioanalyzer Plant RNA chip (RIN \u22657.5 for leaves and \u22659 for flower buds) and RNA concentrations were determined using a Qubit Fluorometer . 0.5 \u03bcg total RNA was then reverse transcribed to cDNA according to the standard protocol using the QuantiTect Reverse Transcription Kit  including the genomic DNA Wipeout buffer. qRT-PCR reactions were performed in triplicates on a 7500 Fast Real Time PCR system  using SYBR FAST Universal 2X qPCR mix with low ROX concentration  in a total volume of 11 \u03bcl. To assess the quality of our primer assays, we tested for dimer formation and the absence of amplification products in NTCs (no template controls), and Sanger sequenced  all amplified products to confirm amplification of target transcripts. Transcripts were considered undetermined if their cycle threshold (Ct) and were therefore not used further in the statistical analysis. Outliers were removed (<25th or >75th percentile) and fold changes and mean standard errors over the 5-7 biological replicates per sex were calculated using R. We considered contigs to be significantly differentially expressed between males and females if fold changes were \u22651.5 and Wilcoxon tests remained significant after performing Benjamini-Hochberg corrections for multiple testing (p\u22645%) We used the same cDNAs as for the reference genes and eight randomly selected sex-linked genes that were previously found to have sex-biased gene expression patterns , based on RNA-seq data S. latifolia flower buds., We could not design primer assays for two of these contigs, and one of the 22 validated candidate reference genes was excluded because it did not pass our quality control  observed for most contigs . We fountrol see   reference genes . The sucSeven of the eight contigs that were originally inferred to have sex-biased expression based on RNA-seq data RNA-seq data allow the analysis of thousands of genes in one single experiment and make it possible to screen the transcriptome for candidate genes showing expression patterns of interest. qRT-PCR is an effective, robust and inexpensive method for the subsequent validation of such RNA-seq experiments and for detailed studies of identified candidate genes. Medium and high throughput qRT-PCR experiments typically allow inclusion of more biological and technical replica compared to RNA-seq based transcriptome analyses. For an appropriate normalization of the qRT-PCR data it is, however, essential to have two to four suitable reference genes available in order to reduce non-specific expression variation that can otherwise lead to incorrect biological conclusions de novo assembly of reference transcriptomes that can be searched for the most stably expressed contigs. In this study, we observed that only a small proportion of contigs could be used as candidate reference genes because expression of the great majority of genes varied substantially between biological replica and the two sexes. It is therefore important to evaluate a large number of expressed genes for their suitability as reference genes. The approach we used here to identify reference genes was straightforward. We used two different RNA-seq datasets from multiple individuals to reduce technical variation, and population effects to identify candidate reference genes that span a broad expression range. These genes  individuals from an inbred line (U10) and (B) individuals from an intraspecific cross. Low CV values indicate high expression stabilities between the sexes. The 1% most stably expressed contigs are highlighted in green (bottom left of A and B).Genome-wide expression stability estimates of genes in flower buds of male and female (TIF)Click here for additional data file.Figure S2t) and stabilities of candidate reference genes ordered by decreasing stability across both sexes and tissue types. (A) Boxplots of tC values across all tested samples and tissues for candidate reference genes arranged by decreasing (left to right) stability rank as inferred from RefFinder. (B) Average expression stability (M) estimates for all candidate reference genes across all samples and both tissue types. Traditional reference genes are indicated in bold.Expression values (C(TIF)Click here for additional data file.Figure S3Gene expression stabilities of candidate reference genes depend on RNA quality. Average expression stabilities of candidate reference genes in cDNA from flower buds after long-term storage (two years) at \u221280\u00b0C (A) and short-term storage (one year) at \u221280\u00b0C (B).(TIF)Click here for additional data file.Table S1Traditional reference genes found among the 10%, 5% and 1% most stably expressed contigs between male and female flower buds based on RNA-seq data.(XLSX)Click here for additional data file."}
+{"text": "Gene set analysis is moving towards considering pathway topology as a crucial feature. Pathway elements are complex entities such as protein complexes, gene family members and chemical compounds. The conversion of pathway topology to a gene/protein networks (where nodes are a simple element like a gene/protein) is a critical and challenging task that enables topology-based gene set analyses.Unfortunately, currently available R/Bioconductor packages provide pathway networks only from single databases. They do not propagate signals through chemical compounds and do not differentiate between complexes and gene families.graphite, a Bioconductor package addressing these issues. Pathway information from four different databases is interpreted following specific biologically-driven rules that allow the reconstruction of gene-gene networks taking into account protein complexes, gene families and sensibly removing chemical compounds from the final graphs. The resulting networks represent a uniform resource for pathway analyses. Indeed, graphite provides easy access to three recently proposed topological methods. The graphite package is available as part of the Bioconductor software suite.Here we present graphite is an innovative package able to gather and make easily available the contents of the four major pathway databases. In the field of topological analysis graphite acts as a provider of biological information by reducing the pathway complexity considering the biological meaning of the pathway elements. A great deal of effort has been recently directed towards the study of gene sets (hereafter GSA) in the context of microarray data analysis. The aim is to identify groups of functionally related genes with possibly moderate, but coordinated, expression changes. Several GSA tests, both univariate and multivariate, have been recently developed. See  for a coSPIA) attempting to capture several aspects of the data: the fold change of differentially expressed genes (DEGs), the pathway enrichment and the topology of signaling pathways. In particular, SPIA enhances the impact of a pathway if the DEGs tend to lie near its entry points. Massa et al. [1] \"acetylation and deacetylation of rela in nucleus\"[2] \"actions of nitric oxide in the heart\"[3] \"activation of camp-dependent protein kinase pka\"> biocarta[[\"ras signaling pathway\"]]\"ras signaling pathway\" pathway from BioCartaNumber of nodes = 18Number of edges = 22Type of identifiers = nativeRetrieved on = 2011-05-12or its position in the list of pathways:> p <- biocarta [[175]]> p@title[1] \"ras signaling pathway\"In the network, nodes represent genes and edges functional relationships among them. Nodes can have heterogeneous IDs  and edges can be characterized by multiple functional relationships.pathwayGraph builds a graphNEL object from a pathway p:The function > g <- pathwayGraph(p)> gA graphNEL graph with directed edgesNumber of Nodes = 18Number of Edges = 23> edgeData(g) [1]$ 'EntrezGene:10928 | EntrezGene:5879'$ 'EntrezGene: 10928 | EntrezGene:5879 '$weight[1] 1$ 'EntrezGene:10928 | EntrezGene:5879 '$edgeType[1] \"catalysisOut (ACTIVATION)\"converterIdentifiers allows the user to map such variety of IDs to a single type (Entrez-Gene or Gene Symbol). For the ID conversion graphite uses the data provided by the Bioconductor package org.Hs.eg.db. This mapping process, however, may lead to the loss of some nodes  and has an impact on the topology of the network (one ID may correspond to multiple IDs in another annotation or vice versa).The function > pEntrez <- convertIdentifiers > pEntrez\"ras signaling pathway\" pathway from BioCartaNumber of nodes = 20Number of edges = 20Type of identifiers = Entrez GeneRetrieved on = 2011-05-12> nodes(pEntrez)[1:10][1] \"10928\" \"1147\" \"3265\" \"387\" \"4303\" \"5295\" \"572\" \"5879\" \"5894\" \"5898\"graphite uses the Rcytoscape package to export the network to Cytoscape [Several pathways have a huge number of nodes and edges, thus there is the need of an efficient system of visualization. To this end ytoscape . Cytosca> cytoscapePlot)The network will be automatically loaded into Cytoscape. See Figure In order to verify our signal propagation strategy we perform a simulation study. Using the insulin signaling pathway of the KEGG database we select as differentially expressed 22 genes lying on the signal paths highlighted in Figure FC \u03bc~ U ; 2) we randomly generate log fold change values  of the differentially expressed genes as i \u03b4~ N  ; 3) we run the SPIA[Our simulation is based on the following steps: 1) we randomly generate  the SPIA algorithAs shown in Figure The dataset, recently published by , characthttp://www.bioconductor.org/help/publications/2003/Chiaretti/chiaretti2/) Expression values, appropriately normalized according to rma and quantile normalization, derived from Affymetrix single channel technology, consist of 37 observations from one experimental condition  and 41 observations from another experimental condition . Probes platform have been annotate using EntrezGene custom CDF version 14 [Data is available at the Bioconductor site  on the entire list of genes belonging to a pathway. Here, differentially expressed genes required for SPIA package have been identified using RankProd test [F D R <0.01), while the test on the mean has been chosen for topologyGSA package.We report the results obtained by SPIA and topopologyGSA on the grod test  , the results testify the feasibility of performing analyses using Our results highlight that the hierarchical pathway structure and the reduced dimension of the pathways characterizing respectively the Reactome and Biocarta databases jointly with the specialized cancer pathways of the NCI databases allow the user to have deeper insight into the data.graphite networks identified as significantly altered in the previous analysis.To highlight the usefulness of topological analysis in the context of transcriptomic data interpretation, we report two topologyGSA. Figure graphite network from KEGG database with differentially expressed genes mapped with different colors according to fold change sign. It is interesting to note the presence of several OR groups , single members of which resulted to be differentially expressed. Two clear deregulated paths starting from BCR and ABL1 genes towards apoptosis and NFKB pathways highlight the power of topological analysis to deeper investigate signal cascades within large pathways.Chronic myeloid leukemia pathway includes both genes, BCR and ABL1, and was identified as differentially expressed between BCR/ABL positive and negative patients by KEGGgraph[NCIgraph that imports BioPax models from Cytoscape [Currently there are two Bioconductor packages that try to convert pathway to the SIF model. KEGGgraph that parytoscape  without graphite, on the other hand, is an innovative package able to gather and make easily available the contents of the four major pathway databases. In the field of topological analysis graphite acts as a provider of biological information by reducing the pathway complexity considering the biological meaning of the pathway elements.It is evident that gene set analysis is moving towards considering pathway topology as a crucial feature. A correct conversion of the pathway topology to a gene network becomes therefore important. Available packages are not able to correctly reconstruct the signal transduction in most cases. graphite\u2022 Project name: http://www.bioconductor.org/packages/devel/bioc/html/graphite.html \u2022 Operating system(s): Platform independent\u2022 Project home page: \u2022 Programming language: R\u2022 Other requirements: Bioconductor\u2022 License: GNU AGPL\u2022 Any restrictions to use by non-academics: noneGS, EC and CR jointly define the concept proposed. GS, EC developed the methods proposed and performed the analysis on gene expression data. CR supervised the work and wrote the paper. DC Participated in the critical definition of the concept proposed and participated in drafting and commenting critically the manuscript. All Authors read and approved the final manuscript.Example of KGML and owl. Additional file 1: bmc-supp.pdf, 116 K. http://www.biomedcentral.com/imedia/1501537976613594/supp1.pdfClick here for file"}
+{"text": "The random nature of transgene integration harbours various pitfalls for development of production cell lines including clonal variation in expression level and growth characteristics. The CEMAX system is an expression system for targeted integration of expression cassettes via DNA double-strand break induced homologous recombination. Stable high producers are available within 4 weeks without the need of extensive clone screening and process development.Stable and high expression rates are ensured with the CEMAX system due to targeted integration of a single copy of the gene of interest at a transcriptionally highly active site in the host cell genome. Producer cell lines for various therapeutic product candidates were established. These cell lines produced antibodies and highly glycosylated antibody fusion proteins and showed high clonal similarity. This made a platform fed-batch process profitable.The CEMAX expression system is based on a genetically modified CHO cell line bearing a tag at a highly active genomic transcription site. The gene of interest (GOI) is integrated via site-directed DNA double-strand break-induced homologous recombination. The target site comprises a screening and selection cassette, which was used for initial development of the high producer host cell. This exchangeable cassette is flanked by elements that facilitate site-directed integration by homologous recombination. These elements include regions of homology for recombination with the CEMAX vector, rudimentary selection markers that are activated during recombination, and cleavage sites for the homing endonuclease I-SceI (Meganuclease).Transfection of the CEMAX vector comprising the GOI along with transient Meganuclease activity triggers a chain of events after cotransfection: DNA gets cleaved by I-SceI and cellular DNA repair machinery is induced by free DNA double-strand breaks. The CEMAX vector comprising the GOI functions as a repair matrix using recombination between homologous elements flanking the DNA lesion. The GOI gets integrated and the rudimentary selection markers become activated upon homologous recombination. CEMAX producer cells were selected at multi-well plate scale followed by analysis for outgrowth of stable producer cells. The platform process for fed-batch cultivation of various CEMAX producer cells was applied after expansion to the scale needed for production of protein material.The idea of a platform process that is suitable for all CEMAX producer cells was based on theoretical consideration about similarity of cells due to site-directed integration and the observation that cell growth and metabolism of CEMAX cell lines were comparable. This was verified by the results of this study. Applying the fed-batch process cell growth of CEMAX host cells and CEMAX producer cells was comparable Figure . The devThe fed-batch process comprises a chemically defined and commercially available basal medium and the chemically defined feed solution CeloFeed (Celonic) supplemented according to the improved feeding regime. The glucose level was maintained between 4.5 g/L and 7.5 g/L. Glutamine was kept at a concentration above 0.8 mM. By applying the platform fed-batch process product concentrations up to 690 mg/L were achieved with CEMAX cell lines producing a glycosylated Fc fusion protein after site-directed integration of the GOI Figure . AchievaThe platform fed-batch process was developed by optimization based on commercial available and proprietary basal and feed media formulations. It was suitable for all producer cell lines derived of a particular CEMAX host cell due to highly similar growth behavior after site-directed integration of the gene of interest. The platform process made product concentrations of up to 0.7 g/L achievable. Animal derived component free chemically defined medium and feed solution ensure a robust and regulatory compliant process. By combining the platform process with site-directed integration timelines in cell line development and process development were shortened for faster entry in first-in-man studies."}
+{"text": "Blunt chest trauma (BCT) is a common clinical presentation seen in emergency departments. Few cases of cardiac conduction abnormalities due to BCT have been reported in the medical literature. This dysrhythmias may present as permanent conduction defects requiring permanent pacemaker or may have temporary conduction abnormalities requiring temporary pacemaker or supportive care. We present the case of a young woman who suffered from BCT after being kicked by a horse with the development of a significant substernal hematoma. She developed temporary atrioventricular block, which was completely resolved with the decrease in the size of the substernal hematoma suffered. Blunt cardiac injury (BCI) inducing cardiac conduction abnormalities is not a common medical occurrence and probably underreported in the medical literature. An initial review by Dolara and Pozzi in 1966 presented 23 cases of atrioventricular block (AVB) from BCI [\u03bcg/L (0.00\u20130.08\u2009\u03bcg/L). These were felt to be secondary to a blunt cardiac contusion. Her elevated cardiac enzymes reverted back to normal within 48 hours.A 25-year-old woman with no past medical or surgical history was brought to the Emergency Department (ED) after being kicked by a horse in her chest. The patient was found to have a midsternal fracture with underlying hematoma on computed tomography (CT) chest see . Her bloThe patient's electrocardiogram (EKG) on admission revealed normal sinus rhythm with rate of 65\u2009bpm (beats per minute) with first-degree atrioventricular block (AV Block) and left anterior hemiblock as depicted in According to the American Association for the Surgery of Trauma, the effects of BCI can range from being asymptomatic with minor EKG abnormalities to rupture of the cardiac anatomy, heart failure, and even traumatic avulsion of the heart . ConductMost conduction abnormalities are postulated to arise from myocardial infarction or ischemia, stunning of the conduction system, or excessive cholinergic activation . Basic aDysrhythmias (including AVB) following blunt chest wall injury can be self-limited or may require permanent pacemaker. Despite the resolution of our patient's AVB, most sources suggest close observation and followup in case delayed complications arise."}
+{"text": "CTNS gene, encoding a cystine efflux channel in the lysosomal membrane. In Ctns knockout mice, the pathologic intralysosomal accumulation of cystine that drives progressive organ damage can be reversed by infusion of wildtype bone marrow-derived stem cells, but the mechanism involved is unclear since the exogeneous stem cells are rarely integrated into renal tubules. Here we show that human mesenchymal stem cells, from amniotic fluid or bone marrow, reduce pathologic cystine accumulation in co-cultured CTNS mutant fibroblasts or proximal tubular cells from cystinosis patients. This paracrine effect is associated with release into the culture medium of stem cell microvesicles (100\u2013400 nm diameter) containing wildtype cystinosin protein and CTNS mRNA. Isolated stem cell microvesicles reduce target cell cystine accumulation in a dose-dependent, Annexin V-sensitive manner. Microvesicles from stem cells expressing CTNSRed transfer tagged CTNS protein to the lysosome/endosome compartment of cystinotic fibroblasts. Our observations suggest that exogenous stem cells may reprogram the biology of mutant tissues by direct microvesicle transfer of membrane-associated wildtype molecules.Cystinosis is a rare disease caused by homozygous mutations of the  CTNS gene on the short arm of chromosome 17q, encoding a ubiquitous cystine-selective transport channel in the lysosomal membrane Cystinosis is a rare disorder caused by homozygous mutations of the 2/day typically reduces leukocyte cystine levels to about 15% of baseline. However, the odour and gastric side-effects of oral cysteamine make adherence extremely difficult. Furthermore, even well-treated patients eventually require kidney transplantation and develop profound distal myopathy, cerebral atrophy and other complications as young adults In the late 1980's, it was discovered that the pathologic accumulation of cystine could be substantially reduced by cysteamine therapy. This drug attacks the internal disulfide bond of cystine to form mixed disulfides that are able to efflux from the lysosome via alternative transport channels Ctns \u2212/\u2212 knockout mice et al infused allogeneic wildtype bone marrow stem cells into Ctns \u2212/\u2212 knockout mice after partial ablation of the bone marrow. The exogenous stem cells were progressively retained by cystinotic organs, resulting in 90% decrease in tissue cystine levels and, in the case of the kidney, leading to normalization of organ dysfunction Ctns transcript level rose to only 10% of normal It was with great interest, therefore, that the medical community learned in 2009 of successful bone marrow stem cell therapy of et al reported that cancer stem cells shed microvesicles from the cell surface and that endocytotic uptake of the microvesicles transfers epidermal growth factor receptors to nearby endothelia; this induces proliferation of the normal endothelial cells, by rendering them responsive to local transforming growth factor-alpha in vitro co-culture model to demonstrate that human stem cells reverse cystine accumulation in cystinotic cells in paracrine fashion. We demonstrate that mesenchymal stem cells shed microvesicles containing wildtype cystinosin protein and CTNS mRNA into the culture medium and that uptake of isolated microvesicles transfers CTNS protein to the lysosomal compartment of cystinotic fibroblasts and reverses pathologic cystine accumulation.Stem cells are known to exert a number of useful paracrine effects, including the release of soluble factors that suppress inflammation or stimulate proliferation of endogenous cells following acute organ injury The cells used in this study were obtained from the Cell Repository from the Montreal Children's Hospital with ethical approval from the Montreal Children's Hospital Research Ethics Board. For cell lines previously published, ethical approval was obtained and stated in the corresponding reference.Red was previously described CTNSCTNS(f) 5\u2032-gcagtcacgctggtcaagta-3\u2032, and CTNS(r1) 5\u2032-caggaaagtggccttcagag-3\u2032 or CTNS(r2) 5\u2032-cgaagacgatggagaagacc-3\u2032; GAPDH(f) 5\u2032-gagtcaacggatttggtcgt-3\u2032, GAPDH(r) 5\u2032- gatctcgctcctggaagatg -3\u2032. Genotyping for CTNS mutation was performed with primers LDM1 flanking the common 57 Kb deletion or CTNS Exon 4 Total RNA was isolated with RNeasy kit (Qiagen). Purity and concentration of RNA were determined with a NanoDrop ND-1000 . Transcripts were amplified (35 cycles) using: Normal human amniotic mesenchymal stem cells  and adult bone marrow cells  \u22128 mol/l; Sigma-Aldrich) for 4 weeks and then stained with 1% Alizarin Red S (Sigma-Aldrich). In order to test for adipogenic differentiation of MSCs, cells were exposed to complete media supplemented with insulin (5 \u00b5g/ml), dexamethasone , 3-isobutyl-methylxanthine , and indomethacin  for 14 days, and then stained with Oil Red O (Sigma-Aldrich).One million cells were incubated for 30 minutes at +4\u00b0C with the following monoclonal antibodies: phycoerythrin-labeled HLA-DR (clone LN3) from eBioscience, allophycocyanin-labeled CD34 (clone 581), phycoerythrin-labeled CD44 (clone G44-26), phycoerythrin-labeled CD31 (clone WM59), phycoerythrin-labeled CD105 (clone 266), phycoerythrin-labeled CD45 (clone HI30), fluorescein isothiocyanate-labeled CD90 (clone 5E10), phycoerythrin-labeled CD73 (clone AD2) from BD Biosciences . Cells were analyzed with CellQuest Pro software on a FACSCalibur flow cytometer (BD Biosciences), using antibody isotype controls. In order to test for osteogenic differentiation of MSCs the cells were exposed to complete media supplemented with \u03b2-glycerol phosphate , ascorbic acid 2-phosphate , and dexamethasone  equipped with a 1.4 NA 63\u00d7 oil lens, Leica DMI6000 B microscope, Yokowaya CSU-10 spinning disc confocal head and a Hamamatsu ImagEM (EM-CCD) camera. Images were acquired using 0.2 micron optical sectioning and analysed using the Improvision Volocity software. Images were registration corrected and deconvolved. Briefly, cells were grown on Lab-tek II chambered coverglass slides . In some experiments, MV bearing CTNSRed were added to mutant cell monolayers 4 hours before confocal microscopy. LysoTracker probe  was added 10 min before image capture.CTNSStatistical analysis were performed using paired, two tailed Student's t-test. Data bars and error bars indicate mean \u00b1 standard deviation., right panels).To study the paracrine effects of wildtype stem cells on nearby adjacent mutant cell targets, we first isolated mesenchymal stem cells from bone marrow of healthy adults (bmMSC)  containing high intracellular levels of cystine . After 4 days in co-culture, we measured the cystine content of the mixed cell population and calculated the cystine attributable to the subset of mutant target cells. As seen in We then co-cultured amniotic mesenchymal stem cells (amMSC) with various proportions of mutant fibroblasts from a cystinosis patient with homozygous deletion of the GFP) after co-culture with a variety of donor cells. The target ciPTEC(\u2212/\u2212)GFP cells were from a cystinosis patient bearing the common homozygous 57 kb deletion of the CTNS gene GFP targets compared to baseline. In another set of experiments, ciPTEC(\u2212/\u2212)GFP cell cystine was unaffected by co-culture with untagged mutant proximal tubular ciPTEC(\u2212/\u2212) donor cells; on the other hand, co-culture of ciPTEC(\u2212/\u2212)GFP with genetically corrected (transfected with wildtype CTNS) ciPTEC(\u2212/\u2212) cells again showed significant reduction of cystine content et al suggested that an important characteristic of stem cells is that they shed plasma membrane-derived microparticles into the local environment and these are taken up by neighboring cells Al-Nedawi CTNS mutant target cells, we isolated microvesicles from bmMSC or amMSC and transferred them to separate monolayer cultures of CTNS mutant fibroblasts (\u2212/\u2212) for 24 hours (1\u20132 mg microvesicles/mg fibroblast protein). The cells were then harvested and assayed for cystine content as above. As seen in To ascertain whether MSC microvesicles can reduce cystine content of Red GFP fibroblast targets; there was no evidence of fusion between donor and target cells. As seen in Red particles are visible in a single confocal plane within a cluster of amMSC GFP fibroblasts, indicating transfer of the tagged protein from amMSC to the target cell.To test the possibility that microvesicles mediate direct CTNS protein transfer between donor and recipient cells, we stably transfected amMSC with CTNSRed vesicles ( inset) applied directly to cultured CTNS(\u2212/\u2212) fibroblasts stained with a green-fluorescent endosomal/lysosomal dye. As seen by confocal microscopy GFP fibroblasts with either amMSC or unlabelled CTNS(\u2212/\u2212) fibroblast donors for 48 hours and then separated the CTNS(\u2212/\u2212)GFP fibroblasts by FACS. As seen in CTNS transcripts were detectable by RT/PCR in the mutant recipient target cell co-cultured with amMSC, but not with the mutant fibroblast donors.Other investigators have shown that microvesicles contain mRNA and miRNA as well as protein Long regarded as inactive cellular debris, microvesicles shed from the surface of viable cells are increasingly recognized as important vehicles for the transfer of complex biologic information between neighboring cells. Microvesicles arise either through vesiculation of the plasma membrane to generate 100\u2013500 nm diameter particles exposing phosphatidyl serine residues shifted to the outer leaflet (ectosomes) or through redirection of endosomal structures to multivesicular bodies that disgorge their 40\u201480 nm diameter particles (exosomes) into the extracellular environment Ctns knockout mice While many cells shed microvesicles, flux from the surface of stem cells and cancer cells is thought to be especially high and may exert important influence on the stem cell niche or on tumour invasiveness. Here, we show that mesenchymal stem cells shed microvesicles containing wildtype cystinosin protein and mRNA. Uptake of these microvesicles by mutant CTNS(\u2212/\u2212) fibroblasts or proximal tubule cells delivers CTNS to the endosomal/lysosomal compartment and reduces the pathologic accumulation of cystine. This provides a plausible mechanism to explain the clinical effects of bone marrow stem cell infusion on et al, optimal clinical effect was obtained by infusion of 20 million wildtype hematopoietic stem cells (HSC) into Ctns knockout mice Ctns(\u2212/\u2212) mouse tissues noted by Syres et al could be explained by microvesicle shedding.In the study by Syres Our studies show that the majority of microparticles shed by amMSC or bmMSC monolayers into culture medium containing 0.5% BSA are between 100\u2013400 nm in diameter, characteristic of microvesicles (ectosomes). Unlike exosomes (<100 nm diameter) which arise during endosomal recycling within the cell, microvesicles arise through regulated outward blebbing of lipid raft-associated areas of the plasma membrane et al have shown that MSC infused into mice with glycerol-induced renal injury ameliorate tissue damage by suppressing apoptosis and enhancing proliferation of endogenous cells Bruno et al have reported a second cystinosin isoform (CTNSLKG), constituting about 15% of total cellular cystinosin, which lacks the lysosomal targeting sequence and readily appears at the plasma membrane CTNS gene and the capacity to shed microvesicles should be able to reduce cystine content of adjacent mutant cells. Indeed, we found that mutant cell cystine accumulation was reduced by co-culture with either amMSC or genetically corrected proximal tubular cells and by microvesicles from either amMSC or bmMSC.In our studies, transfection of amMSC with an expression vector containing Red-tagged CTNS generated microvesicles richly supplied with the tagged fusion protein. Wildtype cystinosin contains a 3\u2032sequence which targets most of the protein to the lysosomal membrane CTNS mRNA, it is uncertain whether de novo CTNS synthesis in the mutant cell contributes to the rescue effect. It is likely that some cells shed more microvesicles than others and this could influence therapeutic efficacy. Furthermore, delivery of wildtype protein to the plasma membrane could limit the rate of protein transfer to the mutant cells. Steinherz showed that the efflux half-time of cystine dimethylester from heterozygous cystinotic lysosomes is 86.3+/\u22125 vs normal 43.1+/\u22123 minutes Microvesicles are known to contain proteins as well as mRNA and miRNA A wide range of lysosomale storage diseases have been treated with allogeneic hematopoietic stem cells derived from umbilical cord For years, the therapy of genetic disease has focused on: a) vector-mediated gene transfer to mutant tissues; b) transplantation of long-lived wildtype cells that can metabolize systemic load of toxic metabolites; c) transplantation of stem cells that can transdifferentiate and become integrated into mutant organs. Our observations suggest an additional type of cell-based therapy for genetic diseases in which microvesicle-mediated transfer of membrane-bound proteins may correct the defect in nearby mutant cells. This shifts the primary therapeutic consideration toward the ability of stem cells to shed microvesicles that transfer molecules to the mutant tissue rather than their transdifferentiation potential."}
+{"text": "Establishment of sinus rhythm (SR) following radiofrequency ablation (RFA) for longstanding persistent atrial fibrillation (AF) is not necessarily an equivalent to physiological atrial mechanical activity. We aimed to determine the influence of atrial ultrastructural remodeling on the recovery of its mechanical transport following restitution of SR.We enrolled 32 patients operated for severe mitral regurgitation. Half of the patients had no history of AF constituting the SR group. The remaining half had concomitant RFA for longstanding persistent AF, the RFA group. Intraoperative transesophageal echocardiography was used for tissue Doppler indices (TDI) data acquisition at the left atrial (LA) lateral wall. During post-procedural data acquisition all patients were in SR. LA biopsies were obtained during surgery and quantified for fibrosis after Mallory\u2019s trichrome staining.Atrial mechanical contraction was noted in both groups following surgery, although TDI values of late diastolic strain rate (SRI A\u2019) and tissue velocity (TVI A\u2019) were superior in the SR group . Post-procedural atrial filling was compromised in the RFA  and the SR group . Negative correlation between fibrosis and the pre-procedural SRI A\u2019 was noted in the SR group , although not significant throughout both groups .We have shown that the restoration of SR following RFA and mitral valve surgery is not equal to normal atrial mechanical transport. Interstitial fibrosis, a symbol of ultrastructural remodeling, is a negative precursor of LA mechanical activity. Our data did not corroborate clear difference in the extent of fibrosis between groups, although a tendency towards more severe ultrastructural remodeling was noticed in patients with history of AF."}
+{"text": "Diastolic dysfunction is often used as a marker for allograft rejection and may even precede systolic abnormalities. However, diastolic indices provided by echocardiography can be of inconsistent quality with low sensitivities. Cardiac magnetic resonance (CMR) with high temporal resolution cine imaging offers an alternate noninvasive method for evaluating ventricular function. The purpose of this study is to describe CMR LV diastology indices in a cohort of heart transplant patients, comparing CMR results to echocardiography.A retrospective search was performed for cardiac transplant patients with echocardiograms and CMR examinations with high temporal resolution steady state free precession (SSFP) cine images in long axis orientation (average TR: 11.86 ms) obtained within 1 week of each other. The study cohort comprised 18 patients . SSFP cine images were analyzed using prototype software evaluating deformation fields to automatically identify and track the mitral base plane at lateral and septal insertions, extracting lateral e' values . Lateral e' values were obtained for each patient from available echo data as well. Additionally, in 13 patients, 3-chamber high temporal resolution SSFP cine images were adequate in orientation for calculation of time elapsed between aortic valve closure and mitral valve opening (IVRT). Bland-Altman analysis was performed. Lateral e' values were reviewed between methods and across estimates of LV filling pressure with E/lateral e' ratios obtained from echo to determine a threshold CMR e' value suggestive of elevated LV filling pressures.Representative lateral mitral annular velocities are shown in Figure High temporal resolution SSFP cine imaging enabled semiautomated quantification of LV diastolic function parameters in heart transplant patients. While CMR consistently underestimated lateral e' values in our cohort, high temporal resolution SSFP cine imaging provided acceptable estimates of IVRT. Additionally, there may be a threshold lateral e' value at CMR  that is suggestive of elevated LV filling pressures. Our conclusions are limited due to the small number of patients in this retrospective study; work is ongoing to confirm our findings in a larger cohort.Dr. Collins has funding from RSNA Research & Education Foundation."}
+{"text": "Cardiac MRI imaging showed a very large ventricular septal cystic mass most consistent with a primary cardiac teratoma causing mild LVOT obstruction.CMR is an established method for evaluation of cardiac masses. It is superior to other modalities as it can provide tissue characteristics, thus allowing highly accurate differentiation of benign from malignant tumors, as well as local mass effects such as outflow compression.Using Cardiac MRI for assessment of etiology of a massive, septal tumor as well as its effect on LVOT flow and LV filling.A 5 day old full term female with a prenatal diagnosis of a large intracardiac tumor underwent post-natal echocardiography. Echo confirmed the suspected diagnosis as a large cystic mass compressing both ventricles without significant outflow tract obstruction. Cardiac MRI was performed specifically for further morphologic characterization. Imaging was performed using non-breatheld technique with multiple signal averages while under general endotracheal anesthesia on a 1.5 Tesla GE Excite magnet utilizing an 8-channel phased-array cardiac coil. The CMR sequences included SSFP 2, 3, and 4 chamber views and short axis multislice cine stacks; tagged SPAMM cines in 3 short and 2 long axis planes; gadolinium-enhanced myocardial first pass perfusion and delayed enhancement imaging in both short and long axis planes. Pre- and post-contrast T1 FSE single phase short axis stacks. Both right and left ventricular volumes and tumor volume were measured at end systole and end-diastole using MEDIS QMass software.All the sequences show a large heterogeneous intraventricular cystic mass surrounded by thinned myocardium (Fig.CMR provided exquisite anatomic localization and tissue characterization of this pediatric cardiac tumor. It also delineated the extent of viable function within the heart chambers allowing for proper patient management. Based on the MR imaging, no interaction was undertaken. At the time of the last evaluation at 4 months of age, the patient was doing well and was without symptoms. The tumor size was unchanged and the cardiac function remains normal.There are no financial disclosures."}
+{"text": "Cor triatriatum sinister is a rare congenital cardiac anomaly with an incidence of between 0.1 and 0.4%  whereby A 64 year old man with a 4 year history of long-lasting persistent drug refractory AF and previous failed attempts at cardioversion was referred for catheter ablation. There was no history of hypertension, coronary artery disease or obstructive sleep apnea. Previous transthoracic echocardiogram had been reported as demonstrating mildly dilated left atrium at 4.2cm with a membrane within the left atrium. There was mild mitral regurgitation with no evidence of impaired trans-mitral flow. The left ventricle was undilated (left ventricular end diastolic diameter 4.9cm) with normal systolic function (ejection fraction 70%). These findings were confirmed by a pre-operative multi-slice CT scan which clearly demonstrated a membrane dividing the left atrium into 2 chambers. The supero-posterior chamber received the 4 pulmonary veins whilst the infero-anterior chamber contained the left atrial appendage and was in direct continuity with the mitral valve  and 1b.The patient was in AF at the commencement of the procedure. Under general anaesthesia, bilateral femoral venous access was obtained. A 6Fr quadrapolar catheter was advanced from the left femoral vein to the His position and a 7Fr steerable decapolar catheter was advanced from the right femoral vein to the coronary sinus. Intra-operative transesophageal echocardiogram (TEE) was performed to further delineate left atrial anatomy and aid trans-septal access to the left atrium.Standard and 3-dimensional TEE confirmed the diagnosis of cor triatriatum with a fenestrated membrane arising from the anterior roof of the left atrium extending partly down the chamber in the antero-inferior direction  . The seAccess to the infero-anterior chamber was gained via the PFO using an SL1 sheath advanced from the right femoral vein. A decapolar circular catheter  was advanced into this chamber via the sheath and a 4mm irrigated catheter  was passed alongside using a single wire, dual access approach. Intravenous heparin was used to maintain an ACT of 300-350 seconds. Both catheters were inserted into the antero-inferior chamber. The supero-posterior chamber was accessed relatively easily by rotating the catheters posteriorly under the membraneA 3 dimensional multichamber geometry of the left atrium and pulmonary veins was created using the Ensite NavX system  without CT integration. Given that the left atrium was functionally and anatomically divided by the membrane, the supero-posterior and infero-anterior aspects were created as separate chambers  and 1d. The strategy employed was pulmonary venous antral ablation with isolation as the end point. Further ablation within the supero-posterior chamber was performed with linear ablation across the roof connecting the right and left superior pulmonary veins. Complex fractionated electrograms were then targeted within the two left atrial chambers, the right atrium and within the coronary sinus  and 3b. During 7 months of follow up the patient has remained symptomatically free of atrial fibrillation without any antiarrhythmic drugs.  24 hour holter monitoring 3 and 6 months post procedure did not show any evidence of atrial fibrillation.Cor triatriatum sinister is commonly thought to result from failure of the common pulmonary vein to become fully incorporated into the left atrium during foetal development. This results in a fibro muscular septum like structure which divides the left atrium into a postero-superior chamber receiving the pulmonary veins and an antero-inferior chamber in direct continuity with the mitral valve. It usually presents in childhood, often in association with other cardiac abnormalities. However with improvements in diagnostic imaging it is being diagnosed with increasing frequency in adults  either iAlthough there are two previous case reports of AF ablation in the literature, these involved only single chamber ablation with isolation of the pulmonary veins and no attempt at additional substrate modification. It is generally recognized that pulmonary vein ablation with isolation alone is insufficient in the treatment of persistent atrial fibrillation and that additional substrate modification is required -12. To tThe use of a 3 dimensional mapping system and good pre- and intra-operative imaging were essential in the planning and execution of the ablation procedure. Our experience would suggest that these patients can be effectively treated with a good outcome."}
+{"text": "Inferoseptal crypts have been previously reported as a marker of hypertrophic cardiomyopathy (HCM) as well as genotype positive/phenotype negative HCM. We hypothesized that the presence of such crypts would have incremental predictive value for the presence of a disease-causing mutation compared to prediction based solely on left ventricular morphologic pattern of hypertrophy.Cardiovascular magnetic resonance (CMR) data sets of 300 consecutive unrelated HCM patients who underwent genetic testing were reviewed independently by two experienced clinical CMR readers who were blinded to results of genetic testing. Readers assessed for presence or absence of deep basal inferoseptal crypts (DBISC) on cine steady state free precession and late gadolinium enhancement sequences and documented the imaging plane in which DBISC were convincingly visualized. Imaging and genetic testing results were correlated.Deep basal inferoseptal crypts occurred more commonly in patients with disease-causing mutations than in patients without them  and the presence of DBISC was a stronger predictor of the presence of disease-causing mutations than reverse septal curvature morphologic phenotype (p=0.025). 91.2% of patients with both reverse septal curvature and DBISC had disease-causing mutations . Mutations discovered in patients with DBISC had a higher likelihood of being disease-causing than non-disease-causing (p<0.001). DBISC were more commonly identified in patients with reverse septal curvature than in all other morphologies combined (p<0.001). In approximately half of cases, DBISC were missed on short-axis cines.Presence of deep basal inferoseptal crypts in HCM patients demonstrate incremental predictive value for genotype-positive status over that of left ventricular morphologic phenotype based prediction. Assessment for DBISC is best performed with the use of multiplanar CMR data sets. Additional imaging planes double the sensitivity for detection of deep basal inferoseptal crypts. Where genetic testing is not available, or a limited resource for economic reasons, the presence of CMR-detectable crypts may represent one factor among several that may guide decision-making for genetic testing. They may also have a role in investigating patients with modest degrees of hypertrophy (13-15mm).None."}
+{"text": "A major challenge in HIV vaccinology is the development of appropriate immune monitoring models to determine vaccine efficacy. Studies of HIV-specific CD8 T cells (CTL) suggest that these responses play an important role in infected individuals capable of spontaneous viral control (HIV elite controllers) and that they will likely play a role in immune interventions. However, no single CTL assay is uniquely associated with the controller phenotype.We compared functionality of HIV-1-specific CTLs in individuals with spontaneous viral control and subjects with treated or untreated progressive infection. A model integrating multiple features of epitope-specific CTL responses that delineate HIV controllers from subjects with treated or untreated progressive infection was built.Area Under the Receiver Operating Characteristic (ROC) Curve showed that proliferative capacity, absolute early cytokine production and kinetics of cytokine secretion were all associated with HIV control. However, only integrated modeling of these different dimensions of data allowed reaching the remarkable 90% accuracy, which was validated in separate cohorts.Our results suggest that while the search for a common determinant of protective immunity remains elusive, combining parameters generated by various well-established assays in models that can be iteratively refined may have important applications for predicting disease outcome and for immune monitoring of HIV-1 vaccine trials."}
+{"text": "Vibrio cholerae, the enteropathogenic gram negative bacteria is one of the main causative agents of waterborne diseases like cholera. About 1/3rd of the organism's genome is uncharacterised with many protein coding genes lacking structure and functional information. These proteins form significant fraction of the genome and are crucial in understanding the organism's complete functional makeup. In this study we report the general structure and function of a family of hypothetical proteins, Domain of Unknown Function 3233 (DUF3233), which are conserved across gram negative gammaproteobacteria . Profile and HMM based sequence search methods were used to screen homologues of DUF3233. The I-TASSER fold recognition method was used to build a three dimensional structural model of the domain. The structure resembles the transmembrane beta-barrel with an axial N-terminal helix and twelve antiparallel beta-strands. Using a combination of amphipathy and discrimination analysis we analysed the potential transmembrane beta-barrel forming properties of DUF3233. Sequence, structure and phylogenetic analysis of DUF3233 indicates that this gram negative bacterial hypothetical protein resembles the beta-barrel translocation unit of autotransporter Va secretory mechanism with a gene organisation that differs from the conventional Va system. Vibrio cholerae, Vibrio parahaemolyticus, Vibrio splendidus and Vibrio vulnificus are pathogenic to human and aquatic life. Vibrio cholerae causes seasonal outbreaks of cholera of epidemic proportions in developing countries with high mortality rates Domain of Unknown Function (DUF) 3233 (PFAM: PF11557) is a family of uncharacterised hypothetical proteins conserved among gram negative gammaproteobacteria. Representative members of this domain include marine bacteria from genus Vibrio, Shewanella, Colwellia and Alcanivorax of which th release lists about 3000 DUF families. Many of these DUF families are kingdom specific , limited/shared between kingdoms  or restricted/specific to certain organisms . The specific and ubiquitous nature of these domains suggests their functional importance in organism specific niches or a common biological role.Significant fraction of genomes of Vibrio species lack structure function annotation and most of these gene products are classified as hypothetical proteins or domains of unknown function In silico structure prediction methods together with sequence similarity detection methods assist the annotation of fold-function space. Fold recognition methods like I-TASSER Identifying homologous protein families through sequence based search marks the first step in the annotation of DUFs, providing an initial broad picture of the protein's probable family and function. Sequence homology search becomes increasingly powerful when we advance from normal sequence-sequence based searches to methods that uses profile or HMM information like HHsenser In this study we analyse the sequence and structural characteristics of DUF3233 using computational approaches and try to infer various properties of this domain. Sequence search by HHsenser identifies similarity with the beta-barrel translocation unit of autotransporter Va secretory proteins. Sequence homology combined with secondary structure prediction indicates a beta-barrel domain of 12 beta-strands. The predicted 3D model from I-TASSER shows the structure with an overall beta-barrel topology with an N terminal helix running along the central barrel axis perpendicular to the 12 antiparallel strands that form the barrel. Amphipathicity and membrane barrel discrimination analysis suggest the domain is a potential outer membrane gram negative beta-barrel protein.Autotransporter translocation units belong to the transmembrane beta-barrel fold in SCOP database Vibrio cholerae DUF3233 (RefSeq: NP_232949) against the NCBI nr database with a threshold 0.005, reached convergence at the 4th iteration. The resulting sequences identified were hypothetical proteins conserved among gram negative proteobacteria. For improved search and better coverage of homologous sequence space, information from aligned regions of DUF3233 sequences in the form of a multiple sequence alignment profile was queried with HHsenser. From the resulting sequences in the permissive alignment list we were able to infer homology between DUF3233 and the outer membrane beta-barrel translocation domain of autotransporter proteins. DUF3233 shares sequence similarity with outer membrane beta-barrel domain of Ochrobactrum intermedium autotransporter , Rhizobium leguminosarum adhesin autotransporter  and Yersinia aldovae AidA adhesin autotransporter . Interestingly, a number of gram negative hypothetical proteins were picked up as potential homologues, which showed fair amount of similarity to the autotransporter beta-domain . This cluster comprises profile HMMs of autotransporter sequences whose 12 stranded beta-barrel transmembrane domains conform to the translocation unit of autotransporter NalP Position specific scoring matrix (PSSM) profile based discrimination analysis using TMBETADISC-RBF Proteins targeted for transport across membranes posses leader sequence or signal peptide at their N-terminus, which directs translocation. We analysed DUF3233 sequences using a combination of artificial neural networks and HMMs implemented in SignalP We browsed DUF3233 genomic region of all representative organisms with STRING N) followed by 12 consecutive \u03b2-strands (\u03b21\u2013\u03b212) interspersed by two short turns of \u03b1-helices \u03b11 and \u03b12 predicted to occur between \u03b21\u2013\u03b22 and between \u03b25\u2013\u03b26 respectively. With no suitable template with significant sequence homology available, we used the fold recognition algorithm implemented in I-TASSER to predict a 3D model of DUF3233. The translocation unit of NalP from N. meningitidis  was identified by I-TASSER in the top four threading templates to model V. cholerae DUF3233. The predicted structure of V. cholerae DUF3233  fetched results with a maximum alignment length covering 51 residues. Secondary structure assignment by PSIPRED  DUF3233  resemble DUF3233 . Using aTo infer evolutionary relation with type V secretory proteins, we analysed DUF3233 representatives with members of both Va and Vb family . The thiA vital part in the survival and adaptation mechanism of bacteria lies in the constant interaction with their extra-cellular environment. Bacteria secrete a wide range of molecules into the extra-cellular milieu that includes enzymes, which break down carbohydrates, proteins and lipids, and virulence factors such as adhesins and toxins by those involved in pathogenesis. Transport of these molecules is mediated by protein complexes through conserved secretory pathways. Of the 6 types of secretory mechanisms known in gram-negative bacteria (type I to type VI), type V represents the simplest transport system. Proteins of the type V secretory system fall under the autotransporter (Va), two partner secretion (Vb) and the AT-2 (Vc) families, and share a similar domain organisation: an N-terminal signal peptide for inner membrane translocation followed by a passenger protein which is normally a virulence determinant and a C-terminal translocation unit for transporting the upstream passenger protein Proteins of the autotransporter (Va) family were the first to be described The present work describes sequence and structure based characterization of proteobacteria DUF3233 as a beta-barrel transmembrane domain of autotransporter proteins. DUF3233 packs an average 312 amino acid residues  and is currently classified as a domain of unknown function.DUF3233 is encoded as a single domain protein, homologous to the translocation unit of autotransporters. One aspect of DUF3233 that distinguishes it from other main class autotransporters is that it lacks a covalently linked N-terminal passenger domain, to which C-terminal translocation units of all autotransporters are committed to transport. Few autotransporter representatives of two-polypeptide architecture V. cholerae are organised in clusters or operons Few representative members from the Vibrio genus express DUF3233 and upstream putative GGT or response regulatory proteins in a single operon . Over exet al., H. influenzae Hap translocation unit. Deletion of terminal 12 residues proved detrimental to the outer membrane localisation; while the stability and/or outer membrane localisation of the translocation unit was affected with the deletion of all three terminal residues, point mutations of these residues showed no effect on the outer membrane localisation or secretion of the mature protein The translocation units of autotransporters exhibit conserved amino acid consensus motif at their carboxy terminus, the barrel closing beta-strand displays alternate arrangement of polar and hydrophobic residues terminating with a conserved aromatic amino acid at the barrel terminus which is usually a phenylalanine or a tryptophan DUF3233 exhibits certain features that are in common with the translocation units of type Va secretory proteins and yet possesses characteristics that are not typical to the proteins of the above system. DUF3233 represents a translocation unit that is devoid of a secretable passenger unit. Considering its location in the representative genomes alongside other virulence genes, we hypothesize that this domain is involved in pathogenesis. However, the mechanism apparently looks new and different than a typical type Va secretion system.Our study on the proteobacterial protein DUF3233 with a combination of methods like sequence similarity searches, outer membrane beta-barrel discrimination, phylogenetic analysis, and fold recognition has led us to a consensus at annotating fold and function to this domain.Sequence similarity search suggests that DUF3233 has remote homology with the translocation unit of autotransporter proteins of the type V secretory system. The domain's outer membrane beta-barrel nature was further emphasised by signal peptide, outer membrane beta-barrel discrimination and amphipathicity analysis. Secondary structure prediction and alignment with translocation units, and inputs from the predicted model suggests that DUF3233 and the translocation unit of autotransporter proteins share a similar domain organisation.in silico prediction methods it appears that DUF3233 is a cluster of remote homologues of autotransporters. This is the first report of an autotransporter like protein family in Vibrio species, and though within the realm of bioinformatics we were able to infer its probable family and fold, the pathogenic mechanism still remains to be explored and seeks further experimental studies.Drawing a consensus from various 20 DUF3233 genes from NCBI comprising one sequence each from Aliivibrio, Colwellia and Ferrimonas, five sequences from Shewanella and twelve from Vibrio species were fetched using their corresponding RefSeq ids. YP_001366070 and YP_001555810 were excluded because of their short domain size and a total of 18 DUF3233 sequences were included in this study. The signal peptides of DUF3233 sequences have not been included in various analyses of this study unless mentioned. PSI-BLAST The presence of N-terminal signal peptide and the putative cleavage sites were predicted with SignalP 3.0 V. cholerae DUF3233 (RefSeq: NP_232949) was predicted using I-TASSER fold recognition method Secondary structure assignments were made using PSIPRED V. cholerae (RefSeq: NP_232949), C. psychrerythraea (RefSeq: YP_269983) and S. loihica (RefSeq: YP_001095898) along with beta-barrel domain sequences of the Va, Vb secretory systems were analysed with MEGA 4 Amino acid sequences of translocation unit of autotransporters, and pore forming beta-domain of two-partner secretion (TPS) family members, reported in Figure S1Sequence alignment of DUF3233 representative sequences. DUF3233 has an average 23 amino acid N-terminal signal sequence (gray) which guides inner membrane translocation. The signal peptidase I cleavage site is marked by a red arrow. Cps_Colwellia psychrerythraea (YP_269983.1), Vfi_Vibrio fischeri (YP_206466.1), Vpa_Vibrio parahaemolyticus (NP_800436.1), Vvu_Vibrio vulnificus (NP_762291.1), Vch_Vibrio cholerae (NP_232949.1), Vsp_Vibrio splendidus (YP_002395311.1), Sba_Shewanella baltica (YP_001052604.1), Slo_Shewanella loihica (YP_001095898.1), Spi_Shewanella piezotolerans (YP_002312093.1), Fba_Ferrimonas balearica (YP_003912385.1).(TIF)Click here for additional data file.Table S1List of DUF3233 homologous sequences. Sequence search by HHsenser (permissive) picked gram-negative and cyanobacterial (Cyn) hypothetical proteins that share significant homology with DUF3233. These hypothetical proteins posses sequence characteristics that apparently resemble the autotransporter beta-domain. # Insignificant Pfam A hits, $ Significant Pfam A hits.(DOC)Click here for additional data file.Table S2List of representative sequences used for phylogeny analysis. C-terminal translocation unit sequences of Autotransporter (Va) (DOC)Click here for additional data file."}
+{"text": "Nanog locus. These results suggest that chondrogenic cells induced by this approach are free from a risk of teratoma formation which associates with cells prepared through generation of iPS cells followed by redifferentiation into the target cell type. The dox-inducible induction system demonstrated that induced cells are able to respond to chondrogenic medium by expressing endogenous Sox9 and maintain chondrogenic potential after substantial reduction of transgene expression. This approach could lead to the preparation of hyaline cartilage directly from skin, without going through pluripotent stem cells, in future regenerative medicine.Repair of cartilage injury with hyaline cartilage has been a challenging clinical problem. Articular cartilage damage sometimes heals with fibrocartilage, which is different from hyaline cartilage. Fibrocartilage is a type of scar tissue that expresses types I and II collagen. In contrast, hyaline cartilage does not express type I collagen. When aiming to induce hyaline chondrogenic cells directly from dermal fibroblasts, in addition to activation of cartilage-specific matrix genes, elimination of expression of type I collagen is needed for generation of hyaline cartilage. Otherwise, the presence of type I collagen impairs cartilage extracellular matrix architecture, which leads to formation of fibrocartilage. The generation of induced pluripotent stem cells has provided a tool for reprogramming dermal fibroblasts to an undifferentiated state by ectopic expression of reprogramming factors. We found that retroviral expression of two reprogramming factors (c-Myc and Klf4) and one chondrogenic factor (SOX9) induces polygonal chondrogenic cells directly from adult dermal fibroblast cultures. Induced cells expressed marker genes for chondrocytes but not fibroblasts; the promoters of type I collagen genes were extensively methylated. Transduction of c-Myc, Klf4, and SOX9 produced two types of cells: chondrogenically reprogrammed cells and partially reprogrammed intermediate cells. Chondrogenically reprogrammed cells generated stable homogenous hyaline cartilage-like tissue without tumor formation when subcutaneously injected into nude mice. Hyaline cartilage-like tissue expressed type II collagen but not type I collagen. On the other hand, partially reprogrammed intermediate cells expressed type I collagen and produced tumor when injected into nude mice. Induced chondrogenic cells did not undergo pluripotent state during induction from dermal fibroblast culture, as time-lapse observation did not detect GFP reporter expression during induction from dermal fibroblasts prepared from transgenic mice in which GFP is inserted into the"}
+{"text": "We report a case of a persistent left superior vena cava (PLSVC) with absent right superior vena cava (RSVC). It is a very rare congenital anomaly also known as isolated PLSVC.This venous malformation was identified in a 75-year-old woman during cardiac magnetic resonance imaging (MRI), which was performed with the suspicion of a paracardiac mass.We performed an MRI and a multislice computed tomography (MSCT) evaluation.Cardiac MRI revealed a persistent left superior vena cava which descended on the left side of the mediastinum and drained into the right atrium (RA) via a markedly dilated coronary sinus (CS) which mimicked a paracardiac mass. The RSVC was absent.These findings were confirmed by MR and MSCT venography.The patient had no additional cardiac abnormality.Although PLSVC is usually asymptomatic, it is important to be aware of its existence, since it may cause problems performing central venous catheterization, pacemaker implantation and cardiothoracic surgery.This anomaly is also associated with high incidence of congenital heart disease, arrhytmias and conduction disturbances.Modern imaging techniques including computed tomography and magnetic resonance imaging provide precise diagnosis of this anomaly."}
+{"text": "This study sought to demonstrate the potential for myocardial arterial spin labeling (ASL) to identify the ischemic myocardial segments due to stenosis in coronary arteries as detected by X-ray angiography.stress/MBFrest), which is a common indicator for the severity of coronary artery disease. In healthy myocardium, perfusion reserve is known to be approximately four [Myocardial ASL is a technique for the assessment of myocardial blood flow (MBF) without contrast agents. It can be safely applied to patients with end-stage renal disease who are not candidates for first-pass imaging with contrast agents. Myocardial ASL perfusion imaging performed at rest and during adenosine stress provides perfusion reserve (MBFely four .Twenty nine patients were recruited from those scheduled for routine cardiac MR (CMR) and X-ray angiography. Myocardial ASL measurements were obtained from a single mid short-axis slice at rest and during adenosine infusion (dosage: 0.14 mg/kg/min) on a GE Signa 3T scanner. The ASL sequence was composed of flow-sensitive alternating inversion recovery (FAIR) tagging and balanced steady-state free precession (SSFP) imaging . PerfusiTen of the twenty-nine patients were found to have significant stenosis on X-ray angiography. Table There was visual agreement  and no statistically significant difference between ischemic myocardial segments identified by ASL perfusion reserve maps and by X-ray angiograms. This suggests that myocardial ASL with vasodilation may have a potential to identify ischemic myocardial segments in patients with stenosis."}
+{"text": "Borrelia burgdorferi, as a model to test the prediction that natural selection favors amino acid diversity among unexpressed vls cassettes and thereby promotes evolvability in a primary surface antigen, VlsE. The hypothesis that diversity among vls cassettes is favored by natural selection was supported in each B. burgdorferi strain analyzed using both classical (dN/dS ratios) and Bayesian population genetic analyses of genetic sequence data. This hypothesis was also supported by the conservation of highly mutable tandem-repeat structures across B. burgdorferi strains despite a near complete absence of sequence conservation. Diversification among vls cassettes due to natural selection and mutable repeat structures promotes long-term antigenic evolvability of VlsE. These findings provide a direct demonstration that molecular mechanisms that enhance evolvability of surface antigens are an evolutionary adaptation. The molecular evolutionary processes identified here can serve as a model for the evolution of antigenic evolvability in many pathogens which utilize similar strategies to establish chronic infections.The hypothesis that evolvability - the capacity to evolve by natural selection - is itself the object of natural selection is highly intriguing but remains controversial due in large part to a paucity of direct experimental evidence. The antigenic variation mechanisms of microbial pathogens provide an experimentally tractable system to test whether natural selection has favored mechanisms that increase evolvability. Many antigenic variation systems consist of paralogous unexpressed \u2018cassettes\u2019 that recombine into an expression site to rapidly alter the expressed protein. Importantly, the magnitude of antigenic change is a function of the genetic diversity among the unexpressed cassettes. Thus, evidence that selection favors among-cassette diversity is direct evidence that natural selection promotes antigenic evolvability. We used the Lyme disease bacterium,  Borrelia burgdorferi, evades immune detection through a system consisting of numerous unexpressed \u2018cassette\u2019 sequences that alter the expressed protein via recombination. Importantly, the potential for evolutionary change in the expressed protein, and thus its ability to repeatedly escape a directed immune response, is correlated with the diversity among the cassettes. We analyzed genetic data from diverse B. burgdorferi strains to test the hypothesis that natural selection favors diversity among the unexpressed cassettes in order to promote evolvability. The data provide significant evidence of natural selection acting to increase among-cassette diversity, but only in regions that are targeted by immune antibodies when expressed. Further, these antigenically-important regions contain mutation-prone DNA sequence structures that are conserved despite high levels of sequence divergence among strains. The empirical evidence of selection favoring mutation-prone sequences and favoring among-cassette diversity supports the hypothesis that natural selection can shape the evolvability of populations.The hypothesis that natural selection shapes the ability of a population to evolve is highly controversial due primarily to a paucity of empirical evidence. However, the ability to constantly and rapidly evolve may be selectively adaptive in pathogens due to the constantly changing environment created by the vertebrate immune response. The Lyme disease bacterium,  The ability of a biological trait to evolve by natural selection, or evolvability, varies substantially among species, among populations within species, and even among traits within populations. The hypothesis that differences in evolvability result from past natural selection acting on the ability to evolve, however, remains highly controversial for two primary reasons The major objections to the evolvability-as-adaptation hypothesis lose force when applied to many microbial pathogens as a result of two biological features of these organisms. First, microbial pathogen cells within a host are often nearly clonal such that the fitness interests of individuals and groups are closely aligned Borrelia burgdorferi, rapid evolution of the surface antigen, VlsE, is required for immune evasion and long-term infection in vertebrate hosts In vivo studies have shown that the vlsE antigen expression locus is indeed highly evolvable; a near-complete replacement of vlsE alleles occurs every 14\u201328 days in experimentally infected mice vls cassettes into the vlsE expression site; six regions in the unexpressed vls cassettes are known to vary among cassettes and correspond to the antigenically important extracellular loop structures of the VlsE protein vls cassettes and vlsE are not recognized by antibodies that target previously detected VlsE antigens vlsE locus during infection is tightly correlated with the amount of diversity among the unexpressed vls cassettes, as mutations in the vlsE locus are rare except by recombination  are substantially more frequent than synonymous differences (per synonymous site) among the six regions of the unexpressed vls cassettes that correspond to the antigenically important loop regions of VlsE , nor the ospC or erp loci Sequence alterations in the eletions , Fig. S5B. burgdorferi, the rate of genetic change, or antigenic evolvability, at VlsE is tightly correlated with the amount of genetic diversity contained in the unexpressed vls cassettes  and thus be more likely to persist within hosts vls cassettes and promotes antigenic evolvability was supported by molecular evolutionary analyses of the cassettes of 12 B. burgdorferi strains  mutations at unstable tandem-repeat motifs, which are present in all  in VlsE , Fig. S1 in VlsE . Tandem B. burgdorferi occur as triplets in line with the reading frame and thus have the potential to alter antigenic epitopes, when recombined into VlsE, without introducing stop codons or frameshifts that would have deleterious effects on the protein structure. The tri-nucleotide repeats show little variation at the first and third codon positions but are significantly more variable at second codon positions resulting in differences in the amino acids they encode  from the beneficial alleles they create (VlsE escape antigens), thereby inhibiting hitchhiking Sexual eukaryotic pathogens conceivably experience fluctuating selective pressures similar to those experienced by B. burgdorferi strains that differ only in the diversity among vls cassettes in a repeated mouse-tick-mouse transmission cycle would provide an experimentally-controlled evaluation of the strength of selection on evolvability in this system. Analyses of the mutations introduced into the cassettes of each strain at each mouse-tick-mouse transmission could also elucidate the role of tandem repeats and other mechanisms that result in greater diversity among cassettes. In particular, comparing experimental infections in immunologically active and immunocompromised mice can determine the role of cassette diversity in establishing and maintaining persistent infection during an adaptive host immune response.The data reported here exhibit the genetic signatures expected given selection on antigenic evolvability. Future experimental evolution assays can be used to experimentally validate these conclusions and to further dissect the molecular mechanisms involved. For example, assays competing isogenic vls unexpressed cassettes in which strong diversifying selection leads to elevated amino acid diversity in regions that correspond to antigenically important domains in order to promote the evolvability at VlsE that allows for continual immune evasion. Such selection for cassette diversity could be a common strategy for maintaining antigenic evolvability in a diverse range of pathogens that generate antigenic variation by intragenomic recombination pilE locus of Neisseria gonorrhoeae are maintained despite common gene conversion events Our results support a model of evolution in the vls unexpressed cassettes both within and among B. burgdorferi strains for which genome sequence data was available We analyzed the genetic diversity of the The hypothesis that diversity among unexpressed cassettes is favored by natural selection to promote antigenic evolvability was tested using three molecular evolutionary analyses. First, the proportion of non-synonymous polymorphic nucleotides (dN) and synonymous polymorphic nucleotides (dS) were estimated Tandem-repeat motifs were identified using the mreps server B. burgdorferi strains JD1 and N40 were predicted using the SWISS-MODEL server B. burgdorferi strain JD1 were determined using the reported VlsE sequence (Genbank [CP002306]), whereas the protein structure in strain N40 was predicted by replacing the cassette region of vlsE in B31 with the unexpressed cassettes of N40.Structural models of VlsE in A nucleotide Neighbour-Joining (NJ) phylogeny  was constructed in Geneious v. 5.3 B. burgdorferi strain N40 7 cells/ml and the genomic DNA was purified using the DNeasy Blood and Tissue Kit protocol for gram negative bacteria . The vls cassette region from each isolate was cloned into BigEasy v2.0 Linear Cloning Kit  by either 1. ligating total genomic DNA treated with Mung Bean Nuclease and DraI (New England Biolabs (NEB); Beverly, MA) into the cloning vector (derived isolate 2(44B)) or 2. ligating a long-range PCR fragment containing the unexpressed cassettes into the cloning vector . Long-range PCR amplification was conducted using the primers N40-vlsLR-R (5\u2032 Phos - GCT GGA CTT GAA TTT GGT AGG GAT TC 3\u2032) and N40-vlsLR-F (5\u2032 Phos - GGT GAT GGT GCC GAT TCA AAA TCT GG 3\u2032) which anneal to the unique conserved regions flanking the unexpressed cassettes. The PCR reactions contained 2\u20136 ng/\u00b5l of genomic DNA, 0.2 mM of each dNTP, 0.4 \u00b5M of each primer, 7% DMSO, 1\u00d7 GC buffer and 0.02 U/\u00b5l of Phusion Hot Start II DNA Polymerase (NEB) and were amplified with 25 cycles of 30 s at 98\u00b0C and 90 s at 72\u00b0C.A clonal isolate of E.coli and isolated using a Qiagen Mini-prep kit. The TSA cell line used in transformation of the BigEasy vector (Lucigen) contains RecA and EndA mutations that make them recombination-deficient and minimize the chance that gene-conversion was introduced during cloning. Purified plasmid DNA was sheared using a Nebulizer  to 500\u20133000 bps, purified by ethanol precipitation, and subcloned using the Zero Blunt PCR cloning kit for sequencing (Invitrogen). Additionally, the ospA and rrs-rrlA IGS loci were PCR amplified from each culture as previously described BigEasy vectors containing an intact cassette region were amplified in Figure S1Indels are more abundant in antigenic loop regions containing 3 bp tandem repeat motifs. The average number of indel events in regions of the cassettes corresponding to antigenic loop regions (ALR) of VlsE was significantly larger in those that contained tandem repeats compared to those in which no repeats were detected . This suggests that tandem repeats contribute to diversification among the cassettes by increasing the rate of indel mutations and contributing to length variation among cassettes in the antigenic loop regions.(TIF)Click here for additional data file.Figure S2Greater diversity at second codon position of tandem repeats. Diversity at the second positions of identified 3 bp tandem repeat motifs, which are inline with the reading frame, were significantly greater than diversity at the first and third positions . All differences at the second positions resulted in amino acid changes in the expressed proteins. Diversity was measured by parsing each of the 3 bp elements within a repetitive region and calculating the entropy at the first, second, and third position.(TIF)Click here for additional data file.Figure S3Concerted evolution of the vls unexpressed cassettes.A) The unrooted Neighbor-Joining phylogeny of individual unexpressed cassettes demonstrates high degrees of similarity within B. burgdorferi strains and high degrees of divergence among cassettes of different strains. This pattern of concerted evolution is typical of multi-copy sequences and results from sequence homogenization within strains due to gene conversion. The nucleotide Neighbour-Joining (NJ) phylogeny  was constructed in Geneious v. 5.3 B) Diversity among the vls unexpressed cassettes within each strain is localized to six antigenic loop regions. In both antigenic loop and alpha helical regions, cassettes are far more divergent between strains compared to diversity contained among cassettes within individual strains. Although recombination from the cassettes into the vlsE expression locus is unidirectional and does not affect the sequence of unexpressed cassettes C) Moderate sequence divergence was observed between cassettes belonging to strains that co-occurred on the same branch of the phylogeny. Three evolutionary lineages in the phylogenetic analyses consisted of unexpressed cassettes from more than one strain. The average pair-wise genetic distance among strains at alpha helical regions  and antigenic loop regions  shows a slight increase in diversity between strains compared to divergence within strains  indicating incipient divergence. Divergence among strains was not sufficient to produce a signal in the phylogenetic analysis, possibly due to recent ancestry, which is further supported by the observation that strains with similar unexpressed cassettes contain the vls antigenic variation system on the same linear plasmid ( plasmid .(TIF)Click here for additional data file.Figure S4Experimental evolution of B. burgdorferi reveals mutations caused by gene conversions among unexpressed cassettes. Evolutionary changes observed in the cassette regions during experimental infections are characterized primarily by gene-conversions and large deletions. The parental N40 isolate differs from a previously sequenced N40 laboratory isolate in a 70 bp segment of cassette 19 which contains 12 substitutions and a 6 bp deletion. These sequence changes are identical to the homologous region of cassette 20 and are shared in all derived strains. Mutations that occurred during infection consisted of gene conversion events in derived isolates 1 and 3 and large deletions in derived isolates 2 and 3. The mutations in cassette 13 of derived isolate 3 are depicted with different colors to represent gene conversion from different donor cassettes. At least 6 overlapping gene conversion events from other cassettes are necessary to account for the mutations that occurred in this cassette. Of the two single-nucleotide substitutions in cassettes occurred during experimental evolution, the substitution that occurred in an antigenically important region (cassette 2 of derived isolate 1) was non-synonymous, whereas the substitution that occurred in a alpha helical region (cassette 15 of derived isolate 3) was synonymous.(TIF)Click here for additional data file.Figure S5Southern hybridization confirms large deletions in the vls cassette region. The large deletions observed in the unexpressed cassette region of derived strains 2 and 3  which cuts at the recognition site, TTTAAA. Recognition sites for this enzyme occur throughout the AT rich genome of B. burgdorferi but are present at only one site within the vls unexpressed cassette region of each strain. The digested DNA was separated for four hours on a 0.4% agarose gel, transferred to a nylon membrane, and allowed to hybridize with two fluorescein labeled probes specific to the vls cassette sequences (5\u2032 Fluor- TTC GGT TRG TGG KGA GCA GA 3\u2032 and 5\u2032 Fluor- ACA ATC CCC TTC ATC CCC TTA 3\u2032). Southern blot analysis revealed two fragments (\u223c3 kb and \u223c4.5 kb) in both the parental strain (cN40) and derived isolate 1 (36B) consistent with the single DraI site expected 2949 bp from the beginning of cassette 1 of a 7.467 kb fragment given the sequence data obtained in this study. The single fragment (\u223c4.3 kb) apparent in derived isolate 3 (39B) is consistent with the single DraI site expected 4204 bp from the beginning of cassette 1 of a 4.381 kb fragment. The 177 bp fragment was likely not detected because it ran off the gel. Similarly, derived isolate 2 (44B) revealed only a single fragment (\u223c5.9 kb) which is consistent with the single expected DraI site 5893 bp from the beginning of cassette 1 in a 6.073 kb fragment. 2 and 3  were con(PDF)Click here for additional data file.Table S1Summaries of the silent cassette loci in B. burgdorferi strains analyzed in this study.(DOC)Click here for additional data file.Table S2Statistical analysis of positive selection within silent cassettes of B. burgdorferi strains.(DOC)Click here for additional data file.Table S3Genbank accession numbers of the vls cassette region, ospA and IGS loci sequenced in isolates after one year of experimental infection.(DOC)Click here for additional data file."}
+{"text": "Lung cancer is the leading cause of cancer related death in the world. Current therapies are only partially successful and relapse is frequent in a large number of patients. Hence, new therapeutic strategies are needed to improve the quality of life and survival of NSCLC patients.The Notch pathway is a key pathway involved in cell fate determination during development in many tissues and also in tissue homeostasis during adulthood . DeregulKras that can be experimentally induced on adult mice resulting in NSCLC [Kras-driven lung carcinogenesis is strictly dependent on the presence of a functional Notch pathway.In our recent work , we havein NSCLC . Importain NSCLC . This inKras-driven NSCLC [Previous studies have demonstrated that phosphorylated ERK is a critical mediator of oncogenic en NSCLC -8. Interen NSCLC . This isen NSCLC .Kras-driven NSCLC, detected by positron emission tomography (PET), arrested their growth after 15 days of GSI treatment (with Eli Lilly\u00b4s GSI LSN-411575). This therapeutic response was associated to biomarkers of Notch pathway inhibition and ERK dephosphorylation [Gamma-secretase inhibitors (GSIs) have been used during the last years to inhibit the Notch pathway . ImportaKras-driven NSCLC [Our results open a new therapeutic opportunity to treat NSCLC using GSIs. Interestingly, GSIs have been used in long-term treatments in Alzheimer\u00b4s patients without major side effects . The accumulated knowledge on the pharmacology of GSIs should pave the way to test these compounds in NSCLC patients. MEK inhibitors (MEKi) have shown some therapeutic activity in murine en NSCLC . In this"}
+{"text": "Current clinical assessment of borderline aortic coarctation may involve cardiovascular magnetic resonance(CMR) but if inconclusive, invasive catheterization pressure measurements are required to evaluate the pressure gradient at rest and during pharmacological stress.To predict the aortic pressure distribution in patients with aortic coarctation at rest and pharmacological stress using a transient rigid-walled computation fluid dynamics model(RW-CFD).The study cohort comprises 5 patients with native or recurrent aortic coarctation and 2 control patients with healthy aortic archesTable , who und1)Ascending aortic root: The inlet flow is extracted from the phase-contrast CMR flow. Supra-aortic vessels2) :The flow rate is calculated as a proportion of the inlet flow based on the assumption of a constant wall shear stress .Diaphragmatic aorta3) : The pressure waveform is extracted from the invasive catheter investigation.The model workflowFigure  requiresThe clinically invasive aortic pressure gradients were compared with the predicted pressure distribution along the centreline in the RW-CFD model at the time of peak flowTable .mean\u00b1standard deviation) and invasive pressure gradient drop across the coarctation .For patients with aortic coarctation,the RW-CFD simulations accurately predict the pressure gradient at rest and give indication of the gradient severity during stress.Furthermore, no gradient was predicted in control patients with normal aortae.These preliminary results, whilst using a simple CFD approach and a small cohort of patients, are quite promising. This study represents the first step towards an image-based fluid-solid-interaction CFD analysis. This more sophisticated approach is likely to overcome the current limitations and might grant additional information.In the future, it is envisaged that CFD models could be based on a patient-specific, non-invasive and non-ionising radiation assessment such as CMR in order to predict the hemodynamic conditions in the aorta and avoid invasive cardiac catheterization.The pressures assessed by clinically invasive catheterization at the level of the ascending aorta, diaphragmatic aorta and the pressure gradient across the coarctation  are compared with the RW-CFD model pressure gradient prediction (\u0394P CFD). The absolute pressure differences values are shown in the final column. Pressures expressed as mean \u00b1 standard deviation. bpm, beats per minute."}
+{"text": "Right ventricular apical pacing-related heart failure is reported in some patients after long-term pacing. The exact mechanism is not yet clear but may be related to left ventricular dyssynchrony induced by right ventricular apical pacing. Right ventricular septal pacing is thought to deteriorate left ventricular function less frequently because of a more normal left ventricular activation pattern.We report the case of a 55-year-old Tunisian woman with preserved ventricular function, implanted with a dual-chamber pacemaker for complete atrioventricular block. Right ventricular septal pacing induced a major ventricular dyssynchrony, severe left ventricular ejection fraction deterioration and symptoms of congestive heart failure. Upgrading to a biventricular device was associated with a decrease in the symptoms and the ventricular dyssynchrony, and an increase of left ventricular ejection fraction.Right ventricular septal pacing can induce reversible left ventricular dysfunction and heart failure secondary to left ventricular dyssynchrony. This complication remains an unpredictable complication of right ventricular septal pacing. Right ventricular apical (RVA) pacing results in abnormal left ventricular (LV) electrical and mechanical activation and is associated with an increased risk of developing heart failure -3. RightWe report the case of a 55-year-old Tunisian woman with preserved ventricular function, implanted with a dual-chamber pacemaker for complete atrioventricular block. RVS pacing induced a major ventricular dyssynchrony, severe left ventricular ejection fraction deterioration and symptoms of congestive heart failure. Upgrading to a biventricular device was associated with a decrease in the symptoms and ventricular dyssynchrony, and increased left ventricular ejection fraction (LVEF).A 55-year-old Tunisian woman presented with syncope. An electrocardiogram (ECG) upon admission showed complete heart block with a narrow QRS complex <120 ms) and an escape ventricular rate of 45 bpm. Our patient's medical history included arterial hypertension. She did not have diabetes mellitus, and had no family history of coronary artery disease. A two-dimensional echocardiography showed normal LV function with a 60% EF, the absence of significant valvulopathy and no regional wall motion abnormalities or pulmonary artery hypertension. A conventional dual chamber pacemaker  was implanted with the right ventricular (RV) lead positioned to her RV septum. The septal position was confirmed by fluoroscopic images; defined as a leftward orientation of the lead confirmed by 40\u00b0 left anterior oblique projection . The pac20 ms andDespite instauration of optimal medical therapy, our patient remained at NYHA functional class III. She was upgraded to a cardiac resynchronization therapy (CRT)-device with implantation of a lateral left ventricular lead Figure . After oAfter one month, an echocardiography showed a decrease in the aortic PEP (130 ms), LV reverse remodeling, with a reduction of the LVEDV from 153 mL to 135 mL, and significant improvement in LVEF to 40%. She had no symptoms of heart failure or syncope afterwards and device interrogation showed that her cumulative biventricular pacing was 100%.Pacing from RVS sites has been suggested as an alternative to RVA pacing in an attempt to avoid long-term adverse consequences on LV function . This caThere is an increasing body of literature in which the authors investigate the acute and chronic effects of RVS pacing on electrical and mechanical synchrony, systolic and diastolic ventricular function and cardiovascular morbidity and mortality. Alternative RV pacing sites appear advantageous when compared to RVA pacing but their superiority has not been uniformly proven.et al. [et al. [Ten Cate et al.  have dem [et al.  demonstrIn patients with standard indications for pacing, the prediction of heart failure is difficult and the exact mechanism of RV pacing-related heart failure is not clear but may be related to LV dyssynchrony induced by RV pacing . The besThe Pacing to Avoid Cardiac Enlargement study  showed tRVS pacing can induce reversible LV dysfunction and heart failure secondary to LV dyssynchrony. This remains an unpredictable complication of RV pacing. It should be highlighted that not all patients develop LV dyssynchrony and new onset heart failure after RV pacing. Therefore, early predictive factors -15, suchWritten informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.The authors declare that they have no competing interests.SO was the major contributor in writing the manuscript. All authors read and approved the final manuscript."}
+{"text": "Arterial Spin Labeling (ASL) is a well-known technique that allows the non-invasive acquisition of angiograms without the need of a contrast agent 2]. ASL . ASL 2].The proposed method is a modified Quadruple Inversion Recovery  sequenceRenal arteries including small branches were successfully visualized in all subjects with excellent suppression of background Figure ,4. The pWe demonstrate a new ASL approach for non-contrast enhanced MR angiography with excellent background tissue suppression and without the need of subtraction. In comparison to DIR-ASL, mQIR-ASL yielded better background suppression and improved vessel delineation."}
+{"text": "Acute ascending aortic dissections is the most common catastrophe of the aorta that requires emergency surgery. There is still a debate regarding the optimal surgical approaches for construction of the distal anastomosis in replacing the ascending aorta. The purpose of this study was to evaluate early clinical outcomes of two different surgical techniques: open distal anastomosis in hypothermic circulatory arrest (OHCA) compared to anastomosis with clamped aorta while continuing on extracorporeal circulation (CECC).A prospective randomized study in 84 consecutive patients who were operated, between September 2008 and September 2010, for acute type A aortic dissection with isolated replacement of the ascending aorta. The influence of two techniques  on clinical outcome was investigated.No significant difference was found between the two groups in terms of age and sex distribution. The groups were comparable with respect to all preoperative and intraoperative predictive risk factors for early clinical outcome and complications. The mean period of circulatory arrest lasted 30,46 min (15-61 min) at an average nasopharyngeal temperature of 23.57\u00b0C (16-28\u00b0C). Treatment method (OHCA vs CECC) was not associated with differences in intrahospital mortality  nore in early major postoperative complications: de novo focal neurolocigal deficits , acute renal failure , blood loss  or reexploration for hemorrhage .While there is no difference in clinical outcome in surgical treatment of acute type A aortic dissection with or without circulatory arrest, there are some practical technical advantages if the distal anastomosis is performed in an open manner. Probably the long-term outcome would also be better with this anastomosis technique."}
+{"text": "Acute renal failure after exposure to contrast media in patients at risk for CIN increases substantially 90-day mortality and morbidity. Biomarkers for outcome after CIN are missing so far.We analyzed in a prospective study 233 patients with either diabetes or preexisting impaired kidney function getting intra-arterial contrast media (CM) for coronary angiograms. Urinary cGMP concentrations were analyzed 24 hours after exposure to intra-arterial CM in spot urine. The patients were followed for 90 day for the following events: death, need for transient or permanent dialysis, doubling of serum creatinine and unplanned re-hospitalization. 51 out of the 233 patients had such an event during the follow up period of 90 days after contrast media exposure. The urinary cGMP to creatinine ratio was significantly increased in patients having an event during the follow up period (p=0.011). We furthermore performed a multivariate regression analysis considering age, baseline kidney function before contrast media exposure and preexisting diabetes - all important risk factors for CIN. These analysis revealed that the urinary cGMP to creatinine ratio is an in dependent predictor of the occurrence of the composite endpoint: death, need for transient or permanent dialysis, doubling of serum creatinine and unplanned re-hospitalization .The urinary cGMP to creatinineratio isan independent predictor of major advers events after contrast media exposure during a follow-up of 90 days."}
+{"text": "HIV-1 evolves rapidly within the host, resulting in the development of diverse variants called a viral \u201cquasispecies\u201d population. A major goal of vaccine efforts is the design of Envelope (Env)-based immunogens effective at eliciting broadly neutralizing antibodies. We hypothesize that B cells become programmed to develop broad NAbs by exposure to Envs presented by the viral quasispecies variants. We propose that similar programming could be achieved by a vaccine concept exposing the host to such Env quasispecies variants isolated from an individual who developed broad NAbs over time.Full-length functional env genes were cloned longitudinally from elite neutralizer CI10014 by single genome amplification, and a combination of in silico sequence analysis and in vitro neutralization was used to select vaccine candidates. Four immunization strategies were tested in rabbits: (1) sequential env evolution as it occurred in CI10014, with multiple clones per timepoint ; (2) sequential vaccine approach using only one clone per timepoint ; (3) an approach uniquely focused on env clones derived from timepoints where env evolution drove the development of breadth (Jump into Breadth); and (4) single env variant . The gp160-DNA and gp140-trimer immunogens were co-administered.NAbs were detected at six weeks, after only two immunizations and increased after additional immunizations. The Jump into Breadth strategy elicited significantly higher NAbs than the Clonal and Sequential strategies. Modest heterologous neutralization was obtained against Tier 1 clade A and B viruses.Exposure to env immunogens derived from timepoints preceding and contemporaneous with the appearance of neutralization breadth elicited higher NAbs than exposure to a single variant or a longitudinal collection of Envs. This study explores the use of multiple native, related HIV-1 Envs as immunogens and emphasizes the critical importance of understanding the development of breadth in an elite neutralizer subject."}
+{"text": "Left ventricular (LV) myocardial wall thickness is influenced by non-ischemic conditions like cardiomyopathies (CMP) as well as ischemic disorders, i. e. coronary artery disease (CAD). For CMP, regional wall thickness under resting conditions has prognostic value and serves as risk predictor for future cardiovascular events. In CAD, aside from perfusion also inadequate dobutamine wall thickening indicates myocardial ischemia and leads to coronary intervention. Therefore, quantitative resting and stress regional wall thickness provides relevant diagnostic and prognostic information. To date there is only scarce data regarding reference values of regional wall thickness in healthy volunteers.We sought to investigate differences in age and gender of LV rest and stress regional wall thickness with a state-of-the-art SSFP sequence in a modified AHA 17-segment model and present reference values for myocardial rest and stress wall thickness.We studied 119 healthy volunteers in two gender groups  which both consisted to equal parts of three age groups to minimize its possible influence. 30 of the male and 29 of the female participants were pharmacologically stressed with dobutamine up to their age-depended maximal heart rate according to present guidelines. Long axis were obtained on a 1.5T whole body MRI scanner (Philips Achieva) using the SSFP sequence. Images of the left ventricle were analyzed applying a modified 17-segment model. P<0.05 was considered significant.The acquired normal values are shown in figure Applying a state-of-the-art SSFP MRI sequence in three different age groups of male and female healthy volunteers, we provide reference values for myocardial LV wall thickness at rest and under dobutamine stress which could lead to a clinical reference frame for the detection of abnormal myocardial thickness in CMP or thickening in CAD. The values for each segment of the left ventricle are significantly different between men and women as well as rest and stress. Further investigations with larger patient cohorts may address the issue of age dependency.None."}
+{"text": "Arithmatic computational modeling permits improved prognostic detection via a combinatorial or independent method.Quantitative analysis can improve myocardial perfusion imaging (MPI) for prediction of prognosis. We have designed a novel approach, Decisions Informed by Computed Entities (DICE), to enhance the prognostic ability of MPI data to predict major adverse cardiovascular events (MACE) in women with suspected ischemic heart disease. We applied DICE to cardiovascular magnetic resonance imaging (CMRI) and Single Positron Computed Tomography (SPECT) MPI data sets in the Women\u2019s Ischemia Syndrome Evaluation (WISE) Study.Women (n=228), mean age 59\u00b111yrs, with symptoms suggestive of myocardial ischemia underwent MPI and cardiac function evaluation separately by CMRI and SPECT and were followed (40\u00b117mo) for time to MACE . Abnormal perfusion defects were noted for each MPI modality . Cardiac regions were separately evaluated and at least one abnormal region was considered a positive study. The CMRI data were evaluated using qualitative (QLMR) and semi-quantitative (SQMR) approaches. Multiple linear regression models (DICE models) were generated, each predicting MPI status from one modality (e.g. CMRI) using data from a second modality (e.g. SPECT). Two DICE models were constructed from pairs of data sets and included variables such as end-systolic volume and myocardial wall thickness in addition to the clinical MPI reading.MACE occurred in 29 women (13%). The percentage of MACE occurring in pts with abnormal perfusion was 43% using the average of the clinical MPI readings vs. 75% for the average of the DICE models (p<0.01). The average percentage of pts having abnormal perfusion was 27% for the clinical readings vs. 35% for the average of the DICE models (p=0.09). Increasing the number of variables in each DICE model increased the percentage of MACE captured.DICE modeling, incorporating the clinical MPI reading and cardiac variables derived from one imaging modality predicted the clinical MPI reading of a second modality while increasing the prognostic value as compared to just the clinical reading. The predictive power of the DICE model increases with the number of variables measured while simultaneously reducing noise and bias.NHLBI/Internal."}
+{"text": "Type 2 Diabetes Mellitus (T2DM) and prediabetes are associated with an increased cardiovascular risk and heart failure independent of the presence of obstructive coronary artery disease, caused in part by myocardial microvascular dysfunction. Recent studies have reported contractile dysfunction and increased rotation with the onset of diabetic cardiomyopathy in uncomplicated T2DM patients. Independently, higher resting myocardial blood flow (MBF) has been reported in T2DM. The objective of this study was to determine whether there is a correlation between LV Epicardial Rotation (LV ER) and resting MBF in T2DM patients with angiographically normal coronaries, measured by tissue tagging and perfusion cardiovascular Magnetic Resonance (CMR).Sixty five patients with no coronary stenosis >30% on invasive angiography were recruited and categorized into T2DM, prediabetes and normal controls groups according to American Diabetes Association guidelines. All patients underwent rest and adenosine stress myocardial perfusion CMR at a single mid-LV location, cine imaging covering the entire heart and myocardial tissue tagging in three LV short axis locations . LV volumes and mass were calculated from cine images. LV rotation in three myocardial layers  was calculated from CSPAMM tissue images using Tag Track . For this study, only rest MBF was calculated using Fermi-constrained deconvolution for the entire myocardium.Patient characteristics and results are shown in Table T2DM patients when compared to age-matched patients with prediabetes and normal controls have higher peak LV ER. Resting MBF correlates with LV ER. These results suggest that LV ER analysis in uncomplicated T2DM patients may be useful for non-invasive screening of early subtle contractile dysfunction associated with microvascular dysfunction in diabetes patients.This work has been funded by British heart foundation in part with the Libyan ministry for higher education and scientific research."}
+{"text": "PfHslV, a homolog of \u03b2 subunit of 20S proteasome forms the proteolytic core of the PfHslUV machinery in P. falciparum [PfHslV has no homolog in the human host and it is a promising drug target essential to the plasmodial metabolism. The use of single proteasome inhibitor targeting these threonine proteases has a potential to be antimalarial drug candidate. One of our recent studies identified several promising inhibitors against 20S \u03b25 subunit of P. falciparum [. The present study adopts a similar knowledge based virtual screening strategy using Support Vector Machines (SVM) and molecular docking to build a focused library of potential PfHslV inhibitors. SVM model has been trained using 170 molecular descriptors of 64 inhibitors and 208 putative non-inhibitors. The non-linear classifier based on Radial Basis Function (RBF) kernel yielded classification accuracy of 97%. The SVM model rapidly predicted inhibitors from NCI library and were subsequently docked in to the active site of an optimised three-dimensional model of PfHslV. The novel drug-like PfHslV inhibitors with very good binding affinity and novel scaffold can be a good starting point to develop new antimalarial drugs.lciparum ,2. PfHsllciparum . The pre"}
+{"text": "Abnormal diffusion tensor imaging (DTI) measurements have been found in human and experimental subjects with severe hydrocephalus (HCP) [1-3]. Because ventriculomegaly can often be variable, the present study aimed to investigate the degree of DTI abnormality in neonatal rats with less severe HCP.Seventeen Sprague-Dawley rats were divided into three groups: (1) HCPS - 5 rats with intracisternal kaolin injections leading to severe hydrocephalus; (2) HCPM - 5 rats with the same kaolin injection procedure that developed mild HCP; (3) Control - 7 rats with intracisternal saline injections. Either kaolin or saline injection was performed at P2. DTI were acquired at P9-10 on a 7T Bruker MRI scanner. Evan\u2019s ratios of ventricular size and DTI metrics  and mean diffusivity (MD)) were calculated and compared using ANOVA and other statistical comparisons.The three groups were significantly different (p<0.0001) in Evan\u2019s ratios with HCPM rats  slightly higher than controls  but lower than the HCPS group . Both FA and MD values were significantly different among the three groups in cortex, corpus callosum and internal capsule . Post-hoc comparisons showed that the HCPM group was not significantly different from the control group, while the HCPS group was significantly different  from the control group  and the HCPM group. In the HCPM group, it was found that the MD values in the external capsule increased proportionally with ventricle size , while FA values in the internal capsule decreased with increasing ventricle size .Although the DTI measurements in the HCPM rats with mild ventriculomegaly were not significantly different from normal controls, the correlation between ventricle size and DTI values in this group suggested that different levels of abnormality in brain tissues can be detected with DTI during various stages of hydrocephalus. Our results demonstrate that DTI is potentially a sensitive biomarker for monitoring the progression of ventricle enlargement and may help to determine the optimal window for surgical intervention."}
+{"text": "Of patients with left-sided endocarditis 20\u201347% have septic embolization to the spleen with varying degrees of clinical presentation. The natural history varies based on the size and location of the infarct. Larger and more peripheral infarctions are more prone to form abscesses and cause splenic rupture, whereas smaller infarcts may go largely unnoticed and only be detected on incidental imaging. Splenic abscesses are felt due to embolized septic material or secondary infection in a patient with bacteremia.The patient in this case is a 45-year-old female with a history of substance abuse, end-stage renal disease on dialysis, and aortic endocarditis status post bioprosthetic valve replacement. The patient presented to the emergency department with a 1-day history of 10/10 left upper quadrant abdominal pain. A computed tomography (CT) scan of the abdomen revealed a large splenic infarct . A subseThe CT scan appearance of splenic infarction includes a typically triangular region of low radiodensity on portal phase images, following intravenous contrast administration which does not show enhancement on the delayed images. Splenic abscess is strongly suspected if there is gas within the hypodense region. Additional signs of bulging of the splenic capsule, a focal fluid collection, or perisplenic inflammatory stranding are non-specific and each can be seen with bland infarction. Cardiac technique CT scan has shown excellent sensitivity and specificity for detecting aortic valve vegetations as well as for complications such as adjacent abscess or pseudoaneurysm. Pre-operative scanning has been recommended for those who need valve surgery."}
+{"text": "Ecological communities are increasingly exposed to multiple chemical and physical stressors, but distinguishing anthropogenic impacts from other environmental drivers remains challenging. Rarely are multiple stressors investigated in replicated studies over large spatial scales (>1000 kms) or supported with manipulations that are necessary to interpret ecological patterns. We measured the composition of sediment infaunal communities in relation to anthropogenic and natural stressors at multiple sites within seven estuaries. We observed increases in the richness and abundance of polychaete worms in heavily modified estuaries with severe metal contamination, but no changes in the diversity or abundance of other taxa. Estuaries in which toxic contaminants were elevated also showed evidence of organic enrichment. We hypothesised that the observed response of polychaetes was not a \u2018positive\u2019 response to toxic contamination or a reduction in biotic competition, but due to high levels of nutrients in heavily modified estuaries driving productivity in the water column and enriching the sediment over large spatial scales. We deployed defaunated field-collected sediments from the surveyed estuaries in a small scale experiment, but observed no effects of sediment characteristics (toxic or enriching). Furthermore, invertebrate recruitment instead reflected the low diversity and abundance observed during field surveys of this relatively \u2018pristine\u2019 estuary. This suggests that differences observed in the survey are not a direct consequence of sediment characteristics  but are related to parameters that covary with estuary modification such as enhanced productivity from nutrient inputs and the diversity of the local species pool. This has implications for the interpretation of diversity measures in large-scale monitoring studies in which the observed patterns may be strongly influenced by many factors that covary with anthropogenic modification. The intense and extensive development by humans across the planet has subjected much of the world's biological diversity to multiple severe anthropogenic stressors Environmental monitoring studies often rely on ecological measures of community composition and diversity as indicators of anthropogenic change Chemical stressors that are released into estuaries accumulate in benthic sediments We tested whether impacts of large-scale anthropogenic stress in estuaries could be detected over and above natural spatial variation across regional scales (100 s of kms) using an observational approach to assessing the outcome of contamination on benthic diversity. We surveyed benthic sediments in three heavily modified and four relatively \u2018pristine\u2019 estuaries This study surveyed benthic invertebrate distributions across estuaries and experiments were conducted on invertebrate communities. Sampling in each location was approved and carried out in strict accordance with the New South Wales Department of Primary Industries and New South Wales Marine Parks (Permit No. P09/0072-1.0).We investigated variation in soft-sediment assemblages in relation to anthropogenic contaminants and other environmental variables at seven sites within seven estuaries. Estuaries were assigned a \u2018modification category\u2019 according to the level of anthropogenic modification and the study was conducted in three heavily modified and four relatively unmodified estuaries stretching across 400 km of the coast of New South Wales, Australia . In this3 for a minimum of 24 h and then rinsed in deionised water (Milli-Q\u2122). All sediments for chemical analyses were kept in the dark on ice for transport to the laboratory and then frozen at \u221220\u00b0C until analysis.Benthic sediments were collected between February and March 2010. Two replicate sediment grabs and water quality measures were collected at each site from 5 m depth using a Van Veen grab to target 5 kg surficial sediments. Each sediment grab was homogenised in a clean tray and sub-sampled for infauna (250 mL) and measures of toxic contaminants  (150 g), organic enrichment indicators (sediment Chl-a levels and organic carbon) (150 g) and sediment grain size (50 g). An additional two sediment grabs were taken from sites in 6 of the surveyed estuaries  for the experimental deployment (details below). Plasticware used in sediment collection was previously soaked in 5% HNOTemperature, salinity, turbidity, pH, oxygen and Chl-a levels in the water column directly above sediment collection sites were measured using a multiprobe  calibrated according to the manufacturer's instructions.We used benthic recruitment containers (10 cm diameter \u00d720 cm height Perspex cylinders) to experimentally investigate the contribution of sediment characteristics to observed patterns by deploying sediments collected during our field survey. Bulk surficial sediment was collected from 5 m depth at 7 sites with unvegetated sediments within 6 estuaries . The sediments collected from multiple sites within each estuary were combined and homogenised then sieved (2 mm) to remove shells and larger fauna and flora. This created one sediment homogenate to represent each estuary. The six homogenates represented different sediment characteristics. Homogenate sediments were then divided into 7 replicate sub- samples (0.5 kg), which were applied as a top sediment layer (\u223c2 cm) to replicate recruitment containers (N\u200a=\u200a42). Approximately 1 kg of sand was used to line the bottom of each of the recruitment containers with the homogenate sediments layered on top. Sand was collected from a site in Port Jackson where the chemical composition had been previously characterised as uncontaminated Infaunal sub-samples (125-ml) were stained with Rose Bengal and preserved in a 7% formalin solution then passed through a 2 mm mesh (to remove large debris) and onto a 500-\u00b5m sieve. The remaining organisms were sorted with a dissecting microscope and identified to the lowest feasible taxonomic level (mostly order). Polychaetes comprised >70% of all assemblages and were therefore identified to family and we used this higher taxonomic resolution to focus on patterns in polychaete family diversity and polychaete abundance in response to anthropogenic modification. A reference collection was deposited at the Australian Museum.Sediment characteristics were investigated from benthic sediments collected at each site in the survey and analyses included concentrations of major metal and PAH contaminants, total organic carbon and Chl-a and sediment grain size according to the techniques described in Sediment metal analyses were undertaken using a microwave-assisted acid digestion according to Method 3051A 10, phenanthrene-d10, chrysene-d12 and perylene-d12) were spiked into all samples and recoveries were 111\u00b119%. Individual PAHs were summed for each sample to give a value of total PAHs Sixteen PAHs were analysed including naphthalene, acenaphthylene, acenaphthene, fluorene, phenanthrene, anthracene, fluofranthene, pyrene, benz(a)anthracene, chrysene, benzo(a)pyrene, benzo(b)fluoranthene, benzo(k)fluoranthene, indenopyrene, dibenzoanthracene and benzoperylene. Analyses of PAHs in sediments followed Method 8260 Sediment Chl-a analysis were undertaken following extractions of pigments in acetone with a spectrophotometer (Lambda 35 UV/Vis) according to Greenberg et al. Porewaters were extracted from the sediments by centrifugation at 800 g for 5 min and then filtered  immediately to minimise exposure to air. Samples were taken for ammonia . Dissolved ammonia was analysed colorimetrically using a Merck Spectroquant Kit (14752).In all analyses \u2018Modification Category\u2019 (heavily modified or relatively unmodified) was treated as a fixed orthogonal factor and \u2018Estuary (within Modification Category)\u2019 was a random nested factor. Replicates in each analysis were either sites (survey) or recruitment containers (experiment). Infaunal community composition was compared between modification categories with permutational multivariate analysis of variance (MANOVA) and Principal Components Analysis (PCO). We also investigated changes in taxa richness and abundance between modification categories because these measures are closely linked to contaminants (both inorganic and organic) Principal components analysis (PCA) was used to visualize the entire surveyed infaunal assemblages at each site or in each recruitment container. All analyses were done in PRIMER v6 with PERMANOVA+ Benthic sediments had higher metal  and PAH concentrations in heavily modified estuaries than relatively unmodified estuaries . Many exThe infaunal community composition differed significantly between heavily modified and relatively unmodified estuaries and also among individual estuaries . A combiPolychaete richness (number of families) and abundance  differed significantly between modification categories ; Table 2In summary, sediments from heavily modified estuaries were more contaminated with metals and PAHs and organically enriched than the relatively unmodified estuaries. These measures of toxic and enriching contamination also varied between estuaries Grain sizes were finer in heavily modified estuaries; conversely most variation in water quality was between estuaries rather than between heavily modified and relatively unmodified estuaries. Therefore differences in the infaunal community and measures of polychaete richness and abundance with modification category are likely to be related to contamination or sediment grain size. Infaunal differences between estuaries could be related to metal concentrations, sediment grain size or environmental variables.Characteristics  of the field-collected sediments differed consistently between modification categories at the start and the end of the field experiment . AdditioMost national biomonitoring guidelines recommend the use of multiple lines of evidence when assessing environmental impacts including the use of experiments to establish causation Habitats that are severely stressed by anthropogenic activities are reported to have substantially reduced species richness  that would enrich the nutrients within the estuary and may increase the diversity of the local species pool However, large-scale anthropogenic impacts may not be reflected in smaller-scale manipulations The outcomes of this study have relevance for environmental managers as the patterns we observed across regional scales provided important information about the ecological condition of estuaries and useful directions for future research. The scale of field manipulations may also be an important consideration, as the patterns of increased polychaete richness we observed in heavily modified estuaries across regional scales were not found in our small-scale manipulations within one estuary. This suggests that increases in diversity are related to parameters that co-vary with estuary modification over larger scales such as the productivity of the entire system and the diversity of the regional species pool, and patches of contaminated sediments will not result in similar effects. If environmental managers rely solely on small-scale surveys or manipulations together with meta-analyses from the literature this may lead to a poor understanding of actual impacts over regional scales. Ecological monitoring of human impacts should, as a matter of course, use multiple lines of evidence including field surveys and field experiments in order to reliably identify the drivers of biological patterns and initial observational studies can inform the design of manipulative experiments to further investigate causation.Figure S1Mean (+S.E.) proportional abundances of different taxa analysed from benthic sediment grabs collected in seven estuaries.(DOCX)Click here for additional data file.Figure S2Mean (+S.E.) metal and total PAH concentrations (dw), sediment Chl-a, TOC, porewater ammonia and percent fines (<63 \u00b5m) analysed from benthic sediment grabs collected in heavily modified (filled bars) and relatively unmodified (open bars) estuaries.(DOCX)Click here for additional data file.Figure S3Mean (+S.E) values for water quality variables  collected in heavily modified (filled bars) and relatively unmodified (open bars) estuaries.(DOCX)Click here for additional data file.Figure S4Mean (+S.E.) end metal concentrations (dw) and percent fines (<63 \u00b5m) analysed from deployed sediments sourced from heavily modified (filled bars) and relatively unmodified (open bars) estuaries. Starting concentrations are indicated as a single figure above the bars.(DOCX)Click here for additional data file.Table S1Details of limits of detection for each of the analytes sampled from sediments.(DOCX)Click here for additional data file.Table S2Soft sediment infauna sampled in benthic sediment surveyed from seven sites in seven NSW estuaries that were either heavily modified or relatively unmodified.(DOCX)Click here for additional data file.Table S3Soft sediment infauna sampled in field manipulated sediment.(DOCX)Click here for additional data file.Table S4Permutational ANOVA results for sediment quality measures in benthic sediment surveyed from seven NSW estuaries.(DOCX)Click here for additional data file.Table S5Permutational ANOVA results for water quality variables surveyed from seven NSW estuaries.(DOCX)Click here for additional data file.Table S6Permutational ANOVA results for metal contaminants and sediment quality variables measured at the start and end in sediment field experiments deployed in the Clyde estuary.(DOCX)Click here for additional data file."}
+{"text": "Cervus elaphus) to playbacks of red deer vs. sika deer (Cervus nippon) male mating calls, with the prediction that females will prefer conspecific calls. While on average female red deer preferred male red deer roars, two out of twenty females spent more time in close proximity to the speaker broadcasting male sika deer moans. We suggest that this absence of strict vocal preference for species-specific mating calls may contribute to the permeability of pre-zygotic reproductive barriers observed between these species. Our results also highlight the importance of examining inter-individual variation when studying the role of female preferences in species discrimination and intraspecific mate selection.Males of all polygynous deer species (Cervinae) give conspicuous calls during the reproductive season. The extreme interspecific diversity that characterizes these vocalizations suggests that they play a strong role in species discrimination. However, interbreeding between several species of Cervinae indicates permeable interspecific reproductive barriers. This study examines the contribution of vocal behavior to female species discrimination and mating preferences in two closely related polygynous deer species known to hybridize in the wild after introductions. Specifically, we investigate the reaction of estrous female red deer ( According to the biological species concept, reproductive isolating mechanisms are integral to the process of speciation Acoustic signals can play an important role in the process of mate choice, functioning in both intraspecific mating decisions  and interspecific mating decisions (species discrimination) Cervus elaphus) and Asian sika deer (Cervus nippon). Although closely related This study examines the possible role of acoustic communication in hybridization between two species of Cervinae: European red deer  vs. heterospecific (sika deer) male mating calls on female red deer during estrus and comparing the females' behavioral reactions to calls from these two species exemplars. Given the strong acoustic differences that characterize the species-specific male mating calls of these two species, we predicted that female red deer should show more attention and preference towards the conspecific red deer roars over the heterospecific sika deer moans.Playback trials were conducted during the 2008 breeding season (August 28\u201329) at the Institut National de la Recherche Agronomique (INRA) Redon Experimental Farm, Clermont-Ferrand, France. Twenty female red deer of reproductive age (age range\u200a=\u200a2\u201315 years old) were used in the experimental trials. This work follows the Association for the Study of Animal Behavior/Animal Behavior Society guidelines for the ethical use of animals in research, and was carried out under the procedural and ethical authorization of the French Ministry of Agriculture .Female reactions to male mating calls may be influenced by the hormonal state of the female The 20 females used in this study were randomly separated into two groups of 10 females each (Group A and Group B). Group A underwent the protocol for estrus synchronization (and the subsequent playback experiments) one day before Group B.Playbacks were created using mating calls recorded from four different male red deer and four different male sika deer. All male exemplars used in this study are unfamiliar to the current experimental subjects. Roars from four adult male red deer were recorded at Redon in 1996 using a Telinga pro-III-S/(DAT) microphone used without the parabolic reflector (flat frequency response\u200a=\u200a80\u221216 kHz\u00b13 dB) and a DAT Sony TCD-D7 recorder  at distances of 2\u201310 m. Moans from four adult male sika deer were recorded in 2007 at a farm in Waterford, Ireland using a Sanken CS-1 directional condenser microphone (flat frequency response\u200a=\u200a50\u221220 kHz\u00b13 dB) and a Fostex FR-2 digital field recorder . Male red deer roars were re-sampled to 44.1 kHz and the intensity all red and sika deer calls were normalized to 98% of maximum intensity using Cool Edit Pro 2.0 (Syntrillium).Calls were arranged into bouts (or groups) of calls for each male exemplar. To create playbacks that mimicked natural calling patterns for each species exemplar, red deer bouts consisted of one to four roars (separated by 0.5 sec) while sika deer bouts contained only one moan.Playbacks consisted of paired sequences of consecutive calling bouts from both species exemplars. Each playback contained six call bouts from both species exemplars, broadcast in a paired dyadic fashion from two different speakers . The \u2018leader\u2019 of each bout pair was alternated for each consecutive pair. The individual bouts within a matched pair of consecutive bouts were separated by 2 sec while bout pairs were separated by 20 sec . A LatinThe total duration of all calls from each species played during the playbacks was equalized so that females were exposed to each species for a similar total amount of time. Each individual red deer playback contained 16 roars (constructed from a pool of 11 different roars with no roars repeated consecutively or within the same bout and no roars used more than twice) arranged in six calling bouts with an average bout duration of 4.93 sec and an average total call duration of 29.59 sec per playback. Each individual sika deer playback contained six different single moan bouts with an average bout duration of 4.96 sec and an average total call duration of 29.81 sec per playback. Overall, the total duration of each dyadic playback was approximately three minutes.2), two Anchor Liberty 6000HIC amplified speakers were hidden behind mesh screens (2 m high\u00d74 m wide) on two ends of the enclosure, facing the entrance (enclosure similar to 2) were demarcated with white chalk lines starting at 8 m outward from the speakers.In a roughly triangular shaped experimental enclosure  SPL at 1 m as measured by Radio Shack Sound Level Meter set for C-weighted fast response. Female behavior was video recorded with a Sony Mini DV DCR-TRV19E camcorder from a hidden, elevated observational room.s\u200a=\u200a+0.999, p<0.01) on all behavioral measures . Because we could not normalize the data distribution for all the response variables, two-tailed Wilcoxon matched-pair signed-rank tests were used to determine if significant differences were present between the behavioral responses of the females to playbacks of the two species exemplars. All statistical tests were performed using SPSS  and 0.05 levels of significance are quoted.We predicted that females would show more attention and preference towards conspecific calls than heterospecific calls. \u2018Attention\u2019 was measured as looking towards the speakers and \u2018preference\u2019 was measured as entering proximity zones in front of the speakers. The number of instances and the cumulative duration of these two behaviors were quantitatively coded using the digital video analysis software Gamebreaker 7.0.121  at a 25 fps. Behaviors were coded from the initiation of the playback sequence until 2 min after the last call was broadcast. Looking towards a speaker was defined as occurring when the animal was in a standing position or if moving, when the animal stopped within two steps of initiating the look. A look began when the head first started to orientate to a fixed position facing the speaker and ended when the head started moving away from this fixed position. Entering a proximity zone was defined as starting when the first front leg breaks the outer plane of the zone boundary  and ending when the last front leg passes out of the zone boundary. Video analyses were carried out by MTW with 20% of trials (n\u200a=\u200a4) double-coded by DR, resulting in an overall agreement of 99.9%  or in the total duration of looks given by females towards red deer roars or sika deer moans,     . However=\u200a0.015) . Interes=\u200a0.091) , with twOur experiment simulated a situation where allopatric species are brought together and females in estrus are confronted with an unfamiliar species with whom they can hybridize. While these females had been exposed to male red deer and their roars , they had never been exposed to male sika deer. Thus, the playbacks presented during each trial contrasted a familiar conspecific stimulus  with an unfamiliar heterospecific stimulus .p\u200a=\u200a0.091) for females to spend more total time in the conspecific proximity zone. Mating preferences for conspecifics over heterospecifics is well documented While female red deer showed no significant difference in attention behaviors between the novel heterospecific and the conspecific stimulus, they entered the conspecific proximity zones significantly more times than the heterospecific proximity zones, indicating an overall preference for conspecific calls. There was also a non-significant trend  combined with geographic isolation and phylogenetic contingencies. Indeed, several experimental studies have confirmed the function of key acoustic properties of male red deer roars in female choice decisions While most female red deer in our experiment preferred conspecific calls, some individuals displayed preferences towards heterospecific calls, possibly as a result of the mechanisms discussed above. Regardless of why some female red deer approach male sika deer moans, in the absence of a harem-holding male red deer, the act of moving towards a reproductively compatible heterospecific caller in the wild could lead to hybridization if the female does not oppose or successfully avoid mating attempts by a male sika deer. Inter-individual differences in mate choice or species discrimination have been correlated with a variety of factors such as the environment This study is an important step in investigating the role that vocalizations may play in intra- and interspecific mating decisions in the context of hybridization. We demonstrated that in a simulated situation where female red deer in estrus encounter both conspecific male red deer roars and novel heterospecific male sika deer moans, most, but crucially, not all females approached the conspecific call. The minority of females that spend more total time near the sika deer speaker may represent cases of incorrect species discrimination where hybridization could occur in the wild. Additionally, we highlight the potential importance of inter-individual differences in mate preferences. Additional studies are being conducted to quantify interspecific and intersexual differences in male and female behavioral and physiological responses to conspecific, heterospecific, and hybrid male mating calls."}
+{"text": "Laparoscopic ventral mesh rectopexy using a composite mesh is a technique gaining more recognition for management of pelvic floor disorders such as full thickness rectal prolapse, obstructive defecation symptoms and vaginal vault prolapse. A recent Cochrane review concluded that laparoscopic rectopexy results in fewer post-operative complications and an earlier dischargeTwo longitudinal pieces of the standard 3cm x 20cm strip of polypropylene or polyester mesh are used; the second piece is placed at right angles to prepare a T shape. The second piece is stitched with four sutures, forming a T shape .This prepared mesh is cheaper than pre-packed/shaped meshes. The T shape allows better sitting in the pelvis. It improves area for fixation to the anterior rectum and offers better support."}
+{"text": "Rapid diagnosis of influenza not only facilitates timely clinical management, time series test results can also serve for disease surveillance purpose. We evaluated the performance of a community based system using QuickVue Influenza A+B test  for influenza surveillance in Hong Kong.As part of a large community study, subjects older than 2 years reporting at least two symptoms of influenza-like-illness were recruited from 30 outpatient clinics in Hong Kong prospectively from February 2007 to July 2010 around the influenza seasons [A total of 5,824 subjects were recruited throughout the study. We define each study week as either high influenza activity or low influenza activity using fixed thresholds after removing extreme values two standard deviations above the mean. The sensitivity of QuickVue data for picking up high influenza activity was 78% when compare with the laboratory data and was 100% when comparing with the community data.Although the sensitivity of QuickVue Influenza A+B test decreases with specimen viral load, in which may miss out mild influenza infection cases , its exc"}
+{"text": "Understanding how the intervention works is a primary objective in most pragmatic trials. Although good evidence exists for the effectiveness of cognitive behaviour therapy (CBT), there is little evidence presently that cognitive factors, such as dysfunctional attitudes (DAS) or meta-cognitive awareness (MAQ), mediate the effect of CBT on depression outcomes. Standard regression methods adjusting for such mediators produces biased estimates. Using data from the CoBalT trial, we use a \u2018causal inference' approach to examine the mechanism through which CBT affects depression outcomes.The proportion of the causal effect of CBT on depressive symptoms mediated by DAS and MAQ was estimated  using the \u2018potential outcomes' approach. The outcome was the Beck Depression Inventory (BDI-II) score at 12 months. Mediators were measured at 6 months post-randomisation.Approximately 25% of the treatment effect observed at 12 months was mediated through changes in DAS  or MAQ at 6 months . This equated, on average, to a one point reduction in the difference in mean BDI-II scores between treatment groups. Sensitivity analyses suggested that a modest degree of \u2018hidden' confounding (\u03c1\u22450.3) would violate the key assumption of no confounding between any of the three sets of variables.Changes in cognitive variables contributed a modest proportion of the observed treatment effect. Causality is intuitively counterfactual and use of potential outcomes provides valid causal inference. However, sensitivity analyses suggested that our findings need to be interpreted with caution as hidden confounding may explain the mediated effect."}
+{"text": "Participant retention is challenging in long term trials and attrition can threaten trial validity, especially for patient-reported outcomes which cannot be ascertained otherwise. The evidence base to maximise retention is limited so we investigated factors influencing questionnaire response rates with a mixed methods research approach.ProtecT is an ongoing randomised trial of localised prostate cancer treatments in men currently aged 53-76 years (ISCRTN 20141297) with six years follow-up. Symptoms and QoL were collected annually by postal questionnaire with a reminder letter for non-responders at six weeks (phase I). Three additional interventions were sequentially investigated to increase retention. Firstly, clinical centre staff commenced telephoning non-responders at four weeks (phase II). A study pen was included with reminder letters and a shortened questionnaire was sent to non-responders at nine weeks (phase III). Questionnaire response rates over six months were compared by phase. 1279 participants were asked in the questionnaires about online completion. 18 participants gave in-depth interviews about trial follow-up which were transcribed verbatim and analysed thematically.The questionnaire response rate was 76.4% (phase I: 1045/1367) with a median return of 13 days (IQ range 8-22 d) and the reminder letter increased this to 86.8% (1187). Telephoning increased rates to 90.5% (phase II: 1105/1221). The additional incentive of a study pen was ineffective  whilst the short questionnaire had some impact . One quarter of men wished to complete on-line questionnaires .In interviews, most men found questionnaires acceptable and understood their purpose although they were regarded as a less enjoyable aspect. Some men saw questionnaires becoming less relevant over time either because they felt they were cured or they had become repetitive, although they continued to complete them. Participant newsletters were interesting and gave a sense of belonging to a group although some men wanted preliminary trial findings. The study website was infrequently accessed (four men did not use the web), partly because men assumed it contained no extra information.A reminder letter and telephone call increased questionnaire response rates in a trial with older men. A study pen provided no incentive but response rates were already 90%. Men understood the purpose of questionnaires but some attitudes could increase attrition and need to be addressed by trialists. Newsletters maintained participant interest, unlike the website.The ProtecT study is funded by the Health Technology Assessment programme."}
+{"text": "Dual left anterior descending artery (LAD) is a rare coronary anomaly that is important to recognize at coronary imaging as it may influence reperfusion strategies. Four types of dual LAD are described by the traditional literature. We present a novel case of dual LAD with coronary computed tomographic angiographic correlation that does not fit into this classification system. Rather, our case supports the recently proposed notion of adding a fifth variant to the traditional dual LAD classification system. Dual left anterior descending artery (LAD) is an extremely rare coronary anomaly traditionally classified into one of four types. Recognition at coronary imaging is critical as both surgical and percutaneous reperfusion strategies may be altered by its presence .A 37-year-old Caucasian male presented with a 1-year history of atypical left-sided chest discomfort. Past medical history was negative for major cardiac risk factors but positive for borderline diabetes, increased body mass index, and gastroesophageal reflux. Physical exam was unremarkable. EKG demonstrated a left anterior fascicular block. Biochemical markers of cardiac ischemia were negative.Single photon emission computed tomography stress myocardial perfusion imaging (SPECT-MPI) revealed a heterogeneous inferolateral and apical myocardial perfusion defect with partial reversibility. Conventional coronary angiography identified an aberrant left anterior descending artery (LAD) originating from the right coronary cusp without evidence of atherosclerosis. To further characterize the anatomy of this aberrant artery, coronary computed tomography angiography (CTA) was performed.CTA revealed a novel case of dual LAD. The long LAD segment arises from a common coronary ostium on the right coronary cusp. It takes an aberrant course posterior to the right ventricular outflow tract. The long LAD has a hammock-like downward slope that closely resembles, on coronal imaging, the hammock sign described on conventional angiography . The lonDual LAD is a rare type of coronary artery anomaly that is important to recognize and characterize as it may critically influence surgical or angiographic reperfusion strategies , 4. In dThere are four types of dual LAD described in the traditional literature that are distinguished by the origins and courses of the long and short segments of the dual LAD system, as well as the supply of the septal perforators and diagonal branches , 4 Tabl. RecentlIn summary, we present an unusual case of dual LAD that does not fit within the traditional classification system. A similar case of this anatomic variant has recently been described in the literature, which the authors have presented as a novel Type V dual LAD  Table 1Table 1."}
+{"text": "It is often recommended to test patients presenting for HIV care for tuberculin skin test reactivity at the initial visit if they have a prior stay in tuberculosis-endemic areas.To assess whether incident cases of tuberculosis (tb) in our cohort could have been prevented by such testing and subsequent preventive treatment of patients with a positive skin test.HIV clinic in northern Europe caring for about 1000 patients. During the observation time preventive treatment was only rarely prescribed.File review of all tb cases occurring more than two months after presenting for HIV care during the ten years 2000-2009. Cases were classified as possibly preventable, probably non-preventable or non-preventable based on residence and travel history, strain typing by restriction fragment length polymorphism technique and/or skin test reactivity.24 cases in 23 patients were identified. 9 (38%) were classified as possibly preventable, 3 (13%) as probably non-preventable and 12 (50%) as non-preventable.A minority of tb cases occurring during HIV care is preventable by a policy of testing new patients from endemic areas and treating patients with positive skin tests."}
+{"text": "A consistent line of investigation suggests that autonomic nervous system dysfunction may explain the multi-system features of fibromyalgia (FM); and that FM is a sympathetically maintained neuropathic pain syndrome. Dorsal root ganglia (DRG) are key sympathetic-nociceptive short-circuit sites. Sodium channels located in DRG (particularly Nav1.7) act as molecular gatekeepers for pain detection. Nav1.7 is encoded in gene SCN9A of chromosome 2q24.3 and is predominantly expressed in the DRG pain-sensing neurons and sympathetic ganglia neurons. Several SCN9A sodium channelopathies have been recognized as the cause of rare painful dysautonomic syndromes such as paroxysmal extreme pain disorder and primary erythromelalgia. The aim of this study was to search for an association between fibromyalgia and several SCN9A sodium channels gene polymorphisms.We studied 73 Mexican women suffering from FM and 48 age-matched women who considered themselves healthy. All participants filled out the Fibromyalgia Impact Questionnaire (FIQ). Genomic DNA from whole blood containing EDTA was extracted by standard techniques. The following SCN9A single-nucleotide polymorphisms (SNP) were determined by 5' exonuclease TaqMan assays: rs4371369; rs4387806; rs4453709; rs4597545; rs6746030; rs6754031; rs7607967; rs12620053; rs12994338; and rs13017637.P = 0.036) mostly due to an absence of the GG genotype in controls. Interestingly; patients with this rs6754031 GG genotype had higher FIQ scores  than patients with the GT genotype  and the TT genotype .The frequency of the rs6754031 polymorphism was significantly different in both groups (In this ethnic group; a disabling form of FM is associated to a particular SCN9A sodium channel gene variant. These preliminary results raise the possibility that some patients with severe FM may have a dorsal root ganglia sodium channelopathy. The background information leading to the present investigation has been already published as a hypothesis  and is sDRG are nodules that lie along the spinal column. They play a key role in pain perception. DRG house the cell bodies of sensory neurons; the dendrites of which are located in the skin; muscles; tendons; joints; and internal organs. DRG act also as viral sanctuaries. Under normal circumstances; DRG have scant sympathetic innervation. Nevertheless; trauma and/or infection trigger sympathetic sprouting within DRG via nerve growth factor over-expression. Such aberrant neuroplasticity enables catecholamines and sympathetic traffic to induce sensory neuron firing. Sodium channels play a pivotal role in this hyperexcitability. These mechanisms are the basis of the sympathetically-maintained pain concept .Sodium channels located in DRG act as molecular gatekeepers of pain detection at peripheral nociceptors. Nine sodium channel subunits have been identified (Nav1.1-Nav1.9); each with a unique central and peripheral nervous system distribution. An isoform Nav1.7) encoded in gene SCN9A of chromosome 2q24.3 is predominantly expressed in the DRG pain-sensing neurons and sympathetic ganglia neurons . Several encoded This information lead us to the present investigation whose objective was to search for an association between several SCN9A sodium channels gene polymorphisms and fibromyalgia.We studied 73 Mexican women suffering from FM according to the 1990 American College of Rheumatology criteria. These patients were referred from different private rheumatology practices in Mexico. As controls; we studied 48 Mexican women who considered themselves to be healthy and who denied having chronic pain. Patients and controls were matched by age. Mexicans have diverse ethnicity. The great majority have European and Native American background. \"Mestizo\" is the term used to name this mixed heritage. All individuals included in the study were born in Mexico and were catalogued as Mestizo. No further genealogical characterization was done. Both patients and controls filled out a validated Spanish translation of the Fibromyalgia Impact Questionnaire (FIQ) [This research complies with the Helsinki Declaration. Informed consent was obtained from all participants; and the Human Research Committee of the National Institute of Cardiology of Mexico approved the study. This group of subjects is the same reported in our previous genetic studies in FM looking for polymorphisms of the adrenergic receptor  and cateGenomic DNA from whole blood containing EDTA was extracted by standard techniques . Ten difP > 0.05 by Shapiro-Wilk statistics); therefore; data were measured as median and interquartile range. The Kruskal-Wallis test was used to compare visual analog scale (VAS) scores on the FIQ with SNPs and genotypes. Proportions of patients and controls per SNP were estimated and compared using chi square or Fisher's exact tests; as required; and presented as absolute frequencies and proportions. Statistical significance was set at an alpha level of less than or equal to 0.05. Pair wise linkage disequilibrium  estimations between polymorphisms and haplotype reconstruction were performed with Haploview version 3:32 .Statistical analysis was carried out with Stata 8.0 software for Windows . A chi-square test was used to evaluate Hardy-Weinberg equilibrium for each polymorphism. In the exploratory analysis; numeric data showed a non-normal (non-Gaussian) distribution (P = 0.036) mostly due to an absence of the GG genotype in controls. Correlation analysis between SNPs and total FIQ score showed that patients with the rs6754031 GG genotype had higher total FIQ scores  than patients with the GT genotype  or the TT genotype   had strong LD. One SNP (rs6746030) was not studied because too few individuals were determined for this variant. In light of the strong LD; we analyzed the most frequent haplotypes in patients and healthy controls to determine whether some of these haplotypes could be associated with the risk of developing FM. The distribution of the different haplotypes was similar in patients and healthy controls (data not shown).This group of Mexican patients suffering from FM displayed different distribution of SCN9A rs6754031 genotypes when compared to ethnic; age; and gender matched controls. The difference was due mostly to the absence of the rs6754031 GG genotype in controls. Additionally; in this group of FM patients; the rs6754031 GG genotype is associated with severe disease; as assessed by the FIQ. To our knowledge there is no prior research linking rs6754031 with any particular illness. Although no causality could be derived from the present investigation; these preliminary results raise the possibility that some patients with severe FM may have a DRG sodium channelopathy.We are not aware of previous studies looking at SCN9A sodium channels gene variation in FM. However; Reimann et al. studied several SCN9A polymorphisms in patients with different painful syndromes; including osteoarthritis; sciatica; amputee phantom pain; spine surgery and pancreatitis. They found a link of rs6746030 with pain intensity. They did not study the SNP rs6754031 that we found associated to FM severity . Nav1.7 After the submission of this manuscript Faber et al. published a gain of function SCN9A mutation associated to idiopathic small fiber neuropathy. This novel finding points to a broader role of Na(V) 1.7 mutations in painful neurological disease than previously considered from studies on rare genetic syndromes .Our previous genetic studies in this group of patients found an association of two catechol-o-methyl transferase (COMT) enzyme gene polymorphisms with FIQ subscales. COMT rs6269 was associated with pain and fatigue; and COMT rs165599 with morning stiffness and disability . The resWe recognize limitations in this pilot study. The sample size is not large enough to withstand multiple comparisons of common gene polymorphisms; therefore a type II statistical error is possible. Nevertheless; the following two findings favor a real linkage between rs6754031 GG genotype and Mexican FM patients: 1) rs6754031 polymorphism was significantly different in both groups mostly due to an absence of the GG genotype in controls. 2) In the patients group the same rs6754031 GG genotype was associated to a severe disease. Studies in other ethnic groups with a larger sample size are needed to verify or amend these preliminary observations.Another limitation of our study is the lack of rs6754031 functional profiling. Techniques such as patch methods or functional expression assays are beyond our capabilities. So; at the present time; the link between SCN9A polymorphism and severe FM is just associative. Nevertheless; our findings raise the possibility that DRG could be an important element in the pathogenesis of FM; a site in which physical; emotional; or infective stimuli could be converted into chronic pain . GeneticThe results of the present investigation may have potential therapeutic implications. If future investigations confirm the Nav1.7 sodium channels dysfunction in FM; then sodium channel blockers may become a therapeutic option. Preliminary evidence supports this contention. Lignocaine; a non-specific sodium channel blocker; appears to reduce FM pain . DuloxetOur results show that; in this group of Mexican women; there is an association of the rs6754031 polymorphism with the risk of developing FM; as well as with the FIQ score. This association raises the possibility that some patients with severe FM may have a DRG sodium channelopathy.FM: Fibromyalgia; DRG: Dorsal root ganglia; FIQ: Fibromyalgia Impact Questionnaire; SNP: Single nucleotide polymorphism; COMT: Catechol o methyl transferase; VAS: Visual analogue scale; AR: Adrenergic receptorThe authors declare that they have no competing interests.GVA; EAL and VMF carried out the genetic studies. AM and AG recruited patients and were involved in the clinical part of the investigation. MV performed the statistical analysis. All authors read and approved the final manuscript. MML conceived the study; participated in its design and coordination and helped to draft the manuscript. All authors read and approved the final manuscript.We gratefully recognize the financial support of the American Fibromyalgia Syndrome Association.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2474/13/23/prepub"}
+{"text": "Navicular stress fracture (NSF) is a relatively uncommon injury according to Australian Rules Football (AFL) injury surveillance data. Like all stress fractures, a disproportionate amount of compression / strain (dose) versus remodeling (response) accounts for bone breakdown. The exact mechanism of injury or anthropometric factors involved in navicular stress fracture remains largely unknown however; several authors speculate a short first metatarsal and metatarsus adductus as contributing factors. It is thought that a long second metatarsal transmits forces unevenly through the medial cuneiform creating shearing stress at the avascular central zone of the navicular. To date no prospective data is available to support these theories. Navicular stress fracture is deemed high risk due to the potential of delayed or non union and often excessive time away from activity.2), Force and Pressure Time Integrals were used for further anaylsis.Retrospective plantar pressure mapping of two elite AFL footballers who\u2019d sustained NSF injury were recorded. Testing involved unshod across a floor mounted pressure sensing mat  using a two-step method following familiarisation. Five (5) trials were performed for each foot with the averages of the middle three (3) trials used for further analyses. Subsequent testing using an in-shoe pressure mapping system,  was performed with custom moulded foot orthoses in situ. Data from twenty (20) steps were recorded, allowing for acceleration and deceleration with the middle ten (10) steps used for further analyses. Computer software generated data for Peak Pressure across 10 masked areas (kPa), Instant to Peak Pressure (ms), Contact Area  beneath the 2Presented is the use of plantar pressure mapping in NSF injury in two Elite AFL footballers. The results suggest increased FF pressure and anatomical variations such as a short 1st metatarsal and metatarsus adductus could contribute to NSF injury. Technology such as plantar pressure mapping may be used prospectively to assess or screen at risk groups for NSF injury."}
+{"text": "Neuropeptides play a critical role in regulating these processes. Neuropeptide Y (NPY) is highly expressed in limbic brain areas, including the amygdala. Depending on the receptor subtypes involved  mice display a dramatically accelerated acquisition of conditioned fear while fear extinction was impaired. Interestingly this phenotpye was only reproduced in mice lacking both the Y1 and Y2 receptors are involved in these processes. Y1 receptors in the basolateral amygdala are modulating the acquisition and extinction of fear while Y2 receptors in the central amygdala are preferentially inhibiting the expression but facilitating the extinction of learned fear. Furthermore, Y2 receptors are crucially involved in the discrimination of fear-related stimuli.Taken together, our data demonstrate that NPY delays acquisition and reduces expression of conditioned fear whereas it promotes fear extinction. Both Y"}
+{"text": "Acute respiratory failure (ARF), a common syndrome, is still poorly clinically appreciated. Literature review reports only a few attempts in neonatology (Silverman score) and in adults (Patrick score ) constru2/FiO2 <250 and/or ventilatory support).A prospective study among 70 patients with ARF on previously healthy lungs. ARF was rated in a randomized blinded manner respectively by residents and seniors. An inter-rater reliability analysis using the kappa statistic was performed to determine consistency among raters. Clinimetric properties were assessed by examining the prognostic prediction by the ROC curve using a composite gold standard (PaOP < 0.001), indicating an almost perfect agreement [The inter-rater reliability for the raters was found to be \u03ba = 0.82 (This new and validated score could drive some advantages in daily practice, allowing accurate assessment of ARF severity, more objective monitoring of patients and easier communication between care providers. It may accurately guide oxygen supplementation and ventilatory support and afford accurate monitoring of patho-physiological and etiological treatment of ARF. It could be a valuable tool in randomized clinical trials or physiological studies evaluating treatments in ARF. Finally it could be used as an educational tool."}
+{"text": "The rewarming benefit of anterior torso heat pad application in mildly hypothermic conscious adult trauma patients remains inconclusive in this randomized comparative clinical trial. There was no between-group rewarming gain in ear canal temperature when an anterior torso chemical heat pad was compared with blankets. Patient awareness, and favorable perception of, being administered the active intervention (heat pad) could explain the significant improvement in patient-rated cold discomfort discerned with the heat pad. In the context of marginal demonstrated benefit, it would have been informative to ascertain adverse effects related to the heat pad, including burn injury to the chest wall. In their randomized clinical trial of managing hypothermia in trauma, Lundgren at al  attempt Improvements in heart rate, systolic blood pressure and respiratory rate seem to not be clinically consequential; the heat pad was associated with - 4 beats/min for heart rate compared with -1 beat/min in patients that were allocated blankets. The favourably biased view that a patient holds of any active treatment in a non-blinded intervention trial  could suA heat pad weighing 1400 grams  could thAlthough spontaneous hypothermia in conjunction with acidosis and coagulopathy is harmful in severe trauma , there i\u00b0C: degrees centigradeThe author declares that they have no competing interests."}
+{"text": "Cyanobacteria are a rich source of natural products with interesting biological activities. Many of these are peptides and the end products of a non-ribosomal pathway. However, several cyanobacterial peptide classes were recently shown to be produced through the proteolytic cleavage and post-translational modification of short precursor peptides. A new class of bacteriocins produced through the proteolytic cleavage and heterocyclization of precursor proteins was recently identified from marine cyanobacteria. Here we show the widespread occurrence of bacteriocin gene clusters in cyanobacteria through comparative analysis of 58 cyanobacterial genomes. A total of 145 bacteriocin gene clusters were discovered through genome mining. These clusters encoded 290 putative bacteriocin precursors. They ranged in length from 28 to 164 amino acids with very little sequence conservation of the core peptide. The gene clusters could be classified into seven groups according to their gene organization and domain composition. This classification is supported by phylogenetic analysis, which further indicated independent evolutionary trajectories of gene clusters in different groups. Our data suggests that cyanobacteria are a prolific source of low-molecular weight post-translationally modified peptides. Bacteriocins are secondary metabolites and have been found in all major lineages of bacteria in silico screening for bacteriocins in Gram-negative bacteria had revealed the presence of sixteen double-glycine-type precursors and ten cognate transporters from strains of the cyanobacteria Nostoc, Prochlorococcus, Synechococcus and Synechocystis3E(I/L)X2(I/V)XG(G/A) Prochlorococcus marinus MIT9313 Cyanobacteria are a prolific source of natural products and secondary metabolites In order to explore the genetic potential for bacteriocin production in cyanobacteria, we mined 58 cyanobacterial genomes to identify the organization of bacteriocin-processing gene clusters. Surprisingly, we found more than a hundred new putative bacteriocin gene clusters from genomes of nearly all examined cyanobacterial species. Nearly 300 putative precursor genes were encoded in close proximity to the bacteriocin gene clusters. Our results demonstrate the widespread presence of bacteriocin gene clusters in cyanobacteria. The genetic diversity of the core peptides of these bacteriocin precursors is enormous with little sequence conservation.A total of 145 putative bacteriocin gene clusters were identified in 43 cyanobacteria , Table 1Cyanothece PCC 7425 and Nostoc punctiforme PCC 73102 each have four LanM encoding gene clusters, the other strains each have only one. Twelve gene clusters belong to group V were found in nine genomes . Protein sequences of these genomes were extracted and formatted for local BLAST searches. Three tailored query files containing FASTA format protein sequences of bacteriocin synthesis genes were constructed. The first one consisted of 30 representative proteins of the C39 peptidase domain-containing ABC transporter (cd02259), the second contained 14 HlyD family proteins (TIGR01843). Sequences in these two files were collected from the NCBI Conserved Domains database Genomic data of 58 cyanobacterial strains  were dowE < 0.00001) The three query files were utilized for searching against the database containing all proteins of the collected cyanobacterial genomes. Protein hits of blastP (E < 0. 1) Precursor genes were searched in a 20 Kb range upstream and downstream for each gene cluster. Small ORFs and intergenic regions were manually checked by searching for the double glycines. These predicted precursors were compared to known precursor families Gammaproteobacterium HdN1, Bradyrhizobium japonicum USDA 110, and Escherichia coli UMN026. The second midpoint tree  int tree  is generFigure S1Sequence alignments of putative novel cyanobacterial bacteriocin precursors. (A) Ten selected HetP substrates are shown in a ClustalW alignment (PDF)Click here for additional data file.Figure S2Sequence logo of motif with double-glycine found in the putative HetP precursors in cyanobacteria. A conserved region was found near the peptide cleavage site with Gly-Gly motif from the putative HetP precursor proteins in cyanobacteria. Here the sequence logo with relative frequency of acidic residues of the conserved sequences is demonstrated. This figure was generated by web-based software (PDF)Click here for additional data file.Table S1Cyanobacterial genomes analyzed in this study .(PDF)Click here for additional data file.Table S2Conserved domains identified in cyanobacterial bacteriocin gene clusters.(PDF)Click here for additional data file.Table S3Cyanobacterial precursors identified in this study.(XLS)Click here for additional data file."}
+{"text": "Systemic light chain amyloidosis (AL) is associated with a high cardiovascular morbidity and mortality. Cardiovascular involvement and determination of prognosis is underestimated by standard imaging parameters. Recently, cardiac deformation analysis of global circumferential and longitudinal strain has been shown to have great clinical impact on the assessment of prognosis and survival in this rare disease. For quantification of cardiac deformation analysis we applied a novel non-invasive post-processing feature tracking algorithm (FTI) on pre-acquired regular CMR SSFP images in healthy volunteers and in patients with AL and sought to investigate wall motion differences between both groups.65 patients  with biopsy proven systemic AL were scanned on a clinical 1.5 T CMR scanner (Philips Achieva). Short axis slices covering entirely both ventricles as well as 2-, 3- and 4-chamber were acquired using standard SSFP-sequences before initiation of specific pharmaceutical AL therapies. The control group consisted of 50 healthy subjects . Besides the standard CMR parameters for volumes, ejection fraction (EF) and myocardial mass and wall thickness we measured global circumferential and longitudinal strain on SSFP images by the application of the post-processing feature tracking algorithm.Global circumferential strain and global longitudinal strain correlated well with left ventricular ejection fraction . In patients with AL global longitudinal strain was significantly reduced compared to healthy subjects , whereas global circumferential strain was not . In the subgroup analysis of AL patients without cardiac involvement  global longitudinal strain showed significantly reduced values in comparison to healthy control subjects , whereas global circumferential strain did not show a significant difference. Patients with an ejection fraction \u226550% already had reduced global longitudinal strains , again global circumferential strain did not show a significant difference.FTI strain analysis derived from regular SSFP sequences offers the possibility for a retrospective or prospective fast quantitative wall motion assessment of myocardial deformation patterns without specific and time-consuming strain imaging techniques. FTI allows distinguishing between healthy subjects and subjects with AL. Further investigations are necessary to analyze the impact of this new method on clinical outcome in AL patients.none"}
+{"text": "The upper mini-sternotomy and right mini-thoracotomy can confer the advantages off a smaller surgical wound for aortic valve replacement.236 patients were included in our study, to whom aortic valve was replaced. The purpose of this study was to examine the potential benefit of double venous cannulation through superior vena cava (SVC) for venous drainage for aortic valve replacement (AVR) in upper mini-sternotomy and right mini-thoracotomy approaches. Five to 7 cm skin incision was made at the level of third intercostal space, through which the pericardium was opened longitudinally. Shortly after the patient was fully heparinized, venous drainage was achieved by vacuum assisted (40-60 mmHg) double venous cannulation through SVC (22 French) while arterial return was established by right femoral artery or ascending aorta (standard arterial cannula. We cross-clamped the aorta and infused antegrade cold blood cardioplegia into the ascending aorta and retrograde cold blood cardioplegia into the coronary sinus to achieve cardiac arrest. The aortic valve was approached through a transverse aortotomy. The native valve was removed completely and replaced with biological or mechanical valve, secured by Teflon pledges and sutures.Our study confirmed that even though technically challenging, upper mini-sternotomy and right mini-thoracotomy approaches for aortic valve replacement have potential advantages over conventional median sternotomy. They can offer easier exposure of ascending aorta and effective aortic valve replacement especially when using double drainage of SVC and when patients are reasonably selected for these procedures. These mini approaches were proved to be safe and efficacious.Upper mini-sternotomy and right mini-thoracotomy can be performed with standard equipment and instruments and are potentially compatible with new technologies such as suture-less aortic valve prosthesis which could be easily placed this way with a very short CPB time."}
+{"text": "Ruling out Legionella sp. in patients presenting with community-acquired pneumonia (CAP) is important due to differences in treatment regimens. Yet antigen tests as well as blood cultures have low sensitivity and an important time delay, making empirical broad spectrum coverage necessary particularly in severe cases. Fiumefreddo and colleagues recently proposed a clinical score based on six clinical and laboratory variables  which allowed assessing the likelihood of Legionella . Yet theWe analyzed data from a large multinational database of patients with CAP (CAPO)  between Data for 8,278 CAP patients were analysed; the infectious organism was known in 2,321 cases (28%), including a total of 101 patients with urinary antigen-confirmed Legionnaires' disease and 983 patients with confirmed pneumococcal disease. All variables were predictors for Legionella with odds ratios ranging from 1.002 to 5.767. Combining the variables in a joint logistic regression model showed a high predictive accuracy with an AUC of 0.86.This analysis validates the Legionella score in an independent sample and shows high diagnostic accuracy. Interventional trials with adapted antibiotic regimes for non-inferiority in a real live population are warranted."}
+{"text": "Our studies used human pancreatic carcinoma cells, cells stably transfected with human transporter cDNAs, or cells in which a specific transporter was knocked down by RNA interference. We have previously shown that 5-fluorouracil treatment affects the expression profile of relevant cellular transporters including multidrug resistance proteins (MRPs), and that MRP5 (ABCC5) influences chemoresistance of these tumor cells. Similarly, cell treatment with the nucleoside drug gemcitabine or a combination of chemotherapeutic drugs can variably influence the expression pattern and relative amount of uptake and export transporters in pancreatic carcinoma cells or select for pre-existing subpopulations. In addition, cytotoxicity studies with MRP5-overexpressing or MRP5-silenced cells demonstrate a contribution of MRP5 also to gemcitabine resistance. These data may lead to improved strategies of future chemotherapy regimens using gemcitabine and/or 5-fluorouracil.Pancreatic cancer ranks among the tumors most resistant to chemotherapy. Such chemoresistance of tumors can be mediated by various cellular mechanisms including dysregulated apoptosis or ineffective drug concentration at the intracellular target sites. In this review, we highlight recent advances in experimental chemotherapy underlining the role of cellular transporters in drug resistance. Such contribution to the chemoresistant phenotype of tumor cells or tissues can be conferred both by uptake and export transporters, as demonstrated by"}
+{"text": "Sir,Percutaneous tracheostomy has become an appropriate alternative to conventional surgical tracheostomy and has gained worldwide acceptance as a bedside procedure. Despite We describe a technique using a standard nasogastric tube (NGT) that allows precise and safe placement of tracheostomy tubes in patients under emergency situation of false passage. This method eliminates the need for specialized equipment and skills like fiberoptic which is usually not available at bedside where percutaneous tracheostomy actually takes place.A 22-year-old male patient operated for right fronto-temporo-parietal subdural hematoma required tracheostomy. Attempt to percutaneous tracheostomy using the Ciaglia\u2019s Blue Rhino technique created a false passage. Repeated attempts to negotiate tracheostomy tube over guide wire failed, leading to airway emergency scenario. We devised a novel technique to overcome the false passage.in situ [An endotracheal tube (ETT) which had been withdrawn upto glottis was pushed caudally so that it occupied the distal end of the trachea, sealing off the rent created by dilation of the tracheostomy tract. A Ryle\u2019s tube with its tip cut was inserted through the ETT already in situ . The ETTin situ . The NGTin situ . Initialin situ  and previn situ  Limitati"}
+{"text": "We provided a cross-tissue comparative analysis of between-subtype molecular commonality for ovarian cancer, breast cancer, hepatocellular carcinoma, glioma, lung squamous carcinoma and nasopharyngeal carcinoma. Our analysis showed that molecular subtypes with similar phenotype or similar clinical outcome could be correlated by their transcriptional profile and pathway profile. Pathway dysregulation across multiple cancer subtypes was also revealed by Gene Set Enrichment Analysis. Dysregulation of \u2018complement and coagulation cascades\u2019 was observed in a total of eleven subtypes across five tissues, implicating that the role of this process in personalized immune-based therapy may be worth further exploring. Based on high-through genomewide transcriptome data, molecular subtypes of human cancer have been identified and characterized by different biology. For example, distinct subtypes of breast cancer were associated with different patterns of therapeutic response , differe-low intrinsic subtype of breast cancer were characterized by expression of mesenchymal markers and immune response [A recent study depicted the molecular commonality between basal-like breast cancer and ovarian cancer by correlation analysis of transcriptional profile , but it response \u20138. TakinAll microarray datasets were downloaded from GEO. For Affymetrix data, we recalculated gene expression signal intensities by RMA  using DaThree published gene expression signature of Epithelial-Mesenchymal Transition (EMT) or Mesenchymal Transition (MT) were used in our analysis. The Taube\u2019s \u2018EMT core signature\u2019 represent genes that shared by independent gene expression signatures (GESs) in human mammary epithelial cells (HMLE) induced to undergo an EMT by expressing Gsc, Snail, Twist, or TGF-\u03b21 or by knocking down expression of E-cadherin . The GroData was median-centered by genes in each cohort separately at first . Then alThe median of spearman rank correlation of transcriptional profile between two subtypes was minus by 1 and then adopted as the dissimilarity distance. Average-linkage hierarchical clustering of the resulting dissimilarity matrix was performed in R.Hierarchical clustering of the pathway profile matrix (rows for pathway and columns for subtype) was performed in Cluster 3.0  using SpGSEA analysis  was perfWe first asked whether subtypes with similar phenotype or similar clinical outcome could be correlated by transcriptional profile and/or pathway profile. To answer this question, we measured between-subtype commonality by correlation analysis of transcriptional profile and pathway profile. A similar landscape was found for both two molecular profiles but the overall level of spearman rank correlation coefficients of pathway profiles was higher than that of transcriptional profiles . This maHere we demonstrated molecular commonality between cancer subtypes using breast cancer as an example  become available, we may expect more and more cancers being classified into molecular subtypes. Our method, and of course other improved and enhanced methods, could be applied to construct a more comprehensive map of cancer subtypes. With such a map, knowledge for a particular cancer subtype could provide clues for an extended understanding of its \u2018friend\u2019 subtypes in other cancers and bring potential novel therapeutic opportunities.Figure S1Scatter plot of correlation coefficient. A linear model was fit to the data using correlation coefficients by transcriptional profile as the independent variable. The resulting p-value and coefficient were showed.(TIF)Click here for additional data file.Figure S2Comparison of ovarian cancer and other cancer. Tumor samples were grouped by subtype. Yellow grids represented positive correlation while blue grids represented negative correlation. The number of samples per subtype was inside the brackets.(TIF)Click here for additional data file.Figure S3Comparison of glioma and other cancer. Tumor samples were grouped by subtype. Yellow grids represented positive correlation while blue grids represented negative correlation. The number of samples per subtype was inside the brackets.(TIF)Click here for additional data file.Figure S4Comparison of hepatocellular carcinoma and other cancer. Tumor samples were grouped by subtype. Yellow grids represented positive correlation while blue grids represented negative correlation. The number of samples per subtype was inside the brackets.(TIF)Click here for additional data file.Figure S5Comparison of lung squamous carcinoma and other cancer. Tumor samples were grouped by subtype. Yellow grids represented positive correlation while blue grids represented negative correlation. The number of samples per subtype was inside the brackets.(TIF)Click here for additional data file.Figure S6Comparison of nasopharyngeal carcinoma and other cancer. Tumor samples were grouped by subtype. Yellow grids represented positive correlation while blue grids represented negative correlation. The number of samples per subtype was inside the brackets.(TIF)Click here for additional data file.Table S1A brief description of all the microarray dataset used in this study. A \"*\" in the research type column indicated that the corresponding study defined the molecular subtypes.(XLSX)Click here for additional data file.Table S2GSEA results for KEGG pathways and published EMT signature. Only those with q-values less than 0.25 were included .(XLSX)Click here for additional data file.Table S3Results of DAVID functional analysis of published EMT signatures. (XLSX)Click here for additional data file."}
+{"text": "We previously identified miRNA promoter regions active in normal mammary cell types and here we analyzed which of these promoters are targets of aberrant DNA methylation in human breast cancer cell lines and breast tumor specimens. Using 5-methylcytosine immunoprecipitation coupled to miRNA tiling microarray hybridization, we performed comprehensive evaluation of DNA methylation of miRNA gene promoters in breast cancer. We found almost one third (55/167) of miRNA promoters were targets for aberrant methylation in breast cancer cell lines. Breast tumor specimens displayed DNA methylation of majority of these miRNA promoters, indicating that these changes in DNA methylation might be clinically relevant. Aberrantly methylated miRNA promoters were, similar to protein coding genes, enriched for promoters targeted by polycomb in normal cells. Detailed analysis of selected miRNA promoters revealed decreased expression of miRNA linked to increased promoter methylation for mir-31, mir-130a, let-7a-3/let-7b, mir-155, mir-137 and mir-34b/mir-34c genes. The proportion of miRNA promoters we found aberrantly methylated in breast cancer is several fold larger than that observed for protein coding genes, indicating an important role of DNA methylation in miRNA deregulation in cancer. MicroRNAs (miRNA) are short single-stranded RNA molecules that regulate gene expression at the posttranscriptional level by stimulating the degradation or inhibiting translation of target mRNAs Aberrant DNA methylation linked to silencing of individual miRNA genes has been found in many cancer types including breast cancer in vitro cell lines, LCM samples), they are more difficult to analyze in heterogeneous tumor specimens since, in addition to tumor cells, these specimens generally contain significant and variable proportions of normal epithelial and mesenchymal cells In this study we identified miRNA promoters that undergo aberrant DNA methylation in human breast cancer using 5-methylcytosine immunoprecipitation coupled to analysis by a custom designed miRNA tiling microarray. The active human mammary miRNA promoter locations were previously determined by H3K4me3 ChIP analysis and miRNA expression correlated with H3K4me3 status of the promoters Results from this study show that miRNA promoters are widely targeted for aberrant DNA methylation in breast cancer. Almost one third (55/167) of miRNA promoters active in mammary cells displayed hypermethylated DMRs in analyzed breast cancer cell lines. This percentage greatly exceeds the percentage of protein coding genes targeted for aberrant DNA methylation in cancer We have previously identified the promoter regions of miRNA genes expressed in normal breast cells represented by HMEC and HMF in vitro and in vivo samples form two clusters on the left side of the multidimensional scaling plot, while the tumor samples are more dispersed. The most separated are the pure cancer cell lines and the pure normal HMEC and HMF strains. Probably due to their heterogeneous nature, the distance between tumor and non-tumor tissues is smaller, nevertheless the direction of the change is the same, indicating similar DNA methylation differences in both cancer cell lines and tumor tissue. To discern possible effects of in vitro culture versus heterogeneity of in vivo tissues we also analyzed the in vitro and in vivo samples separately  of miRNA promoters active in normal mammary cells became hypermethylated in cancer cells , while oWe have previously shown that normal CTS miRNA expression is often regulated by epigenetic mechanisms including DNA methylation in vitro cultured cancer cell lines also occur in vivo in breast tumors and therefore may have clinical relevancy. To avoid possible confounding effects from different proportions of differentially methylated normal cell types (HMEC and HMF) in individual tissue samples, we also restricted this analysis to non-CTS miRNA promoters. Hypergeometric test revealed highly significant overlap between non-CTS miRNA promoters containing hypermethylated DMRs in cancer cell lines and those hypermethylated in a group of twelve tumor tissues  as well as those hypermethylated in individual tumor tissue samples only  were analyzed by Sequenom MassARRAY . In addiPolycomb targeted genes are frequent targets of aberrant DNA methylation in cancer Aberrant DNA methylation in cancer cells is often linked to gene silencing. We therefore analyzed the expression levels of the aberrantly methylated miRNA genes using quantitative real-time PCR. In general, negative or no correlation between miRNA expression and DNA methylation was observed , no posiin vitro and in vivo representations of normal and diseased mammary cells. We found a large portion of analyzed miRNA promoters to be hypermethylated in breast cancer cell lines, and the same promoters were targeted in breast tumor tissues, although less frequently. The hypermethylation of selected miRNA promoters was verified using MassARRAY technology. MassARRAY DNA methylation data combined with miRNA expression data revealed that in six out of twelve cases the hypermethylation of miRNA promoters was linked to silencing of miRNA expression; in the other six cases DNA methylation did not correlate with the miRNA level. Overall, our study has shown aberrant DNA methylation of a large portion of miRNA genes leading frequently to silencing of miRNA expression in breast cancer. Since miRNAs play an important role in the regulation and maintenance of cell identity, our observations suggest that the deregulation of miRNA expression due to aberrant DNA methylation is involved in human breast carcinogenesis.In this study, we sought to determine the DNA methylation status of miRNA promoters in breast cancer cells on the whole genome scale. To this end, we used 5-methylcytosine immunoprecipitation linked to a custom tiling microarray hybridization to analyze DNA methylation level in a variety of Almost one third of miRNA promoters active in normal mammary cells were found to contain hypermethylated DNA regions in breast cancer cells; this high proportion is several fold greater than usually observed for protein coding genes We have previously found a significant portion of miRNAs expressed in normal breast cells to be cell-type specific The incidence and magnitude of miRNA promoter hypermethylation found in breast tumor tissues was lower than in breast cancer cell lines . Two facOur study has shown that in six out of twelve miRNA genes analyzed in more detail the aberrant DNA methylation was linked to decreased levels of miRNAs in cancer. In addition to mir-137 and mir-34b/mir-34c genes, that were previously reported to be silenced by DNA methylation in various cancers in vivo breast tumor tissues and might be therefore clinically relevant. The miRNA targets of aberrant DNA methylation might be potentially used for diagnostic purposes. miRNA genes silenced by aberrant DNA methylation in cancer are potential targets for epigenetic drugs.Overall, our study reports the first systematic identification of aberrant DNA methylation of miRNA gene promoters in breast cancer. Aberrant DNA methylation found in breast cancer cell lines is also detectable in HMEC and HMF were previously described Genomic DNA was extracted using the DNeasy Blood and Tissue Kit  according to manufacturer protocol and quantified spectrophotometrically. Total RNA was extracted using the miRNeasy kit (Qiagen) according to manufacturer protocol except that Trizol  was used instead of Qiazol for the cell lysis. Each tissue sample was ground frozen in liquid nitrogen and resulting powder was then split for RNA and DNA extractions, respectively, to achieve homogenous representation of tissue components in both DNA and RNA samples.http://www.ncbi.nlm.nih.gov/geo/) under accession no GSE38254.The design of the microarray used in this study and MeDIP chip procedure was previously described H3K27me3 domain data from H1 ESC were downloaded from two sources: supplemental data from DNA methylation analysis by Sequenom MassARRAY  was performed as described Expression of microRNAs was performed in triplicate using EXIQON miRCURY LNA\u2122 Universal RT kit and EXIQON miRCURY LNA\u2122 Universal RT microRNA PCR, Pick-&-Mix, Ready-to-use Panels . Real-time PCR was conducted on an ABI Prism 7500 Sequence Detection System  using PerfeCta SYBR Green SuperMix, Low ROX  with a 95\u00b0C denaturation for 3 minutes followed by 40 cycles of 95\u00b0C for 15 seconds and 60\u00b0C for 45 seconds. Differences in expression were determined using the comparative Ct method described in the ABI user manual. SNORD38B and SNORD49A expression was used for normalization of miRNA expression.The significance of promoter region overlaps was calculated in R using hypergeometric test as described previously Figure S1MicroRNA promoters hypermethylated in cancer are frequently occupied by polycomb specific H3K27me3 in normal cells. Left, Venn diagram showing the overlap between the non-CTS miRNA promoters occupied by H3K27me3 in ESC and those hypermethylated in tumor tissue samples (TT). Right, Venn diagram showing the overlap between the non-CTS miRNA promoters occupied by H3K27me3 in HMEC and those hypermethylated in TT. Both overlaps are highly significant (hypergeometric test).(PDF)Click here for additional data file.Table S1DNA methylation status for all analyzed miRNA promoters. The table shows the presence or absence of DMRs for individual miRNA promoters for groups of samples and individual samples. The first column shows the names of individual miRNA genes: non CTS genes have yellow background, HMEC-specific green background and HMF-specific red background. The second column shows the expression ratio of these miRNA between two normal mammary cell types: HMEC and HMF. The next three columns indicate whether the promoter region is occupied by polycomb specific H3K27me3 in three normal cell types: H1 ESC, HMEC and HMF. Then folows the DNA methylation data for all cancer cell lines compared to HMEC, all tumor tissue compared to nontumor tissue and for HMF compared to HMEC. The last section shows hypermethylated DMRs for individual cancer cell lines relative to HMEC and individual tumor tissue samples relative to nontumor tissue. The data are color coded, hypermethylated DMRs are indicated by brown color, hypomethylated DMRs by green color. The area of cell type specific miRNA promoters for tissue samples is shaded grey since this part of data is prone to missinterpretation.(XLS)Click here for additional data file.Table S2Positions of MassARRAY amplicons in hg18 and sequences of MassARRAY primers used for DNA methylation analysis.(PDF)Click here for additional data file."}
+{"text": "Native T1 mapping is promising non-invasive method for quantitative assessment of diffuse myocardial processes. The aim of the current study was to interrogate normal values for T1 measurement within native myocardium for age and gender using most commonly used sequences and field strengths.Ninety-nine subjects with no history of cardiovascular or systemic disease or regular medication underwent native T1 imaging with modified  and shortened modified look-locker inversion recovery sequence  at either 1.5T or 3T. The images were analyzed using an Osirix plug-in with manual motion correction of the ROI placed conservatively within the septal myocardium. For comparison, lateral myocardium and blood values were also derived.There was similar representation for age and gender across both field strengths Table . Mean vaWe report age-gender normal values for native myocardial T1 mapping by the two most commonly used sequences and field strenghts. We show that there are neither gender differences in a cohort as a whole nor within separate age groups.NIHR"}
+{"text": "Atlantic Bluefin Tuna (ABFT) shows complex demography and ecological variation in the Mediterranean Sea. Genetic surveys have detected significant, although weak, signals of population structuring; catch series analyses and tagging programs identified complex ABFT spatial dynamics and migration patterns. Here, we tested the hypothesis that the genetic structure of the ABFT in the Mediterranean is correlated with mean surface temperature and salinity.We used six samples collected from Western and Central Mediterranean integrated with a new sample collected from the recently identified easternmost reproductive area of Levantine Sea. To assess population structure in the Mediterranean we used a multidisciplinary framework combining classical population genetics, spatial and Bayesian clustering methods and a multivariate approach based on factor analysis.ST analysis and Bayesian clustering methods detected several subpopulations in the Mediterranean, a result also supported by multivariate analyses. In addition, we identified significant correlations of genetic diversity with mean salinity and surface temperature values revealing that ABFT is genetically structured along two environmental gradients. These results suggest that a preference for some spawning habitat conditions could contribute to shape ABFT genetic structuring in the Mediterranean. However, further studies should be performed to assess to what extent ABFT spawning behaviour in the Mediterranean Sea can be affected by environmental variation.F Assessing the correlation between landscape features with the genetic variation of populations might lead to identifying environmental factors that are involved in the adaptive divergence of populations Thunnus thynnus) shows a spatial population structure, which is stable over short and long time periods The Mediterranean is a temperate sea with sharply different oceanographic conditions in the western and eastern parts Multidisciplinary seascape genetics sensu  addresseHere, we test the hypothesis that dispersal and reproduction of the ABFT populations in the Mediterranean correlate with the physical environmental heterogeneity. We do that by comparing measures of ABFT genetic structure at microsatellite loci with surface temperature and salinity variation. For this purpose, we numerically and geographically expanded the ABFT sampling We also used the spatial Bayesian clustering models implemented in the software GENELAND Thunnus thynnus used in this study were collected from Mediterranean individuals caught during scientific research programs under the permission of the Italian Ministry of Agricultural and Forestry Policies  and by commercial long-liners and purse-seiners within the Total Allowed Catch quotas assigned by the International Commission for the Conservation of Atlantic Tunas (ICCAT) to National Governments . No specific approval of this vertebrate work is required since the Bluefin tuna individuals sampled in this study were obtained from scientific and commercial fishing activities.Tissue samples of the Atlantic Bluefin tuna In this study we have reanalysed the genetic variation of six ABFT Mediterranean population samples (N\u200a=\u200a256) previously genotyped at potentially neutral microsatellite loci by STST under the hypothesis of panmixia. A global HWE test was performed by GENEPOP 4.0 Allelic richness was estimated using FSTAT version 2.9.3.2 The software STRUCTURE The spatially explicit Bayesian clustering program GENELAND 3.2.4 http://gher-diva.phys.ulg.ac.be/web-vis/), a Pan-European infrastructure for managing, indexing and providing access to ocean and marine data sets and data products, acquired via research cruises and other observational activities, in situ and remote sensing. Temperature data were averaged over the period 1985\u20132007, while S data were averaged over the period 1900\u20132009.Seawater salinity  and surface temperature  data from the sampled sites were obtained from SeaDataNet Climatologies Pan-European Infrastructure for Ocean and Marine Data Management  Multilocus genotype data were finally analysed under a model of isolation by distance (IBD). A matrix of geographical distances was obtained considering the shortest sea-paths between each pair of sampling sites using Google Earth version 6.0.2 OOB; genetic distances between populations were expressed by the ratio FST values were significantly greater than 0 except four , suggesting that different Mediterranean areas roughly correspond to distinct ABFT subpopulations. The LIG-SAR FST became insignificant after the sequential Bonferroni correction  implemented in GENELAND did not reach convergence and this poor MCMC mixing could be due to departures from model assumptions . On the contrary the spatially explicit model with correlated allele frequencies reached the convergence of MCMC and the most likely value of K identified was for K\u200a=\u200a3. Individual assignments performed in GENELAND with K fixed to 3 identified distinct subpopulations splitting the southernmost samples  and STY from the central (SAR) and northernmost samples  . These fThe Correspondence Analysis (CA) displayed a spatial pattern of differentiation largely consistent with those detected by the Bayesian clustering analysis. The CA separated the Central Northern Mediterranean ADR and LIG samples form the other samples, identified the group SAR-ALB and revealed the genetic similarity between STY and CYP .A significant correlation between genetic distances and both geographical and mean-S distances, was revealed by the Mantel test . On the The CCA analysis was carried out using mean-S and mean-t data as constraining factors and correlations at both axes were significant at the ANOVA 95%-significance test , from the central-southern samples  and differentiating the SAR sample from all the others .STs. Nevertheless the level of genetic divergence detected by STs\u2019 range 0.011\u20130.021) was higher than in previous surveys ST\u200a=\u200a0.02) showing that such structuring of the Mediterranean ABFT is probably stable through time. These results, along with the evidence for a recent colonization of the Mediterranean Click here for additional data file.Table S2Thunnus thynnus samples.Summary statistics at the seven microsatellite loci of (DOC)Click here for additional data file.Table S3Thunnus thynnus samples.Gene diversity and Hardy-Weinberg equilibrium deviation test of (DOC)Click here for additional data file.Table S4Percentages of variations explained by CA and CCA axis.(DOC)Click here for additional data file.Table S5Ordination scores of mean temperature (Mean-t) and mean salinity (Mean-S) values.(DOC)Click here for additional data file.Text S1DNA extraction, Microsatellite marker analysis protocols, Correspondence Analysis (CA) and Canonical/Constrained Correspondence Analysis (CCA) results and references.(DOC)Click here for additional data file.Dataset S1Microsatellite dataset in gtx format.(GTX)Click here for additional data file."}
+{"text": "MLH1 mutation, developed early-onset GI cancer. In contrast to LS with clear GI screening and surveillance recommendations, there are no recommendations for surveillance of individuals with biallelic mutations and no literature describing the long term outcome.Lynch syndrome (LS) is caused by heterozygous germline mutations in the DNA mismatch repair (MMR) genes and is a highly penetrant autosomal dominant condition. A novel childhood cancer syndrome caused by biallelic germline MMR gene mutations and characterized by brain tumors, leukemias, gastrointestinal (GI) polyposis, GI cancer and caf\u00e9-au-lait spots (CALS) has been described. We reported the first biallelic kindred in which 2 of 3 siblings proven to have a homozygous germline To prospectively describe long-term outcome of our two young patients with biallelic MMR mutations, and to develop a generic cancer screening protocol for other patients with biallelic MMR mutations.On the basis of the molecular results, the 2 surviving sisters and parents of a deceased child with metastatic duodenal cancer began a surveillance protocol based on our crude estimates of cancer risks and available cancer screening modalities.During endoscopic screening the youngest sister developed colonic polyps with high grade dysplasia and underwent a subtotal colectomy with ileorectal anastomosis. At 11 years she developed polyps in the duodenum with low grade dysplasia which were excised endoscopically. At 13 years of age, surveillance MRI revealed a left parieto-occipital anaplastic astrocytoma enabling total resection. Endoscopy in the older sister who had a subtotal colectomy with ileorectal anastomosis at 9 years of age for metastatic colorectal cancer has low grade polyps in the duodenum, ileum and rectum which were excised endoscopically. Gynecological follow-up of both sisters with annual pelvic ultrasounds have shown functional ovarian cysts. All neoplastic lesions identified during surveillance were asymptomatic at diagnosis. The sisters are currently fifteen and seventeen years old with no evidence of disease 10 years after their brother\u2019s diagnosis. The parents (43 and 44 years) have annual colonoscopy with no evidence of polyps or cancer. Gynecological screening for the mother has not revealed any abnormalities. Based on our experience to date and review of available literature, we have developed the screening guidelines shown in Table Biallelic carriers who participated in oncologic surveillance had presymptomatic neoplasms identified and treated. These siblings are alive with no evidence of disease at 10-year follow-up. Aggressive surveillance in biallelic MMR carriers is feasible, allows early detection and improves long-term survival."}
+{"text": "Our laboratory is examining the profiles of microRNA expression in ATLL cells and infected T-cell lines using microarrays and small RNA libraries.Microarray analysis of ATLL samples revealed 6 upregulated and 21 downregulated microRNAs in ATLL cells compared to CD4+ T-cell controls. Potential targets for deregulated microRNAs were identified by integrating microRNA and mRNA expression profiles. Current experiments are aimed at verifying these predicted microRNA-target interactions.Mass sequencing of small RNA libraries prepared from normal CD4+ cells and two chronically infected T-cell lines yielded panels of known and candidate new microRNAs for each library. Comparison of frequencies of known microRNAs led to the identification of a small number of microRNAs differentially expressed in both infected cell lines compared to controls. Most of the candidate new microRNAs were intragenic with poor species conservation, suggesting that they might have particular roles in human T-cell function. Two sequences mapped to the HTLV-1 genome, suggesting that the virus may produce its own microRNAs. Further analyses of the new cellular and viral microRNA candidates are in progress."}
+{"text": "The extend of lymph node involvement in patients NSCLC is the cornerstone of staging and influences both multimodality treatment and final outcome. We studied safety, accuracy and characteristics of intraoperative ultrasound guided systematic mediastinal nodal dissection in patients with resected NSCLC.Prospective randomized trial of intraoperative surgical staging after radical surgery for NSCLC was carried out. Intraoperative hand held ultrasound probe was used in systematic mediastinal nodal dissection in 124 patients after radical surgery for NSCLC and compared with 120 patients who underwent radical surgery followed by standard systematic mediastinal nodal dissection. Mapping of the lymph nodes by their number and sation followed by histopathologic evaluation was performed. Patients data were statistically analyzed.The surgical procedure used was comparable in both groups of patients. Operating time was prolonged for 10 ( 6-20 ) minutes in patients with US guided mediastinal nodal dissection, but number and stations of evaluated lymph nodes were significantly higher ( p<0.001 ) at the same group of patients. Skip nodal metasteses were found in 24 % of patients without N1 nodal involvement. We upstaged 12 ( 10 % ) patients using US guided mediastinal lyphadenectomy. Median follow-up was 38 ( range 10-52 ) months. Standard staging system seemed to be improved in US guided mediastinal lyphadenecetomy patients. Complication rate showed no difference between analyzed groups of patients.Higher number and location of analyzed mediastinal nodal stations in patients with resected NSCLC using hand held ultrasound probe siggested to be of great oncological significance. Procedure showed absolute safety and high accuracy. Our results indicate that intraoperative US may have important staging implication. Further clinical studies should be performed in order to improve intraoperative staging in NSCLC patients."}
+{"text": "Cardiac imaging has been identified as a potential use of hybrid PET-MRI. This new technology allows simultaneous Positron Emission Tomography (PET) and MR scanning to occur.This case study features a 34 year old male with known pulmonary sarcoidosis which was diagnosed in 2006 and initially treated with immunosuppressants. He presented with NYHA functional class 2 symptoms. ECHO showed asymmetrical LV anterior and lateral wall hypertrophy with a maximum wall thickness of 18mm in the basal and mid anterior and lateral wall.The patient was referred for a cardiac18F Fluorodeoxyglucose (FDG) PET-MR study to determine the cause of the hypertrophy. The possible differential diagnoses included hypertrophic cardiac myopathy with pulmonary sarcoidosis or cardiac sarcoidosis.Prior to the scan, the patient followed a high protein, low carbohydrate diet for one day. This was then followed by a 12 hour fast to suppress physiologic glucose metabolism by the heart.The patient was administered with 355mBq of 18F FDG 180 minutes prior to the PET-MR study.A simultaneous PET-MR study was acquired. A standard CMR protocol was undertaken in conjunction with a simultaneous 10 minute single PET bed using a Siemens Biograph mMR hybrid PET-MR scanner. This is a 3T magnet containing a 260mm field of view PET detector located at the isocentre.The scan demonstrated mediastinal 18F FDG avid lymphadenopathy with anterio-lateral myocardial thickening with mid-myocardial LGE and focal 18F FDG uptake compatible with active myocardial inflammation within an area of \"scar\" in keeping with active cardiac sarcoidosis.The oedema sensitive STIR sequence did not differentiate between the hyper-metabolic active disease and the chronic \"burnt out\" disease.This patient is one of the first examples of imaging active cardiac sarcoidosis using a hybrid PET-MR technique. It demonstrates the potential for differentiating between active and chronic cardiac sarcoidosis during one scan. This new imaging technique could have a substantial impact on the diagnosis and management of cardiac sarcoidosisUCL\\UCLH receives a proportion of funding from the Department of Health's NIHR Biomedical Research Centres funding scheme."}
+{"text": "More than 240 million people worldwide are infected with hepatitis B virus (HBV) and are at risk of developing liver cirrhosis and hepatocellular carcinoma (HCC). Reducing this pool of infected people is a necessity since despite an effective prophylactic vaccine, about 2% of the vaccinated individuals in high endemic areas still develop chronic HBV infection (CHB). A battery of antiviral drugs based on nucleoside or nucleotide analogues that target the HBV reverse transcriptase are available. They efficiently suppress HBV replication and reduce liver inflammation linked with cirrhosis but rarely achieve virus eradication. HBV is present in hepatocytes in a mini-chromosomal form  that is untouched by reverse transcriptase inhibitors. As a consequence, response to the treatment is hardly durable and a majority of patients experience HBV reactivation when antiviral therapy is withdrawn 6 copies/ml) Efficient control of HBV infection is associated with the induction and persistence of helper and cytotoxic T cells targeting different HBV proteins and production of anti-HBV envelope antibodies. This antiviral immune response is composed of T cells able to secrete Th1 cytokines, proliferate and lyse HBV infected hepatocytes After years of exposure to HBV antigens, HBV-specific T cells are deleted or functionally exhausted in chronic patients. Virus-specific T cells express inhibitory molecules like PD-1 Blocking inhibitory pathways associated with T cell exhaustion has shown therapeutic efficacy in cancer patients Vaccine therapy aims to induce functionally efficient HBV-specific T cells on the background of virus-specific T cell exhaustion. Several strategies have been tested in clinical trials with disappointing results. Often, vaccine therapy did not induce an HBV-specific T cell response, or when such response was boosted, it did not have a therapeutic effect However, more radical approaches could be needed to circumvent HBV-specific T cell deletion in patients with high viral loads. Engineering HBV-specific T cells through transfer of HBV-specific T cell receptors or HBV-specific chimeric antigen receptors (CAR) showed encouraging results in vitro and in animal models Several other factors have also hampered the restoration of efficient adaptive immunity in CHB. Epigenetic programs were suggested to preserve the T cell exhaustion state in chronic viral infection The duration of exposure and antigen burden in chronic HVB infection are believed to be the primary factors affecting virus-specific T cell function. Thus, modulating the quantity of viral antigens secreted by HBV might have a beneficial effect as has been observed in HBV transgenic mice The important role played by innate immunity in the early stages of infection has stimulated therapeutic strategies to specifically target this branch. IFN-\u03b1 therapeutic efficacy is associated with NK cell activation + T cells Other approaches in clinical development seek to induce intrahepatic IFN-\u03b1 production through oral administration of TLR agonists. TLR7 agonists stimulate robust IFN-\u03b1 production in plasmacytoid dendritic cells. However, prolonged efficacy in TLR-7 agonist\u2013treated, HBV-infected chimpanzees was not only related to the production of IFN-\u03b1, as its production was transient and not liver specific. Antiviral efficacy was more consistent with a boost of intrahepatic NK, NKT, and T cell responses associated with production of IFN-\u03b3 The immunotherapeutic strategies we reviewed aim to control HBV infection by increasing antiviral immunity and as such terminate the chronic inflammatory process. However, activation of intrahepatic adaptive or innate cellular immunity requires tight control because it could also exacerbate liver inflammation. Even though mechanisms like IL-10 production, release of arginase from hepatocytes, and even the dampening of T cell responses by activated NK cells A radically different perspective in chronic HBV treatment is to consider CHB a necro-inflammatory rather than viral disease. Recent data in HBV transgenic mice clearly indicate that suppressing intrahepatic CTL activity in the liver using anti-platelet therapy prevents hepatocellular carcinoma. Platelets promote the accumulation of CD8 T cells in the liver and anti-platelet therapy blocks this process, reducing hepatocellular injury and fibrosis In conclusion, the current immunotherapeutic strategies designed to suppress and control HBV replication have strong scientific support. However, they are restricted by our limited knowledge, and further understanding of the relationship with the virus in the unique environment of the human liver will almost certainly provide opportunities to enhance them or perhaps develop totally novel approaches."}
+{"text": "Somatic embryogenesis (SE) in forest trees is considered as one powerful approach in cloning elite genotypes. However, SE is difficult to achieve in tissue or cell beyond the mature embryo phase in trees and its physiological process involved are also poorly understood. Recently metabolic profiling studies have been contributed to understand the mechanism involved in SE process of plant -3. In ad"}
+{"text": "Caenorhabditis elegans are free-living in nature and serve as model organisms for studying parasitic infections. Excretory/secretory proteins play an important role in parasitic helminth infections which make these proteins attractive targets for therapeutic use. In the case of helminths, large volume of expressed sequence tags (ESTs) has been generated to understand parasitism at molecular level and for predicting excretory/secretory proteins for developing novel strategies to tackle parasitic infections. However, mostly predicted ES proteins are not available for further analysis and there is no repository available for such predicted ES proteins. Furthermore, predictions have, in the main, focussed on classical secretory pathways while it is well established that helminth parasites also utilise non-classical secretory pathways.Helminths are important socio-economic organisms, responsible for causing major parasitic infections in humans, other animals and plants. These infections impose a significant public health and economic burden globally. Exceptionally, some helminth organisms like We developed a free Helminth Secretome Database (HSD), which serves as a repository for ES proteins predicted using classical and non-classical secretory pathways, from EST data for 78 helminth species  ranging from parasitic to free-living organisms. Approximately 0.9 million ESTs compiled from the largest EST database, dbEST were cleaned, assembled and analysed by different computational tools in our bioinformatics pipeline and predicted ES proteins were submitted to HSD.http://estexplorer.biolinfo.org/hsd, for checking the sequence similarity of new protein sequences against predicted helminth ES proteins.We report the large-scale prediction and analysis of classically and non-classically secreted ES proteins from diverse helminth organisms. All the Unigenes (contigs and singletons) and excretory/secretory protein datasets generated from this analysis are freely available. A BLAST server is available at  Caenorhabditis elegans (the most studied helminth till date) serve as models to understand parasitism   unverified}. Each annotated ES protein is also tagged as verified or unverified based on the presence or absence of sequence similarity to experimentally determined parasitic helminth ES proteins  technologies, there are many transcriptomic studies completed especially for individual helminth species with good coverage but we have focussed on the coverage of a large number of helminth organisms for secretome analysis. The earlier analysis from our group using the EST2Secretome pipeline has now been extended to cover non-classical secretory proteins, with validation against experimentally known excretory/secretory proteins. We plan to carry out further prediction of ES proteins using more comprehensive helminth transcriptomic datasets from NGS platforms and provide the results through HSD.Several billion people worldwide are afflicted by infections caused by parasitic helminths. Infections from parasitic helminths, especially from nematodes also results in heavy economic losses worth billions of dollars due to agricultural crop and livestock infection each year. In this study, we have predicted and analysed ES proteins from the largest freely available EST data of several helminth organisms from dbEST.Fasciola hepatica . The. The13].Our bioinformatics approach made possible the large scale prediction and analysis of ES proteins. As a result of our analysis we develop a unique resource HSD (Helminth Secretome Database) of ES proteins for the parasitology/infectious diseases/pharmacy communities. Our approach can be used on new large-scale transcriptomic data sets from NGS platforms, for rapid prediction and annotation of ES proteins. The approach can be applied to any organism but its main application is for neglected organisms with limited knowledge.BRITE: Biomolecular Relations in Information Transmission and Expression; KEGG: Kyoto Encyclopedia of Genes and Genomes; KAAS: KEGG automatic annotation server.The authors declare that they have no competing interests.SR directed the study. GG developed the database and carried out the analysis. SR and GG contributed to writing the manuscript.Summary of large scale helminth EST analysis. Statistics of excretory/secretory proteins and Unigenes across different helminth species (Table S1)Click here for fileGene Ontology distribution of helminth ES proteins. Statistics of Gene Ontology distribution across different helminth species (Table S2)Click here for fileHelminth ES protein domain mapping. Represented Interpro domains found in helminth ES proteins. (Table S3)Click here for fileKEGG BRITE objects mapping of helminth ES proteins. Represented KEGG BRITE objects found in ES proteins predicted by KAAS (Table S4)Click here for fileC. elegans (Wormpep) and S. mansoni proteinsComparison of putative helminth ES proteins with . Statistics of sequence similarity results of helminth ES proteins with C. elegans (Wormpep) and S. mansoni proteins using BLASTP across different helminth species (Table S5)Click here for fileComparison of putative helminth ES proteins with NR database proteins. Statistics of sequence similarity results of helminth ES proteins with NR database proteins using BLASTP across different helminth species (Table S6)Click here for fileS. japonicum, human proteinsComparison of putative helminth ES proteins with . Statistics of sequence similarity results of helminth ES proteins with S. japonicum, human proteins using BLASTP across different helminth species (Table S7)Click here for fileComparison of putative helminth ES proteins with interaction databases proteins. Statistics of sequence similarity results of helminth ES proteins with interaction databases proteins using BLASTP across different helminth species (Table S8)Click here for file"}
+{"text": "Non-replicating virus-like particles (VLPs) have been suggested as a promising platform for viral vaccines. Recently several studies have introduced VLPs produced in insect cells as a vaccine candidate against influenza infection. Neuraminidase (NA), one of the two membrane glycoproteins of influenza A viruses has been employed to construct such influenza VLPs to induce protective immunity.In this study, the human influenza virus ) was propagated in MDCK cell culture. Viral RNA was extracted using RNX-plus solution. Complementary DNA synthesis was carried out using uni-12 primer. NA open reading frame (1413 bp) was amplified by RT-PCR using high fidelity Taq DNA polymerase. The amplicon was purified from the gel and cloned into pFastBac1 plasmid through SalI/XhoI sites. After verification of cloned NA by restriction analysis, it was subjected to automated sequencing bidirectionally. The recombinant pFastBacNA vector was transformed to E.coli DH10Bac cells which harbor bacmid DNA and helper plasmid to create NA recombinant bacmid. Restriction map analysis and sequencing results confirmed the fidelity of NA sequence. Homologous recombination between pFastBacNA and bacmid and creation of NA recombinant bacmid was verified by PCR using NA specific and M13 universal primers.In an ongoing study, the cultured Sf9 (Spodoptera frugiperda) insect cell line will be transfected with NA recombinant bacmid to produce recombinant baculovirus expressing NA gene. This production is in its native highly glycosylated form appropriate to use in vaccine research projects. Recombinant baculovirus expressing NA gene can be also used with other individual recombinant baculoviruses expressing HA and M1 genes in production of influenza VLPs."}
+{"text": "Pneumothorax is a rare complication of percutaneous venous access and blind subclavian puncture. The incidence of pneumothorax related to blind subclavian puncture is reported to be 1% [A 78-year-old male patient underwent implantation of cardiac resynchronization devise with defibrillator (CRT-D) for dilated cardiomyopathy and congestive cardiac failure. Patient received a Guidant CRT-ICD. RV lead during implantation, subclavian access was obtained by venogram assisted extra thoracic puncture of the subclavian vein. Right atrial (RA) lead was initially attempted in the right atrial appendage (RAA), but the sensing and pacing thresholds were found unacceptable and right atrial free wall was chosen after few initial trials in RAA. The atrial lead was an active fixation lead, Guidant Flextend SN 4087. Right ventricular (RV) lead (Guidant Endotak Reliance SN 184420) was positioned at RV apex and left ventricular lead (Guidant easy track 2) was positioned in posterolateral tributary of coronary sinus. Patient tolerated the procedure well and there were no acute complications. Immediate post operative X ray of the chest showed satisfactory lead positions without any evidence of any pleural pathology 2 hours after the procedure patient experienced pleuritic chest pain and shortness of breath. His chest X Ray revealed moderate right-sided pneumothorax .  A draiA CT scan of the chest was done to identify the location of the lead tip. Right atrial lead was identified along the lateral aspect of the RA without any gross displacement. . There wSince the pneumothorax got resolved and there were no pericardial effusion or indicators of major lead displacement right atrial lead was not repositioned.Pneumothorax is usually a complication of subclavian venous access .  Lead pThe lead parameters especially pacing thresholds and sensing thresholds will show significant changes in case of lead perforation . In micrMany operators prefer Atrial screw in leads as they reduce the chances of lead dislodgement. However screw in leads increase the chance of perforation of thin walled atrium. Acute lead related complications were 2.4% in one series .In conclusion, contralateral pneumothorax in atrial based pacing systems is a rare complication and almost always is caused by atrial lead perforation. Pericardial effusion can also be a part of the problem in case of a macro perforation. This etiology has to be investigated by a CT scan in a suspected case. Extra caution should be taken when selecting RA lateral wall for deployment of screw in atrial lead especially in patients with associated lung pathology like bullous emphysema. Minimum number of turns to deploy the helix and extra post procedure vigilance should be considered in these patients."}
+{"text": "We report a young male patient who developed plasma cell myeloma/plasmacytoma 11 years after having received an allogeneic hematopoietic cell transplantation for AML. The patient received a second transplantation from the same donor without immunosuppression and developed graft-versus-host disease (GVHD). Our observation has two aspects that warrant attention: first, insufficiency of long-term tolerance to prevent GVHD in the absence of immunosuppression and second, a stromal or genetic susceptibility to develop hematologic malignancies despite of a complete donor-type chimerism. Allogeneic hematopoietic cell transplantation (HCT) is the only therapy successful in achieving cure for hematological malignancies. However, long-term survivors of allogeneic HCT face the risk of developing second malignancies, mainly the posttransplant lymphoproliferative diseases (PTLDs), secondary MDS/AML, and secondary solid malignancies . Posttra++ and CD117+ atypical plasma cell infiltration with kappa monoclonality. He had IgG kappa monoclonal gammopathy on immune electrophoresis and an elevated erythrocyte sedimentation rate along with a mild anemia and normal renal function tests. Bone marrow (BM) examination revealed 9% plasma cells with CD38+CD138+CD19\u2212CD56\u2212CD44+CD28\u2212CD20\u2212 immunophenotype and kappa predominance. The cytogenetic study did not detect any abnormality. Bone marrow chimerism analysis was consistent with 100% donor type in both T-and non-T-cell lineages. Chimerism study was also done with the DNA extracted from the plasmacytoma and revealed 18% donor and 82% recipient cells  and received an allogeneic peripheral blood stem cell transplantation from his 37-year-old HLA identical brother in 1997. The conditioning regimen consisted of busulfan and cyclophosphamide, and the GVHD prophylaxis was done with cyclosporin and short-term methotrexate. He did not develop any acute or chronic GVHD and remained in CR with complete donor-type chimerism until 2008 when he was admitted to the neurosurgery clinic with back pain. The vertebral MRI revealed a tumor invading the 6th thoracic vertebrae causing pathological fracture. The tumor was completely excised, and the pathological evaluation was consistent with CD38nt cells . The pre Posttransplant lymphoproliferative diseases are a heterogenous group of disorders which develop after solid organ or hematopoietic stem cell transplantation as a result of immunosuppression. In contrast to the high incidence of posttransplant lymphomas, PTLDs manifesting as plasma cell myeloma/plasmacytoma are extremely rare. Most of the reported cases have developed after solid organ transplantation, mainly renal transplantation. The incidence of PTLD after allogeneic HCT is 1-2%, mostly diagnosed within the first year and strongly associated with EBV. On the other hand, EBV-negative PTLDs usually occur later . The ris Although the patient was in complete donor-type chimera when he was retransplanted from the same donor 11 years later with fresh peripheral blood stem cells, he still developed GVHD and required immunosuppression. We were not able to find any reports to guide us in our decision making regarding the immunosuppression strategy at the time of retransplantation. Spontaneous occurrance of autologous GVHD in myeloma patients undergoing autologous HCT has been recently reported . On the"}
+{"text": "Early detection of subclinical manifestations of obesity is important to initiate early effective treatment aiming at reversing the process. Recent studies using echocardiography tissue doppler or strain rate imaging have suggested the potential of motion tracking methods to characterize subtle systolic changes that may be associated with obesity in children .The aim of the present study was to investigate LV global and intra-myocardial regional systolic mechanics using CMR tagging in obese and non-obese adolescents in order to better characterize the subclinical early changes associated with obesity in children.InTag post-processing toolbox  implemented in OsiriX software  to perform quantitative myocardial strain analysis. Motion estimation is based on the Sine Wave Modeling approach(3). Regional and global peak circumferential(Ecc), longitudinal(Ell) strains as well as peak rotation and torsion were calculated.Standard CMR global and regional LV function study and cine-tagging with complementary myocardial tagging(CSPAMM) were performed in 25 obese children and 25 lean controls. Inclusion criteria were: no previous diagnosis of hypertension and treatment with antihypertensive/anti-diabetic drugs or drugs known to affect glucose and lipid metabolism; no history of familial hypertension/dyslipidemia; absence of diabetes or other chronic disease. The study protocol has been approved by the Mother&Child Ethics Committee. Magnitude CSPAMM images were processed using cc displayed only a trend to lower values in basal level  similarly to what was observed for Ell . Torsion was also not significantly increased in obese children .Gender distribution was not different between the two groups but obese children were older. BMI(30.4\u00b15.4vs18.9\u00b11.9),Z-score, systolic  and diastolic blood pressure  were greater whereas heart rate was lower in the obese group. Measurements of LV mass  and EDV  were significantly greater in the obese children. Although global systolic function was not different among the two groups, obese children exhibited a significantly increased stroke volume . In obese children, EIf our data confirm that obese children have early morphological changes in LV mass, EDV and SV, regional circumferential and longitudinal strains are not yet altered from normal. The trend to increased torsion and increased wall thickness may be an adaptation to increased LV ED volume and may lead to early impairment of LV diastolic function."}
+{"text": "Retrospective molecular profiling of untreated Diffuse Large B-Cell Lymphoma (DLBCL) samples has recognised distinct sub-classifications of this disease, each with unique biological features and clinical outcomes.(i) To demonstrate superior clinical efficacy, of bortezomib in combination with rituximab and CHOP (RB-CHOP) versus R-CHOP for the treatment of previously untreated patients with DLBCL.(ii) To assess whether the molecular phenotype determines benefit from the addition of bortezomib.The trial uses an adaptive design and aims to recruit 940 patients across 100 sites in the UK and Switzerland (currently recruited 398 patients). After being profiled within real time (during cycle 1), ABC, GCB and unclassifiable molecular phenotype patients are randomised to receive RB-CHOP or R-CHOP with equal allocation. Two interim analyses will be carried out to stop the good prognosis GCB group early if required using a Case Morgan [(i) The first will be a safety analysis performed after the first 55 GCB RB-CHOP patients have been followed for 6 months. If 6 month PFS<80%, the GCB group will close.(ii) The second will be for futility in the GCB group and performed after the first 73 GCB RB-CHOP patients have been followed for 1 year. If 1 year PFS<85%, the GCB group will close.If the GCB group closes the trial will then be modified to a randomised Phase II trial in ABC patients and sample size calculations will be revised."}
+{"text": "The tenuous blood supply of traditional flaps for wound cover combined with collateral damage by sacrifice of functional muscle, truncal vessels, or nerves has been the bane of reconstructive procedures. The concept of perforator plus flaps employs dual vascular supply to flaps. By safeguarding perforators along with supply from its base, robust flaps can be raised in diverse situations. This is achieved while limiting collateral damage and preserving nerves, vessels, and functioning muscle with better function and aesthesis.The perforator plus concept was applied in seven different clinical situations. Functional muscle and fasciocutaneous flaps were employed in five and adipofascial flaps in two cases, primarily involving lower extremity defects and back. Adipofascial perforator plus flaps were employed to provide cover for tibial fracture in one patients and chronic venous ulcer in another.All flaps survived without any loss and provided long-term stable cover, both over soft tissue and bone. Functional preservation was achieved in all cases where muscle flaps were employed with no clinical evidence of loss of power. There was no sensory loss or significant oedema in or distal to the flap in both cases where neurovascular continuity was preserved during flap elevation. Fracture union and consolidation were satisfactory. One patient had minimal graft loss over fascia which required application of stored grafts with subsequent take. No patient required re-operation.Perforator plus concept is holistic and applicable to most flap types in varied situations. It permits the exercise of many locoregional flap options while limiting collateral functional damage. Aesthetic considerations are also addressed while raising adipofascial flaps because of no appreciable donor defects. With quick operating times and low failure risk, these flaps can be a better substitute to traditional flaps and at times even free tissue transfers. The cornerstone of reconstructive work is the provision of wound flap cover which requires a delicate balance between vascularity and reach, while limiting collateral damage. It is desirable to provide wound cover without sacrifice of functional muscles, neurovascular supply, or aesthetics.2Traditional flaps, at times, suffer the disadvantage of flap ischemia and loss over critical areas. Free flaps offset this problem but are technically demanding, time consuming, and equipment intensive. Perforator anatomy and mapping allow diverse locoregional fasciocutaneous flaps albeit with limitations imposed by perforator location and size. The concept of perforator \u201cplus\u201d flaps aims to offset the disadvantages of traditional and perforator flaps while increasing applicability. Traditional fasciocutaneous flaps have vascular supply only from the base whereas true perforator flaps are island flaps based on a single perforator. By marrying the two concepts, perforator \u201cplus\u201d flaps are those which are designed based on a perforator input \u201cplus\u201d additional vascular supply from a retained base. These arThe perforator plus concept was applied to various flap types including adipofascial, muscle, and myocutaneous. In all cases, primary defect closure was obtained without flap failure in any patient. Morbidity and collateral damage were minimized without compromising on end result, wound stability, or fracture union.The defects were assessed clinically and possible traditional flaps in the vicinity were considered based on the availability of regional muscle, adipofascial, or skin. Flaps were chosen based on the principle of minimal morbidity and collateral damage. It was attempted to avoid functioning muscle sacrifice, preserve cutaneous nerves/vessels, and follow esthetic needs. Known perforators within the flap circumference were located by a handheld Doppler. Limb surgeries were performed under tourniquet control without exsanguination. Perforator dissection was performed by the naked eye/loupe using microsurgical instruments from the defect margins till the selected perforators were identified, mobilized, and flap raised. The flap base was always retained and narrowed if required to permit tensionless inset. Detached muscles were reinset after mobilization and achieving wound cover to minimize/avoid functional deficit. Creation of secondary defects was avoided, and immediate grafting of residual defects was done. Subcutaneous vessels and nerves underlying the flap were preserved in continuity while retaining inputs to the flap itself. Suction drains were employed on need basis. No special flap monitoring techniques or drugs were employed in any case.Seven patients underwent perforator plus flaps based on posterior trunk, inguinal region, and lower extremity trauma. The age ranged from 28 to 67 years with a mean of 44 years. Follow-up was on an average of 11 months . Three flaps were myocutaneous perforator plus flaps where the muscle origin/insertion were retained as the additional blood supply along with perforator inputs. One sliding muscle flap employed tibialis anterior (TA) and flexor digitorum longus (FDL), retaining segmental perforators while shifting muscle origins. Two lower extremity perforator fasciocutaneous flaps were raised without sacrifice of saphenous neurovascular bundles passing through their substance. There was no sensory loss distal to the flap and no clinically apparent distal limb oedema. Retained neurovascular inputs to the flap limited their oedema and resulted in sensate flaps. The remaining two cases underwent perforator plus adipofascial flaps with subdermal dissection and no consequent secondary defects. The adipofascial flap peninsular base was retained while the preserved perforator provided the main vascular input. None of the flaps exhibited loss and stable wound cover was achieved in all on follow-up. One adipofascial flap exhibited minor graft loss due to \u03b2-hemolytic streptococcus wound infection. Stored graft was applied with subsequent successful graft take. Operative time averaged 130 min . Exposed fracture sites exhibited sound bony union with no evidence of osteomyelitis and none required re-operation. One patient expired 1 month postoperatively due to uncontrolled iliofemoral bleed from metastatic penile carcinoma.2 defect overlying thoracolumbar spine of 6 months duration resulting postexcision and radiotherapy for soft tissue sarcoma. Two attempts elsewhere for wound closure and grafting failed due to the ischemic ulcer. A muscle \u201cfill\u201d and overlying stable sensate skin cover was deemed essential. Lateral paraspinal perforators were marked by Doppler, the medial row of lumbar perforators being sacrificed during tumor extirpation. The ulcer was excised and a V-Y skin flap was raised over the superior segment of Latissmus dorsi. The paravertebral muscle origin was detached and intercostal perforators and nerves dissected intramuscularly. Segmental dissection preserved thoracodorsal vessels and nerve and permitted movement of the entire superior segment of latissmus with the overlying skin paddle into the defect. The muscle origin was resutured across the midline and the skin closed in a V-Y advancement while leaving the humeral insertion intact. The blood supply to the Latissmus was retained both from the thoracodorsal trunk as well as lateral paraspinal perforators. Preservation of intercostals nerves resulted in sensate cover. Healing was uneventful, and the patient noted no discernable deficit of shoulder power or movement. On follow-up at 12 months, the cover remained stable [A 48-year veteran presented with a 15 \u00d7 7 cmd stable A 28-year soldier sustained a compound comminuted fracture lower third left leg in a road accident and was referred 7 weeks later with exposed bones at the fracture site. Two posterior tibial perforators were identified and a distally based perforator plus flap planned due to a deep proximal laceration . The ski2 extending from penile base till right ilium. The femoral vessels were exposed and covered with slough with risk of impending rupture. Histopathological examination confirmed metastatic penile carcinoma. Doppler revealed two anterolateral thigh perforators in close proximity. After careful debridement of the ulcer, an anterolateral thigh flap was raised including the tensor fascia lata origin. The proximal perforator was dissected along its pedicle after ligation of the distal one. Adequate perforator length permitted flap rotation by 110\u00b0 based on vascular supply both from the perforator and muscle origin. The secondary defect was split skin grafted [A 36-year soldier was referred with a progressively enlarging malignant ulcer in the right groin of 25 \u00d7 9 cm grafted . The patA 47-year old diabetic suffered multiple fractures right leg due to collapse of a wall under construction. The compound comminuted lower third tibial fracture was stabilized with an external fixator and wound debrided. He was referred 4 weeks after the injury with an exposed fracture site. A fasciocutaneous medial leg V-Y perforator advancement flap was planned based on posterior tibial artery perforator. The flap was elevated on the perforator while preserving the underlying saphenous neurovascular bundle . DissectA 48-year security personnel sustained a fracture of the right patella following a fall. Tension band fixation was done following which he had wound breakdown. He was referred 5 weeks later with a 2\u2033 \u00d7 2\u2033 open wound over the knee with exposed patella and hardware. A medial knee perforator was marked and proximally based fasciocutaneous flap elevated. The underlying perforator was safeguarded while preserving and maintaining the continuity of the great saphenous vein, saphenous artery, and nerve . Neurova2 indolent ulcer with pale granulation. The lower medial tibial perforator was localized just above the ulcer. A turnover fascial flap was dissected subdermally from the medial leg skin and based distally. The perforator and distal flap base of the adipofascis were retained. This dual supply flap was inset into the defect and grafted. The elevated skin flaps were primarily closed leaving no secondary defect [A 67-year diabetic presented with a nonhealing venous ulcer over left medial ankle of 8 months duration. He had refused surgery for varicose veins and was on conservative therapy for the same with no deep vein thrombosis. Conservative therapy for the ulcer and split skin grafting elsewhere had been unsuccessful. He had a 5 \u00d7 3 cmy defect . Graft t2 raw area in the lower leg with exposure of 5 cm tibia devoid of periosteum. Wound culture was positive for \u03b2-hemolytic streptococcus. Two perforators were identified by Doppler along the medial leg. The patient was operated 5 weeks after the injury after a negative culture report. An adipofascial perforator flap was planned and subfascial dissection done along the medial wound edge till the perforators were identified and mobilized. Dissection was then completed till the earmarked flap margins. Subcutaneous dissection separated the medial skin from the underlying fascia. Scissors inserted through stab incisions at flap margins permitted adipofascial flap mobilization without devascularization of the skin. A superiorly based adipofascial transposition flap was raised and inset after ligating the lower perforator [A 37-year soldier fell from a truck and sustained a comminuted fracture of the lower end right tibia. After debridement and skeletal fixation, he was referred 3 weeks after the injury with a 6 \u00d7 8 cmrforator . The fasAttention to regional flap applied anatomy has been refocused with the advent of perforator flaps. These fl6Latissmus dorsi is a versatile reliable flap with varied uses. Large spinal defects closure has been variously described by Desprez et al.,[et al.,[et al.[The z et al., Moore et,[et al., and McCr.,[et al. VariatioEssential to lower extremity salvage trauma protocols is adequate and early soft tissue coverage requiring use of vascularized locoregional or free flaps. Exposureen masse is achievable as in case 3. Extensor digitorum longus and peroneus longus with overlying skin were employed by Bloch et al., but they not only divided both the tendons but advocated ligation of several lower perforators making the flaps tenuous.[Muscle flaps have been traditionally favored for providing cover at exposed lower limb fracture sites with a view to providing additional blood supply and tolerance to infection. The gast14 tenuous. We effacThe anterolateral thigh flap has been described as an ideal soft tissue flap by Chen and Tang. Our patiFasciocutaneous flaps are back in favor and studies prove an equal efficacy and long-term results of fracture union compared to muscle flaps. Numerous recent articles have questioned the role of musculocutaneous flaps and advocate fasciocutaneous flaps with good results.1220 Ther1224et al. in their series of fascial feeder and perforator based V-Y advancement flaps advocate preservation of cutaneous veins to prevent congestion since the fascial perforating artery is not accompanied by draining veins in all cases.[Adipofascial flaps have been of limited use in lower limb trauma due to to the inherently imposed limit on their length to base ratio in order to remain viable. This restricted their utility despite favorable outcomes. The knowledge of perforator anatomy has given us the freedom to manipulate adipofascial flap designs. With perforator plus approach, adipofascial flaps are planned over Doppler identified perforator sites. Fascial dissection is done safeguarding the supplying perforators. The peninsular base of the fascia serves as an additional source of arterial input and helps in venous drainage. Niranjanll cases.The present approach of \u201cperforator plus flap\u201d allows fascial flaps to be used in 1:4 or larger ratios with good results. These flaps have numerous advantages over the muscle and fasciocutaneous flaps. There is no sacrifice of any muscle mass with full preservation of function in an already traumatized limb. No skin requires to be moved thus avoiding any additional defect. The flap being pliable can be turned over while perforator dissection permits a wide reach allowing coverage with esthesis.The \u201cperforator plus\u201d approach lends itself to diverse uses employing muscles, skin or adipofascia either alone or as composite tissues. Central to the approach is the preservation of dual vascular inputs via perforators and flap base. Minimal limitations on flap axiality, position of base, length to breadth ratios, or use in the presence of scarring/infection are the result of double blood supply. Functioning muscle and neurovascular preservation while minimizing secondary defects are advantageous outcomes, which are feasible without compromising flap requirements. This versatility allows functional preservation of muscles and nerve while permitting esthesis. Stable wound cover is achievable with minimal collateral damage."}
+{"text": "A 42 year male presented with episodic headache and vomiting. Two years earlier he had similar symptoms when a diagnosis of tuberculous meningitis was made after CSF examination. He was treated with antitubercular drugs and a ventriculoperitoneal shunt was placed with good relief. One year later he had recurrence of headache when second scan showed persistent of hydrocephalus . ConsideIn India, both NCC and tuberculosis of central nervous system (CNS) are common endemic problems. Obstructive hydrocephalus by CNS tuberculosis is common, but hydrIt is important to consider that hydrocephalus in the absence of obvious obstruction might not be due to CNS tuberculosis. New imaging such as three-dimensional constructive interference in steady state 3D-CISS) or heavily T2W sequences could improve the diagnosis. In casesD-CISS or"}
+{"text": "Mesocricetus auratus as an important model for dyslipidaemia because it mirrors many aspects of human disease and pharmacological responses. We show that complementary use of two independent next generation sequencing technologies combined with mapping to multiple genome databases allows unambiguous transcript annotation and quantitative transcript imaging. We refer to this approach as \u201ctriple match sequencing\u201d (TMS).Whole transcriptome analyses are an essential tool for understanding disease mechanisms. Approaches based on next-generation sequencing provide fast and affordable data but rely on the availability of annotated genomes. However, there are many areas in biomedical research that require non-standard animal models for which genome information is not available. This includes the Syrian hamster Contigs assembled from a normalized Roche 454 hamster liver library comprising 1.2 million long reads were used to identify 10\u2019800 unique transcripts based on homology to RefSeq database entries from human, mouse, and rat. For mRNA quantification we mapped 82 million SAGE tags (SOLiD) from the same RNA source to the annotated hamster liver transcriptome contigs. We compared the liver transcriptome of hamster with equivalent data from human, rat, minipig, and cynomolgus monkeys to highlight differential gene expression with focus on lipid metabolism. We identify a cluster of five genes functionally related to HDL metabolism that is expressed in human, cynomolgus, minipig, and hamster but lacking in rat as a non-responder species for lipid lowering drugs.The TMS approach is suited for fast and inexpensive transcript profiling in cells or tissues of species where a fully annotated genome is not available. The continuously growing number of well annotated reference genomes will further empower reliable transcript identification and thereby raise the utility of the method for any species of interest. Mesocricetus auratus has become an important animal model for pre-clinical dyslipidaemia research because HDL-c levels are raised in response to drugs designed for human target proteins. M. fascicularis liver expression data came from a previous study[http://www.reactome.org/), because their functional interactions are well documented. Hierarchical clustering generated six distinct clusters of genes with similar gene expression patterns across all species  are missing in the draft genomes of the pig[M.auratus AMN receptor gene (cluster 5) was not present in our long read library.The primary motivation for our study was to compare liver gene gene expression in hamster with humans and model organisms used in metabolic disease research. For this study we constructed SAGE-based liver RNA libraries from us study. The gen the pig or the mWe show that triple match sequencing (TMS) allows robust deep sequencing based transcript imaging in absence of an annotated genome. Using a SAGE based comparison of liver gene expression across five species we show that TMS derived data are comparable to mRNA quantification data using conventional genome based mapping. Similar to other vertebrates about 10\u2019800 genes are expressed in hamster liver at comparable levels  an animal model for experimental hepatitis B infection and hepatocellular carcinoma[http://www.ensembl.info/blog/2011/05/24/human-bodymap-2-0-data-from-illumina). TMS does not attempt to annotate species-specific transcripts because the approach relies on mapping to known mRNAs in other species. We note that any unmapped long reads are candidates for species specific transcripts of hamster. Normally, unique 454- reads or contigs matched the same RefSeq transcript from more than one species  had only limited value for our project[C. griseus focused mainly on pathways relevant for protein production and modification. Furthermore, the evolutionary distance between C. griseus and M.auratus is comparable to that between mouse and rat[As it turned out, the genome sequence or the partial transcriptome analysis of the  project,15, beca and rat. FinallyTriple match sequencing is a robust and rapid method for annotation and quantification of transcripts in the absence of a reference genome. The method is especially useful in projects where reliable mRNA quantification rather than primary sequence information is important. TMS does not require implementation of specialized hard- or software which makes it fast, affordable and user friendly. It might even contribute to the identification and selection of novel animal models prior to a genome sequencing effort.Male Syrian hamsters, weighing 125 \u00b1 5 g were obtained from Charles River Germany (Sulzfeld). The animals were kept at standard housing conditions . They were supplied with standard laboratory chow and water ad libitum, and left to acclimatize for 1 week before the experiments. The harvested liver was cut in small pieces (approximately 3 \u00d7 3 mm) and snap frozen immediately for further processing. All experimental procedures were carried out in accordance with international guidelines for care and use of laboratory animals.http://www.ellegaard.com). Normal human liver RNA was provided by the Human Tissue and Cell Research foundation (project-nr: 2012\u201313 approved 06/25/2012).RNA was isolated from Syrian hamster liver samples using RNeasy Mini Kit from Qiagen (No.74104). RNA integrity was analyzed using an Agilent Bioanalyzer (RNA 6000 Nano Kit) and all samples reached a quality score (RIN) above 9.7. Total Wistar rat liver RNA was a gift from Dr T. Heckel and snap-frozen minipig liver tissue was a gift from Dr Niels-Christian Ganderup (The Applied Biosystems SOLID 3 System SAGE kit (No.4443756AB) was used for library construction. Presence of the expected 100-base pair SAGE templates was confirmed using an Agilent Bioanalyzer (High Sensitivity DNA Assay). The emulsion PCR (ePCR) library was constructed using DNA at a concentration 0.75 pM. The ePCR was carried out on a SOLID EZ Bead amplifier and the enriched beads were quantitated using a NanoDrop 2000 spectrophotometer. Sequencing was performed on a SOLiD4 instrument with DOLF-TOP sequencing chemistry Frag-Lib F3 Tag MM35 (No. 445352).\u2032-kit primer is replaced by polTdeg (5\u2032-AAG CAG TGG TAT CAA CGC AGA GTA CTT TTG TTT TTT TTT CTT TTT TTT TTV N -3\u2032) The kit PCR primer M1 is substituted by polTM1 (5\u2032-AAG CAG TGG TAT CAA CGC AGA GTA CGG-3\u2032). The product of the full-size preparation of ds cDNA is used for normalization with the TRIMMER kit using 700-1300 ng of purified cDNA. The normalization is performed according to the supplied protocol without any changes. emPCR was carried out with 5cpb input on SOLID EZ Bead Amplifier. Typically a GS FLX+ Sequencing Run generated about 800\u2019000 reads with an average length of 410 bases.To normalize the levels of cDNA prior to library construction we used a competitive hybridization protocol provided with commercial kits . For 454 sequencing the use of special cDNA primers is required. The 3de novo using the software Trinity with the option \u201cinchworm\u201d as assembly method (release 2012-01-25)[bona fide transcripts. Re-aligning the raw reads to the set of transcripts with Roche-454\u2019s Newbler software (version 2.7) yielded a mapping efficiency of 97%.Following depletion of ribosomal sequences, 454-sequencing reads were assembled 2-01-25). Unassem\u2032-UTRs  with the tag length set to 22 bases and a maximum of two mismatches allowed. The read frequencies per transcript for all species included in this study are available in Additional file.10 with SAGE: Serial analysis of gene expression; CDS: Protein coding sequence; NGS: Next generation sequencing; emPCR: Emulsion polymerase chain reaction; qPCR: Quantitative polymerase chain reactionThe authors declare that they have no competing interests.RS and MB carried out deep sequencing data processing and transcript analysis and quantification. EK performed library construction and sample normalization. SG provided liver samples from matched hamsters. SL and WT selected a well annotated human liver sample and provided high-quality total RNA. ME designed the workflow and experimental strategy. UC lead the project and drafted the manuscript. All authors have read and approved the final version of this manuscript.Read frequencies of transcripts detected in human, cynomolgus, minipig hamster and rat liver samples. Given are the absolute read frequencies without normalization for the species indicated using standard gene symbols.Click here for file"}
+{"text": "The authors wish to add the following funding source to the financial disclosure information: \"E.C. is recipient of the \"Teresa Ariaudo Fellowship\" from Istituto Pasteur-Fondazione Cenci Bolognetti\"."}
+{"text": "Crystalloids have different electrolyte composition and therefore different strong ion differences (SIDinf). The aim of the study was to investigate the response of the kidney to plasmatic acid-base changes induced by dilution with three crystalloid solutions at different SID.2 constant. A urinary catheter was placed and connected to a urinary analyzer  [Six pigs (22 \u00b1 4 kg) were anesthetized and mechanically ventilated. The respiratory rate was adjusted to maintain pCO, Italy) . Pigs wein vitro studies [Plasmatic changes are consistent with previous  studies . dSID waThe quality of infused fluids affects greatly the acid-base and electrolyte equilibrium of plasma. This in turn alters the quality of urine (pHu)."}
+{"text": "Unipolar brush cells (UBCs) are excitatory glutamatergic interneurons of the cerebellar granular layer receiving both primary and secondary vestibular inputs through mossy fibers (excitatory input) and Golgi axon (inhibitory input). The brush like structure of the dendrite allows to form a giant synapses in the glomerulus and to produce an all or none post synaptic response with short delay and protracted kinetics. The excitable response of UBCs can be either a tonic discharge or a high-frequency burst of action potentials. When injected with progressively increasing depolarizing currents from a negative membrane potential, the UBC generates a burst sustained by a calcium spike Figure , +20pA aHere we present a biologically realistic multi-compartmental mathematical model of the UBC realized with the NEURON simulator. According to literature -4, ionic"}
+{"text": "Pulmonary pulse wave velocity has proven to be an excellent indicator of pulmonary vascular wall stiffness. In this study a novel MRI method was evaluated, showing rapid assessment of pulmonary pulse wave velocity with excellent repeatability and observer reproducibility.Pulmonary pulse wave velocity has proven to be an excellent indicator of pulmonary vascular wall stiffness. The main objective of this study was to evaluate a novel magnetic resonance imaging (MRI) method to rapidly assess pulmonary pulse wave velocity (PWV) and to test repeatability and observer reproducibility of the proposed technique.In 15 healthy volunteers  pulmonary PWV was prospectively assessed between the proximal main pulmonary artery (MPA) and just before the first branching of the distal left pulmonary artery (LPA). One-directional through-plane velocity-encoded (VE) MRI using breath holds was used to assess the pulmonary flow at the levels of MPA and distal LPA with a temporal resolution of 15 ms. Pulmonary PWV was calculated by dividing the pulmonary path length between the measurement sites by the transit time between the arrival of the systolic wave front at these sites. The volunteers were studied twice to test reproducibility in PWV-assessment.Results are expressed as mean\u00b1SD, Pearson correlation coefficient (PCC) and intraclass correlation (ICC). Acquisition time of the MRI examination was 2\u00b11 minutes and image analysis lasted for 2\u00b11 minutes. Both observers showed good agreement for pulmonary distance  and pulmonary PWV . Reproducibility of pulmonary PWV was high for both observers .Rapid non-invasive VE MRI assessment of pulmonary pulse wave velocity shows low interobserver and intraobserver variability and can be determined with high reproducibility.No disclosures."}
+{"text": "Many natural and engineered biofilm systems periodically face disturbances. Here we present how the recovery time of a biofilm between disturbances (expressed as disturbance frequency) shapes the development of morphology and community structure in a multi-species biofilm at the landscape scale. It was hypothesized that a high disturbance frequency favors the development of a stable adapted biofilm system while a low disturbance frequency promotes a dynamic biofilm response. Biofilms were grown in laboratory-scale reactors over a period of 55-70 days and exposed to the biocide monochloramine at two frequencies: daily or weekly pulse injections. One untreated reactor served as control. Biofilm morphology and community structure were followed on comparably large biofilm areas at the landscape scale using automated image analysis  and community fingerprinting (single-strand conformation polymorphisms). We demonstrated that a weekly disturbed biofilm developed a resilient morphology and community structure. Immediately after the disturbance, the biofilm simplified but recovered its initial complex morphology and community structure between two biocide pulses. In the daily treated reactor, one organism largely dominated a morphologically simple and stable biofilm. Disturbances primarily affected the abundance distribution of already present bacterial taxa but did not promote growth of previously undetected organisms. Our work indicates that disturbances can be used as lever to engineer biofilms by maintaining a biofilm between two developmental states. Pseudomonas biofilm  using low-magnification microscopy and community fingerprinting revealed the dynamic development of mixed-culture biofilm systems over several weeks.\u2022Weekly disturbed biofilms showed a resilient morphology and community at the time-scale of the disturbance frequency. A week-long recovery was sufficient to recover the initial biofilm morphology and community structure before recurring disturbances. Even after several weeks, biofilm responses to monochloramine were comparable and no adaptation became apparent. \u2022Aquabacterium dominated the microbial community. Preferential growth of this bacterium after disturbance events may serve as explanation for the observed community dynamics.At high disturbance frequencies, biofilm morphology and community composition continued to simplify. A seemingly resistant bacterium of the genus \u2022Within days, biofilm systems at both disturbance frequencies redeveloped a complex structure when disturbances were stopped.\u2022Monochloramine pulse injections could be used as lever to engineer morphology and community structure in biofilm ecosystems.Figure S1A time-series of top view images of biofilms. Images are acquired with opaque illumination before and after the second (days 27 - 31) and third (days 34 - 38) monochloramine pulse injection in the weekly treated reactor of the first experiment  and four days after the treatment (images to the right); least complex morphologies are observed on images immediately following the treatment. The contrast in the images was globally enhanced in order to improve the display on screen and in print. periment . Darker (EPS)Click here for additional data file.Figure S2Six descriptors with experimental time for the three treatment scenarios in the first experiment . The data were derived from images that were analyzed using the Spatial Gray Level Dependence Matrix (SGLDM) approach. Treatment scenarios are color-coded in each panel. Color-coded arrows indicate monochloramine pulse injections in the treated reactors. Panels A, D and E show results for images taken with transmitted illumination; panels B, D and F show results for images taken with oblique illumination. Mean gray levels from the images can be extracted by transforming the descriptor f6 (see r f6 see : (f6/2)-(EPS)Click here for additional data file.Figure S3A time-series of CE-SSCP profiles during the period of weekly treatment of the first experiment. Arrows indicate the weekly pulse injections of monochloramine. Experimental time in days is given for each profile. A simplification of the profiles is noticeable after each pulse injection. Over the days following a disturbance, profiles diversify once more. (EPS)Click here for additional data file.Figure S4Correlation of PCoA 1 scores with the respective \u2013log Simpson diversity indices for both experiments.(EPS)Click here for additional data file.Figure S5Proof on concept for image analysis method. Correlation between average gray levels from transmitted illumination images and gravimetrical measurements of biofilm biomass as total solids at the same sampling dates. Data from the first experiment described in this publication and an additional control experiment under identical conditions were presented in the figure. Error bars in x-direction indicated the standard deviations of 14 image repetitions. Error bars in y-direction indicated standard deviations of repetitions for total solids measurements that were done in three cases. The linear regression is flanked by 95% confidence intervals. (EPS)Click here for additional data file.Figure S6Morphology and community development with experimental time for the three reactors in the second experiment. Treatment periods were shaded where appropriate (panels C-F). Each monochloramine pulse injection was indicated by an arrow. Vertical gray lines mark Mondays. By performing Principal Component and Principal Coordinate Analyses, most of the variability in the data sets could be summarized in the first Principal Component (PC1) for morphology data and the first Principal Co-ordinate Axis (PCoA1) for the community data. More negative values on PC1 (note inverted axis labels) were related to more complex biofilm morphology. Similarly, the higher the value on PCoA1, the more complex was the community structure. Note the inverted axis in panels (EPS)Click here for additional data file.Figure S7Linear regressions between morphology data PC1 in  and comm Only filled points in panels B and C were considered for the regressions as these data were sampled during the treatment periods. (EPS)Click here for additional data file.Figure S8Development of bacterial diversity over time. We used the \u2013 log Simpson diversity index for individual molecular fingerprints and the Raup-Crick index to compare the composition (presence-absence of peaks) in a moving window of two subsequent samples from the same reactors. The solid lines with symbols represent \u2013 log Simpson diversity. The height of bars indicates the value of the Raup-Crick index for the comparison of the two samples at the left and right edge of the bars. Bar width stands for time between two samples and may vary. Raup-Crick values smaller than -0.95 indicate significantly more similar community compositions than expected from a random draw. Values around 0 indicate that observed differences could be explained by random effects while values greater than 0.95 indicate significant dissimilarities in composition. Shaded areas and arrows show treatment periods and monochloramine pulse injections. Dashed lines are the -0.95 and 0 levels for the Raup-Crick index. (EPS)Click here for additional data file.Figure S9CE-SSCP profiles of majority clones (profiles A-F) and low abundance clones (A'-C'). At the top of the figure, reference profiles for biofilm samples from the first experiment are shown. DNA from these samples was taken for cloning.(EPS)Click here for additional data file.File S1Integrates the supplemental figures in a text document.(PDF)Click here for additional data file."}
+{"text": "Second harmonic generation (SHG) microscopy is a recently developed technique which allows examination of fibrillar collagen structures with a high degree of specificity and resolution. The goal of this study was to examine the potential utility of SHG and multiphoton excitation fluorescence (MPEF) microscopy in understanding the relation between tenocytes and their surrounding collagenous matrix in early tendon overuse lesions.Tenocytes have been implicated in the development of tendinosis, a chronic condition commonly seen in musculoskeletal overuse syndromes. However, the relation between abnormal tenocyte morphology and early changes in the fibrillar collagen matrix has not been closely examined Histological preparations of tendon were prepared from adult male Sprague-Dawley rats subjected to an Achilles tendon loading protocol for 12 weeks (Rat-A-PED), or from sedentary age-matched cage controls. Second harmonic generation and multiphoton excitation fluorescence were performed simultaneously on these tissue sections in at least three different areas.SHG microscopy revealed an association between abnormal tenocyte morphology and morphological changes in the fibrillar collagen matrix of mechanically loaded Achilles tendons. Collagen density and organization was significantly reduced in focal micro-regions of mechanically loaded tendons. These pathological changes occurred specifically in association with altered tenocyte morphology. Normal tendons displayed a regular distribution of fibre bundles, and the average size of these bundles as determined by Gaussian analysis was 0.47 \u03bcm \u00b1 0.02. In comparison, fibre bundle measures from tendon regions in the vicinity of abnormal tenocytes could not be quantified due to a reduction in their regularity of distribution and orientation.SHG microscopy allowed high resolution detection of focal tendon abnormalities affecting the fibrillar collagen matrix. With ongoing repetitive loading, these tenocyte-associated focal collagen defects could predispose to the progression of overuse pathology. SHGI) scales as SHG I\u2248 N2 Here N is the effective number of radiating molecules. Likewise, isotropic macromolecules generate MPEF signal due to their endogenous fluorescence. Multiphoton excitation fluorescence intensity (MPEFI) emitted by these molecules undergoing multiphoton excitation can be expressed as, MPEF I\u2248 N. While SHG signal intensity scales as a square of number of collagen molecules, the MPEF intensity scales linearly with the number of other endogenously fluorescent molecules. Since MPEF and SHG involve different principles and contrast mechanisms, SHG and MPEF can be captured simultaneously to visualize structural changes of biological macromolecules. Particularly, SHG signals originating from the collagen structures can be used to generate high resolution images of individual collagen fibre bundles and quantify collagen density in a given tissue. Hence, SHG provides the potential to investigate precise spatial relations between collagen organization and underlying tenocyte biology.Multiphoton and associated microscopy methods have been widely used for imaging dynamic interactions in cells and tissues with submicron resolution -3. AmongTendinosis is a histological entitity characterized by collagen remodeling and angiofibroblastic hyperplasia. Tendons which rupture often demonstrate evidence of pre-existing tendinosis . HoweverResearch into the early pathogenesis of tendinosis has suggested that tenocytes may initiate degradation and remodelling of the load-bearing collagen matrix in response to mechanical loading. This model runs counter to a traditional \"wear and tear\" hypothesis of collagen microtrauma . Dudhia in vivo model of mechanical overload. We hypothesized that collagen density and fibrillar organization would be significantly reduced in highly localized areas associated with abnormal tenocyte morphology.The goal of the current study was to determine whether SHG microscopy could be used to examine a potential association between abnormal tenocyte morphology and local reductions of collagen density in a relevant Twelve male Sprague-Dawley rats aged 4 months, weight 448.7 \u00b1 10 grams were obtained locally and housed singly in standard cage conditions. Following a 48 hour acclimatization period, rats were divided into controls , or runners , providing 12 tendons per group. Ethic approval for the study was obtained from the UBC animal care committee (A07-0274).Runners were subjected to a previously published mechanical loading protocol (Rat-A-PED) using a dedicated rat treadmill to induce Achilles tendinosis  . Rats we2, and whole bilateral Achilles tendons were removed with the muscle still attached, oriented longitudinally in Tissue Tek embedding medium , then frozen in isopentane chilled in liquid nitrogen. Tendons were cryosectioned onto charged glass slides at 5 micron thickness and processed for H&E , Alcian blue / fast nuclear red (stains sulphated glycosaminoglycans and cell nuclei), or Picrosirius red (enhances birefringence of collagen when viewed under polarized light).Rats were euthanized with COxyR) values follow: 20X/0.7 NA (xyR\u22480.50 \u03bcm); 63X/1.2 NA (xyR\u22480.292 \u03bcm). Upon entering the Leica microscope system, the laser beam was directed to the scanning mirrors, then through a 670 nm long pass dichroic mirror  and subsequently focused on the specimens through the objective lens. The backscattered emission from the sample was collected through the objective lens. Leica Confocal Software TCS SP2 was used for the image acquisition. Non-descanned detectors and spectral scanning mode both in the reflection geometry were used for capturing the MPEF images as well as for the spectral signal characterizations respectively. In the non-descanned PMT detectors , a 700 nm short pass filter  was used to prevent the scattered IR laser radiation from reaching the detector and a 455 long pass dichroic beam splitter  was used to separate SHG signal from the MPEF signal. SHG signal in forward direction was captured using a non-descanned detector in the transmission geometry equipped with a 440/20 nm band pass filter  and high NA condenser. All SHG and MPEF spectral data were generated using the de-scanned PMT detector  located inside the scan head where the emission signals were delivered through the AOBS detection system with the maximum confocal pinhole setting at 600 \u03bcm via the spectral dispersion prism. The width of the slits in front of each PMT could be software adjusted such that each PMT could detect spectral regions spanning from a 5 nm bandwidth up to the overall spectral capacity of the system (400-800 nm). With this instrument configuration, a series of individual images were collected using a narrow detection window with a width of ~5 nm, and each image detected at this specific emission wavelength band (i.e. ~ 5 nm) provided a data point in the spectral graph. The gain and the offset of the PMTs were adjusted for optimized detection using the color gradient to avoid pixel intensity saturation and background. Images (8 bit) acquired at slow scan speed i.e. 10 sec per 512 X 512 pixels.The microscope system used in our present experiments is the same as described previously . SpecifiLateral line profiles of collagen fibers were generated using Leica comprehensive image processing software from 2D spectrally clean SHG images. The sizes of the collagen fibers and their size distribution were plotted by fitting the lateral line profiles to a Gaussian curve using Origin Lab Software.A Mann-Whitney U test was used to detect differences in collagen density and blood flow. Values are expressed as means \u00b1 SE. Results were considered statistically significant if \u03b1 was less than 0.05.In order to determine the microregional properties of collagen surrounding abnormal tenocytes in mechanically loaded tendon, we assessed standard histological preparations using multiphoton and second harmonic generation (SHG) microscopy. Initially, normal tendon was analyzed. Representative images originating from spectrally clean SHG signal originating from collagen (1A) and the MPEF signal originating from endogenously fluorescent tissue components Figure  are showAfter confirming the specificity of collagenous structures visualized with SHG in normal tendons, we next examined the collagen organization in sedentary and mechanically loaded tendons. All Achilles tendons analyzed from animals subjected to the mechanical loading protocol demonstrated microregions of abnormal tenocyte morphology, typified by the appearance of tenocytes with prominent cytoplasm and rounded morphology Figure . These mSHG signals emitted from the Achilles tendon proper region in normal tendon vs tendinosis lesions were next characterized by spectral analysis. The wavelength scans of both normal tendon from sedentary rats, and of tendon surrounding abnormal tenocytes from rats subjected to the mechanical loading protocol, showed a highly specific SHG signal manifested by a narrow peak at 440 nm Figure . The res2) to yield a mean collagen density value. The collagen density from micro-regions corresponding to abnormal tenocytes in rats subjected to the overuse protocol was 729 \u00b1 90.3 AU, compared to the value of 1135 \u00b1 60.1 in normal tendon (p < 0.05).We then applied a noise removal filter to SHG images to define the boundary between foreground and background, and the lower threshold in the histogram was set to 10% of the highest pixel intensity value. The total SHG signal intensity values thus generated were normalized by the cropped collagen area (\u03bcmSecond harmonic generation (SHG) resulted in high resolution, spectrally clean signals originating from fibrillar collagen. The collagen matrix surrounding abnormal tenocytes demonstrated an abnormal organization and a reduced density compared to sedentary cage controls. This reduction in SHG signal occurred specifically in association with the appearance of abnormal tencoytes in the tendons subjected to mechanical loading. These results provide support to an emerging model of tendinosis where degradation and/or remodelling of the load-bearing collagen matrix in response to exercise is mediated by the local activity of tenocytes, rather than being due to a passive accumulation of fatigue damage ,14.increased collagen staining using this overuse tendinopathy model based on assessment of H&E preparations [reduced SHG signal observed in the current study accurately reflects a loss of collagen density in the tendinosis samples. Indeed, H&E evaluation of tendinosis samples may be misleading as tendinosis lesions can be highly eosinophilic, but we have found these eosinophilic regions to generate very weak or absent SHG signals indicating that they may comprise provisional matrix with a higher component of non-collagenous elements. We are therefore able here to refine and further validate the description of early pathology which occurs in this model.Glazebrook et al. recently reported arations . HoweverIn the current study, SHG was used to estimate the collagen fibre bundle diameter with submicron resolution in normal tendons, but not in tendinosis samples. The longitudinal alignment of collagen fibres was reduced in the tendinosis tendons, in association with a reduction of SHG signal intensity. The technique of measuring fibre bundle diameter relied on the fibres demonstrating an orderly, longitudinal orientation, which was disrupted in areas of tendinosis.in vivo are accompanied by highly localized foci of reduced collagen density which may predispose to the progression of overuse tendinopathy.Second harmonic generation analysis of mechanically loaded tendon provides the ability to examine collagen organization in standard histological preparations, providing insight into mechanisms of early load-induced tendon changes. Tenocyte responses to mechanical loading The authors declare that they have no competing interests.AS and TA conceived of the study. AS supervised the tendon mechanical loading protocol and carried out the imaging and histological examination. GF assisted with imaging analysis. TA and AS conducted the image analysis. TA designed and oversaw the SHG and MPEF microscopy. All authors read and approved of the final manuscript.Alex Scott is a physical therapist engaged in full time research and teaching. Gloria Fong is a Research Assistant with a BSc in Medical and Laboratory Sciences. Thomas Abraham is a specialist in optical physics engaged in full time research.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2474/12/26/prepubFigure 1S Glycosaminoglycan distribution in mechanically loaded and sedentary tendon. Alcian blue staining in tendinosis (A) and normal healthy (B) tendon. Tendinosis tendon demonstrates increased sulphated glycosaminoglycan intra- and peri-cellularly, particularly in chains of abnormal-appearing tenocytes. Mast cells also stain blue with this technique in the paratendon regions (not shown). 20\u00d7 objective lens.Click here for file"}
+{"text": "We generated computational 3D pharmacophores based on data derived by both acoustic and tip-based transfer. The computed pharmacophores differ significantly depending upon dispensing and dilution methods. The acoustic dispensing-derived pharmacophore correctly identified active compounds in a subsequent test set where the tip-based method failed. Data from acoustic dispensing generates a pharmacophore containing two hydrophobic features, one hydrogen bond donor and one hydrogen bond acceptor. This is consistent with X-ray crystallography studies of ligand-protein interactions and automatically generated pharmacophores derived from this structural data. In contrast, the tip-based data suggest a pharmacophore with two hydrogen bond acceptors, one hydrogen bond donor and no hydrophobic features. This pharmacophore is inconsistent with the X-ray crystallographic studies and automatically generated pharmacophores. In short, traditional dispensing processes are another important source of error in high-throughput screening that impacts computational and statistical analyses. These findings have far-reaching implications in biological research.Dispensing and dilution processes may profoundly influence estimates of biological activity of compounds. Published data show Ephrin type-B receptor 4 IC There have been many studies which have evaluated aspects of biological assays and the tools involved which could result in errors and erroneous data. Processes like tip-based and acoustic dispensing have a profound influence on estimates of compound activity. Several independent studies of high-throughput screening (HTS) show that the two techniques generate conflicting results 50 values derived using tip-based serial dilution and dispensing tend to be greater  than IC50 values derived using acoustic dispensing. Some compounds appeared hundreds of times more active with the acoustic process Previous research has impugned tip-based techniques because they can generate errors due to leachates from the plastic that may profoundly affect biological assays 50 results in which larger number of molecules are used but the molecular structures are not provided for computational analysis While we are limited by the number of compounds available with data in tip-based and acoustic dispensing, this study suggests a significant impact on drug design, especially when coupled with other reports of poorly correlating IC50 values determined by AstraZeneca scientists 50 values using both serial dilution facilitated by tip-based dispensing  and direct dilution 50 values obtained with acoustic transfers suggested that the compounds were 1.5 to 276.5 times more active than when tip-based techniques were used This paper is based on the published comparisons of ICWe used these published data 50 values  with minimum features (3) and maximum features (6) as are described elsewhere 50 values obtained via tip-based serial dilution and dispensing versus acoustic dispensing with direct dilution is poor  when acoustic transfer was used. Upon statistical analysis of the 14 IC50 values for the two dispensing techniques . This would suggest that there is no statistically significant correlation or ranking between these two measures. That is, the data generated from the two techniques would lead researchers in completely different directions.The correlation between the 14 Ephrin type-B receptor 4 log ICchniques , calcula50 values for the pharmacophore derived via acoustic processes was higher than that for the pharmacophore derived from the tip-based processes  for these additional 12 compounds. We used the data to create a 3D multiple conformer database. This database was searched by the two pharmacophores in order to test whether they could discriminate between those with high and low affinity . That is, the two pharmacophores developed on the comparative data of 14 compounds were used to test an additional 12 compounds to see whether either of the two pharmacophores developed could predict which compounds in the second set of 12 were most active.The pharmacophores specific to the tip-based and acoustic-based processes were used to predict affinity to EphB4 .When the physical properties of the additional 12 compounds Receptor-ligand pharmacophores were created in 8 out of 10 cases and all consisted of hydrophobic and hydrogen bonding features .The pharmacophores derived for the tyrosine kinase EphB4 are dramatically different based upon the process used to set up the dose-response experiments. The pharmacophore derived from the acoustic dispensing data suggests the importance of specific regions of hydrophobicity as well as hydrogen bonding features. The pharmacophore from the tip-derived data suggests only hydrogen bonding features as leading to binding, with no hydrophobic interactions.in vitro data of the original articles and not using the crystal structures of the latter work.In order to further understand the impact of these models, a series of another 4 papers published by AstraZeneca describing structure-based design of tyrosine kinase EphB4 inhibitors were reviewed in vitro data ligand pharmacophores further. Receptor-ligand pharmacophores could be created in 8 out of 10 cases and all consisted of hydrophobic and hydrogen bonding features .A graph of the log IC(DOCX)Click here for additional data file.Results S1Showing pharmacophore model information for acoustic-based liquid handling with direct dilution and tip-based liquid handling with serial dilution.(DOCX)Click here for additional data file.Table S150 data and descriptors.Molecule structures, IC(PDF)Click here for additional data file.Table S2Test set data for searching with \u2018acoustic dispensing\u2019 pharmacophore.(DOCX)Click here for additional data file.Table S3Test set data for searching with \u2018tip-based dispensing\u2019 pharmacophore.(DOCX)Click here for additional data file."}
+{"text": "Hot flashes are a significant clinical problem for many women. Currently there are limited options to hormone replacement therapy as non-hormonal pharmacological agents are associated with only modest activity and many adverse side effects. Hypnosis is one mind-body therapy that seems particularly promising for treating hot flashes and was investigated in the present study. This study examined the efficacy of hypnosis in reducing both self-reported and physiologically determined hot flash frequency and severity among post-menopausal women.One-hundred and seventy post-menopausal women with moderate to severe hot flashes were randomly assigned to either a 5-session hypnosis intervention or a 5-session structured-attention control condition. All sessions were provided consistent with a treatment manual and all therapists were trained to criteria for consistency and treatment fidelity. Primary outcome measures were self-reported hot flash frequency and severity (determined via daily diaries) and physiologically monitored hot flashes . Physiological assessment of hot flashes were made using 24-hour recordings of sternal skin conductance. Measures were obtained at baseline, at the end of the five weeks intervention, and at 12 week follow-up.Results demonstrated that hot flash scores (self-report of frequency and severity of hot flashes) for the participants that received the therapist delivered hypnosis intervention decreased by approximately 70% at 5 weeks and continued to decline to approximately 80% at the 12 week follow-up. Physiologically assessed hot flashes demonstrated a 50% reduction at 5 weeks and approximately 60% reduction at 12 weeks for participants in the therapist delivered hypnosis condition.To our knowledge, this is the first study to demonstrate a clinically significant reduction in physiologically measured hot flashes using a hypnosis intervention. This study has important implications for women experiencing hot flashes who are contraindicated for hormone replacement therapy."}
+{"text": "Sepehrvand et al. demonstrated a considerable seroprevalence rate of anti-HEV in Iranian kidney transplant recipients . The impIn otherwise healthy kidney transplant recipients, HEV might be considered the etiological agent for the development of hepatitis in those who live in endemic regions . Viral hDecreasing the numbers and doses of immunosuppressive drugs remains the first approach toward controlling viral hepatitis E in renal transplant recipients. A prolonged follow-up period might be required to assess the eventual outcome . In addi"}
+{"text": "Patients with ischemic cardiomyopathy have an increased risk for ventricular arrhythmia, since myocardial infarction can be the substrate for re-entrant arrhythmias. Contrast-enhanced cardiac magnetic resonance imaging (CMR) has proven to reliably quantify myocardial infarction. Aim of our study was to evaluate correlations between functional and contrast-enhanced CMR findings and spontaneous ventricular tachy-arrhythmias in patients with ischemic cardiomyopathy who underwent implantable cardioverter-defibrillator (ICD) therapy.Forty-one patients with ischemic cardiomyopathy and indication for ICD therapy were examined in a 1.5-T whole-body CMR system. Cine images for quantification of left ventricular volumes and function and late gadolinium enhancement images for quantification of myocardial scar extent were acquired in all patients covering the entire left ventricle.During a follow-up period of 1184 \u00b1 442 days 68 monomorphic and 14 polymorphic types of ventricular tachycardia (VT) could be observed in 12 patients. Patients with monomorphic VT had larger scar volumes  than patients with polymorphic VT. Moreover myocardial infarction involved more segments in the LAD perfusion territory  than in patients with polymorphic VT.Patients with spontaneous monomorphic VT during the long-term follow-up period had more infarcted tissue, which was more often present in the LAD perfusion territory than patients with polymorphic events. These data strengthen the diagnostic benefit of CMR in patients with ischemic cardiomyopathy. CMR may be used for comprehensive risk stratification in patients with ischemic cardiomyopathy undergoing ICD therapy."}
+{"text": "This paper describes a case of early (7 months after transplant) cardiac allograft vasculopathy. This-43-year-old  female patient underwent an orthotopic heart transplant with a  donor heart. She had a history of herpes zoster infection and postherpetic neuralgia in the past. The patient's panel reactive antibodies had been almost undetectable on routine surveillance testing, and her surveillance endomyocardial biopsies apart from a few episodes of mild-to-moderate acute cellular rejection (treated adequately with steroids) never showed any evidence of humoral rejection. The postoperative course was complicated by multiple admissions for upper respiratory symptoms, and the patient tested positive for entero, rhino, and coronaviruses serologies. During her last admission (seven months postoperatively) the patient developed mild left ventricular dysfunction with an ejection fraction of 40%. The patient's endomyocardial biopsy done at that time revealed concentric intimal proliferation and inflammation resulting in near-total luminal occlusion in the epicardial and the intramyocardial coronary vessels, suggestive of graft vasculopathy with no evidence of rejection, and the patient had a fatal ventricular arrhythmia. Cardiac transplantation is a well-defined therapy for end-stage heart failure. Following transplantation, median survival is 10 years rising to 13 years for those who survive the first year [We present a case of early (7 months after transplant) cardiac allograft vasculopathy (CAV) in a cytomegalovirus (CMV) positive patient with a history of herpes zoster infection and multiple other viral infections in the postoperative course possibly contributing to graft vasculopathy.A 43-year-old Caucasian female with a history of nonischemic dilated cardiomyopathy with left ventricular ejection fraction (LVEF) of 10\u201315% status following Thoratec Heart-Mate II left ventricular assist device (LVAD) (implanted 2 years prior as a Bridge to Transplant) was transferred to our tertiary care facility for management of unresolving pseudomonas driveline infection. The patient secondary to persistent pseudomonas bacteremia despite adequate treatment with intravenous antibiotics underwent LVAD removal with reimplantation with another VAD. The patient also underwent an AICD lead extraction with generator change secondary to questionable vegetation on the defibrillator lead on transesophageal echocardiogram. The patient did well following that and remained home for 4 months while awaiting a cardiac transplant. Her past history was significant for hypertension, dyslipidemia, recurrent pulmonary embolism, history of herpes zoster infection with postherpetic neuralgia, and intracerebral hemorrhage.2) and elevated right sided pressures on right heart catheterization while the EMB remained negative for cellular or humoral rejection. An echocardiogram at the time revealed a mildly depressed left ventricular ejection fraction at 40% with mild right ventricular dysfunction. The patient's panel reactive antibodies were undetectable. Four months later the patient was electively admitted for transplant evaluation. Her panel reactive antibody (PRA) levels were found to be low at 4% as measured by flow cytometry using HLA class I Luminex-coated beads. The patient (CMV positive) finally underwent a CMV negative, Epstein-Barr virus (EBV) positive orthotopic heart transplant without the need for desensitization. The patient's immediate postoperative course was complicated by multiple failed attempts at extubation secondary to fluid overload that required tracheostomy and acute kidney injury requiring temporary hemodialysis . The patient after 4 weeks, on routine surveillance endomyocardial biopsy (EMB), was found to have ISHLT grade 2R acute cellular rejection which was successfully treated with intravenous pulsed steroids and mycophenolate mofetil. The patient was eventually discharged home 2 weeks later and was followed as an outpatient. Three months subsequent to transplant the patient started to develop signs and symptoms of upper respiratory tract infections manifesting as unremitting cough. The patient admitted was found to have viral infection with positive serologies for entero, rhino, and coronaviruses, and the EMB was negative for rejection. The patient was managed conservatively without any antiviral treatment except prophylactic ganciclovir for CMV prophylaxis and discharged home. The patient did present again with similar respiratory symptoms a month later at which time it was decided to treat the patient with a course of oseltamivir (Tamiflu) for a clinical suspicion of influenza. The patient was discharged only to be readmitted 2 months later (6 months after transplant) for symptoms of exertional dyspnea, nausea, and abdominal pain. The patient was found to have low cardiac index  inhibitors (everolimus and sirolimus), and possibly diltiazem  .Our case is an addition to a list of very limited number of cases of early allograft vasculopathy (within the first year after transplant) that aims to highlight its poor clinical outcome and survival compared to the form that develops after the first year. The lack of data on the patients viral titres is an important limitation of this case. Allograft coronary disease remains one of the greatest obstacles to long-term recipient survival after cardiac transplantation. This process has been extensively studied, yet remains poorly understood. Although it typically becomes clinically significant years after transplantation, it can also occur early and result in recipient death as early as 6 months following transplant. Why a given patient develops an aggressive form of the disease early after transplantation and another patient may live ten or even twenty years without evidence of clinically significant disease is unknown."}
+{"text": "Aortic cusps originating arrhythmias are rare; they have special electrocardiogram features that help to locate the site of origin. We report on a 20-year-old male patient without structural heart disease presenting with accelerated idioventricular rhythm; electrocardiogram analysis was typical of left coronary cusp origin. Outflow tract ventricular arrhythmias (VAs) usually have a benign course when occurring in the setting of normal structural heart. Left coronary cusp (LCC) originating arrhythmias have special electrocardiogram (EKG) characteristics; these are well established in the literature ; recogniWe report on a 20-year-old male patient presenting with palpitations; his EKG  showed accelerated idioventricular rhythm with EKG characteristics compatible with a LCC origin . The patient had no relevant past medical history; physical examination was normal, cardiac echogram showed no structural heart disease, and laboratory parameters including cardiac markers were normal. Reversion to sinus rhythm occurred with a 75\u2009mg bolus of Xylocaine. Given the refusal of any electrophysiological procedure (diagnostic or therapeutic), the patient was discharged home on day 3 with verapamil. Holter and stress test on days 10 and 30 after discharge showed no VA and were normal.Supravalvular left ventricular outflow tract arrhythmias originate usually from the aortic sinus of valsalva (aortic cusps) . VA origLCC-VA is known to be the most common form of coronary cusp arrhythmia; it exhibits an (r) wave in V1 [LVOT-VA displays earlier precordial transition zones (median V3 versus V5) compared to RVOT-VA ; this feThe absence of (S) wave in left precordial leads is also typical of left VA originating from coronary cusps, in contrary to VA originating in the left ventricular myocardium resulting in late right ventricular activation and typical right bundle branch pattern with prominent (S) wave in V5-V6 .The presence of rS pattern in D1  is also When invasive electrophysiological studies could not be performed, surface EKG becomes of utmost importance to diagnose this type of VAs and accordingly to differentiate it from other VAs, especially non-outflow tract VA which have a more critical prognosis if they are not treated adequately . OutflowLCC-VAs have special EKG characteristics and accordingly they can be diagnosed with sufficient accuracy based on surface EKG.in this presented case, there was no invasive electrophysiological procedure performed due to patient denial and so intracavitary mapping of the arrhythmia is lacking.The authors declare that there is no conflict of interest.According to our institutional Ethics Committee, a written consent was obtained from the patient before proceeding with this paper.Figure 1. Legend: EKG showing accelerated idioventricular rhythm with EKG characteristics compatible with a left coronary cusp origin.Figure 2. Legend: EKG (s) of different types of Coronary cusps ventricular arrhythmias. ).Click here for additional data file.Click here for additional data file."}
+{"text": "Eucalyptus camaldulensis seedlings derived from three natural populations. Physiological and growth traits were measured and gene and allelic expression in leaves was examined by RNA sequencing (RNA-seq). Water stress had a significant impact on all the physiological and growth traits, while differences between the populations were not significant. Genes differentially expressed in leaves were identified by de novo assembly and by ab initio transcriptome mapping using the Eucalyptus grandis reference genome sequence. Gene ontology (GO) enrichment tests with 2,500 significantly differentiated genes revealed 128 stress-related gene categories were up-regulated while 28 gene categories belonging to photosynthesis and other metabolic processes were down-regulated under stress treatment. More than 190,000 single nucleotide polymorphisms (SNPs) and small indels were detected and 4,053 of these revealed differential allelic expression between control and drought stressed seedlings. Allelic expression of 70% of these variants was correlated with total gene expression. These variants may be cis-acting variants or in high linkage disequilibrium with such variants. The SNPs and indels identified in this study form a useful resource for further testing in association studies.Water stress limits plant survival and production in many parts of the world. Identification of genes responding to water stress conditions will underpin efforts to breed plants better adapted to drought. We studied the effect of water stress on"}
+{"text": "Alcohol based hand rubs (ABHRs) are extremely effective at reducing microbial contamination and are central to established best practices for hand hygiene. Modern dispensing systems have brought benefits such as hygienically sealed cartridges with integral pumps for dosing liquids, gels or foams. A remaining issue concerns the measured efficacy of such products and their use in practice as dictated by pump volume.ABHRs for professional use must demonstrate efficacy through standard in-vivo tests; either EN1500 or ASTM E1174. Products typically pass such tests using standard doses not necessarily related to real use by healthcare workers. In this study we set out to identify the optimal dose for an ABHR product based on observation of real behavior.Data from the DebMed GMS Hand Hygiene Monitoring System was used to establish product dose applied in clinical settings via the number of dispenser presses per hand hygiene event. In a separate study healthcare workers applied ABHR using best-practice methodology to establish product drying time as a function of dose. Hand coverage was assessed using a laboratory method based on product coverage. In-vivo efficacy was established using both ASTM E1174 and EN 1500 methods.Healthcare workers intuitively calibrate ABHR dose based on drying time, hand coverage and product ergonomics. In our studies using Deb dispensers, over 90% of healthcare workers used a single pump of ABHR, even when multiple pumps are indicated. Our studies established that 1.5ml of ABHR in foam format dries in approximately 30 seconds and fully covers most hands. Both ASTM 1174 and EN 1500 tests confirmed that 1.5ml of Deb ABHR in foam format with 30 seconds contact time was sufficient to provide effective hand hygiene.Product drying time, hand coverage and measured efficacy data are considered to determine the optimal dose for an ABHR in foam format dispensed from a sealed cartridge wall-mounted unit. This is combined with observed behaviour of healthcare workers to design a pump that delivers the optimal dose in a single press, connecting for the first time measured in-vivo efficacy standards with real-world use to ensure effective sanitization.None declared"}
+{"text": "New bioinformatic tools are needed to analyze the growing volume of DNA sequence data. This is especially true in the case of secondary metabolite biosynthesis, where the highly repetitive nature of the associated genes creates major challenges for accurate sequence assembly and analysis. Here we introduce the web tool Natural Product Domain Seeker (NaPDoS), which provides an automated method to assess the secondary metabolite biosynthetic gene diversity and novelty of strains or environments. NaPDoS analyses are based on the phylogenetic relationships of sequence tags derived from polyketide synthase (PKS) and non-ribosomal peptide synthetase (NRPS) genes, respectively. The sequence tags correspond to PKS-derived ketosynthase domains and NRPS-derived condensation domains and are compared to an internal database of experimentally characterized biosynthetic genes. NaPDoS provides a rapid mechanism to extract and classify ketosynthase and condensation domains from PCR products, genomes, and metagenomic datasets. Close database matches provide a mechanism to infer the generalized structures of secondary metabolites while new phylogenetic lineages provide targets for the discovery of new enzyme architectures or mechanisms of secondary metabolite assembly. Here we outline the main features of NaPDoS and test it on four draft genome sequences and two metagenomic datasets. The results provide a rapid method to assess secondary metabolite biosynthetic gene diversity and richness in organisms or environments and a mechanism to identify genes that may be associated with uncharacterized biochemistry. Genome sequencing has revealed that the secondary metabolite potential of even well studied bacteria has been severely underestimated Polyketide synthases (PKSs) and non-ribosomal peptide synthetases (NRPSs) are large enzyme families that account for many clinically important pharmaceutical agents. These enzymes employ complimentary strategies to sequentially construct a diverse array of natural products from relatively simple carboxylic acid and amino acid building blocks using an assembly line process When the challenges associated with PKS and NRPS gene assembly can be overcome, a number of effective bioinformatics tools have been developed for domain parsing Phylogenomics provides a useful approach to infer gene function based on phylogenetic relationships as opposed to sequence similarities Here we introduce the web tool Natural Product Domain Seeker (NaPDoS), which extracts and rapidly classifies KS and C domains from a wide range of sequence data. The results can be used to assess the potential for PKS and NRPS secondary metabolite biosynthesis in organisms or environments and to identify new phylogenetic lineages, which can subsequently be investigated as a source of new mechanistic biochemistry. We tested NaPDoS on four draft bacterial genome sequences and two metagenomic datasets. The results reveal a remarkable level of secondary metabolite gene diversity among closely related strains and provide a mechanism to assess secondary metabolism from poorly assembled genomic data.http://www.nii.res.in/searchall.html) KS and C domains were extracted from select PKS and NRPS genes associated with experimentally characterized biosynthetic pathways using the online program NRPS-PKS (http://www.phylogeny.fr/) The amino acid sequences of all reference KS and C domains were aligned using either MUSCLE The NaPDoS web portal identifies candidate KS and C domains through a combination of hidden markov model (HMM) searches and the basic local alignment search tool (BLAST) algorithm BLAST results are linked to a back-end MySQL relational database via CGI-scripting to retrieve and report domain classification and related pathway information. Query sequences are trimmed according to their BLAST match coordinates by a custom Perl script then aligned to each other and their database matches using MUSCLE S. arenicola strain CNH-643 (accession number PRJNA84391), S. arenicola strain CNT-088 (accession number PRJNA84269), \u201cS. pacifica\u201d strain CNS-143 (accession number PRJNA84389), and \u201cS. pacifica\u201d strain CNT-133 (accession number PRJNA84271) were obtained at 8\u00d7 coverage at the J. Craig Venter Institute using 454 GS FLX pyrosequencing and 0.5\u00d7 Sanger sequencing as previously described S. arenicola strains were mapped onto the complete S. arenicola strain CNS-205 genome and the S. pacifica strains were mapped to the complete S. tropica CNB-440 genome Salinispora genomes were mined for KS and C domains using NaPDoS with default settings. The metagenomic datasets  and the resulting sequences further subjected to a loose BLAST analysis with an e-value cut-off of 1 to obtain more precise coordinates and assign initial domain classifications.Draft genome sequences of http://npdomainseeker.ucsd.edu/) was created to detect and classify KS and C domains in nucleotide and amino acid sequence data. The query data can be PCR amplicons, genes, contigs, genomes, or metagenomes. The current query size limits are <30 MB and <50,000 individual sequences. The website provides a detailed tutorial on the use of this tool, which is implemented using a web interface  against the NCBI nr database is also highly recommended to check for matches that do not occur in the reference database.To generate a final classification for each domain sequence, it is highly recommended to construct a phylogenetic tree, especially in cases where the percent sequence identity to the top database match is low. If that option is chosen, a profile alignment is generated in which the query sequences are incorporated into a carefully curated reference alignment generated from the sequences in the reference database. This alignment is then used to create a phylogenetic tree, which needs to be manually interpreted to establish a final classification for each sequence. Interpreting sequences in the context of a phylogenetic tree is particularly important given that the NaPDoS pipeline is intentionally set to low stringency in an effort to detect all possible KS and C domains. Thus, homologs not involved in secondary metabolism such KSs associated with fatty acid biosynthesis are regularly detected. These sequences can be readily classified based on the phylogenetic tree.trans-AT KSs, which evolved by extensive HGT and exploit considerably greater modular architectures than the cis-AT group, which has largely evolved by gene duplication KS and C domain phylogenies form the basis of the NaPDoS classification system . KS domaIn the case of C domains, the sequences generally clade based on substrate specificity, i.e. the stereochemistry of the amino acids incorporated and the subsequent tailoring reactions they perform . Eight cStreptomyces avermitilis strain MA-4680. This analysis revealed 67 KS and 15 C domains (S. tropica (strain CNB-440) and S. arenicola (strain CNS-205) Salinispora genome sequences. These low coverage drafts were generated using pre-Titanium 454 technology (avreage read length 244 bp) and yielded poor assemblies and a large number of contigs  to those associated with the biosynthesis of salinosporamide A  genomes . While tNaPDoS was further tested on metagenomic data sets generated from a Minnesota farm soil and whale fall Rapid advances in DNA sequencing technologies are providing unprecedented opportunities to incorporate DNA sequence data into the natural product discovery process. The effective use of this information requires bioinformatic tools that can rapidly analyze large datasets in the context of a wide array of complex biosynthetic paradigms. While a number of excellent bioinformatic tools targeting secondary metabolism have been developed The Natural Product Domain Seeker (NaPDoS) is a web-based bioinformatic tool that was developed to detect and classify KS and C domains from a wide variety of sequence data. The use of domain sequence tags as proxies for the biosynthetic genes in which they reside is based on the well established and highly informative phylogentic relationships they maintain. These relationships form the foundation of the NaPDoS classification system and provide a rapid mechanism to delineate secondary metabolite biosynthetic gene richness and diversity within a genome or environmental sample. Short sequence tags (e.g. 600 bp) can be effectively analyzed using NAPDoS and thus minimum coverage, next generation sequence assemblies are well suited for this tool. The resulting estimates of biosynthetic potential can be used to guide more extensive sequencing efforts or targeted operon assembly. In cases where query sequences closely match domains derived from experimentally characterized biosynthetic pathways , it has proven possible to make accurate predictions about the structural class of the secondary metabolite(s) produced trans-AT (b) clade is comprised of KS sequenced derived from what appears to be an evolutionarily independent lineage of trans-AT sequences as well as genes associated with beta-branching There is ample evidence that the mechanistic diversity of polyketide and non-ribosomal peptide assembly is considerably greater than that currently recognized Salinispora genome sequences. Seventeen of these domains were not observed in either of the two complete Salinispora genomes providing evidence of the considerable biosynthetic variability that may occur among closely related strains. In addition, two C domains fell into the \u201cModified AA\u201d clade, a lineage whose biochemical function has yet to be experimentally characterized. While the metagenomic datasets revealed similar total numbers of KS domains, the classification of those domains revealed dramatic differences in functional types. Analyses such as these provide insight into the potential significance of secondary chemistry in mediating population and community dynamics while at the same time identifying environments that can be prioritized for secondary metabolite discovery efforts.Despite poor assembly, a large number and diversity of KS and C domains were detected among the four draft Traditional natural product discovery paradigms have become increasingly inefficient At present, NaPDoS is optimized for the identification and classification of bacterial PKS and NRPS genes. Nonetheless, it is possible for NaPDoS to identify eukaryotic KS and C domains given their shared evolutionary history with prokaryotic homologs. The results obtained for non-bacterial sequences should be interpreted with caution however, as the reference database has not been adequately populated with these sequences to provide a robust classification system. Future plans include the expansion of NaPDoS to include additional eukaryotic sequences and subgroups within the FAS and PUFA lineages, the later of which were recently shown to cluster phylogenetically based on functional type Table S1NaPDoS derived KS and C domains from the S. avermitilis MA-4680 genome.(DOC)Click here for additional data file.Table S2NaPDoS results for six Salinispora genomes.(DOC)Click here for additional data file.Table S3KS and C domains detected in four draft Salinispora genomes.(DOC)Click here for additional data file.Table S4NaPDoS and antiSMASH-derived KS and C domains.(DOCX)Click here for additional data file.Table S5NaPDoS KS results for metagenomic data sets.(DOC)Click here for additional data file.Table S6KS domains detected in the whale fall metagenomic data set.(DOC)Click here for additional data file.Table S7KS domains detected in the Minnesota farm soil data set.(DOC)Click here for additional data file."}
+{"text": "Approximately one third of women diagnosed with ovarian cancer is 70 years or older. Information on the treatment reality of these elderly patients is limited.275 patients with primary epithelial ovarian cancer FIGO stage II-IV undergoing cytoreductive surgery and platinum-based chemotherapy were prospectively included in this European multicenter study. Patients <70 and \u226570 years were compared regarding clinicopathological variables and prognosis.Median age was 58 years (18\u201385); 47 patients (17.1%) were 70 years or older. The postoperative 60-day-mortality rate was 2.1% for elderly and 0.4% for younger patients (p\u2009<\u20090.001). Elderly patients were less likely to receive optimal therapy  compared to patients <70 years  and their outcome was less favorable regarding median PFS  and OS . However, in multivariate analysis age itself was not a prognostic factor for PFS while the ECOG performance status had prognostic significance in elderly patients.Elderly patients with ovarian cancer are often treated less radically. Their outcome is impaired despite no consistent prognostic effect of age itself. Biological age and functional status should be considered before individualized treatment plans are defined. Women aged 65 and above represent the fastest-growing population segment with consecutively rising incidence of malignancies . Median Irrespective of age, ovarian cancer is still regarded the most lethal gynecological malignancy with a median overall survival of approximately 44 months [In contrast to the well-established prognostic factors postoperative residual tumor load, FIGO stage at first diagnosis and lymph node involvement the role of age itself for ovarian cancer patients has been controversially discussed in the past. While several studies found higher age to be associated with poor survival -7, it coTo further understand the role of age for outcome and treatment of ovarian cancer we analyzed the cohort of prospectively enrolled patients from the Sixth Framework Programme (FP6) EU project \u201cOVCAD \u2013 Diagnosis of a Silent Killer\u201d with focus on age. The project was implemented in 2005 by 5 large European gynecologic cancer centers to identify and verify clinical and molecular prognostic factors for ovarian cancer. The present analysis investigates the prognostic value of age itself as well as possible confounders impairing the prognosis of elderly patients and further elaborates the need for trials specifically designed for age-related questions.Patients with advanced epithelial ovarian cancer FIGO II-IV were prospectively enrolled into the OVCAD project between February 2005 and December 2008 by five European Gynecological Cancer Centers . Data from other clinical subprojects of the OVCAD project has recently been published -11.http://www.ovcad.eu). Clinical data were anonymized and collected in a centralized online database  solely accessible by the OVCAD partners.Patients had to be 18 years or older without evidence of any other primary tumor affecting prognosis or treatment of ovarian cancer. Patients were eligible for study entry if radical surgery was performed with the intention of optimal cytoreduction and platinum-based chemotherapy was applied. Systemic treatment could be given either postoperatively or as neoadjuvant treatment. Patients were selected for neoadjuvant therapy if they were not eligible for surgery (e.g. acute thromboembolism) or initial achievement of complete tumor resection was judged to be very unlikely with upfront debulking surgery by the treating gynecologic oncologist in pre-operative evaluation. Complete surgical staging consisted of total hysterectomy and bilateral salpingo-oophorectomy, peritoneal washings, omentectomy, appendectomy, and resection of all visible tumor if possible. All histopathological reports were re-evaluated for the inclusion criteria after surgery to guarantee accurate diagnosis and staging. To measure treatment response, CA-125 levels were assessed before and after treatment completion and the diagnosis of disease recurrence or progression was established based on CA-125 variations (GCIG criteria), imaging studies, and results of performed biopsies [All statistical analyses were conducted using SPSS software version 20.0  and Stata 11.0 . P-values <0.05 were considered statistically significant.To evaluate the impact of age on treatment and prognosis patients were separated in those <70 years and those \u226570 years as previously proposed . The subA total of 275 patients met the inclusion criteria and were prospectively enrolled into the OVCAD study. Median age of the total cohort was 58 years range 18\u201385) with 228 patients younger than 70 years  and 47 patients aged 70 or older . The median follow up was 36 months. Detailed clinical patient characteristics are provided in Table\u00a08\u201385 withDespite the non-randomized setting both patient cohorts (<70 years vs. \u226570 years) were well balanced in terms of tumor stage, grading, histological subtype and presence of ascites or peritoneal carcinomatosis Table\u00a0. The majIn addition, analysis of treatment-related patient characteristics Table\u00a0 revealedAll included patients received platinum-based chemotherapy according to the inclusion criteria but there were significantly more elderly patients receiving single-agent platinum instead of a combination regimen . Approximately 3/4 of the younger patients experienced clinical response to primary chemotherapy compared a significantly lower rate in the elderly cohort . Taken together only 40.4% of the elderly compared to 70.1% of the younger patients received optimal oncologic treatment as it is considered for the overall patient population consisting of complete tumor resection and platinum-based combination chemotherapy  of 12 vs. 20 months for elderly patients compared to younger patients  is currently planning a prospective trial specifically tailored for elderly women with ovarian cancer (EWOC) that evaluates optimal treatment strategies for elderly patients with the disease but will also address possible new endpoints.Elderly patients with ovarian cancer are often treated less radically than younger patients which has been confirmed in this European multicenter study. Their outcome is significantly impaired despite no consistent prognostic effect of age.Notwithstanding this treatment reality, age itself should not be a reason to withhold optimal oncologic treatment from elderly patients. Comprehensive preoperative assessment should be performed considering the biological age and functional status of the patients. With this information individualized treatment plans can be defined accounting for co-morbidities and expected complications.The authors declare they have no competing interests.FT, LW and SM were responsible for the concept and design of the presented study, analyzed the data and prepared the manuscript. CE participated in the study design and performed the statistical analysis. All authors were involved in the data acquisition and quality control for the trial. All authors supported the manuscript editing, read and approved the final manuscript."}
+{"text": "The results of the RV144 trial support the ability of vaccine induced Antibodies to protect from HIV acquisition. The STEP trial also appears to have impacted viral load in individuals who produced strong T cell immunity. The HVTN has recently reported that our enhanced DNA (Pennvax) can drive T cell immunity as robust as Adenoviral and Pox platforms in an accelerated format in humans. We have now focused on further driving T and B cell immunity by utilizing prime boostGroups of rabbits or Indian Rhesus macaques were vaccinated with enhanced DNA vaccine plasmids encoding pGAG, pPOL + combinations of 3-5 consensus or COT designed envelopes that were either gp140 or gp160 constructs. Both IM as well as a novel minimally invasive skin delivery EP arrays (MID) were studied. DNA vaccinated animals were boosted two months following the final DNA immunization with SF162 gp120 in MF59.In rabbits, nAb titers against a broad panel of Tier 1 viruses was observed by the combination immunization approaches. Titers in the hundreds were induced by DNA and these titers were enhanced almost a log by a protein boost. Similar data was also observed when these studies were extended to the non-human primate model. Importantly, DNA-prime protein-boost had detectable ADCC activity as measured by the GTL and luciferase assay. A bias for improved antibody responses driven by the MID delivery array is also observed.Building on the success observed in HVTN 080 we report that further enhancement of DNA constructs in a prime boost setting (E-DNA prime + protein Boost) is capable of eliciting high binding, broad antibody responses and neutralization titers against a panel of tier 1 viruses. Combining improved E-DNA with other strategies shown to enhance antibody responses such new gene adjuvants are being investigated."}
+{"text": "The recognition that HIV originated from nonhuman primates (NHP) heightens concerns associated with transmission of simian retroviruses to humans. Although recent studies document frequent infection with simian foamy virus (SFV) among primate hunters in Cameroon and primate handlers in North America, little is known about the spread and geographic distribution of SFV outside these populations.We tested 3467 plasma samples collected in 2007 in a population-based survey in 15 rural villages in central Democratic Republic of Congo (DRC). Participants completed a questionnaire about exposure to NHPs. Plasma samples were screened for SFV antibodies using a new Luminex-based EIA; reactive specimens were also tested by a second EIA utilizing recombinant SFV Gag proteins. Specimens dually reactive in both EIAS were then tested using a Western blot (WB) assay that can detect monkey and ape-type SFV reactivity. PCR amplification of DNA from buffy coats and phylogenetic analysis was used to define the NHP species origin of SFV.54 (1.6%) plasma samples were dually EIA reactive and 25 (0.72%) were WB positive. Buffy coats were available for PCR testing from 21 persons with WB positive or indeterminate results. SFV polymerase and LTR sequences were amplified from the DNA of three women 23, 50, and 57 years old. Phylogenetic analysis showed novel SFV infection in two women originating from Angolan Colobus (Colobus angolensis) and in one woman from a red-tailed guenon (C. ascanius), viral variants not previously seen in humans. Both monkeys are native to DRC. Two of these women reported exposure to NHPs via butchering and cooking, and specifically to Angolan Colobus or red-tailed guenons. One woman did not report exposure to NHPs. These women lived in three separate villages, suggesting a wide and potentially diverse distribution of SFV infections across DRC. The younger woman reported a history of monkey pox-like illness. All these women were married and had at least three children but specimens were not available from close contacts for testing. Animal exposure data were available for 3034 persons; 2413 (79.3%) reported NHP exposure.Our study documents SFV infection in the DRC for the first time and identifies human infection with new SFVs from Colobus and red-tailed monkeys. Our findings suggest that SFV is prevalent across Africa in persons exposed to NHPs inhabiting a specific region. Our results highlight the importance of determining if SFVs are transmitted from person-to-person and can cause disease. SFV infection of humans exposed to NHPs also highlights the increased potential for zoonotic transmission of other simian retroviruses with known pathogenic consequences."}
+{"text": "A 35 years old woman presented with allergic rhinitis and asthma with cat epithelium's sensitivity (Skin prick test positive) treated with antihistamines, nasal and bronchial steroids.The patient has been maintening the cat in her apartment. After a couple of years from the onset of respiratory allergic disease, she presented an oral allergy syndrome type clinical reaction, gastric pain and diarrhea at once after eating cooked pork meat . Skin prick test (SPT) performed with commercial extracts and fresh meat were positive for pork meat according with the 'pork-chat syndrome'.Subsequently she presented the same symptoms after eating goat cheese and goat meat.A prick by prick for the culprit foods confermed the food allergy. Recently the same symptoms presented after eating not well cooked beef meat. In her personal history we focused on an anaphylactic reaction occurred at 23 y.o. after injection of antirabbit serum used for antipneumococcal vaccination. The specific IGEs dectection (microarray IMMUNOCAP ISAC system) was positive only for :bovine (Bos d6), cat (Fel d2) ,dog (Can f3), horse (Equ c3) serum albumin and cat, dog lipocalin .No other foods or respiratory allergens specific IGEs were detected.Meat allergy is a rare allergic disorder, more frequent during the first year of life but unusual in adults.Unusually the sensitization to pork meat presented before the goat and beef allergy.Interestingly no milk allergy was found associated to meat allergy (while in children is frequent ). As it's common the patient presented cat sensitivity and subsequently a crossreactivity towards dog,cat and beef serum albumins. The patient avoids pork, sheep,goat meat but she can eat well cooked beef meat."}
+{"text": "Arteriogenesis as a way to restore blood flow after arterial occlusion has been under investigation for the treatmentof coronary artery disease (CAD) for decades. Therapeutic approaches so far have included delivery of cytokinesand growth factors as well as mechanical stimulation such as external counterpulsation. As knowledge on the mechanismsof arteriogenesis expanded, new therapeutic approaches have emerged.This review summarizes recent attempts to stimulate the growth of the coronary vasculature and discusses their potentialin clinical application. This article also delivers an overview of current studies and trials on coronary arteriogenesis. For decades ischemic heart disease (IHD) has been the leading cause of death in industrialized western societies . MacrovaThe following review describes different approaches including inflammatory as well as mechanical stimuli but also highlighting new experimental approaches and possible downsides of an increased coronary collateral vasculature.Approaches to promote collateral artery growth have advanced from animal studies to clinical investigations studies. Arteriogenesis being an inflammatory process  it seemeVascular endothelial growth factor in Ischemia for Vascular Angiogenesis), in which vascular endothelial growth factor (VEGF) was tested versus placebo in IHD had neutral results. Similarly, the AGENT [Angiogenic GENe Therapy) and FIRST [FGF Initiating RevaScularization Trial) studies enquiring the effects of fibroblast growth factor (FGF) on capillary growth showed no benefit over placebo treatment. In the AGENT trial, an adenoviral vector containing a human fibroblast growth factor gene was applied via an intracoronary route in patients with stable IHD. Treadmill exercise testing was used to evaluate efficacy of treatment. Overall, there was a non-significant increase in exercise time between treatment and placebo group. A significant difference in the increase of exercise time was only reported in patients with baseline exercise time of less than 10 minutes. Similarly, the FIRST trial assessed single-shot intracoronary application of recombinant FGF2 (rhFGF2) for improvement of exercise tolerance in patients with coronary artery disease. Again, there was no significant difference reported in comparison to placebo treatment. The VIVA trial focused on recombinant human vascular endothelial growth factor (rhVEGF) in angina patients. Study endpoint was angina frequency and exercise time evaluated by treadmill test. The intracoronary application of rhVEGF resulted in no significant difference of angina frequency and exercise time when compared to placebo. Most of the studies first concentrated on angiogenesis as the main mechanism of blood flow restoration. The VIVA trial   was tested in swine suffering from metabolic syndrome. Treatment with NPY resulted in up-regulation of pro-arteriogenic proteins while down-regulating anti-angiogenic factors  and coulStudies involving a visual angiographic grading of collateralization and analyzing serum concentrations of inflammatory cytokines proved modulation of inflammatory cytokines in patients with good collateralization. Angiostatic ligands such as C-X-C motif chemokine 10 (CXCL10) and C-X-C motif chemokine 11 (CXCL11) were decreased, while higher concentrations of angiogenic ligands were associated with a well-developed collateral circulation .transient receptor potential cation channel family (TrpV4)  in the vessel walls which in turn induce inflammatory mediators [In accordance with the pathophysiology of arteriogenesis corroborating animal experiments, physical exercise was shown to have positive effects on collateral artery growth in the clinical setting , 30. Theediators  and concediators . Also, eediators . Inducedediators . Simultaediators  and thusediators . Consequediators . Generalediators . However1). In the MUST-EECP-study  an increase of coronary flow reserve and alleviation of angina were reported after treatment with ECP [Given the fact that mechanical factors influence arteriogenesis , there hwith ECP . This isTwo studies have directly tested the hypothesis that ECP enhances coronary collateral artery growth. Arteriogenesis Network) trial patients with stable coronary artery disease underwent a 35 1-h sessions of ECP in 7 weeks [In the non-randomized Art.Net.-2  next to an ECP-group (300 mmHg) [Another investigation by Gloekler 00 mmHg) . PatientIn an attempt to reduce angina in symptomatic CAD-patients not suitable for revascularization, the Coronary Sinus Reducer was implanted in fifteen patients. The Coronary Sinus Reducer is an expandable stainless steel stent inserted percutaneously through the internal jugular vein narrowing the coronary sinus (CS) and thus increasing coronary venous pressure. After 6 months, angina was reduced as well as myocardial ischemia as evaluated by dobutamine echocardiography and thallium single-photon emission computed tomography (SPECT) . ConsideCLaudication: Exercise Vs. Endoluminal Revascularization) has proven SE to be even superior to stent revascularization (ST) and sole optimal medical care (OMC) in patients with aortoiliac peripheral artery disease by a significant increase in peak walking distance [An active means of increasing collateral flow and shear stress, particularly in peripheral artery disease (PAD), is supervised exercise (SE). The CLEVER study (distance . Both SE2). Because of similar mechanisms a beneficial effect of exercise can be expected on the coronary circulation as well. In an individual athlete\u2019s report, different levels of physical activity resulted in an increase on both CFI and coronary flow reserve (CFR). At baseline fitness level the healthy sportsman experienced anginal chest pain during a one minute left anterior descending coronary artery (LAD) occlusion, which he did not suffer from at a higher fitness level, suggesting a shear-stress induced arteriogenesis of pre-existing coronary collaterals . A cliniet al. for the first time increased fluid shear stress (FSS) by creation of arteriovenous (AV) side-to-side-anastomoses in the porcine peripheral circulation following femoral artery occlusion [in-vivo has been sought to find a means to translate mechanical arteriogenesis into an exogenously applicable pro-arteriogenic drug. Nevertheless, the conception of an arteriovenous shunt is potentially conceivable in the clinical situation as well, where percutaneous or surgical creation of a coronary AV-shunt in a patient with end-stage coronary artery disease and lack of therapeutic options is theoretically feasible. Pipp cclusion . Here, Acclusion  for the As mentioned above, eNOS is induced during arteriogenesis. Past studies have shown that the presence of NO is critical in arterial growth. Application of NO donating moieties has been demonstrated to stimulate arteriogenesis . SubstanAnimal studies showed increased flow restoration in a femoral artery ligation model following heart rate reduction by If-channel blockade through administration of Ivabradine. In this study, the augmented pulse amplitude is most likely the key to increased circumferential wall stress and increased arteriogenesis . HoweverIvabradine is the first substance assessed for the stimulation of arteriogenesis which has demonstrated proarteriogenic capabilities while attenuating systemic inflammation . Strong Cell therapy has gained vast interest in regenerative medicine in the past years. A prospective study on cell therapy for the stimulation of collateral artery growth using quantitative outcome measures (CFI) is currently lacking. One promising approach could lie in the application of vascular progenitor cells. A recent paper has shown the possibility of applying reprogrammed vascular progenitor cells to increase collateral artery growth , 56. ThiThere are possible downsides to a well-developed coronary collateral circulation that should be considered carefully. A meta-analysis comprising seven studies on restenosis after percutaneous coronary intervention (PCI) and drug-eluting stent (DES) implantation shows that good collateralization before intervention is associated with a 40% increase in restenosis when compared to patients with poor collateralization . In anot"}
+{"text": "We describe the case of a 50-year-old man in whom the finding of avid 18F-FDG uptake of pectoralis major muscle was encountered during investigation of metastatic melanoma.Avid functional  Nevertheless, 18F-FDG is not a tumour-specific substance as it shows non-specific affinity in other normal tissue especially in the skeletal muscle [18F-FDG uptake in muscle are also observed in diabetic patient following administration of insulin, surgical intervention or following immunosuppressive therapy.Active skeletal muscle is a common area for interpretative pitfall which is related to physiological FDG uptake . In addiMuscle uptake can be attributed to voluntary or involuntary muscle activity. Voluntary muscle activity consists of activities such as talking, chewing, and exercising-induced rhabdomyolysis. Involuntary muscle activity would include laboured breathing or stress-induced muscle spasms.Normal muscles accumulates little FDG, uptake of grade 1 or less. Muscles exercised just prior to or around the time of FDG injection can exhibit uptake of grade 3 to 4 . NotwithA 50-year-old gentleman with a small right ankle melanoma had been successfully managed with surgical removal of the melanoma in 2001. He had right inguinal nodal recurrence after 6 years disease-free progression. A PET-CT study performed in June 2007 revealed unexpected intense symmetrical uptake of the pectoralis major muscle . The pat18F-FDG uptake in pectoralis major muscle is conceptually attributed to some form of strenuous eccentric exercise 24 hours prior to PET-CT study.In our case, an avid Exercise is a well known mechanism that is capable of inducing various components of the immune system . IL-6 isThe fact is that a substantiated FDG accumulation in skeletal muscle as shown in our case cannot be entirely explained by the influence of intramuscular glucose uptake for more than 24 hours following exercise.A possible explanation of what appears to augment FDG avidity in this case might have been attributed to ongoing rhabdomyolysis following strenuous exercise. Rhabdomyolysis appears to be a relatively common sequela of strenuous exercise . Of noteIt is noteworthy that the cause of prolonged avid FDG muscle uptake in our case remains unclear as there were neither symptoms related to muscle damage i.e aching nor available biochemical analysis pertaining to the level of creatinine kinase and urine myoglobin levels.Unexpected FDG muscle uptake may occur more than 24 hours following exercise as illustrated in our case. The exact explanation is unclear but underlies the importance of adequate patient preparation and instructions before a FDG PET scan."}
+{"text": "Transesophageal echocardiography detected atrial level hypoxemic right-to-left shunting through a patent foramen ovale (PFO). Percutaneous closure of the PFO was achieved with a PFO occluder device. After placing the PFO occluder device oxygenation increased significantly (\u0394 paO2 119 Torr). The patient received heart transplantation 20 weeks after BVAD implantation and was discharged from ICU 3 weeks after transplantation.We describe the interdisciplinary management of a 34-year-old woman with dilated cardiomyopathy three months postpartum on a cardiac biventricular assist device (BVAD) as bridge to heart transplantation with delayed onset of intracardial shunting and subsequent hypoxemia due to massive pulmonary embolism. After emergency surgical embolectomy pulmonary function was highly compromised (PaOAn increase in pulmonary vascular resistance in patients on BVAD can reopen a PFO resulting in atrial right-to-left shunting and subsequent hypoxemia. The case demonstrates the usefulness of transesophageal echocardiography examinations in the detection of this unexpected event. Percutaneous placement of a PFO occluder device is an appropriate strategy to stop intracardiac shunting through PFO in fixed elevation of pulmonary vascular resistance. In a literature review, few cases of atrial level right-to-left shunt in patients with left ventricular assist devices are described. All these cases were detected either intraoperatively -3 or witA 34 year old female patient was admitted to our hospital with dilated cardiomyopathy three months after birth of her third child. She had a known history of familial dilated cardiomyopathy. Recompensation was not achieved despite maximum medical therapy and insertion of an intra-aortic balloon pump. BVAD  was implanted using a bi-atrial cannulation technique as bridge to heart transplantation. Perioperative transesophageal echocardiography did not show a patent foramen ovale (PFO). Postoperative recovery was immediate and the patient was discharged from the ICU on the third postoperative day.iO2 of 1.0 was necessary to achieve sufficient oxygen saturation (paO2/FiO2 54). Modification of ventilator setting with adjustments of PEEP and peak inspiratory pressure did not lastingly improve oxygenation. Transesophageal echocardiography detected atrial level intracardial shunting . Weaning from mechanical ventilation was successful after 15 weeks.Four weeks after device implantation the patient developed fulminant pulmonary embolism despite therapeutic anticoagulation. Emergency surgical embolectomy for massive pulmonary embolism was performed since thrombolysis was not an option after recent implantation of an artificial heart Figure . Pulmona5 with activated assist device and 160 dyne\u2022s/cm5 with deactivated assist device.After 5 weeks of therapeutic anticoagulation the residual emboli diminished and pulmonary vascular resistance was measured at 184 dyne\u2022s/cmHeart transplantation was performed 20 weeks after implantation of the BVAD and 16 weeks after pulmonary embolism and placement of the PFO occluder device. Discharge from ICU was 3 weeks after transplantation. Informed consent for publication was obtained from the patient.The problem with PFO and left ventricular assist device leading to atrial level right-to-left shunt with consecutive hypoxemia is well described -7. PFO hTherefore, intraoperative transesophageal echocardiography with colour Doppler imaging and contrast with agitated saline is highly recommended before cardiopulmonary bypass and after LVAD activation ,13. AlteThere is only one other case of delayed onset of atrial level right-to-left shunt in patients on ventricular assist device . In thisPersisting elevation of right atrial pressure due to persisting change of the pulmonary vascular resistance in a patient with a BVAD has not been described. An etiologic reason for persisting elevation of pulmonary vascular resistance can be massive pulmonary embolism as described in our case. Our report is the first description of a patient surviving massive pulmonary embolism while on BVAD, followed by successful orthotopic heart transplantation. To the best of our knowledge there is only one other published case of pulmonary embolism in a patient with a BVAD. This patient died shortly after the event .5 to 285 \u00b1 214 dyne\u2022s/cm5 .Click here for file"}
+{"text": "Fully flexible 3D alignment method without the need for sampling the conformational space is presented. This approach offers advantages over methods that rely on multiple conformations:\u2022 Higher accuracy is achieved, since unlike discrete sampling it is not prone to missing optimal conformation.\u2022 Smaller database size is needed, pre-calculated conformers are not stored.The alignment procedure maximizes a score resembles the intersection of the volume of the molecules being aligned. The volume itself can be colored by atomic properties enabling the use of various similarity scores, like shape-, atom type or pharmacophore type similarity.Similarity scores serve as the basis for 3D virtual screening. However, the calculation of 3D similarities is computationally intensive. In order to achieve high performance fast pre-filtering by 3-dimensional molecular descriptors has been introduced. Intra molecular distance ranges are used as shape descriptors and are pre-calculated by the application of the alignment machinery itself in an initialization stage.The presentation overviews the mathematical apparatus introduced, elaborates on the implemented methods and presents results."}
+{"text": "We have previously reported that potent, long-lasting HIV-1 Env-specific cell-mediated immune responses could be elicited in rhesus macaques and mice using plasmids encoding env DNA as the immunogen. Subsequent experiments showed that combination of DNA and protein in the form of inactivated virus particles provided significant protection from infection and high viremia. We examine a vaccine platform combining DNA and recombinant Env protein co-immunization at the same time to generate both strong cellular and humoral immune responses.Mice or macaques were immunized with HIV env gp120 DNA vaccine and/or purified gp120 protein from clade B or clade C isolates. Mice were immunized twice at 4 weeks interval with DNA only, protein only formulated in EM005 adjuvant, or DNA&protein/EM005. Macaques were immunized twice at 4 weeks interval with DNA only, DNA&protein, DNA&protein/EM005.DNA&protein co-immunization enhances the Ab responses compared with DNA or protein only in mice. DNA&protein co-immunization generated similar levels of cellular immune responses compared to mice immunized with DNA only but those levels were significantly higher than those obtained in mice immunized with protein only. The establishment of a mouse model that gives similar results with the macaque model enhances our ability to test many variations and optimize the vaccine. Importantly, in macaques this strategy elicited higher binding and neutralizing Ab responses than DNA only and the neutralizing Abs showed broad activity. The presence of the EM005 adjuvant further enhanced the Ab responses. These responses were correlated with the up-regulated activation of dendritic cells by EM005. The longevity of the Ab response was superior.The strategy of DNA and protein co-immunization has potential for development as a prophylactic HIV-1 vaccine. Our challenge studies show that DNA and protein co-immunized animals developing long-lasting Ab titers were protected from infection."}
+{"text": "Priming of random hexamers in cDNA synthesis is known to show sequence bias, but in addition it has been suggested recently that mismatches in random hexamer priming could be a cause of mismatches between the original RNA fragment and observed sequence reads. To explore random hexamer mispriming as a potential source of these errors, we analyzed two independently generated RNA-seq datasets of synthetic ERCC spikes for which the reference is known. First strand cDNA synthesized by random hexamer priming on RNA showed consistent position and nucleotide-specific mismatch errors in the first seven nucleotides. The mismatch errors found in both datasets are consistent in distribution and thermodynamically stable mismatches are more common. This strongly indicates that RNA-DNA mispriming of specific random hexamers causes these errors. Due to their consistency and specificity, mispriming errors can have profound implications for downstream applications if not dealt with properly. RNA-seq is a widely used tool for transcriptome analysis and gene expression estimation. Most commonly, mRNA is fragmented followed by reverse transcription into first strand cDNA primed by random hexamers. Subsequently, second strand cDNA is synthesized from first strand cDNA by DNA polymerase, again initiated by random hexamer priming. Bias in hexamer distribution and CG content affects abundance estimates and several bias correction algorithms have been developed e.g. -5. Apart from bias in hexamer priming sites, random hexamer mispriming has recently been implicated in sequence read to reference mismatches. Because mismatches mainly occur in the first seven nucleotides of first strand cDNA ,6 and arThis paper deals with sequence read to reference mismatches commonly observed in RNA-sequencing data. Mismatches are defined as any position in sequencing reads that deviate from the reference to which these reads align. Mismatches can reflect 1) true biological variation, both in genomic DNA or caused by RNA-editing, or 2) errors in the library preparation process caused by hexamer mispriming or PCR errors, and finally 3) sequencing errors caused by the erroneous identification of bases in the sequencing process. We focus on errors that most likely arise in the library preparation phase. During RNA-seq library preparation, polyA+ RNA is fragmented and reverse transcribed into first strand cDNA initiated by random hexamer priming. We refer to mismatches between the reference fragment and the observed sequence that are caused by RNA-DNA hexamer mispriming during first strand cDNA synthesis as RD-mismatches. Similarly, we use the term DD-mismatches to describe errors caused by DNA-DNA hexamer mispriming during second strand cDNA synthesis.Errors caused by random hexamer mispriming have thus far received limited attention. While read trimming to exclude error-rich first stretches of RNA-seq reads is done in some studies ,11, therTaraxacum officinale RNA mixed with ERCC RNA spikes. Twenty-three libraries were multiplexed using Illumina\u2019s multiplex sequencing assay and pooled with a 2% ERCC spike [We conducted a RNA-seq experiment of CC spike . SubsequCC spike ; GSM5170We analyzed two independently generated RNA-seq datasets, focusing on reads mapping to ERCC spikes which are artificial RNA fragments of known sequence that are added during library preparation. ReverseFirst strand cDNA mismatches in the first seven base pairs corresponding to the hexamer binding site and the base immediately downstream of this show position-dependent and nucleotide-dependent mismatch patterns . These sThus we conclude that mispriming is non-random and can be heavily biased, as RNA binding sites with a U at positions three and four (relative to the hexamers 5\u2019 end) misprime with hexamers having a G at that position in ~88% of the mispriming cases. These specific mismatch patterns were observed consistently in two independent data sets . The disConsistent mismatch patterns observed in the first seven nucleotides of first strand cDNA will affect downstream applications such as de novo assembly, SNP calling and RNA-editing analysis. For instance, consistent and high (20%) mismatch rates can be problematic for k-mer assembly strategies, as these erroneous k-mers cannot be effectively combined with \u201ctrue\u201d k-mers. Because mispriming rates are not random and for some positions heavily biased  they canIdentification of the hexamers that are most commonly involved in mispriming as well as the type and position of the mismatches this generates can aid in the design of strategies to counter the effects that these errors can have in downstream applications. Our results suggest that it could be useful to explore less aggressive approaches than trimming. Such approaches could include post-mapping correction of 5\u2019 mismatches, modifications to random hexamer design to exclude commonly mispriming hexamers and specific bias correction models that mask or remove the observed mismatches in the first seven bases of reads. Our analyses shows strong and consistent bias in sequence errors in 5\u2019 ends of RNA-seq reads, which (1) strongly supports the hypothesis that random hexamer mispriming during first strand cDNA synthesis causes the errors, and (2) highlights the risk of errors in downstream applications as well as suboptimal data use. We conclude that technical artifacts in sequencing data are insufficiently described. Further research on random hexamer mispriming will inform optimized strategies to mitigate their negative effect on downstream analysis."}
+{"text": "The application of molecular profiling methods to a wide variety of infections suggests that a polymicrobial community is much more common than suggested by standard clinical culture . Our goaCulture and DNA extraction protocols were evaluated using synthetic bacterial communities inoculated into whole blood. Disruption of blood cells with a blood cell lysing detergent, with or without hypotonic osmotic shock, was carried out and evaluated for the ability to recover the community. Viable bacterial cells were recovered on solid media. Total DNA was examined by terminal-restriction fragment-length polymorphism (TRFLP) profiling. Efficiencies of recovery and limits of detection were determined. The optimized methodology was applied to clinical samples collected from consented patients in both the ICU and ED from two Calgary hospitals. Cultured organisms were identified by 16S rRNA gene sequencing. Molecular profiling was carried out using TRFLP and bacterial tag-encoded FLX amplicon pyrosequencing (bTEFAP).Treatment of synthetic community organisms with a 5% wt/vol detergent added at a 1:1 or 1:5 ratio did not significantly impact their viability. TRFLP analysis indicated that the DNA from these communities could be recovered from whole blood following lysis and removal of host cells. Whole blood samples were analysed from septic patients. In three case studies we identified two to 16 bacterial species in the primary infection samples using direct culture and molecular methods. Conventional diagnostics only reported one organism. Molecular profiling of blood samples from these patients also identified correlating polymicrobial communities. Blood cultures for these samples were either negative (two of three cases) or monomicrobial (one of three cases), thereby underestimating the diversity seen with the TRFLP and bTEFAP analysis. These methods have been applied to 88 adult ICU blood samples, 20 primary infection samples, 36 adult ED samples, and seven pediatric ED samples with analysis ongoing.We have successfully developed a novel method to analyse whole blood in order to characterize the microbiome of sepsis infections. Preliminary results indicate that sepsis infections are polymicrobial in nature."}
+{"text": "Diabetic cardiomyopathy is a specific disease process distinct from coronary artery disease and hypertension. The disease features cardiac remodeling stimulated by hyperglycemia of the left ventricle wall and disrupts contractile functions. Cardiac mast cells may be activated by metabolic byproducts resulted from hyperglycermia and then participate in the remodeling process by releasing a multitude of cytokines and bioactive enzymes. Nedocromil, a pharmacologic stabilizer of mast cells, has been shown to normalize cytokine levels and attenuate cardiac remodeling. In this study, we describe the activation of cardiac mast cells by inducing diabetes in normal mice using streptozotocin (STZ). Next, we treated the diabetic mice with nedocromil for 12 weeks and then examined their hearts for signs of cardiac remodeling and quantified contractile function. We observed significantly impaired heart function in diabetic mice, as well as increased cardiac mast cell density and elevated mast cell secretions that correlated with gene expression and aberrant cytokine levels associated with cardiac remodeling. Nedocromil treatment halted contractile dysfunction in diabetic mice and reduced cardiac mast cell density, which correlated with reduced bioactive enzyme secretions, reduced expression of extracellular matrix remodeling factors and collagen synthesis, and normalized cytokine levels. However, the results showed nedocromil treatments did not return diabetic mice to a normal state. We concluded that manipulation of cardiac mast cell function is sufficient to attenuate cardiomyopathy stimulated by diabetes, but other cellular pathways also contribute to the disease process. Diabetic cardiomyopathy is defined as a primary disease process distinct from coronary artery disease and hypertension Mast cells are recognized as active participants in allergic and anaphylactic reactions There is indirect evidence that cardiac mast cell activation may contribute to cardiac remodeling. Mast cell degranulation has been observed in the human heart Based on these previous studies, we propose to use an experimental diabetic cardiomyopathy model to observe if hyperglycemia is associated with cardiac mast cell activation and if mast cell activation correlated with collagen deposition and cardiac remodeling in the heart. We modulate cardiac mast cell activity by administering the mast cell-stabilizing agent nedocromil (Ned) to diabetic mice and then monitor cardiac function, cardiac mast cell activity, expression levels of proteins associated with cardiac remodeling, and the extent of collagen deposition as indirect measurements of the contribution of cardiac mast cell degranulation in diabetic cardiomyopathy.The study protocol was approved by the medical ethics committee of Shanghai Changzheng Hospital, conforms to the Principles of Laboratory Animal Care , and was conducted according to National Institutes of Health guidelines.We used previously described methods to induce diabetes in our mouse model Diabetic mice (13-week-old) were randomly divided into three groups: 1) untreated group; 2) nedocromil group, with nedocromil released at the rate of 30 mg/kg per day from a subcutaneous (s.c.) pellet implantation 2 and 5% CO2 continuously bubbled into the solution. The physiological pressure transducer was sutured to the apical area with 4-0 thread.To assess cardiac function, mouse hearts were isolated and perfused using the Langendorff system Cardiac function indicators were recorded using Powerlab multi-channel physiological recorder. The recorded indicators include maximal contractile rate (+dF/dt), maximal relaxation rate (-dF/dt), heart rate (bpm), and heart work (g.bpm). Heart work was calculated by multiplying the force (g) by the heart rate and normalized to heart weight. After the recording, the left ventricle was placed on ice and then cut transversely into three equal slices perpendicular to the long axis. The slices were either processed immediately for molecular characterization or flash-frozen in liquid nitrogen and stored at -80\u00b0C for future analysis.Histological analyses were performed as previously described Immunohistochemical analysis was performed to determine the number of mast cells and mast cell activation based on chymase expression Real time-polymerase chain reaction (RT-PCR) was used to measure mRNA expression levels of type I and III collagen, and to confirm chymase mRNA expression. Total cellular RNA was extracted using Trizol  according to the manufacturer's instructions. RNA (0.2 \u00b5g) was reverse-transcribed using High-Capacity cDNA synthesis kit . RT-PCR was performed using the QuantiFast Sybr Green PCR kit . The samples were amplified using Light Cycler 480 real-time PCR machine . GAPDH expression was used for normalization. mRNA levels were expressed as fold-change relative to untreated normal or untreated diabetic mice. Primers specific for the target genes, the primer's annealing temperature and amplicon length are listed in Western blots were used to detect the protein expression levels of type I and III collagen, MMP-2, MMP-9, tryptase, histamine, and chymase in cardiac tissues. Protein extraction was performed using a protein extraction kit  and the concentration was determined using a protein assay kit . The extracts were resolved on SDS-PAGE gels by electrophoresis and transferred onto nitrocellulose membranes . The membranes were block with 5% nonfat milk in PBS-T. The primary antibodies used were: rabbit anti-mouse collagen I and collagen III antibodies (dilution 1\u22365000); rabbit anti-mouse MMP2 and MMP9 antibodies (dilution 1\u22361000); rabbit anti-mouse tryptase (dilution 1\u2236100), rabbit anti-mouse histamine (1\u22361000), and goat anti-mouse chymase antibody (dilution 1\u2236200). Goat anti-rabbit HRP conjugated IgG (dilution 1\u22362000), and donkey anti-Goat HRP conjugated IgG (dilution 1\u22365000) were used as secondary antibodies to resolve the signal. All antibodies were purchased from Abcam .Commercial ELISA kits  were purchased to determine the levels of tumor necrosis factor-\u03b1 (TNF-\u03b1), interferon-\u03b3 (IFN-\u03b3), interleukin (IL)-6, IL-10, and angiotensin (Ang) II in cardiac tissue. The assays were performed according to manufacturer's instructions using extracted proteins as described above.Data are expressed as mean \u00b1 standard deviation (SD). ANOVA with Scheffe's-F test was used to determine statistical significance between treatment groups, when appropriate. A p-value of <0.05 was considered significant.Hyperglycemia has long been implicated in the development of cardiac diseases including cardiac remodeling As shown in Cardiac function was evaluated based on four parameters: maximal cardiac contractility, maximal cardiac relaxation, heart rate, and heart work. Heart work was calculated by multiplying the contraction force by the heart rate and normalized to the heart weight. Nedocromil-treated diabetic mice showed significantly improved heart function compared with controls . The conPrevious studies have shown that cardiac mast cells are activated in injured cardiac tissue to mediate cardiac remodeling We performed immunohistochemical studies on cardiac tissues from normal and diabetic mice that underwent nedocromil treatment. We examined mast cell activation by assessing chymase level because the enzyme is overexpressed and released during the degranulation process The number of chymase-positive cells was significantly higher in the cardiac tissues of diabetic mice than in normal mice. Nedocromil significantly reduced the number of chymase-positive cells in samples from diabetic mice, and had little effect on samples from normal mice . The calWe further confirmed cardiac mast cell activation by evaluating the protein levels of additional mast cell-associated enzymes, which are also induced upon mast cell activation We have observed nedocromil treatment improved overall cardiac function in diabetic mice . So, we Trace amount of collagen deposits were observed in the hearts from normal mice, while those from diabetic mice showed significant areas of collagen deposition  that corCardiac mast cell activation was reported to modulate cytokines that contribute to cardiac remodeling Hyperglycemia has long been implicated in cardiac diseases by producing metabolic stress and triggering cardiac remodeling We have presented data that showed cardiac mast cell activation and cardiac remodeling occurs following hyperglycemia. The hearts of STZ-induced diabetic mice showed significantly impaired contractile function that resulted from increased collagen deposits and initiation of extracellular matrix degradation. We also examined chymase and tryptase levels in the heart because the enzymes are known mast cell products and have been linked to increased collagen production and to induce remodeling of the extracellular matrix by cleaving pro-forms of MMP-2 and MMP-9 Many of these features were reversed upon mast cell stabilization using nedocromil. We showed the drug had protective effects against cardiac dysfunction in diabetic mice by reducing mast cell density and chymase secretion, and confirmed the expression of remodeling factors had decreased using biochemical assays.We also observed aberrant cytokine levels in diabetic mice, which may contribute to cardiac remodeling. Nedocromil treatment was able to normalize them in diabetic mice. Cardiac mast cell activation has been reported to modulate cytokines that contribute to cardiac remodeling Tumor necrosis factor-\u03b1 (TNF-\u03b1), interferon-\u03b3 (IFN-\u03b3), and angiotensin Ang (II) have long been associated with cardiac remodeling. They were all significantly increased in diabetic mice. TNF-\u03b1 is known to increase collagen production by stimulating the angiotensin II type 1 receptor The role of IL-6 in cardiac remodeling is unclear because its expression has been shown to vary greatly at different stages of cardiac remodeling in hypertensive rats Our data also showed nedocromil had no effect on blood glucose levels in diabetic mice, indicating mast cell activation is likely correlated with blood glucose levels and not by possible nonspecific effects from nedocromil. We also confirmed the effects of nedocromil had no significant effects in normal mice. However, the drug did not completely inhibit the degranulation process, as shown by the stable tryptase and histamine levels. We speculate that heightened levels of tryptase and histamine in diabetic mice may contribute to cardiac remodeling by an unknown mechanism, which may explain why nedocromil treatment did not completely abrogate the molecular changes observed in diabetic hearts.We have shown a correlation between mast cell activation and cardiac remodeling in diabetic mice. We concluded that regulating mast cell activity was sufficient to significantly improve heart function in diabetic mice, and reduce signs of collage deposition and extracellular matrix destablization. Nedocromil treatment alone normalized the levels of several cytokines that are known contributors to cardiac remodeling. Our results propose that the manipulation of cardiac mast cells can attenuate cardiomyopathy by modulating aberrant cytokine levels. However, this mechanism is insufficient to fully restore normal cardiac functions and suggests other cellular pathways may contribute to the disease process. In addition, the molecular mechanisms that link hyperglycemia and cardiac mast cell activation remain unclear and warrant further study.Figure S1Immunohistochemical staining for chymase in cardiac tissues (400X magnification).(TIF)Click here for additional data file."}
+{"text": "The biology of chronic migraine (CM) as a true entity or as a consequence of analgesic overuse is controversial. There are no available biological markers for CM, while CGRP, a marker of trigemino-vascular activation, has been shown to be increased during acute migraine attacks in episodic migraine .To determine CGRP levels in peripheral blood in a series of patients with CM as compared with matched subjects without a headache history.This series comprises 61 women meeting CM diagnostic criteria (IHC-II 2006 revised) with a mean age of 44 years (range 16-63) and 19 women  without any headache history. CGRP levels were determined in blood samples obtained from right cubital vein between 9-12 am with an ELISA kit from USCN following manufacturer's instructions. Acute medication had not been taken the day before.CGRP levels were increased in women with CM  as compared to controls  .CGRP levels are clearly increased in patients with CM, which is compatible with a permanent activation of trigemino-vascular system in this entity. CGRP determination may constitute the first reliable biological marker for CM."}
+{"text": "To correlate the persistence of new or worsening induced wall motion abnormalities in dobutamine stress magnetic resonance imaging (DSMR) and the extent of coronary artery disease (CAD) in invasive coronary angiography.DSMR is a highly sensitive and specific non-invasive method for detecting induced wall motion abnormalities (IWMAs) in patients with significant CAD. Yet little is known about the duration of IWMA during the recovery period. We hypothesize that the persistence of IWMAs during recovery may be associated with the extent of CAD.DSMR was performed in twenty-eight consecutive patients with suspected or known CAD scheduled for clinically indicated invasive coronary angiography. Each patient underwent routine DSMR including cine imaging at rest and during dobutamine infusion. Additionally, three standard short axis and longitudinal axis views were obtained after five, ten and fifteen minutes during the recovery period in order to detect persisting wall motion abnormalities in ischemic myocardial territories, which were assigned to coronary arteries based on the 17 segment model. Intermediate and severe coronary stenosis were defined as 50-75% and >75% luminal narrowing using invasive coronary angiography, respectively  and at five  and ten minutes  during recovery phase.Patients with intermediate and those with severe stenoses demonstrated no significant difference in the rate pressure product at maximum stress level , during recovery after five minutes (p=0.38) and ten minutes (p=0.16).We demonstrated that normalization of left ventricular IWMAs is related to the extent of CAD. Cine imaging during the recovery phase may be helpful for additional risk stratification."}
+{"text": "We describe our experience in detecting and containing the first documented CRKP outbreak in Saudi Arabia (SA).A prospective investigation of all cases identified with carbapenem resistance during the outbreak peroid and six months prior.During March 2010, a cluster of 6 patients with CRKP was detected. Patients with CRKP were placed under strict contact isolation. Admission and periodic active surveillance cultures showed a downward trend of CRKP clinical cases over the following months to zeros in July and August. All patients had prolonged hospital stay before CRKP detection and the majority had recent history of carbapenem use (75%), colonization/infection with other MDROs (75%), surgical procedures (80%), indwelling devices (83%), and mechanical ventilation (75%). About 33% of patients with CRKP had clinical infection and 58% died during the current hospitalization. PFGE results identified a dominant clone during the outbreak, Figure 1.Infection control practices are not enough to eliminate the emergence of resistant pathogens. More active interventional methods including an antimicrobial stewardship program would be essential to combat the emergence of multidrug resistant organisms.None declared."}
+{"text": "The HIV vaccine regimen showing partial efficacy in the RV 144 study included a canarypox-vectored vaccine (ALVAC). The ongoing HIV vaccine efficacy trial, HVTN 505, involves two gene-based vaccines developed by VRC/NIAID/NIH: plasmid DNA and adenoviral-vectored vaccines. The \u201cNIH Guidelines for Research Involving Recombinant DNA Molecules,\u201d established in 1976, have evolved over time. Current NIH policy is that every clinical trial of rDNA vaccines must have IBC reviews. The primary role of the IBC is to assess risk to public health and the environment.The NIAID Barriers to Clinical Research project identified repetitive IBC review of gene-based vaccines as a barrier. For example, in the last 10 years >100 local IBC reviews have been conducted for the VRC HIV vaccines. IBC reviews for ALVAC vaccines remain a requirement for NIH funding despite completion of a Phase III clinical trial, >20 years of human experience with ALVAC vaccines and widespread community-based use of USDA-approved canarypox-vectored veterinary vaccines, which have not indicated a risk to public health or the environment.The NIAID policy change proposal has been considered by a Recombinant DNA Advisory Committee (RAC) working group. Policy change options were discussed at the September 2011, December 2011 and March 2012 RAC meetings. The RAC proposal will be published in the Federal Register for public comments.Repetitive IBC reviews of rDNA vaccine clinical trials divert time and attention of IBC expertise from truly novel agents and incur a cost to NIH with no added safety benefit. NIAID proposes that IBC review is no longer needed for clinical trials of non-transmissible rDNA vaccines because there are no unique biosafety concerns for this class of vaccines based on their recombinant DNA nature. The IBC specific roles are not applicable for rDNA vaccine protocols and are fulfilled through other regulatory oversight including the FDA."}
+{"text": "Aspergillus nidulans. Fluorescence analysis of haploid and diploid strains expressing KapB::GFP and/or KapA::mRFP showed patches of both karyopherins concurrently translocating long distances in apically-growing cells. Anterograde and retrograde movements allowed those patches to reach cell tips and distal regions with an average speed in the range of \u03bcm/s. This bidirectional traffic required microtubules as well as kinesin and dynein motors, since it is blocked by benomyl and also by the inactivation of the dynein/dynactin complex through nudA1 or nudK317 mutations. Deletion of Kinesin-3 motor UncA, required for the transport through detyrosinated microtubules, strongly inhibited KapA and KapB movement along hyphae. Overall, this is the first report describing the bidirectional dynamics of the main nuclear import system in coenocytic fungi. A functional link is proposed between two key cellular machines of the filamentous fungal cell: nuclear transport and the tip-growth apparatus.Karyopherins are transporters involved in the bidirectional, selective and active transport of macromolecules through nuclear pores. Importin-\u03b21 is the paradigm of karyopherins and, together with its cargo-adapter importin-\u03b1, mediates the general nuclear import pathway. Here we show the existence of different cellular pools of both importin-\u03b1 and -\u03b21 homologues, KapA and KapB, in the coenocytic ascomycete  Cells develop polarity to orient their activities in a variety of different ways . For exaNeurospora crassa and Aspergillus nidulans 82]. Video S1KapB::GFP movement through the cytoplasm of vegetative hyphae . Videos were constructed using MetaMorph\u00ae and/or ImageJ software . Time scale is indicated in sec. Note the movement of KapB::GFP patches through the cytoplasm to the tip and distal regions. Patches crossed SPBs and cytoplasmic MTOCs.(AVI)Click here for additional data file.Video S2KapA::mRFP movement through the cytoplasm of vegetative hyphae . Video displays 7 fs and time scale is in sec. KapA::mRFP moves to the tip and distal regions in patches.(AVI)Click here for additional data file.Video S3Movement of KapB::GFP and KapA::mRFP patches through the cytoplasm of diploid vegetative hyphae . Both fusions move simultaneously. KapB::GFP and KapA::mRFP analysis was done using a dual-channel acquisition device . The video combines three streams: green/GFP (up) and red/mRFP (middle) channels with a third merged video in magenta (bottom). Video displays 5 fs and time is indicated in sec.(AVI)Click here for additional data file.Video S4Comparison of KapB::GFP with RabA(Rab5)::mRFP labeled early endosomes . Video displays 7 fs and time is indicated in sec. The upper video shows the green channel (KapB::GFP) and the middle video the red channel (RabA::mCh). The lower is the merged video in magenta.(AVI)Click here for additional data file.Video S5uncA hyphae Click here for additional data file.Video S6uncA hyphae Click here for additional data file."}
+{"text": "Free-floating left atrial ball thrombus is a rare condition. We report a giant left atrial ball thrombus which was removed under surgery uneventfully, in a 48-year-old male patient with the presence of sinus rhythm and no valvular disease with previous off-pump coronary artery bypass surgery. A left atrial free floating ball thrombus is a relatively rare event, especially without a mitral valve disease [2]. Although rare, it is important because of its potentially fatal effects. The thrombus can produce sudden circulatory arrest by obstructing the mitral orifice or can cause severe cerebral or peripheral embolic events [3]. The following report describes the very unusual case of a patient who underwent an off-pump coronary artery bypass (OPCAB) surgery with a large free-floating left-atrial thrombus. Free-floating left atrial ball thrombus is an extremely rare and serious disorder that usually occurs in the setting of a large, dilated left atrium with stagnant flow, commonly the result of severe rheumatic mitral stenosis and accompanying atrial fibrillation . As LV dysfunction is usually associated with an abnormal mitral flow pattern and reduced filling in the left atrial appendix (LAA), the patient is at risk of stasis of blood in the LAA [11]. Our patient had moderate LV dysfunction which might have predisposed LA thrombus formation.  Significant LV systolic and/or diastolic dysfunction predispose to LA thrombus formation via their secondary effect on LA hemodynamic [ In conclusion, we report a giant left atrial ball thrombus which was removed under surgery, uneventfully, in a patient with the presence of sinus rhythm and no valvular disease with previous CABG."}
+{"text": "From December 2009 to July 2010 there were 47 cases of anthrax amongst injecting drug users in Scotland with 13 fatalities. The majority presented as severe soft tissue infection following i.v. injection or muscle popping as described by Ringertz and colleagues [Patients admitted to the ICU with NF or injectional anthrax from 1 January 2008 to 30 June 2011 were identified. The white blood count (WBC) and C-reactive protein (CRP) at presentation were recorded. Demographic data  were retrieved. All data were collected prospectively for routine ICU management.There were six patients with injectional anthrax and 16 with NF. The results are presented in Table Anthrax releases three factors: lethal factor (LF), edema factor (EF) and protective antigen (PA). PA and LF form lethal toxin which kills macrophages and inhibits B-cell and T-cell function so minimising the immune response to anthrax. This is reflected in the inappropriately low CRP levels at presentation. Severe soft tissue infection in an injecting drug user associated with subjectively poor inflammatory response should raise the possibility of anthrax infection."}
+{"text": "Adjuvant imatinib improves recurrence-free survival of patients following resection of primary KIT-positive gastrointestinal stromal tumors. However, it is unknown whether patients who previously received adjuvant imatinib therapy will respond to imatinib rechallenge as treatment for recurrent disease. Here we present the first report documenting the benefits of imatinib rechallenge in a patient previously exposed to imatinib during adjuvant treatment.A 51-year-old Asian woman with a wedge-resected primary gastric gastrointestinal stromal tumor at high risk of relapse underwent two years of adjuvant treatment with imatinib. Only 10 months after the completion of adjuvant imatinib treatment, a computed tomography scan revealed gastrointestinal stromal tumor recurrence in this patient, with multiple peritoneal nodules in the upper abdomen being detected. Our patient was rechallenged with imatinib 400 mg/day and had a partial response after one month of treatment. Imatinib rechallenge was well tolerated by our patient; the only adverse events she experienced were grade 1 edema, anemia and fatigue. Our patient maintained a partial response two years and six months after the imatinib rechallenge. However, computed tomography scans three months later showed that our patient had disease progression.This case report demonstrates that a patient with a gastrointestinal stromal tumor who had previously received adjuvant imatinib therapy responded to imatinib rechallenge as treatment for her recurrent disease. These results indicate that imatinib sensitivity can be maintained in a patient with previous exposure to adjuvant imatinib therapy. Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumors of the gastrointestinal tract. These tumors are characterized by activating mutations of either receptor tyrosine kinase KIT or, less commonly, platelet-derived growth factor receptor \u03b1 (PDGFR\u03b1) . ImatiniKIT exon 11 mutations who are at high risk of relapse following surgical resection of the primary GIST [A recent Korean, single-arm, Phase II study evaluated the efficacy of two years of adjuvant imatinib treatment in GIST patients with ary GIST . The stuary GIST . These rary GIST , it remaKIT exon 11 deletions, a genotype shown to be associated with adverse outcomes after surgery [KIT exon 11-mutant GIST at high risk of relapse [A 51-year-old Asian woman diagnosed with a primary gastric GIST underwent wedge resection, achieving complete removal of the entire tumor with microscopic examination of the margins showing no tumor cells (R0 margins). She was considered at high risk for recurrence based on the tumor size (8 cm \u00d7 7 cm \u00d7 3 cm) and high mitotic rate (>50 mitoses per 50 high powered fields (HPF)) of the excised GIST ,10. In a relapse . Our patTen months after stopping adjuvant imatinib treatment, recurrence was detected in this patient, as computed tomography (CT) scans revealed three gross peritoneal nodules in her upper abdomen Figure  and 1B. The results of this case report demonstrate that a GIST patient who has undergone adjuvant imatinib therapy responded when rechallenged with imatinib as a treatment for her recurrent disease. These results suggest that sensitivity to imatinib was not compromised by prior exposure to adjuvant imatinib.KIT exon 11 mutations at high risk of recurrence  [KIT mutations, along with a high mitotic rate and larger tumor size, was an independent risk factor for poor prognosis in patients with localized GIST [KIT exon 11 mutations appeared to be more sensitive to imatinib treatment than GIST of other genotypes in the metastatic setting [KIT exon 11 mutations at high risk of recurrence would be most likely to benefit from adjuvant treatment with imatinib. The fact that some patients, including our patient described in this case report, developed disease recurrence after stopping adjuvant therapy suggests that two years of adjuvant imatinib treatment may not be sufficient for eradicating residual GIST tumor cells and preventing relapse in these high-risk patients. Our patient's residual tumor cells remained sensitive to imatinib therapy, as evidenced by her good response to subsequent imatinib rechallenge. However, it appears that the sensitive residual tumor cells need to be continuously suppressed with adjuvant imatinib therapy to prevent or further delay disease recurrence. The question of how long patients should be treated with adjuvant imatinib remains. The Phase III study conducted by the Scandinavian Sarcoma Group (SSG) and the Sarcoma Group of the Arbeitsgemeinschaft Internistische Onkologie  recently demonstrated that three years of adjuvant imatinib treatment, compared with one year of imatinib treatment, significantly improves RFS and OS in GIST patients who have a high estimated risk of recurrence after surgery [The Korean adjuvant Phase II study referred to in this case report enrolled patients with resected primary GIST possessing  \u226510 cm) ,10. Our  setting , patient surgery . This su surgery .Our patient in this case report remained progression-free for two years and nine months, which is shorter than the median progression-free survival (PFS) of approximately four years achieved in a Korean Phase II study of patients with advanced GIST , but lonRechallenge with imatinib may provide substantial clinical benefit to patients with recurrent GIST after cessation of adjuvant imatinib therapy.Written informed consent was obtained from our patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.YKK is a consultant for Novartis, and has received research funding and honoraria from Novartis for lectures."}
+{"text": "Radio-frequency catheter ablation (RFCA) in children is difficult because the size of heart chamber change with age and the catheter made for adults is not appropriate for a child. Three-dimensional (3D) images for electroanatomic mapping (EAM) have been used to create from images of multi-detector computed tomography (MDCT) which need to perform entailed by contrast medium injection and radiation exposure. This study sought to evaluate the usability of 3D Cardiac Magnetic Resonance Image (CMR) in pediatrics cases.Between June 2009 and May 2012, 164 young patients  underwent RFCA. 84 patients underwent CMR prior to RFCA without beta blocker and nitroglycerin. CMR was performed by using 1.5-T magnet MR systems  with 5-element cardiac coils. EAM was created by the Carto XP system. CMR results were visually inspected by at least two experienced angiographers whether the image quality of 3D CMR is sufficient for EAM. We also make a comparison of radiation exposure time between with and without 3D CMR images.In spite of dull images because of sinus tachycardia, all CMR images were sufficient for EAM. Radiation exposure time with EAM from CMR was significant shorter than without CMR .CMR image integration into EAM system was successfully performed in pediatrics patients undergoing RFCA. Procedure of CMR didn't require any medication, contrast medium or radiation exposure. In pediatrics cases, almost all cases are considered an indication for CMR imaging for EAM.None."}
+{"text": "Evaluate Internal Flow Fraction (IFF) in Tetralogy of Fallot (TOF) patients before Pulmonary Valve Replacement (PVR) to examine the progression of left ventricular dyssynchrony.Standard of care for TOF patients is a complete surgical repair in infancy but this results in free pulmonary regurgitation as no suitable long-term substitute for the obstructive valve is available. Although chronic pulmonary regurgitation can be well tolerated for decades, many patients (>20%) eventually develop right ventricular dysfunction and often require PVR. Determining the optimal timing of PVR is difficult, and there is no clear consensus within the medical community.In TOF patients before PVR, clinical studies have demonstrated a correlation between QRS duration and RV size with negative electromechanical interaction and dyssynchrony that progresses with RV enlargement. IFF is a quantitative measure of the energy loss throughout the cardiac cycle due to dyssynchronous contraction. We have developed a means of quantifying IFF non-invasively from cardiac magnetic resonance (CMR) images. In this study, we hypothesized that IFF within the left ventricle would increase in serial CMR exams prior to PVR.We retrospectively analyzed two serial CMR studies in 24 pediatric patients with TOF and complete surgical repair before PVR. The average age at the first CMR was 10.8 +/- 5 years and the average age at the second CMR was 14.1 +/- 5.4 years. Images were obtained with 1.5T MRI systems; cine SSFP sequences were acquired in short axis with no gap and covered the entire left ventricle. Global left ventricular IFF was evaluated using an in-house developed MATLAB program.Global left ventricular IFF was significantly increased between the two CMR exams , Figure Left ventricular IFF increased over time in pediatric TOF patients with complete surgical repair. The increased IFF indicated more dyssynchronous contraction developed over time before PVR. The IFF could be a new marker for PVR timing in TOF patients and warrants further investigation."}
+{"text": "Percutaneous transthoracic left ventricular (LV) access and closure would be an enabling technology for a wide range of structural heart, electrophysiologic and proximal aorta procedures. We propose a real-time MRI guided approach to access and close the LV using novel active devices.Sixteen Yorkshire swine underwent percutaneous transthoracic LV access and followed up to three months (n=8).All procedures were guided by real-time bSSFP MRI  using two slices along the needle trajectory and a short-axis slice for cardiac monitoring.Transthoracic ventricular puncture was performed using a customized 18G active needle with integrated loop coil. Puncture trajectory was planned using real-time MRI to identify optimal LV puncture target and trajectory with respect to intraventricular and valvular structures Figure . After nVentricular puncture hole was closed using a modified Amplatzer muscular VSD occluder with a titanium screw to improve MR appearance. A custom active delivery cable incorporating a loopless antenna was used to enhance the visibility of the device deployment.Occluder device was deployed by opening the distal disk at the endocardial surface Figure , separatReal time MRI guidance enabled access to the LV without injuring intraventricular structures in 15/16 animals. In one animal the sheath injured the inter-ventricular septum.Real-time MRI guided LV closure was achieved using the occluder device. Three types of failure modes of VSD occluder device mediated closure were observed during follow up. (1) Device was pulled out of the LV wall and resulted in fatality . (2) Pericardial entrapment by the proximal disc of the device resulted in continuous bleed and mortality . (3) In one animal the puncture was apical and despite appropriate delivery, the device could not effectively occlude the puncture hole.During follow-up (n=9), small pericardial effusion was aspirated on days 3-6 (196\u00b1127 ml). LV function was preserved and histology analysis indicated complete healing process around the device with no distant myocardial effects.Percutaneous transthoracic LV access and closure is a feasible approach using real time MRI and active devices. Transient \u201cpermissive pericardial tamponade\u201d is important for effective deployment of the closure device."}
+{"text": "Populus spp.) is considered a model tree species for genomics research and also a good system in forest pathology [Melampsora poplar rust. We pursued various approaches to identify poplar genes involved in the interaction with the biotrophic Melampsora rust pathogen.With their long life cycle, trees must have accurate mechanisms to perceive microbial invasion and elaborate signalling networks in order to activate the appropriate defense response through transcriptional reprogramming. Transcriptional activators and repressors participate in the tight regulation of the stress response, which is key to minimise the fitness costs associated with an activated response. With the availability of its whole genome sequence, ease of growth and clonal propagation, and routine transformation, poplar  are associated with poplar disease resistance against Melampsora rust [PtiZFP1, which belongs to the C2H2 ZFP family of transcriptional EAR repressors.The JAZ family of transcriptional repressors were recently identified as key negative regulators of jasmonate (JA) responses.Transcript analyses show that some ZFP and JAZ members exhibit hormone-related expression profiles and up-regulation by rust infection. This up-regulation of JAZ and ZFP transcripts after rust infection strongly suggests that a hormonal response including JA is a key component of the poplar defence response against Melampsora. Late and sustained kinetics of PtiZFP1 and specificJAZ up-regulation suggest that the corresponding proteins may be required for late regulation of defense mechanisms.Recent transcriptome analyses from our lab have shown that the expression of genes encoding several transcription factors are up-regulated during infection by ora rust . New datPtiZFP1 through the 26S proteasome.Our work suggests that PtiZFP1 and JAZs are part of Melampsora specific hormone-related responses, and by correlation as putative transcriptional repressors, participate in the regulation of the transcriptional responses downstream of these stress hormones.We hypothesize that the observed gene induction play a negative feedback loop needed to replace PtiZFP1 and JAZ proteins that were degraded following through the 26S proteasome. Newly synthesized repressor proteins could contribute to defense attenuation and therefore prevent a runaway response.Several recent data have shownthat proteolytic cleavage of transcriptional repressors is a general mechanism used by plants to activate gene induction. This mechanism is now well documented for jasmonate signaling, which depends on proteasome-mediated degradation of the JAZ repressors ,4. In thMelampsora. The activation of poplar MAPKs would lead toPtiZFP1 degradation and as a result to transcriptional activation of defense-related genes. In parallel we also observed that several genes involved in the JA response (including JAZ) are induced following Melampsora infection. This model highlights the importance of the 26S proteasome in regulating protein pools of transcriptional repressor. For future studies we intend to uncover which cis elements and target genes are recognized by PtiZFP1 and perform functional approaches to uncover JAZ interacting proteins in poplar.Based on our data, we propose a model Figure  where twPtiZFP1 inhibit the expression of stress-related genes. Following stress perception, a MAPK signaling cascade is activated leading to phosphorylation of PtiZFP1. Phosphorylation targets PtiZFP1 for degradation via the 26S proteasome (P26S), thus relieving repression of defense genes. Defense signaling in turn activates PtiZFP1 gene transcription in order to replenish normal PtiZFP1 protein levels and complete a regulatory cycle necessary to attenuate the defense response. A similar regulatory cycle exists for jasmonic acid (JA) signaling. JA biosynthesis is induced by stress which then promotes proteasome-mediated degradation of JAZ proteins. These indirect transcriptional repressors sequester the bHLH MYC2, thus inhibiting expression of defense genes under non-stressed conditions. Upon release, MYC2 ensures both positive and negative feedback loops by activating LOX3 and JAZ genes respectively. Confirmed and hypothetical pathways are presented in bold and dashed lines respectively.During normal conditions, direct transcriptional repressors such as"}
+{"text": "Antiviral treatment is associated with reduced mortality, length of stay and improved clinical outcomes among patients hospitalized with influenza.We wished to assess trends in use of antiviral treatment of adults hospitalized with influenza before , during and after the 2009 influenza pandemicCNISP has carried out prospective surveillance for laboratory confirmed influenza in hospitalized adults since 2006. These data were reviewed to assess antiviral use.>65 years. A decrease in antiviral use among inpatients >65 years was not observed until the 2011-2012 season. A median of 3 days between symptom onset and antiviral treatment was reported for all three influenza seasons. Among high-risk groups, adults with underlying medical conditions were significantly more likely to receive antiviral treatment during the pandemic than during the post-pandemic seasons . A higher proportion of adults admitted to the ICU during the 2009 pandemic (94.2%) received antiviral treatment compared with the 2010-11 and 2011-12 seasons . There was no difference in antiviral treatment among inpatients who died within 30 days of admission during the pandemic (84.3%) than during the post-pandemic seasons .A higher proportion of adults hospitalized with laboratory-confirmed influenza received antiviral treatment during the 2009 influenza pandemic  compared with the 2010-2011  and 2011-12  influenza seasons. The decrease in antiviral us . e between the 2009 pandemic season and the 2010-11 season was statistically significant in all age groups except for inpatients Antiviral treatment of adults hospitalized with laboratory-confirmed influenza significantly fell in the two seasons following the 2009 influenza pandemic. In order to guide strategies aimed at minimizing the impact of influenza among hospitalized adults, reasons for the decline in antiviral treatment need to be further explored.None declared"}
+{"text": "Epigenetic mechanisms including DNA methylation are supposed to play a key role in fetal development. Here we have investigated fetal DNA-methylation levels of 27,578 CpG loci in 47 chorionic villi (CVS) and 16 amniotic cell (AC) samples. Methylation levels differed significantly between karyotypically normal AC and CVS for 2,014 genes. AC showed more extreme DNA-methylation levels of these genes than CVS and the differentially methylated genes are significantly enriched for processes characteristic for the different cell types sampled. Furthermore, we identified 404 genes differentially methylated in CVS with trisomy 21. These genes were significantly enriched for high CG dinucleotid (CpG) content and developmental processes associated with Down syndrome. Our study points to major tissue-specific differences of fetal DNA-methylation and gives rise to the hypothesis that part of the Down syndrome phenotype is epigenetically programmed in the first trimester of pregnancy. The epigenetic composition of the fetus has gained much attention in the recent past. In particular, the patterns of DNA methylation and their changes during normal and pathologic fetal development are subject of studies in various fields of research. These include reproduction failure, effects of assisted reproduction, disturbances of the maternal-fetal interface, disorders of development, syndromes caused by errors in imprinting, fetal programming of behavior or disease or the impact of maternal factors on fetal development Compared to its sequence the methylation of DNA shows a much higher plasticity both intra- and interindividually. DNA methylation patterns differ between tissues and epigenetic modifications are supposed to be major determinants of the cell type-specific gene expression program and, thus, to imprint the cellular protein expression, function and destiny This figure - besides through the effect of modifier genes - could well be explained by a secondary epigenetic mark influencing cardiac development established or erased directly or indirectly through the effect of a gene on chromosome 21.DNA methylation patterns can also be of relevance for diagnostics. In this regard, a series of locus-specific and genome-wide DNA methylation profiling studies has been performed in the recent past in order to detect methylation patterns differentiating fetuses with chromosomal aberrations from those with normal karyotypes. This led to the development of novel approaches for noninvasive prenatal diagnosis of e.g. trisomy 21 by analysis of fetal-specific DNA methylation in maternal blood It is remarkable, that description of fetal trisomic and non-trisomic fetal DNA methylation patterns, respectively, has so far been almost exclusively based on the analysis of a limited number of placental DNA both from first and third trimester pregnancies In order to characterize and compare DNA methylation patterns between amniotic and chorionic tissue samples we performed an array-based methylation profiling study in an extensive series of 63 fetal tissues derived from routine prenatal AC and CVS sampling. Through analysis of CVS samples from fetuses with trisomy 21 we unravel potential novel markers for non-invasive prenatal testing. Finally, by describing the molecular features shared by the genes differentially methylated between the different tissues as well as the CVS samples with and without trisomy 21 we provide initial insights into the biological processes underlying epigenetic patterns in normal fetal differentiation and development as well as potentially in the manifestation of the typical phenotype of Down syndrome.The study was performed on 63 samples from 61 different women left over from routine prenatal cytogenetic testing. This included 47 chorionic villi samples (CVS) and 16 samples derived from amniocentesis (AC). CVS and AC sampling was performed with written informed consent of the patients according to standard methods. The main indications for invasive prenatal testing were advanced maternal age as well as abnormal ultrasound findings such as elevated nuchal translucency (NT) or abnormal first trimester screening. Clinical details on the pregnancies as well as pregnancy outcome are summarized in DNA was extracted from native CVS tissue left over after setting up direct preparations and long-term cultures for cytogenetic analyses as well as from long-term cultured AC cells. Samples were cryopreserved until DNA extraction. DNA extraction was performed centrally by a single person to widely exclude batch effects applying the High Pure PCR Template Preparation Kit .DNA methylation analysis using the HumanMethylation27k BeadChip  was performed using a custom service provided by AROS Applied Biotechnology AS . The HumanMethylation27 BeadChip was developed to assay 27,578 CpG sites selected from more than 14,000 genes in parallel simple scaling normalization) were done using the lumi package for R Raw hybridisation signals were processed using GenomeStudio software  applying the default settings. Further analyses were performed using the R-package http://igc.otago.ac.nz/home.html26 and http://www.geneimprint.com/site/genes-by-species27) and a previously published review To analyze whether promoter regions of differentially methylated genes showed different CpG compositions, we used a previously described classification into promoters with high (HCP), intermediate (ICP) and low (LCP) CpG content KIAA0575, ECEL1, SOX11 and STG4 has been analyzed in this study.Bisulfite conversion of genomic DNA was performed using the EpiTect Bisulfite Conversion Kit  according to the manufacture\u2019s protocol. Bisulfite Pyrosequencing was performed according to previously published protocols AMEL gene locus using primers yielding different sized PCR fragments from the X-chromosomal  and Y-chromosomal  copy of the gene. PCR fragments were analyzed using an ABI 3100 . DNAs from peripheral blood of normal males (n\u200a=\u200a6), normal females (n\u200a=\u200a5) as well as mixtures of normal male and female DNA  acted as control. The ratios of the peak area of X- and Y-chromosomal specific peaks were calculated. Using the controls as standard values in a regression analysis, the content of fetal tissue in CVS samples has been determined in CVS samples from male fetuses.To determine the content of fetal tissue in CVS samples obtained from male fetuses we performed a PCR based GeneScan analysis on the Applying the \u201cInfinium HumanMethylation27 BeadChip\u201d we investigated 27,578 CpG sites selected from more than 14,000 genes in a series of 63 fetal tissues left over from routine prenatal genetic testing. In particular, we investigated 47 chorionic villi samples (CVS) and 16 samples derived from amniocentesis (AC). Besides samples from fetuses with normal male or female karyotype these included six cases with trisomy 18  and three cases with trisomy 21 . One CVS sample was derived from a fetus with a gonosomal chromosome pattern typical for Turner Syndrome. Two samples  were obtained from pregnancies induced by intracytoplasmatic sperm injection (ICSI). None of the chromosomal aberrations was mosaic. Clinical details are summarized in The reproducibility and validity of the applied array platform for determination of DNA-methylation levels has been extensively demonstrated by us in previous studies using different types of samples and comparison to alternative techniques like methylation specific PCR, bisulfite pyrosequencing or bisulfite sequencing \u221215, t-test) differentially methylated between AC and CVS  of the complete data set from the remaining 50 samples clearly separated AC from CVS samples . This in and CVS . Like in and CVS . We concInterestingly, inspection of the heatmap  suggesteAMELX/AMELY locus in CVS samples derived from male fetuses revealing a detectable maternal contamination of between 0% and 29% (median 17%).The more intermediate methylation levels of the genes differentially methylated between amniotic and chorionic samples could be due to the fact that tissue sampled by CVS is a mixture of various embryonic and also maternal cell compartments. In contrast, cells derived from AC usually lack maternal contamination if the sample is not contaminated by blood. The potential differences in the contribution of maternal cells between AC and CVS prompted us to investigate the correlation of the DNA-methylation patterns with fetal sex. Unsupervised analysis of the 50 samples already suggested that fetal sex was less visible in the methylation pattern of CVS than in AC. To corroborate this observation we focused on the X-chromosomal genes as many  of those are being methylated in 50% of the X-chromosomes of females due to X-inactivation not present in normal males. In an unsupervised approach both AC and CVS samples separated according to fetal sex based on the methylation levels of the X-chromosomal genes. Nevertheless, three CVS samples from male fetuses clustered separately from the other CVS samples of male fetuses , arrow. Next we wondered whether the 2014 genes differentially methylated between amniotic and chorionic samples share certain biological features. Several studies demonstrated that genes with promoters either containing a high CpG content (HCP) or a low CpG content (LCP) show different DNA methylation properties We further investigated whether genes differentially methylated between AC and CVS were enriched for certain biological functions by performing a gene ontology analysis. This approach revealed that the 2014 genes differentially methylated between AC and CVS were significantly enriched for genes involved in various regulatory and developmental processes including e.g. regulation of adenylate cyclase activity which might point e.g. to hormonal or neuronal signaling . In addiOne single locus  was differentially methylated between CVS with trisomy 18 and both normal CVS and peripheral blood samples from normal females (hypermethylated in trisomy 18 samples).Finally, we wondered whether maternal factors could be associated with methylation differences in CVS and AC samples with normal karyotype. Due to the tissue differences shown above we treated both sample sources differently. By PCA we failed to detect any significant effect of maternal age, BMI or smoking status on the methylation pattern in AC and CVS, respectively (data not shown). Probably, the number of samples under investigation was too low to get a conclusive significant result.Having determined the methylation patterns in AC and CVS samples with normal karyotypes we aimed in the second part of the analyses at investigating whether fetal trisomies were associated with an altered DNA-methylation pattern. We limited the bioinformatic analyses to the CVS samples as the number of fetuses with a trisomy in the AC population was too low. In the three CVS samples with a fetal trisomy 21 (including one conceived by ICSI) a total of 464 loci ; q<0.01 In contrast to the samples with trisomy 21, an analysis comparing the five CVS samples with trisomy 18 to the normal controls identified only 15 significantly differentially methylated loci, corresponding to 14 genes . No signFinally, we wondered whether the single sample of AC with trisomy 18, the CVS sample with a gonosomal chromosome pattern typical for Turner Syndrome and the AC samples derived from a pregnancy after ICSI showed peculiar patterns of methylation. Obviously, bioinformatic analysis of single samples is meaningless. Nevertheless, displaying the methylation pattern of the X-chromosomal genes in the Turner sample as compared to the mean values of the normal male and female CVS samples showed lack of both, the typical female X-inactivation pattern and of the male methylation pattern . FinallyIn the present study we performed array-based methylation profiling on an extensive series of fetal samples with normal and aberrant karyotypes obtained by routine prenatal CVS and AC sampling. Obviously, relying on left-over samples from routine prenatal testing implements a certain selection bias as with few exceptions only fetuses at risk for chromosomal aberrations and/or with abnormal ultrasound findings or maternal serum screenings will be sampled due to ethical considerations. Thus, the present series was enriched for pregnancies with normal karyotype but abnormal ultrasound (n\u200a=\u200a12), aberrant first trimester screen (n\u200a=\u200a23) or advanced maternal age (n\u200a=\u200a41) (multiple answers were permitted). Moreover, samples with known chromosomal aberrations were included on purpose. Thus, the analyses provided here reflect the findings of an \u201cat-risk\u201d cohort rather than of the normal distribution of pregnancies.http://www.molcell.rwth-aachen.de/dms. Based on the DNA methylation values of seven CpG loci present on the HumanMethylation27k Bead Chip Koch et al. developed an algorithm to investigate these parameters from in vitro cultured cells Moreover, it needs to be taken into account that whereas native (cryopreserved) CVS samples were investigated without prior culturing the AC cells had to be cultured to obtain sufficient amounts of DNA for the analyses. In this regard it needs to be considered that amplification of unmodified DNA prepared from uncultured AC cells would not have been suitable for the methylation arrays applied as by the amplification process the DNA methylation marks get lost. In turn, amplification of bisulfite treated DNA might have introduced experimental biases due to selective amplification of methylated or unmethylated DNA. The minute DNA amounts left over after routine diagnostics from uncultured amniotic cells might also be the reason why hitherto genome-wide methylation profiling studies focused on CVS or placental samples. Obviously, culturing cells harbors the risk of changing the DNA methylation pattern. Nevertheless, based on our own and others reports on lymphoblastoid cell lines as compared to normal lymphocytes we think that the culture-induced methylation changes are minor as compared to the tissue-specific differences which were in the focus of the present study Even taking into account potential sampling and culturing artifacts the differences in the methylation patterns between CVS and AC samples with normal karyotype were striking. Investigating nearly 800 selected genes using the Illumina GoldenGate DNA Methylation Cancer Panel I array, Yuen et al. A striking feature of loci differentially methylated between CVS and AC were the preferentially intermediate methylation levels of these loci in CVS in contrast to the extreme DNA-methylation levels in AC samples . DNA metAnother feature which explains intra-sample heterogeneity might be contamination with maternal cells. By analysis of X-chromosomal methylation patterns we show (here) that such contamination might be variable and can even affect detection of the fetal sex via methylation-based X-inactivation patterns. In contrast to the CVS samples cultured cells derived from AC usually lack maternal contamination.F2RL3 locus recently shown to be differentially methylated in peripheral blood with regard to the smoking status We failed to identify any association of maternal factors like maternal age, BMI or smoking status on the methylation pattern in AC and CVS likely due to the small size of the cohort for such analyses. In line with this, targeted analysis of the Analyses of the association of karyotypic aberrations with DNA methylation levels had to be restricted to CVS samples due to the low number of AC samples with such changes. The intra-sample variability of CVS samples described above might be the cause that we only detected 15 loci, corresponding to 14 genes  significCOL6A2, H2BFS, RUNX1) and 1/17 hypomethylated (MCM3AP) genes are located on chromosome 21. Thus, the trisomy 21 is associated with a genome-wide perturbance of DNA methylation not restricted to chromosome 21 that predominately leads to hypermethylation. This is in line with the pattern of differentially methylated genes observed by Kerkel et al. Remarkably, in trisomy 21 fetuses studied herein more than 95% (387/404) of the differentially methylated genes were hypermethylated as compared to normal CVS samples. Only 3/387 hypermethylated Click here for additional data file.Figure S2Verification of results obtained from BeadArray analysis by bisulfite pyrosequencing (BPS). 6 CpG loci have been analyzed both by BPS  and by BeadChip technology  in the same samples. The color code indicates methylation value . (B) Scatter plots of results obtained in (A). Pearson\u2019s product-moment correlation r2\u200a=\u200a0.69(TIF)Click here for additional data file.Figure S3The majority of CpG loci present on the array are comparably methylated in CVS and AC samples. Histograms showing the frequency of the DNA methylation values in CVS (A) and AC (B). Scatter plot comparing DNA methylation values of CVS and AC samples (C). Histograms and scatter plots show DNA methylation values of CpG loci not differentially methylated between AC and CVS . Pearson\u2019s product-moment correlation r2\u200a=\u200a0.94.(TIF)Click here for additional data file.Figure S4Hierarchic cluster analysis of DNA methylation values of 767 X-chromosomal CpG loci present on the array. The upper panel on top of the heatmap indicates the sample type  while the second panel indicates the fetuses\u2019 sex . The third panel indicates normal karyotype (yellow) versus Turner syndrome (black). Three CVS samples from male fetuses show a DNA methylation pattern similar to female samples (arrow). A blue bar at the right site indicates genes methylated specifically in male fetuses, an orange bar genes methylated in female samples and a black bar genes with tissue- specific DNA methylation.(TIF)Click here for additional data file.Figure S5The AC sample derived from a pregnancy after ICSI showed a peculiar pattern of methylation. PCA (A) and hierarchic cluster analysis of DNA methylation values of 2418 CpG loci differentially methylated between AC (green sphere (A) or green square (B)) and CVS (red sphere (A) or red square (B)) . One AC sample from ICSI is indicated by a blue sphere (A) or a blue square (B), respectively.(TIF)Click here for additional data file.Table S1Clinical characteristics of the samples included in the study.(XLS)Click here for additional data file.Table S2Gene ontology terms (GO) significantly enriched in the group of genes differentially methylated between CVS and AC samples as compared to the entirety of loci present on the array .(XLS)Click here for additional data file.Table S3Gene ontology terms (GO) significantly enriched in the group of genes differentially methylated between CVS samples without chromosomal imbalances and samples with known trisomy 21 as compared to the entirety of loci present on the array .(XLS)Click here for additional data file.Table S4DNA methylation values  of loci differentially aberrantly methylated in trisomy 21 (sheet 1) and trisomy 18 (sheet 2). Data from CVS (trisomy and CVS) as well as from peripheral blood samples from normal female and male donors are included.(XLS)Click here for additional data file."}
+{"text": "Most vaccines are delivered into the muscle although it contains very few potent antigen presenting cells, such as dendritic cells (DCs) that are critical for driving adaptive immune responses. Understanding the early mechanisms that dictate vaccine responses and why some adjuvants like the oil-in-water emulsion MF59 are shown to be more potent than alum is important for the design of new vaccines. Here, we investigated the recruitment of immune cells to the vaccine injection site and uptake of a clinically relevant HIV-1 envelope glycoprotein (Env) and MF59 in a non-human primate (NHP) model.Rhesus macaques received intramuscular injections of either fluorescently-labeled Env gp120 alone or together with MF59 in the deltoid and quadriceps muscles. Donor-matched injections of PBS and MF59 alone served as controls. At 24-72 hrs, blood, muscle and lymph nodes were sampled for flow cytometry and confocal microscopy.There was a robust infiltration into the muscle of multiple immune cells by MF59+/-Env. CD66abce+ neutrophils were most frequent followed by CD14+ monocytes and CD11c+ myeloid DCs. CD123+ plasmacytoid DCs which do not normally reside in muscle, were also recruited by MF59. Internalization of Env and MF59 was readily detectable in all DC subsets both in the muscle and in the draining lymph nodes. Although injection of Env alone did not lead to cell infiltration, the few resident DCs showed efficient Env uptake. Groups receiving Env together with distinctly different adjuvants  are underway.MF59 as an adjuvant leads to significant influx of cells that efficiently engulf vaccine protein antigen. Antigen/adjuvant carrying DC subsets appear early in the lymph nodes draining the injection site. As NHP DC subsets are similar to humans, this offers a powerful model that can yield data to be translated into optimizing future vaccine formulations and delivery strategies."}
+{"text": "Asthma is a chronic inflammatory disorder of the lung airways that is associated with airway remodeling and hyperresponsiveness. Its is well documented that the smooth muscle mass in asthmatic airways is increased due to hypertrophy and hyperplasia of the ASM cells. Moreover, eosinophils have been proposed in different studies to play a major role in airway remodeling. Here, we hypothesized that eosinophils modulate the airways through enhancing ASM cell proliferation. The aim of this study is to examine the effect of eosinophils on ASM cell proliferation using eosinophils isolated from asthmatic and normal.Eosinophils were isolated from peripheral blood of 6 mild asthmatics and 6 normal control subjects. ASM cells were incubated with eosinophils or eosinophil membranes and ASM proliferation was estimated using thymidine incorporation. The mRNA expression of extracellular matrix (ECM) in ASM cells was measured using quantitative real-time PCR. The effect of eosinophil-derived proliferative cytokines on ASM cells was determined using neutralizing antibodies. The role of eosinophil derived Cysteinyl Leukotrienes in enhancing ASM was also investigated.Co-culture with eosinophils significantly increased ASM cell proliferation. However, there was no significant difference in ASM proliferation following incubation with eosinophils from asthmatic versus normal control subjects. Co-culture with eosinophil membranes had no effect on ASM proliferation. Moreover, there was no significant change in the mRNA expression of ECM proteins in ASM cells following co-culture with eosinophils when compared with medium alone. Interestingly, blocking the activity of cysteinyl Leukotries using antagonists inhibited eosinophil-derived ASM proliferation.Eosinophils enhances the proliferation of ASM cells. This role of eosinophil does not seem to depend on ASM derived ECM proteins nor on Eosinophil derived TGF-\u03b2 or TNF-\u03b1. Eosinophil seems to induce ASM proliferation via the secretion of Cysteinyl Leukotrienes."}
+{"text": "Midbrain dopamine neurons fire in a pacemaker-like fashion in vitro where they are deprived of most afferent input. In vivo, these neurons can emit a burst of action potentials with fast (~50 Hz) frequencies . However"}
+{"text": "Predicting the likelihood of a clinical outcome using biomarkers during the course of a cancer immunotherapy can be a powerful tool for time-sensitive decision making on personalized treatment options. In a clinical trial with the survivin-targeting vaccine DPX-Survivac, we showed using established methods (ELISpot/tetramer/flow cytometry) that a high-dose of DPX-Survivac vaccine in combination with low dose metronomic oral cyclophosphamide (mCPA) induced much stronger immune responses in ovarian cancer patients  compared to vaccine alone  or low dose vaccine with mCPA . Immune responses were detected ex vivo in patients\u2019 PBMCs particularly in cohort C, a reflection of the magnitude of the immune responses generated by the vaccine. We further analyzed the kinetics of various T cell phenotypes of the CD4 and CD8 lineages, including effector/ central memory T cells and late differentiated CD8 T cells. We established a model for the sequential appearance of polyfunctional T cells of the various phenotypes and for the persistence of these cell types following repeated immunizations with DPX-Survivac. In addition, we explored a unique PCR-based \u2018real-time\u2019 method developed by Hitachi Chemical Research Center for analyzing mRNA expression signatures that could be associated with vaccine induced immune responses. For this, small quantities of fresh blood from immunized patients were directly incubated with vaccine antigens and analyzed by qPCR at pre- and one month post-immunization time points. Among 9 immune response-related biomarkers tested, mRNA for molecules such as IFN-\u03b3, GM-CSF, TNF-\u03b1 and CXCL10 were detected de novo in the blood of four out of four subjects tested among six patients from cohort C at one month following the third vaccination. These results are in keeping with the establishment of stronger immune responses and the kinetics of vaccine-induced memory/effector T cells observed at this time point in patients receiving the combination of DPX-Survivac and cyclophosphamide. Taken together, these findings provide a framework for identifying a potential immune response signature soon after initiation of the vaccine therapy. We will determine whether this immune response signature is predictive of clinical activity in a planned randomized phase 2 trial."}
+{"text": "A variety of complications related to endovascular procedures are being reported. We present an annoying complication implying complete migration of stent-graft of subclavian artery into the aortic lumen.A 61 years old man with abdominal endovascular aortic stent-graft inserted previously, had a saccular aneursym of descending aorta distal to left subclavian artery and a small dissection flap with saccular aneursym originating from left subclavian artery. Since the patient refused to have any surgical procedure for left subclavian artery revascularisation, thoracic aortic-stenting for descending aorta just below the subclavian origin and a second stent-graft for left subclavian artery just above the orifice was planned. Coverage of left subclavian artery was not preferred aiming to avoid possible cerebrovascular events. During intervention, stent-graft to be inserted inside subclavian artery migrated totally into aortic arch in a perpendicular fashion.Bilateral femoral and left brachial artery accesses were done. A 16x41mm stent-graft was inserted inside left subclavian artery. While insertion with balloon dilatation, stent-graft migrated distally with the balloon forming a partial prolapse into aortic arch. We tried several endovascular maneuvers including inserting a second graft into subclavian artery to stabilize the first one or trying to press this graft with the one inserted into descending aorta, but unfortunately the stent totally migrated into aorta. We catheterized migrated stent with balloon catheter and were able to move the graft with inflated balloon fixing it. Stent-graft and inflated balloon were pulled slowly back together to proximal part of left arm of the previously inserted abdominal aortic stent-graft and stabilized it carefully. Control DSA showed settled graft without any stenosis.We present a bothering complication and an endovascular solution we performed without complication."}
+{"text": "Current assessment techniques for regional contractility require cardiac magnetic resonance-tagged or strain encoded imaging sequences and their analysis is complex. A new steady-state free precession cine sequence (SSFP) based technique called feature tracking can readily be performed on standard SSFP sequences. To test the feasibility of feature tracking in patients with coarctation of the aorta (CoA) and to quantify regional contractility patterns pre and post percutaneous dilation and stent implantation in the region of CoA.6 consecutive male patients  with CoA underwent cardiac MRI pre and 1 to 2 years post stent implantation in a 1,5 Tesla Achieva MR system  using a 5 element cardiac coil. 3 conventional SSFP cine short axis slices  were analyzed for peak myocardial radial strain, peak myocardial circumferential strain and fractional area change dA/dt (FAC) pre and post catheter intervention using Feature Tracking software . Comparison between groups were calculated using a general linear model for repeated measurements .Patients showed a post-procedural significant increase of myocardial radial strain (p=0.05) with the highest extent within the apical myocardial segments Fig.. CircumfFeature tracking is a new and promising technique for the assessment of regional contractility using robust, standard SSFP images and can therefore be performed without the need of additional imaging sequences or even retrospectively. Measurements in our study group showed as significant increase of radial myocardial contractility after stent implantation. To verify the results of this pilot study an adjacent trial including more patients as well as a healthy control group is required.None."}
+{"text": "Drug desensitization is the induction of temporary clinical unresponsiveness todrug antigens to which patients have presented severe hypersensitivity reactions (HSR). Rapid desensitization in patients suffering immediate hypersensitivity reactions with chemotherapeutic agents and monoclonal antibodies have been widely described and have shown to be successful. Non-immediate hypersensitivity reactions with other drugs have usually required desensitization with several days\u2019 protocols to achieve total doses.Thirty-eight desensitization procedures were performed in 5 patients with a 12-13 step, 6-hour protocol. All patients had developed a delayed maculopapular rash with the use of chemotherapeutic and/or biological agents. Three patients were pretreated with corticosteroids, paracetamol and antihistamines before each desensitization procedure.All the 38 desensitizations undertaken were successfully completed . We observed HSR during 8 (21%) of desensitizations, including 5 inmediate exantema and 3 delayed local macular exantema. Two patients were treated with corticosteroids and anti-histamines after the desensitization protocol to avoid more delayed HSR.Rapid desensitization protocols are safe and effective in getting over delayed HSR to chemotherapeutic and monoclonal antibodies and allow patients with severe diseases to continue their treatment."}
+{"text": "Nasopharyngeal carcinoma (NPC) occurs more frequently in patients with south-east Asian racial backgrounds. This disease may spreads superiorly to the skull base and intracranium followed by skull base destruction. We report a 56 year-old man presented with headache and diplopia. Magnetic resonance imaging (MRI) revealed extension of destructive mass from ethmoid sinus to the parenchyma. Intraoperative touch cytology showed loose syncytial sheets of pleomorphic abnormal epithelial cells, dyskeratotic cells with abnormal chromatin clumping and irregular nuclear outlines, in a necrotic background. These findings were infavor of keratizing squamous cell carcinoma which was confirmed by histopathology. During interpretation of intraoperative imprint cytology of central nervous system tumors, the possibility of local invasive tumors like NPC should be considered. NPC is a rare tumor in many parts of the world, but is prevalent among Southeast Asian. It usually arises from eustachian tube opening in the Rosenmuller fossa. Initial complaints are often due to middle ear obstruction (otitis media or hearing loss) or local invasion . There are few reports of NPC with diffuse skull base destruction, resulting in obstructive hydrocephalus, cerebellopontine involvement or even cavernous sinus metastasis 2]3]4][3][4]2][[4][3][4][3][4]2].We report a 56 year-old man presented with headache, dizziness and diplopia for one-month duration. On physical examination third and sixth cranial nerve palsy were detected. Past medical history was not significant. MRI showed a soft tissue mass originates from ethmoid sinus with upward extension to brain parenchyma  [6]. TheNPC is endemic in Southern China and is associated with Epstein\u2013Barr virus (EBV) as strong aetiological factor. The titre levels of antibodies to EBV immunoglobulin A viral capsid antigen (IgA VCA) and early antigen (IgA EA) have been widely used as screening and diagnostic markers for NPC. Quantitation of EBV DNA viral load using a real-time PCR technique is highly sensitive and specific method for NPC and correlates well with tumor burden. EBV DNA can be used clinically to monitor disease response and recurrence 9]. NPC . NPC 9].In our experience, imprint cytology test is a rapid and inexpensive diagnostic test that tissue integrity is well preserved. In interpretation of imprint cytology of central nervous system tumors, the possibility of local invasive tumors such as NPC should be considered. In these cases, careful examination of the nasopharynx is essential for the exclusion of nasopharyngeal undifferentiated carcinoma because of the obvious differences in treatment and prognosis."}
+{"text": "Renilla Luciferase to determine binary protein:protein interactions (PPIs) of the PKA network. We compared time- and dose-dependent influences of cAMP-elevation on mutually exclusive PPIs of PKAc with the phosphotransferase inhibiting RIIb and RIa subunits and the protein kinase inhibitor peptide (PKI). We analyzed PKA dynamics following integration of patient mutations into PKAc and RIa. We observed that oncogenic modifications of PKAc(L206R) and RIa(\u0394184-236) as well as rare disease mutations in RIa(R368X) affect complex formation of PKA and its responsiveness to cAMP elevation. With the cell-based PKA PPI reporter platform we precisely quantified the mechanistic details how inhibitory PKA interactions and defined patient mutations contribute to PKA functions.The second messenger molecule cAMP links extracellular signals to intracellular responses. The main cellular cAMP effector is the compartmentalized protein kinase A (PKA). Upon receptor initiated cAMP-mobilization, PKA regulatory subunits (R) bind cAMP thereby triggering dissociation and activation of bound PKA catalytic subunits (PKAc). Mutations in PKAc or RIa subunits manipulate PKA dynamics and activities which contribute to specific disease patterns. Mutations activating cAMP/PKA signaling contribute to carcinogenesis or hormone excess, while inactivating mutations cause hormone deficiency or resistance. Here we extended the application spectrum of a Protein-fragment Complementation Assay based on the  As a consequence PKAc phosphorylates compartmentalized substrates which affects enzyme activities, PPI, localization, or protein abundance  and activating PRKACA gene (PKAc) mutations/fusions provoke deregulated PKAc activities. As examples, mutations in RIa and PKAc account for the generation of endocrine tumors, cortisol-producing adenomas, and chimeric fusions with PKAc have been linked to the manifestation of hepatocellular carcinoma  mutations impair cAMP-dependent PKA activation and cause hormone resistance as observed in the rare disease Acrodysostosis    and signal propagation Clapham, . The secHEK293 and U2OS cells were grown in DMEM supplemented with 10% FBS. Transient transfections were performed with Transfectin reagent (Biorad). Cells were treated with Forskolin (Biaffin) or Isoproterenol (Sigma) with indicated concentrations and for the indicated time frames. As primary antibody we used mouse anti-PKAc .Rluc PCA based hybrid proteins RIIb-F[1] and PKAc-F[2] have been designed as previously described  gene (protein accession number: NP_002725.1) and PKI alpha gene  2 and the Rluc PCA fragments (pcDNA3.1 backbone vector). Site directed mutagenesis have been performed to generate the PKAc amino acid (aa) mutations G187V and L206R in the PRKACA gene and the RIa aa mutations R368X  in the PRKAR1A gene. In addition we deleted the corresponding nucleotide sequence from the aa 184\u2013236 in the PRKAR1A gene.The Rluc PCA based reporter constructs in 24 or 12 well-plate formats. In case of the HEK293 cells we exchanged growth medium and resuspended cells in PBS 24 or 48 h post-transfection. Cell suspensions were transferred to 96-well plates and subjected to luminescence analysis using the LMax\u2122-II-384 luminometer (Molecular Devices). Rluc luminescence signals were integrated for 10 s.HEK293 cells were grown in DMEM supplemented with 10% FBS. We transiently overexpressed indicated versions of the Rluc PCA based reporter constructs. 24 or 48 h post-transfection we exchanged growth medium with PBS. We performed luminescence analyses of attached U2OS cells at room temperature using the LMax\u2122-II-384 luminometer (Molecular Devices). Time dependent changes of the Rluc luminescence signals were integrated in 3-s intervals following addition of the Rluc substrate benzyl-coelenterazine  with or without Isoproterenol  .We seeded U2OS cells into white-walled 96 well-plates with transparent bottom. We transiently overexpressed indicated versions of the Rluc PCA) to quantify mutually exclusive PKA interactions directly in living cells. It is the simplicity and sensitivity of the genetically encoded Rluc PCA which enables different kinds of perturbation studies to unveil mechanistic details of PKA dynamics. The Rluc PCA facilitates the precise quantification of cellular PPI in an appropriate in vivo setting  and PKAc which is indicated through alterations of bioluminescence signals. For the cloning of the PPI reporter constructs we fused the carboxy terminus of the PKA subunits  and PKI to complementary fragments of the Rluc PCA (either -F[1] or -F[2]). In all cases the bait/prey proteins and the Rluc PCA fragments are separated by an interjacent 10 amino acid (aa) linker with the sequence (GGGGS)2. It is a standard linker we previously showed to function using the dynamic RIIb:PKAc Rluc PCA reporter , respectively. In this context it needs to be considered that distinct mechanism have been described how \u03b22AR switch their G protein coupling from stimulatory G proteins to inhibitory ones  triggered R:PKAc complex dissociation. We observed no major changes of PPI between PKI:PKAc and RIIb homodimers following 15 min of cAMP elevation  and full length Rluc we observed that Isoproterenol immediately induced the dissociation of heterodimeric type I and type II PKA complexes with similar kinetics. Again, \u03b22AR activation for 4 min has no major effect on the RIIb dimer and on PKAc:PKI interactions  which is caused through a resistance to several hormones  application of the PKA Rluc PCA reporter to detect even modest changes of PPIs in response to second messenger elevations. Overall we underline with this study that the Rluc PCA is a versatile reporter system to map transient and small molecule controlled PPI. Besides linking membrane receptor pathways to alterations of molecular interactions, the consequence of patient mutations on PPI can be tested with a simple protocol and in parallel fashion. The implementation of this PPI reporter platform will unveil consequences of distinct patient mutations on binary PKA network dynamics. We envision that the mutation approach will disclose hot spots in these critically regulated kinase complexes which become pharmaceutical targets to target both PPI and/or cAMP sensing. This will help to gain novel insights into mechanism of PKA activation which will be relevant for the diagnosis and for identifying treatments of kinase involved diseases.We also tested two patient mutations of RIa which are related to two different diseases showing opposite effects on PKA activity. We demonstrated that the Carney complex relevant R1a-\u0394184-236 mutation had a major impact on PKA complex formation when compared to the wild type PKA holoenzyme type I. Our data showed that R1a-\u0394184-236 has less affinity for PKAc. We assume that the reduced affinity for PKAc contributes to disease relevant elevations of PKAc phosphotranferase activities. The second mutation RIa-R368X (= 14aa truncation) caused a defect in PKA activation. The mutation introduces a stop codon and shortens the cAMP binding domain B. The resulting deletion of 14 aa at the C terminus reduced the cooperative binding of cAMP first to binding domain B and then to binding domain A, which is a prerequisite for PKAc dissociation and activation (Kim et al., RR, JM, VB, and ES performed the experiments. RR, JM, VB, and ES analyzed the results. ES wrote the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "A 64-year-old female with history of previous aortoiliac occlusion and aortoiliac bypass operation four months ago presented with dyspnea, ascites and leg edema. She has been suffering from bloody diarrhea since two weeks earlier. Laboratory data showed important eosinophilia and stool examination was positive for Strongyloides stercoralis. Patient had clinical signs of heart failure. A cardiac MRI revealed hypersignal subendocardium in favor of endomyocardial fibrosis. Hypereosinophilic syndrome is defined by persistent hypereosinophilia for more than 6 months. The association with different etiologies is known but the report of cardiac involvement due to S. stercoralis infection is not very common. Cardiac manifestation is characterized by a restrictive cardiomyopathy due to toxic damage produced by activated eosinophils. Figure 2). Thrombus is characterization by no evidence of early or late enhancement and of myocardial fibrosis by late gadoilnium enhancement (LGE). The delayed hyperenhancement explained by myocardial scarring which increases gadolinium concentration. The diagnosis of Endomyocardial fibrosis (EMF) was made on the basis of this typical MRI finding. Cardiac catheterization and biopsy was scheduled but unfortunately was not performed due to patient\u2019s preference. Patient received Ivermectin for S. stercoralis treatment and medication for heart failure. On 6 month follow up she still has dyspnea with minimal exertion. She did not accept the risk of surgery.A 64-year-old female with history of previous aortoiliac occlusion and aortoiliac bypass operation four months ago presented with dyspnea, ascites and leg edema. She has been suffering from bloody diarrhea since two weeks earlier. Laboratory data showed important eosinophilia in count of 2100 cells/\u00b5L and stool examination was positive for S. stercoralis. Patient had clinical signs of heart failure and standard treatment of heart failure started. Chest radiography revealed an enlarged cardiac shadow with a congestive vascular pattern The ECG showed sinus tachycardia with normal QRS morphology and duration. The transthoracic echocardiogram revealed left ventricular ejection fraction of 35%, severe diastolic dysfunction, moderate pulmonary hypertension and severe mitral and tricuspid regurgitation with apical filling of the both ventricles. A cardiac MRI revealed normal wall thickening in pre- and postgadolinium diethylenetriamine pentaacetic acid (Gd-DTPA) infusion dynamic sequences (S. stercoralis infection is not that common (Hypereosinophilic syndrome is defined by persistent hypereosinophilia for more than 6 months. The association with different etiologies is known but cardiac involvement due to t common . Cardiact common . It provt common . Cardiact common . The LGE"}
+{"text": "Dear SirA 26-year-old primigravida with breech presentation came to the emergency in 2nd stage of labor with meconium stained per vaginal leak. Patient was initially taken to a primary health centre were artificial rupture of membrane was done to augment labor but later referred here since labor did not progress. After an emergency cesarean section, a female baby was delivered who on examination had a hematoma over right buttock, anal laceration, perianal edema, and severe rectal bleeding . Anal injury during artificial rupture of membrane was suspected. Patient was managed conservatively by anal pack for 24 hours and later local dressings and antibiotics. The edema and hematoma resolved in 1 week . The child has normal continence. Intrauterine anogenital injury can occur due to repeated maternal vaginal examination in which the examiners fingers traverses the cervical os into the neonatal rectum or vagina. It can also occur during cesarean delivery due to blunt dissection of endometrium or bimanual traction while delivering the breech from maternal pelvis. There are very few case reports regarding anal injuries in breech delivery, [1-4] but this is probably the first such incidence where it occurred due to artificial rupture of membranes. This injury stimulated baby to pass meconium in-utero which could be life threatening. Mal-presentation is a contraindication for labor augmentation or induction procedures like artificial rupture of membrane. Management of such injuries depends on the grade of injury.[5] Mild degree laceration can be managed conservatively like in our case. The more severe degree laceration of sphincter or those extending into rectum or genitalia are managed by a diverting stoma and primary repair. [1-4] Source of Support: NilConflict of Interest: None"}
+{"text": "Several studies suggest that an increased oxidative stress is a key event in migraine, especially in the form with aura. One of the most efficient first line antioxidant defense system of cells exposed to oxygen is Superoxide Dismutase (SOD) system. The SOD1 gene presents a polymorphism (A/C substitution - rs2234694) resulting in lower serum activitiy in subjects carrying CC genotype. SOD2 gene presents a polymorphism  which leads to an instable mRNA and reduced transport of the enzyme in TT genotype carriers.To investigate whether these variants are associated to migraine without aura (MO), migraine with aura (MA), or chronic migraine (CM) in a cohort of Caucasian patients from the Interinstitutional Multidisciplinary BioBank (BioBIM).From 2009 to 2013, 490 Caucasian unrelated migraineurs and 246 healthy control subjects were consecutively recruited at the our Headache and Pain Unit. Demographic and clinical migraine features were carefully detailed and gathered with face-to face interviews.The polymorphisms were determined by direct sequencing analysis.Genotypes and the allele frequencies of polymorphisms in migraineurs and controls did not significantly differ from those predicted by the Hardy\u2013Weinberg equilibrium. When considering unilateral cranial autonomic symptoms (UAs), we observed a significant increase of SOD2 rs4880 TT  genotype in MA (P=0.042).SOD2 TT genotype correlates with MA with UAs. We hypothesize that in SOD2 TT carriers with MA, a defective control of oxidative phenomena characterizing cortical spreading depression leads to a more intense antidromic stimulation of trigeminal endings, thus triggering the trigemino-autonomic reflex.No conflict of interest."}
+{"text": "Early recognition and prevention of deterioration of ward patients can improve patient outcomes and reduce critical care admissions . In low To design a clinically relevant short course for ward nurses in a LMIC to be delivered by local nursing tutors and facilitators.To assess whether such a clinically focused programme would increase ward nurses' knowledge and skills in identifying and managing deteriorating patients.A multi-modal 2 day acute care course for ward nurses was co-designed and delivered by specialist overseas trainers in partnership with national tutors. The courses were sponsored by the Ministry of Health, Sri Lanka. Based upon the NICST model of collaborative course design, local faculty were up skilled in delivery and content through a pre course Train the Trainer programme .Candidates were invited to undertake on-line pre course e-learning. Core clinical guidelines were delivered using mini lectures. Facilitator-led skills stations and structured scenarios were used to develop clinical skills.Short term knowledge acquisition was tested by a pre and post course Multi-Choice Questionnaire (MCQ). Newly acquired skills and their application was assessed through a post course Objective Clinical Skills Assessment (OSCA) station.122 ward nurses were trained over 6 courses in 2 locations. Post MCQ scores were significantly higher for each course compared to pre MCQ (Wilcoxon sign rank test P < 0.0001).Over 71% passed the OSCA (pass mark of 60). Feedback reveals high candidate satisfaction.Our short course results demonstrate an increase in relevant knowledge and clinical skills of the participants. Our NICST model demonstrates the feasibility of a local nursing faculty in a LMIC co-designing and effectively delivering a setting adapted acute care training programme integrated into the local nurse training system."}
+{"text": "E.coli ST131 is a globally disseminated clone of multi-drug resistant E. coli responsible for that vast majority of global extra-intestinal E. coli infections. Recent global genomic epidemiological studies have highlighted the highly clonal nature of this group of bacteria, however there appears to be inconsistency in some phenotypes associated with the clone, in particular capsule types as determined by K-antigen testing both biochemically and by PCR.We performed improved quality assemblies on ten ST131 genomes previously sequenced by our group and compared them to a new reference genome sequence JJ1886 to identify the capsule loci across the drug-resistant clone H30Rx. Our data shows considerable genetic diversity within the capsule locus of H30Rx clone strains which is mirrored by classical K antigen testing. The varying capsule locus types appear to be randomly distributed across the H30Rx phylogeny suggesting multiple recombination events at this locus, but that this capsule heterogeneity has little to no effect on virulence associated phenotypes in vitro.E. coli ST131 and further beyond to ExPEC strains, and highlights how capsular mosaicism may be an important strategy in becoming a successful globally disseminated human pathogen.Our data provides a framework for determining the capsular genetics of The online version of this article (doi:10.1186/1471-2164-15-830) contains supplementary material, which is available to authorized users. Escherichia coli (ExPEC) infections are one of the leading causes of morbidity in the developed world and are particularly associated with infections of the urinary tract (UTI) and with bacteraemia. In recent years one particular clone of ExPEC has emerged to become a globally dominant cause of human infection, E. coli ST131 Additional file 1:"}
+{"text": "Coronary subclavian steal syndrome is a rare ischemic cause in patients after myocardial revascularization surgery. Subclavian artery stenosis or compression proximal to the internal mammary artery graft is the underlying cause. The authors present a clinical case of a patient with previous history of non-ST elevation myocardial infarction, triple coronary bypass, and effort angina since the surgery, with a positive ischemic test. Coronary angiography revealed a significant stenosis of the left subclavian artery, proximal to the internal mammary graft. The coronary subclavian steal syndrome (CSSS) was first described in 1974 and is caused by retrograde or insufficient blood flow through the internal mammary artery graft, with subsequent myocardial ischemia. Proximal atherosclerotic stenosis of the ipsilateral subclavian artery is the most frequent cause . The traThe authors present the case report of a 69-year-old male patient with several cardiovascular risk factors  and history of coronary artery bypass grafting (CABG) 6 years before when the left internal mammary artery (LIMA) was grafted to the left anterior descending artery (LAD), saphenous vein conduit was grafted to posterior descendent artery and left radial artery grafted to the intermediary branch. No medical imaging of the aortic arch and its branches was performed before cardiac surgery.He had recurrence of angina following the surgery (CCS class II) mainly when exerting the upper limbs. His therapy was adjusted and remained only mildly symptomatic until 2011 when he was referred to for coronary angiography because of gradually worsening exertional angina with no response to medical therapy. There were no neurological or claudication complaints. Physical examination only showed an II/VI systolic murmur. Basal EKG and blood analysis were unremarkable. On the transthoracic echocardiogram, there was only mild aortic sclerosis and good global and segmental systolic left ventricle function. He had a positive exercise electrocardiographic stress test, showing a 1.5\u2009mm ST segment depression on anterior and inferior leads accompanied by chest pain on 2nd stage Bruce treadmill protocol. The coronary angiography showed no new lesions in native-vessel circulation or the bypass grafts, except for the occlusion of the saphenous venous conduit grafted to the posterior descendent artery and partial retrograde filling through the LIMA graft from the LAD . Subclavian angiography showed a proximal severe stenosis (83%: quantitative coronary angiography) with slow distal flow; there were no significant stenosis in the carotid arteries .It was performed an ad hoc, left main percutaneous angioplasty, using a drug-eluting stent 4,0/12\u2009mm (Promus Element) without trifurcation involvement, with final angiographic success . In a seNowadays LIMA is the most used graft conduit due to excellent long-term patency, and although CSSS has a low described incidence 0.5\u20136.8%), perhaps this incidence could be underestimated. Ischemic symptoms can present immediately following CABG surgery or up to 7-8 years later , 4. Some\u20136.8%, peControversy remains that to whether or not a routine subclavian artery angiography should be performed before CABG surgery . Some auThe most appropriate management of concomitant brachiocephalic coronary artery disease also remains a matter of debate, but both endovascular stenting and extrathoracic surgical bypass are safe and effective treatments for CSSS in the short and medium term; extrathoracic surgical bypasses are more durable in the long term . Some auOur case demonstrates the need for evaluating the supra-aortic branches in patients previously submitted to CABG surgery and persistent/recurrent angina symptoms, particularly in those without other causes of ischemia. The percutaneous treatment for subclavian stenosis is effective and safe."}
+{"text": "Hybrid nanocomposites were constructed based on colloidal nanofibrillar hydrogels with interpenetrating supramolecular hydrogels, displaying enhanced rheological yield strain and a synergistic improvement in storage modulus. The supramolecular hydrogel consists of naphthyl-functionalized hydroxyethyl cellulose and a cationic polystyrene derivative decorated with methylviologen moieties, physically cross-linked with cucurbit[8]uril macrocyclic hosts. Fast exchange kinetics within the supramolecular system are enabled by reversible cross-linking through the binding of the naphthyl and viologen guests. The colloidal hydrogel consists of nanofibrillated cellulose that combines a mechanically strong nanofiber skeleton with a lateral fibrillar diameter of a few nanometers. The two networks interact through hydroxyethyl cellulose adsorption to the nanofibrillated cellulose surfaces. This work shows methods to bridge the length scales of molecular and colloidal hybrid hydrogels, resulting in synergy between reinforcement and dynamics. Recently, natural structural materials have inspired synthetic solvent-based and solid nanocomposite architectures.\u20136 NaturaOne of the main strategies used by nature is the combination of colloidal-length-scale reinforcement with supramolecular bonds on a molecular level, thus allowing rapid dissociation and reformation. Thus preThe present study focuses on the combination of colloidal and molecular length scales in hydrogels to engineer a dynamic supramolecular sacrificial network that promotes stiffness and connectivity in nanofibrillated cellulose (NFC) colloidal hydrogels. Pure NFC forms hydrogels, in which the skeleton is formed by native cellulose nanofibers with lateral diameters of nanometers and lengths up to several micrometers. NFC has Supramolecular interactions embedded within hydrogels have allowed for stimuli responsivity, controlled unzipping, and supramolecular cross-link reformations without immediate failure of the entire network.,27 SpeciIn more detail, the architecture comprised of a colloidal NFC network enhanced by association with a dynamic supramolecular network Figure\u2005. A CB[8]By combining a variable amount of NFC (0\u20131.5\u2005wt.\u2009%) with fixed amounts of STMV (0.15\u2005wt.\u2009%) and CB[8] (0.1\u2005wt.\u2009%), no apparent increase in the storage modulus was observed. Good compatibility was inferred as no apparent aggregation or phase separation occurred. Next, a fixed amount of HEC-Np (0.5\u2005wt.\u2009%) was added to form the heteroternary complex and to attach the ensuing supramolecular hydrogel to the NFC hydrogel through adsorbing the HEC to the NFC surface. This resulted in synergistic enhancement of the low-strain elastic modulus as the two networks were bound together Figure\u2005. The stoG\u2032, the addition of the CB[8] network to the NFC network resulted in increased yield strain ; however, the yield strain was reduced with repeated gel-to-sol transitions  images support the schematic description of the network Figure\u2005, as the In conclusion, a supramolecular hydrogel bridges the colloidal nanofibrillar NFC hydrogel domains, leading to significantly enhanced storage modulus values and improved maximum elastic yield values. This was promoted by the fast dissociation/association dynamics of the supramolecular CB[8]-based supramolecular cross-links in combination with the adsorption of hydroxyethyl cellulose component of the supramolecular hydrogel to the NFC nanofibers. The work shows biomimetic routes to combine components of different length scales and physical interactions to tune rheological properties."}
+{"text": "Complete removal of breast cancer during a single breast-conserving lumpectomy procedure is often challenging due to the lack of adequate intraoperative tools to accurately determine the margin status. About one-third of lumpectomy patients are found to have positive margins upon final histologic analysis, which usually is reported within a week after surgery. These patients are then required to undergo additional surgeries, which increases the patient morbidity, cosmetic challenges, and healthcare cost. Spectrally encoded confocal microscopy (SECM) is a high-speed confocal microscopy technique  that can\u03bcm). After SECM imaging, each specimen was processed and cut as hematoxylin and eosin (H&E) stained slides. SECM images were analyzed in comparison with the corresponding H&E slides to identify features in the SECM images that distinguished benign from malignant breast tissues.We imaged 44 fresh breast tissue samples with SECM and compared the SECM images with corresponding histologic slides. The specimens were obtained from mastectomy and lumpectomy operations conducted at MGH and according to an IRB-approved protocol. Each specimen was immersed in 5% acetic acid to increase the nuclear contrast in SECM. Large-area SECM images (4\u2009mm by 2\u2009mm to 10\u2009mm by 4.8\u2009mm) were obtained at 5 imaging levels (imaging depth: 0 to 200\u2009SECM images enabled the visualization of architectural and cellular features of normal and diseased breast tissues that were structurally similar to those seen by histopathology. SECM images of normal breast tissues showed morphologic features of adipose cells and benign glands. Low-grade invasive ductal carcinoma showed small glands invading the stroma in a disorganized fashion . High-grResults from this preliminary imaging study showed that SECM can be used to visualize key histomorphologic features associated with breast cancers. We are currently conducting a validation study of testing sensitivity and specificity of SECM for diagnosing breast cancers. When utilized during lumpectomy, SECM may have the potential to rapidly provide margin status and help the surgeon achieve more thorough removal of the tumor in a single surgery."}
+{"text": "Pancreatic metastases are rare, accounting for 2.8% of cases in RCC, occurring as a result of haematogenous spread to the pancreas. High affinity of some renal cancer cells for the pancreatic parenchyma present solely as isolated pancreatic metastases.Literature reviews have highlighted that aggressive surgery for isolated pancreatic metastasis has been shown to increase 5 year survival rates unto 60%; particularly nephrectomy & metastasectomy with adjuvant therapy.The objective of this case study was to identify the benefits of pancreas-preserving enucleation in treatment of isolated pancreatic RCC metastases over traditional pancreatic resections.Patient X was identified as a candidate for this case report.Mr X. is a 77 year old fit and healthy male, presented with 2 day history of frank haematuria & weight loss of 3kg over 6 months with no associated fever, flank pain or dysuria. CT KUB revealed lobulated soft tissue density in the right kidney, suspicious for a tumour. Further staging investigations of CT TAP demonstrated a small enhancing nodule in pancreatic body confirmed as pancreatic metastasis with EUA FNA. The patient subsequently underwent Open Right Radical Nephrectomy with Enucleation of Pancreatic Metastasis.Comparisons drawn between Pancreatic-sparing Enucleations and standard resection (Complete Pancreatectomy) explore variations in surgical challenges & post-operative complications. While there has been no difference in morbidity and recurrence noted compared to complete pancreatectomy; there has been significant reduction in post-operative diabetes mellitus.Pancreatic resections are associated with high rates of morbidity and mortality. A reduction in operative risk following pancreatic surgery have been demonstrated, in recent times. As such, Pancreas-sparing Enucleation & Enucleo-resection has been considered a worthy option. Preservation of pancreatic tissue allows for better quality of life without diabetes mellitus.The patient had signed a written consent for publication of this abstract on Pancreatic Metastases."}
+{"text": "Spasm of the radial artery is the most important cause of failure to perform coronary angiography via the transradial approach. Spasmolytic cocktail may prevent radial artery spasm but is relatively contraindicated in patients with aortic stenosis or diminished left ventricular function. In this case report we describe a recently published technique to overcome severe radial spasm during transradial coronary angiography in a patient with moderate aortic valve stenosis. After a two-decade evolution, the transradial approach (TRA) in coronary angiography and percutaneous coronary intervention (PCI) has become a viable and attractive alternative for the femoral approach \u20134. The iOne of the most encountered problems is radial artery spasm. In a multicenter registry containing over 1900 transradial procedures, the incidence of radial spasm was 2.7%, with multiple puncture attempts and use of larger introducer sheaths (7F) being independent predictors of radial spasm . AnotherRadial artery spasm can be prevented by administration of intraarterial spasmolytic cocktails . HoweverIn this case report, we describe a recently published technique  to overcA 70-year-old male patient was referred for coronary angiography because of chest pain on exertion. In preceding years, he visited our outpatient department for echocardiographic follow-up of a moderate aortic valve stenosis. During the last visit he expressed typical anginal complaints while echocardiographic evaluation of the aortic valve displayed a stable function.Patient underwent coronary angiography via right radial access. After uneventful puncture and cannulation of a 5F introducer sheath  5000\u2009IU of heparin was administered. Initially, no spasmolytic cocktail was used because of patient's moderate aortic stenosis. A 5F JL catheter  over a 0.035\u2032\u2032 standard guide wire could uneventfully cannulate the left main ostium. After visualization of the left coronary artery, over the wire exchange for a 5F JR catheter resulted in severe patient discomfort of the forearm, resulting from spasm. Half-dose spasmolytic cocktail  did not permit the JR catheter to pass and resulted in a significant fall of intra-arterial blood pressure. Visualization of the radial revealed severe and refractory spasm .In order to cross the spastic segment, a 5F Kimny guide (Boston Scientific) was loaded with a 2.0 \u00d7 15\u2009mm Mini Trek PTCA catheter (Abbott Vascular) over a 0.014\u2032\u2032 Sion coronary guide wire (Asahi). The balloon catheter, which was kept partially outside the distal end of the guiding catheter, was inflated at 4 bars to ensure fixation of the guiding catheter onto the coronary wire . As suchThe patient underwent PCI of the ostial lesion of the RCA 1 week later. Radial artery angiography revealed a smooth and undamaged vessel .The evolution of the TRA in the preceding two decades brought along new procedural difficulties that should be overcome by evolving techniques and equipment. As in above-described case, spasm of the radial artery are a major obstacle to a successful TRA and may result in catheter-induced perforation or conversion to a transfemoral approach.The tunica media of the muscular radial artery is comprised of concentric layers of smooth muscle cells. Both circulating catecholamines and mechanical stimuli  may cause smooth muscle cell contraction and hereby spasm of the radial artery. Forced cannulation of a spastic radial artery may cause the catheter tip to brush the endothelium, which may aggravate spasm and cause vascular damage. BAT of the guiding catheter was recently described by Patel and colleagues  to overcIn conclusion, BAT was successful in this patient with radial artery spasm refractory to low dose spasmolytics."}
+{"text": "Respiratory syncytial virus (RSV) infections are associated with thrombocytopenia. The underlying mechanism of thrombocytopenia in this setting is unknown. Herein, we report a case of RSV-related thrombocytopenia associated with transient cytogenetic abnormalities that occurred following umbilical cord blood transplantation. Respiratory syncytial virus (RSV) infections are associated with extra pulmonary manifestations including thrombocytopenia . The undWe report here a case of a 28-year-old male patient who underwent a double umbilical cord blood transplant for acute lymphoblastic leukemia (ALL) in second remission in 2008. Original cytogenetic analysis revealed normal karyotype. Nineteen months after transplant, he presented to clinic with upper respiratory infection symptoms. RSV was detected by molecular tests performed on a nasal wash sample and a CT scan of the chest showed right upper lobe cavitary lesion containing a nodular density concerning pneumonia for which he was treated with aerosolized ribavirin. At the same time, the patient was found to be thrombocytopenic . BecauseWe report a case of RSV-related thrombocytopenia associated with transient cytogenetic abnormalities that occurred following umbilical cord blood transplantation. Development of thrombocytopenia following transplantation is a sign of possible disease relapse. In our case, the patient had no morphologic changes of leukemia. Donor cells leukemia (DCL), on the other hand, is a rare complication following allogeneic hematopoietic stem cell transplant \u20134. Wang The most probable explanation for our findings is RSV infection, though no viral etiology was described in the cases reported by Otero et al. The transient cytogenetic changes in our case occurred at the time of thrombocytopenia and accordingly might provide an explanation for RSV-related thrombocytopenia. Recent data suggest that RSV might infect bone marrow stromal cells  which mi"}
+{"text": "A 59-year-old male patient was referred to our hospital for treatment of paroxysmal atrial fibrillation since 8 years, with frequent presentations to the emergency department for cardioversion. Previously, post-cardioversion sinus bradycardia was observed. After extensive discussion of the treatment options, the patient opted for a minimally invasive surgical pulmonary vein isolation. The ECG shown was recorded during ablation of the left-sided pulmonary veins Fig.\u00a0.Fig 1ECGQuestionWhat is the mechanism of this trigeminy rhythm?You will find the answer elsewhere in this issue."}
+{"text": "Ventricular assist devices have been routinely used in patients with end stage heart failure as a bridge to transplantation. We present a case of using a Bi-Ventricular Assist Device (BiVAD) in a patient with fulminant heart failure as a bridge to recovery.A 36 year old lady with a history of Grave's Disease and three months post-partum presented with fulminant myocarditis.She presented to her local hospital on 2nd January with episodes of ventricular tachycardia (VT) and syncope. She was transferred to a tertiary level cardiology centre as she failed to cardiovert. Echocardiography demonstrated significant left ventricular (LV) thickening and LV stasis. She continued to have VT storms and was referred to our advanced heart failure service.On arrival she rapidly deteriorated with recurrent VT and ventricular fibrillation (VF) episodes causing severe haemodynamic compromise. A decision was made to institute mechanical circulatory support with veno-arterial Extra-Corporeal Membrane Oxygenation (VA- ECMO). During cardiopulmonary resuscitation she was placed onto VA-ECMO and stabilised. That same evening she underwent conversion to BiVAD support for offloading of both ventricles.She was extubated on the first post-operative day. Myocardial biopsy performed during BiVAD implantation confirmed florid myocarditis.Over the ensuing days, she was mobilised and rehabilitated on the ITU and there was a gradual recovery of myocardial function. On the 25th post-operative day her BIVAD circuit was explanted following a successful wean.After further rehabilitation she was discharged home, 39 days after admission. MRI prior to discharge demonstrated satisfactory biventricular function with a small right atrial thrombus.Ventricular assist device therapy can be utilised as an effective primary treatment modality for patients in fulminant heart failure within the spectrum of post-partum cardiomyopathy. We suggest early discussions with regional advanced heart failure centres to facilitate prompt intervention leading to full recovery."}
+{"text": "Our centers have formed an international collaborative group composed of surgeons, pathologists, radiation oncologists, medical oncologists and immunologists working together with biotech and pharma sectors to evaluate biomarkers of immune status and develop effective combination immunotherapy for patients with NSCLC.Two phase I immunotherapies for NSCLC following surgical resection were begun at our institutions. One involved stage I-IIIA patients given an irradiated, autologous whole-tumour cell vaccine following induction of lymphopenia by chemotherapy and reinfusion of autologous peripheral blood mononuclear cells (PBMC). The other recruited stage IV patients given an autophagosome-enriched vaccine generated from irradiated autologous tumour cells. Histologic sections, enzymatically-digested tumour, pleural effusions and apheresis are available from a number of these patients. Current efforts are evaluating immunoscore and immune profiling by IHC and comparing results with flow cytometric analyses of the tumour.Preliminary studies have evaluated CD3+ CD8+ CD45RO+ cytotoxic memory T cells associated with tumour. We are continuing to examine myeloid to lymphoid infiltrate ratios. While preliminary, and with only 4 patients evaluated, preexisting autologous tumour-reactive T cells (IFN-\u03b3) were only detected when T cells predominated in the tumour preparation analysed. Studies comparing this with IHC staining and analysis using Definiens software are underway.A consortium of institutions has come together to improve the outcome of patients with NSCLC. The progress made to date will be used to evaluate immune responses to next generation immunotherapy. Evaluation of gene expression profiling of NSCLC has identified common overexpressed antigens and an off the shelf vaccine of autophagosomes containing at least 9 NCI prioritised cancer antigens, 5 TLR agonists and a DC targeting molecule has been developed. A multi-center phase II trial of combination immunotherapy for NSCLC employing this vaccine is open in the USA and efforts are underway to open this trial in Munich with coordinated efforts to evaluate anti-cancer immunity in patients on this and other trials."}
+{"text": "Cystic Fibrosis (CF) is the most common autosomal recessive disease affecting about 1 in 3200 in Caucasians with increased morbidity, chronic infections, disability and reduced life expectancy. The mutations causing CF are well characterized, but the gene-gene and gene-environment interactions which significantly modify CF disease severity are completely unknown.FAS gene on human chromosome 10q24.1, which includes the binding site of many transcription factors especially the NF\u03baB complex, but no molecular alterations were detected by conventional approaches. Using a combination of functional in-silico gene expression analysis and computational transcription factor binding analysis together with electrophoretic mobility shift and Supershift assays, we have identified that an allele of the regulatory SNP disrupts the binding of the master transcription factor NF\u03baB on FAS and which likely interferes with normal immune activation and programmed cell death.We report the pathogenetic mechanisms underlying how a regulatory SNP modifies Cystic Fibrosis (CF). Association studies of affected individuals with Cystic Fibrosis identified the causal variant, a regulatory SNP rs7910656 on the non-coding region of Thus, our work demonstrates for the first time how a regulatory SNP disrupts the binding of a master transcription factor NF\u03baB and a key signaling pathway FAS in immune regulation and programmed cell death modifying Cystic Fibrosis."}
+{"text": "It remains uncertain whether neuromonitoring reliably predicts outcome in adult post-cardiac arrest patients in the early stage treated with therapeutic hypothermia. Recent reports demonstrated a regional cerebral oxygen saturation of cardiac arrest patients on hospital arrival could predict their neurological outcome. There has been little discussion about the significance of regional cerebral oxygen saturation in patients with post-cardiac arrest syndrome. Amplitude-integrated electroencephalography monitoring may also provide early prognostic information for post-cardiac arrest syndrome. However, even when the initial electroencephalography is flat after the return of spontaneous circulation, good neurological outcome may still be obtainable if the electroencephalography shifts to a continuous pattern. The electroencephalography varied from flat to various patterns, such as flat, epileptic, or continuous during the first 24\u00a0h, while regional cerebral oxygen saturation levels varied even when the electroencephalography was flat. It is therefore difficult to estimate whether regional cerebral oxygen saturation accurately indicates the coupling of cerebral blood flow and metabolism in the early stage after cardiac arrest. Careful assessment of prognosis is necessary when relying solely on regional cerebral oxygen saturation as a single monitoring modality. Monitoring with electroencephalography (EEG) may be able to provide early prognostic information after ROSC in patients with therapeutic hypothermia [2 values tend to vary widely even when EEG patterns are flat in the early stage, which makes it difficult to estimate the neurological outcome using only a single modality for monitoring by rSO2.Recent reports demonstrate a relationship between regional cerebral oxygen saturation  and cerebral blood flow (CBF), which linearly correlates with cerebral venous oxygen saturation and with CBF [2, whereby CBF would be affected by these dysautoregulatory factors. Physicians therefore have to consider many factors when estimating rSO2 values after cardiac arrest. The rSO2 data of brain-dead patients also demonstrates that rSO2 values do not always indicate the cerebral oxygen metabolism [2 value. The rSO2 value may depend on the blood pressure, because CMRO2 is thought be extremely suppressed when the EEG pattern is flat , or hyperperfusion (lower CMRO2 and higher CBF). They can also reflect hyperemia caused by severe metabolic depression due to severe brain damage in PCAS. Cerebral oxygen extraction fraction, however, can be expected to decrease in comatose patients immediately after ROSC as a consequence of the primary cerebral metabolic suppression [2 levels are detected when the EEG is flat, given that the CMRO2 may be drastically suppressed. Figures\u00a02 level that starts at around 80\u00a0% and remains constantly high thereafter. Finally, the aEEG indicated epileptic or suppression-burst EEG patterns of a type thought to portend poor outcome. It was difficult to determine the clinical significance of the high rSO2 values in the early post-resuscitation phase [2 values with epileptic or suppression-burst EEG patterns indicate more severe brain damage after cardiac arrest.Higher rSOpression . This apon phase \u20136. We th2 values in PCAS. The main causes of low rSO2 stem from too little oxygen supply to meet the cerebral oxygen demand, a sign of cerebral ischemia caused by unstable hemodynamics, hypoxia, or decreased PaCO2 rather than a cerebral metabolic suppression. Physicians will be able glean hints for the next steps in their treatment strategies for conditions of these types. Good neurological outcome may be obtainable after PCAS if two conditions are met: first, the patient shows no drastic elevation of rSO2 accompanying an extremely low voltage on the initial EEG; second, the patient shows and no sign of electrographic status epilepticus  in PCAS during therapeutic hypothermia was recently classified into four categories: extremely low voltage ; suppression-burst pattern; electrographic status epilepticus with recurrent epileptic form activity; and continuous EEG [2 values might be reflected by the influences from factors such as blood pressure, CBF, PaCO2 or no-reflow phenomenon. These result demonstrate that rSO2 alone is insufficient for predicting neurological outcome after PCAS and that rSO2 cannot be confirmed to reliably indicate whether CBF and metabolism are coupling or uncoupling in the early stage after ROSC.There has been little discussion about the significance of rSOuous EEG . Status uous EEG \u20136. Patteuous EEG , 5. Alth2 might also be initially depressed while the EEG is suppressed. Given the possible therapeutic implications of continuous rSO2 monitoring in patients with brain injury, the variations of rSO2 and potential influences of many factors at this stage made it difficult to determine the clinical significance of rSO2 in PCAS. Careful assessment of prognosis is necessary when relying solely on rSO2 as a single monitoring modality.The EEG is extremely suppressed after ROSC and gradually changes to various patterns. CMROInformed consent was obtained from all individual participants included in the study.This study was approved by the Clinical Research Institutional Review Board (IRB: RK-140613-3) of this hospital."}
+{"text": "Soybean is an important food allergen and it is often incorporated in complex formulated foods. Thermal processing induces conformational changes of food allergens and accelerates its interaction with carbohydrates. This reaction is called Maillard reaction (MR) and occurs always during food processing. It has been shown to influence allergenic potential of several proteins.The aim of the study was to establish the effect of processing conditions on allergenic potential of soy protein extract containing the major soy allergens Gly m 5 and 6.oC) for 10 or 30 minutes with glucose and SPE heated (121oC) for 10 or 30 minutes without sugar as a control. The allergenic potential of tested extract was examined using the basophil activation test (BAT) and inhibition ELISA. Maillard reaction products (MRP) were identified by western blot.Clinically characterized soy allergic patients (n=15) with specific IgE against Gly m 5 and 6 were selected for the study. Here we show the complete data obtained for seven patients. Five chemically characterized soy protein extracts (SPE) were tested: raw SPE, SPE heated  or decrease  of allergenicity for all processed extracts was seen. For 2 patients miscellaneous changes for different processing conditions were observed. For 70% of the patients SPE heated for 30 minutes with glucose stimulated basophils stronger than control SPE. The neo-allergens formed during heating of SPE with glucose were characterized on blots as high-molecular weight agglomerates of proteins and sugars, which contain advanced MRP. Their inhibitory ability for specific IgE binding was established in ELISA.Maillard-type neoallergens formed during soy processing can trigger stronger basophil stimulation than raw soy proteins in soy allergic patients. The use of only raw soy extracts in diagnostic tests may provide false negative results."}
+{"text": "Our data shows the regional coronary artery calcium scores (lesion CAC) on multidetector computed tomography (MDCT) and the cross-section imaging on MDCT angiography (CTA) in the target lesion of the patients with stable angina pectoris who were scheduled for percutaneous coronary intervention (PCI). CAC and CTA data were measured using a 128-slice scanner  before PCI. CAC was measured in a non-contrast-enhanced scan and was quantified using the Calcium Score module of SYNAPSE VINCENT software  and expressed in Agatston units. CTA were then continued with a contrast-enhanced ECG gating to measure the severity of the calcified plaque condition. We present that both CAC and CTA data are used as a benchmark to consider the addition of rotational atherectomy during PCI to severely calcified plaque lesions. Specifications TableValue of the data\u2022Regional CAC obtained from a non-contrast-enhanced multidetector computed tomography (MDCT) imaging is useful for evaluating regional calcified plaque condition because of a simple marker when the percutaneous coronary intervention (PCI) was scheduled in patients with stenotic coronary artery.\u2022Cross-section imaging of a contrast-enhanced ECG gating MDCT angiography (CTA) is also useful for evaluating the regional calcified plaque condition into the lumen of coronary artery because of a viewpoint from the inside practically when the PCI was scheduled in patients with stenotic coronary artery.\u2022Both CAC and CTA cross-section imaging data are used as a benchmark to consider the addition of rotational atherectomy during PCI to severely calcified plaque lesions.1In this present data 22.1The data of CAC and CTA on MDCT were obtained in patients with stable angina pectoris who were scheduled for first PCI.2.2http://www.fujifilmusa.com/products/medical/radiology/3d/) CAC data were obtained using a non-contrast-enhanced 128-slice scanner  before PCI. CAC data was quantitatively analyzed using the Calcium Score module of SYNAPSE VINCENT software (Fujifilm Co. Tokyo, Japan, 2.3The software displayed the calcified plaque lesion of the coronary artery by color and calculated the quantitative value of the calcified plaque by using the Agatston score method . CAC dat2.4The software extracted the path of the target blood vessels  and visu"}
+{"text": "Woven coronary artery is relatively rare and can be complicated in both acute and chronic phases. A few case reports have been published until now. Herein we report a case with right woven coronary artery managed with drug-eluted stent implantation without complication. Woven coronary artery (WCA) disease is an extremely rare congenital anomaly with unexplained etiology . In this54-year-old male with tightening chest pain and palpitation on exertion for two months was admitted to cardiology outpatient clinic two years ago. Resting electrocardiogram showed q waves and extra systoles on D3 and aVF. Echocardiography showed akinesia at inferior and posterior walls, and ejection fraction was 44%. We performed coronary angiography by using the Judkins technique from right femoral artery. There were plaques at LAD and %50 stenosis at proximal Circumflex arteries, the lesions were considered to be insignificant , and theWoven coronary artery (WCA) is a very rare congenital anomaly which can affect both RCA and LAD and may lead to acute coronary syndromes in some circumstances . It was This anomaly may be accepted as a benign disease. Some reports showed no cardiovascular adverse events during 5-year follow-up \u20135. NeverIn conclusion, WCA may cause myocardial ischemia and damage. All interventional cardiologists might keep this anomaly in mind and should beware of the possible consequences of WCA in catheterisation laboratory. PCI or coronary artery bypass grafting may be treatment options for this anomaly."}
+{"text": "Type II A aortic dissection after mechanic aortic valve replacementis a major complication and may be life threatening.We present a case of a 51 years-old male patient having an acute Type II A aortic dissection after mechanic aortic valve replacement.A 51-years-old male was hospitalized in our clinic on Mach 26, 2015. He had mild aortic insufficiency and mild mitral insufficiency. Ejection fraction was 60%. CT-Scan revealed type II A aortic dissection.He had Type II A aortic dissection with intimal tear at proximal region of the right coronary ostium. Mechanic aortic valve was normal function. Ascending aorta was replaced by using 26 mm Dacron tube graft between annulus of previous mechanic aortic valve and distal ascending aort by using hypothermic circulatory arrest and antegrade selective cerebral perfusion. An 8 mm dacron tube graft was anastomosed between right and left coronary annulus and this tube graft was anastomosed to neo-aorta (Cabrol technique). Postoperative period was event-free. The patient was discharged on 14 postoperative day with warfaine and methoprolol treatment.Although acute aortic dissection after mechanic aortic valve replacement is a rare complication, physicians should keep this potential life-threatening complication in mind.Written informed consent was obtained from the patient for publication of this abstract and any accompanying images. A copy of the written consent is available for review by the Editor of this journal."}
+{"text": "Idiopathic intracranial hypertension (IIH) is a condition of increased intracranial pressure (ICP) without identifiable cause. The majority of IIH patients are obese, which suggests a connection between CSF regulation and obesity. However, the pathophysiological mechanisms remain widely unresolved.To develop a long-term ICP monitoring method and investigate ICP in lean and obese rats. We also aimed to clarify if any ICP difference could be attributed to changes in some well-known ICP modulators; retinol and arterial partial pressure of CO2 (pCO2).ICP was measured in six obese and six lean Zucker rats with a newly developed epidural ICP monitoring method over a period of 31 days. Furthermore, arterial pCO2 and serum retinol were measured in blood samples from each animal.Obese rats had significantly elevated ICP-levels compared to lean controls on all recording days (p < 0.0001). Serum retinol  and arterial pCO2  did not differ between the two groups.Obesity-related intracranial hypertension in rats is not related to altered pCO2 levels or retinol metabolism. This indicates that the increase in ICP might be related to molecular changes in the brain caused by the adipose state. Although further studies are warranted, obese Zucker rats could potentially constitute a model for IIH.No conflict of interest."}
+{"text": "Breast cancer is the main cancer type affecting women in the Kingdom of Saudi Arabia. The relatively young age of onset in this population could be explained by the interplay between common genetic susceptibility background substantiated by increased consanguinity and epigenetic aberrations caused by the shift in life style experienced in this region . GenomicMethyl binding domain-sequencing (MBD-Seq) was applied on DNA extracted from surgically-resected breast tumors using the MethylMiner\u2122 kit from Invitrogen followed by fragment identification using next generation sequencing on the SOLiD platform (Applied Biosystems). Determination of methylation frequency and correlation with clinicopathological parameters was performed using the MethyLight assay on DNA extracted from FFPE tissues. Fisher\u2019s exact test and univariant Kaplan-Meier survival analysis were applied where p<0.05 considered statistically significant.MTNR1B methylation frequency in breast cancer is 35% (n=157). MTNR1B methylation was largely limited to the IDC, ILC and DCIS subtypes. Furthermore, MTNR1B methylation is significantly associated with histological grade I of breast cancer . The association of MTNR1B methylation and disease-free or specific survival is investigated.Finding significant levels of methylation of a key circadian clock gene as the MTNR1B in a tumor-specific fashion may provide an intriguing evidence to the role of environmental factors (day-night cycles) and breast cancer development.This project is funded by KACST grant ARP-29-292."}
+{"text": "However, data on the clinical relevance of right ventricular (RV) failure are limited.To establish the prognostic implications of RV failure in a large series of post cardiac surgery patients.\u00ae, Baxter), enabling continuous RV ejection fraction (RVEF) measurements. RVEF was categorized into three subgroups: RVEF < 20%, 20-30% and >30%. Demographic data and hemodynamic variables were recorded. Primary outcome was predefined as the correlation between the average RVEF over the first 24 hours in the ICU and markers of morbidity.We performed a single-centre retrospective analysis of all high risk cardiac surgery patients in a four year period. By protocol these patients were equipped with a pulmonary artery catheter (VigilanceA total of 1115 patients were included. Patient characteristics are summarized in table A RVEF < 20% is independently associated with increased ICU mortality and morbidity in high risk postoperative cardiac surgery patients."}
+{"text": "Defects in lamin A maturation result in premature aging syndromes and severe atherosclerosis as observed in Hutchinson-Gilford Progeria Syndrome. In age-related atherosclerosis, several features of cells senescence have been characterized in endothelial cells lamin A alterations. We propose a cellular model to study lamin A-related senescence in primary endothelial cells. In this model, lamin A defects were induced by protease inhibitor (PI: Atazanavir) treatment during 48h on normal cells issued from placenta  or cord blood (ECFC)). We showed that PI treatment led to the accumulation of farnesylated prelamin A and induced nuclear shape abnormalities and premature senescence in both HUVEC and ECFC. ICAM-1-dependent activation was present and monocytes adhesion was increased in HUVEC whereas ability to generate microvascular network in matrigel was decreased for ECFC. The effects of PI treatment on nuclei shape were reversed when cells were PI-treated in combination with Pravastatin and Zoledronate in both mature and progenitor endothelial cells. Reversion also was demonstrated with 2 antisens-oligonucleotides targeted toward lamin A specific splice sites. This study confirms that PI treatment reproduces premature senescence due to lamin A maturation defects in primary endothelial cells after a 2 days exposure. The cells used were extracted from full term and healthy neonates i.e. from individuals of age 0. This allows us to consider that other senescence pathways were not activated and that the observed alterations were specific of prelamin A accumulation. This model constitutes a valuable tool to test different approaches aimed at reversing specifically lamin A-related cells senescence."}
+{"text": "Theta-frequency oscillations 8-12 Hz) of large groups of synaptically coupled cells are commonly seen throughout the mammalian brain. The theta oscillations of entorhinal cortex grid cells and hippocampal place cells have received special attention recently due to their role they apparently play in the encoding of positional information. In a previous study 2 Hz of l."}
+{"text": "Joint moments modeled from a musculoskeletal tool differ from those recorded by a dynamometer. In order to solve the problem, numerical methods to minimize the variance of the joint moments have been adopted . The exiNOF was designed to strengthen the linear relationship between: (1) the recorded and modeled joint moments, and (2) the muscle activations and the muscle forces. One male  participated in the study with the informed consent prior to commencing the experimental trials. Surface electrodes were attached to record EMG signals from elbow major muscles using an eight-channel surface EMG system . Dynamometer tasks were performed with Biodex System 3 Pro  to measure elbow joint moments. The participant was asked to perform three maximum isometric contractions at 90\u00b0 (flexed). The subject then generated an elbow flexion moment, rested, and generated an elbow extension moment. To evaluate the effects of NOF compared to EOF briefly, we focused on the changes in biceps brachii long head (BIClong) muscle force and compared the relative root-mean-square error.Modeled joint moments with no parameter calibration (NOT Adjusted) showed undesirable negative offset during the 3-second-rest period, but this problem was solved by the parameter calibration with EOF or NOF Figure . Even thEven though NOF yielded relatively low performance in joint moment prediction, it estimated muscle forces better, providing more reasonable kinetic information about human movements such as walking and running."}
+{"text": "Due to the absence viral vectors and of cytotoxicity the Int based binary system offers advantages over previously described counterparts and may therefore be developed into a safer cancer cell killing system.Binary systems based on site-specific recombination have been used for tumor specific transcription targeting of suicide genes in animal models. In these binary systems a site specific recombinase or integrase that is expressed from a tumor specific promoter drives tumor specific expression of a cytotoxic gene. In the present study we developed a new cancer specific binary expression system activated by the Integrase (Int) of the lambdoid phage HK022. We demonstrate the validity of this system by the specific expression of a luciferase ( The recombinases of the former two systems belong to the tyrosine recombinase family and of the latter system to the serine recombinase familySite-specific recombinases are widely used for genome manipulations by catalysis of site-specific recombination reactions (SSR) between two defined DNA sequences of ~20\u2013200 base pairs (bp) functioning as recombination sites (RSs)12345SSR systems are also used in binary systems for cell and gene specific expression that are based on two DNA modules. One module carries a recombinase substrate comprising a target gene silenced by a transcription terminator placed between two RSs. The second module carries the recombinase gene controlled by a cell type specific promoter. This promoter targets the expression of the SSR to the desired cells where it excises the terminator and thus activates the expression of the gene of interest910Escherichia coli chromosome as well as its excision from the E. coli chromosome. In these regards it acts very much like the well-documented coliphage \u03bb IntegraseattB or BOB\u2032 to indicate its composition of a central 7\u2009bp overlap region (O) and the two flanking incomplete inverted repeats of 7\u2009bp (B and B\u2032). O is the site of DNA exchange while B and B\u2032 are Int binding sites. The phage recombination site termed attP is ~200\u2009bp long. It contains a 21\u2009bp core (COC\u2032) that is similar to attB and is flanked by two long arms (P and P\u2032) that carry additional Int binding sites and others that bind accessory proteins required for the SSR reactions. The phage integration reaction occurs between attP and attB. It yields two hybrid recombination sites flanking the integrated prophage termed attL (BOP\u2032) and attR (POB\u2032). The reverse prophage excision reaction occurs between the attL and attR sites and restores the original attP and attBE. coli host are dispensable in the eukaryotic milieu14151617hTERT promoter. hTERT serves as the catalytic reverse transcriptase subunit of telomerase and is specifically expressed in immortal and cancer cells19hTERT-promoted Int specifically activates a luc reporter in immortalized human embryonic kidney 293 cells (HEK293T) and in mouse lung tumors originating from injected Lewis lung carcinoma line 1 (LLC1). This cancer specific expression system offers certain advantages over those previously described910Coliphage HK022 encodes an Integrase recombinase (Int) belonging to the tyrosine integrase family that catalyzes the integration of the phage genome into its RS on the int gene under the control of the cancer specific promoter hTERT19CMV) promoter as control. The other carries a luc gene separated from a CMV promoter by a transcription terminator (Stop) flanked by tandem attR and attL recombination sites  or under the constitutive CMV promoter (pNA979) that served as a positive control. The quantitative analysis of the Luc activity assay in HEK293T cells  is the most effective. This linear polyethylenimine reagent is used to deliver DNA, siRNA and oligonucleotides. It forms stable complexes with the nucleic acid cargo, protecting it from degradation thereby facilitating in vivo delivery. These complexes pass the capillary barrier in the lung, explaining the propensity of in vivo-jet PEI to deliver its cargo specifically into lungsluc), whose product emits characteristic yellow-green bioluminescence in the presence of its luciferin substrate is most suitable. BALB/c mice were intravenous (IV) tail-injected with a sample of the jet PEI delivery agent complexed with a reporter plasmid (pYM1600) that carries the luc gene under the control of CMV promoter. 24 hours later the mice were injected with the Luciferase substrate luciferin and underwent bioluminescence imaging. The treated mouse . As a positive control two mice were each similarly treated with two doses of a CMV-luc expressing plasmid . 24 hours later bioluminescence imaging of these mice Entacmaea quadricolor known as Katushka cells (LLC-Kat)25Having demonstrated that the jet PEI DNA delivery reagent has delivered the in vivo micro-CT scanning. No tumors were detected in the lungs of the non-injected control [ex-vivo fluorescence detection using the Maestro imaging system [Lung tumor metastases development was examined nine days following the injection of the LLC-Kat cells using  control  whereas  control . The preg system  as compag system  and by ig system  comparedg system . In bothin vivo-jet PEI carrier complexed with different combinations of plasmids [panels (b\u2013e)] while groups (a) remained untreated. In groups (b) the jet PEI carrier was complexed with the CMV-luc reported as positive control; in groups (c) the carrier was complexed with the silent recombination substrate (CMV-RSL-luc) alone to validate the absence of luc leakage; in groups  the carrier was complexed with the silenced substrate and the CMV-promoted Int (d) or with the hTERT-promoted Int (e). 24\u2009hours later all mice were injected with luciferin and underwent bioluminescence imaging. As expected, in both healthy and cancerous mice the negative controls (a) and the ones treated with the silent substrate (c) showed no bioluminescence while the positive controls (b) did. So did the two groups (d) treated with the silent substrate along with the constitutive CMV-Int. However, in groups (e) only the cancerous mice treated with the silent substrate along with the hTERT-Int showed bioluminescence  only the cancerous ones showed an immune response. These results unambiguously confirmed the cancer specificity of our binary system.Finally, to test the cancer specificity of the binary Int-activated cell expression system in mice we performed a comparative analysis of this system between healthy C57BL/6 mice  and LLC-nescence  while innescence  no biolupression . The expCre is one of the most widely SSRs used in mammalian gene manipulations, however, Cre-dependent cellular toxicity has been reported in eukaryotic cells and organisms some even under transient conditions. These include reduced cell growth, chromosome aberrations, brain development, cardiac fibrosis, heart failure, thymic atrophy and severe hematological toxicity28293031hTERT promoter showing that when the expression of coliphage HK022 Int is promoted by hTERT it activates, by a site-specific recombination reaction, the expression of the luc reporter gene exclusively in lung cancer cells without affecting normal tissues. In previous two reports that employed the Cre/lox system in such binary systems one used an adenovirus vector as the gene delivery carrierIn the present study a new cancer specific binary cell expression system was developed that is based on the cancer-specific hTERT promoted substrate, though being cancer specific, may be somewhat leaky on its voyage from its delivery spot to the cancer tissue thereby loosing specificity by damaging healthy tissues. Admittedly, a successful direct adenoviral carrier delivery of an hTERT promoted DTA toxin that cured ovary cancer in mice was reportedWhen using a toxin gene to be specifically expressed in cancer cells it is essential that in the binary system the recombinase, being an enzyme, be promoted by a weak and specific promoter and that the toxic gene of the substrate be completely blocked by a tight transcription terminator. Because more substrate than enzyme needs to be delivered  the direattB sites, such sites need to to carry a perfect wild type 7\u2009bp overlap with two flanking palindromic sequencesattL and attR RS sites in the binary system are incomplete attPs. These and the fact that Int is weakly promoted by hTERT reduce the likelihood of off target Int-catalyzed integration events into human secondary attB sites.With regards to possible off-target chromosomal integration events catalyzed by Int, we have previously shown that for Int to promote integration into secondary attL and attR as recombination sites because they proved more efficient in mammalian recombination activity than does the attB\u2009+\u2009attP pair. Another reason is because their recombination leads to the short 21\u2009bp attB site located between the promoter and the Luc gene  have already shown that with the DTA toxicity is clearly specific in the LLC-Kat as compared to normal human foreskin BJ cells and experiments with live mice using DTA and other toxins to eradicate the lung cancer are in progress. Success may render the system useful with other cancer cases using relevant cell specific promoters and cell specific DNA carries.E. coli K12 strain TAP114 (lacZ)M15The bacterial host used was Human embryonic kidney cells HEK293T (ATCC CRL-3216) were cultured in Dulbecco\u2019s modified Eagle\u2019s medium. Mouse Lewis lung carcinoma LLC1 (ATCC CRL-1642) cells labelled by Katushka fluorescent gene reporter5) were plated in a 6 well plate and 24\u2009hours later treated with 2\u2009\u03bcg circular plasmid DNA using Puro-Fection transfection reagent  or TransIT-XT2 reagent , respectively.For transient transfection of HEK293T and LLC-Kat, the cells  was constructed as follows. A BglII-HindIII hTERT PCR fragment, was generated using primers oEY638\u2009+\u2009oEY639 . The pAE1855 plasmid, used as a substrate for the CMV-Luc assays, was constructed by ligation of a AgeI-NotI luc PCR fragment, obtained using pYM1600 as template and primers oEY807\u2009+\u2009808, into the same sites of the intermediate plasmid construct pAE1855inter carrying CMV- attR-Stop-attL cassette on pCDNA3. All plasmid constructs were verified by DNA sequencing.The pNA1263 plasmid  carrying+\u2009oEY639  and an hluc plasmids were collected 48\u2009hours later by trypsin treatment and centrifugation, resuspension in 100\u2009\u03bcl of x1 Passive Lysis Buffer  followed by sonication and centrifugation. Quantitative Luc analysis of the supernatant was performed using Dual-luciferase reporter assay kit  and Synergy2 plate reader  according to the manufacturer\u2019s instructions.HEK293T or LLC-Kat cells transfected by the appropriate in vivo-jet PEI delivery reagent  complexed with an appropriate luc reporter plasmid. 24\u2009hours later the mice were injected with 250\u2009\u03bcl of 3\u2009mg/ml luciferin solution  and underwent bioluminescence imaging by Biospace Photon Imager .BALB/c or C57BL/6 mice were IV tail-injected with 250\u2009\u03bcl of the 6 LLC-Kat cells were IV tail-injected into 8 week old (17\u201321\u2009gr) female C57BL/6 mice. Lung tumor metastases development was examined nine and twelve days following the injection using in vivo micro-CT scanner . The Katushka fluorescent signal in the lung metastases was analyzed on day 12 by an in vivo fluorescence imaging system .0.8\u2009\u00d7\u200910At the end of the experiments, biopsy specimens from lungs were collected, fixed in 4% paraformaldehyde (PFA), embedded in paraplast and 5\u2009\u03bcm sections were prepared. Healthy and cancer lungs carrying metastases were treated in parallel with H&E stained and immune-stained anti-Luciferase antibody  at 1:100 dilution, with a PCNA kit  and with a TUNEL kit  according to manufacturer\u2019s instructions. Donkey anti-Goat IgG (H\u2009+\u2009L) secondary antibodies conjugated with Alexa Fluor 488 dye  were used for Luciferase detection. Nuclei were detected with DAPI . At least 20 images of five tissue sections from 3 different mice per group were obtained for each analysis. Microscopic observation and image acquisition were performed using a Zeiss 510 Meta \u2013 NLO confocal laser-scanning microscope . TUNEL assay analysis was performed using Image J software.E. coli was prepared using a DNA Spin Plasmid DNA purification Kit  or a NucleoBondTM Xtra Maxi Plus EF kit . General genetic engineering experiments were performed as described by Sambrook and RussellPlasmid DNA from How to cite this article: Elias, A. et al. Cancer-specific binary expression system activated in mice by bacteriophage HK022 Integrase. Sci. Rep.6, 24971; doi: 10.1038/srep24971 (2016)."}
+{"text": "Improving the functional avidity of effector T cells is critical in overcoming inhibitory factors within the tumor microenvironment and eliciting tumor regression.+ T cells and inhibits their functional avidity against tumor.We have found that Cish, a member of the Suppressor of Cytokine Signaling (SOCS) family, is induced by TCR stimulation in CD8Cish in CD8+ T cells enhances their expansion, functional avidity and cytokine polyfunctionality, resulting in pronounced and durable regression of established tumors. Although Cish is commonly thought to block STAT5 activation, we found that the primary molecular basis of Cish suppression is through inhibition of TCR signaling. Cish physically interacts with the TCR intermediate PLCg1, targeting it for proteasomal degradation following TCR stimulation. Furthermore we extend these findings to patients PBL retrovirally transduced with tumor-specific TCRs and shorthairpin microRNAs targeting CISH.Genetic deletion of + T cells and can be manipulated to improve adoptive cancer immunotherapy.These findings establish a novel targetable interaction that regulates the functional avidity of tumor-specific CD8"}
+{"text": "Respiratory motion in PET/MR imaging leads to reduced quantitative and qualitative image accuracy. Correction methodologies include the use of respiratory synchronized gated frames which lead to low signal to noise ratio (SNR) given that each frame contains only part of the count available throughout an average PET acquisition. In this work, 4D MRI extracted elastic transformations were applied to list-mode data either inside the image reconstruction or to the reconstructed respiratory synchronized images to obtain respiration corrected PET images.Five patient datasets acquired on the SIEMENS mMR PET/MR system were used. T1-weighted 4D MR images were registered to the end expiration MR image using an elastic B-spline registration algorithm to derive deformation matrices used to account for the respiratory motion. The derived matrices were subsequently applied during the List Mode OSEM PET image reconstruction of the original emission list-mode data. The corrected images were compared with those produced by applying the elastic transformation after reconstructing PET frames followed by summing the realigned gated frames, as well as with uncorrected motion averaged images.Significant improvement was obtained by using any of the two respiratory motion correction techniques compared to uncorrected motion average images (>30% differences in tumor position and size and 25% SNR increase). Both correction approaches lead to nearly equivalent improvements (differences of <8% and <6% for the lesion FWHM and the SNR respectively).A list-mode reconstruction based respiratory motion correction for PET has been implemented and its performance evaluated. This approach was based on the use of elastic transformations derived from 4D MRI during PET image reconstrucion. Our results show significant respiratory motion compensation when compared to the motion average PET images, with slightly better contrast and SNR compared to an equivalent 4D PET image space elastic motion correction method."}
+{"text": "Glu89Gln transthyretin (TTR) variant is a well-known cause of systemic amyloidosis with a cardiologic, neurologic or mixed phenotype. Even though Glu89Gln transthyretin (TTR) variant has been described worldwide, it remains unknown whether geographical area influences the phenotypic expression of the disease . We hypothesized that significant phenotypic differences exist between patients with Glu89Gln-related amyloidosis according to the specific geographic origin.We retrospectively analysed and compared the clinical, electrocardiographic and echocardiographic findings of 64 patients with Glu89Gln TTR-related amyloidosis from Italy and Bulgaria.Despite a similar age at diagnosis of the disease (55 [52-60] years) patients in Bulgarian cohort have a mixed phenotype. A more severe left ventricular wall thickening was present in Bulgarian cohort compared to Italian one  with a normal ejection fraction in all cases.This is the largest series so far of patients with Glu89Gln TTR-related amyloidosis systematically analysed. Overall, disease onset is late with a mixed phenotypic expression. Despite a similar age at onset and a predominance of neurological routes, Bulgarian patients showed a more pronounced cardiomyopathy."}
+{"text": "Systemic light chain amyloidosis (AL) is associated with a high cardiovascular morbidity and mortality. Cardiovascular involvement and determination of prognosis is underestimated by standard imaging parameters. Recently, cardiac deformation analysis of global circumferential and longitudinal strain has been shown to have great clinical impact on the assessment of prognosis and survival in this rare disease. For further analysis we applied the novel non-invasive post-processing feature tracking imaging (FTI) algorithm on pre-acquired regular CMR SSFP images in healthy volunteers and in patients with AL and sought to investigate different strain patterns.87 patients (mean age 60 \u00b1 11 years) with biopsy proven systemic AL were scanned on a clinical 1.5 T CMR scanner (Philips Achieva). Short axis slices covering entirely both ventricles as well as 2-, 3- and 4-chamber views were acquired using standard SSFP-sequences before initiation of any specific pharmaceutical AL therapies. The control group consisted of 47 healthy subjects (mean age 59 \u00b1 5 years). Besides the standard CMR parameters for volumes, ejection fraction, myocardial mass and wall thickness we measured the circumferential and the longitudinal strain on cine SSFP images by the application of the post-processing FTI algorithm.In patients with AL mean longitudinal strain from the four chamber view  as well as midventricular mean circumferential strain  were significantly reduced compared to healthy subjects. Global circumferential strain and global longitudinal strain correlated with left ventricular ejection fraction . In the subgroup analysis of AL patients with a mean wall thickness less than 12 mm global longitudinal strain showed significantly reduced values in comparison to healthy control subjects , whereas global circumferential strain did not show a significant difference. Patients with an ejection fraction \u226555% already had reduced global longitudinal strains , again global circumferential strain did not show a significant difference.FTI strain analysis derived from regular cine SSFP sequences offers the possibility for a fast quantitative assessment of myocardial strain imaging patterns without additional and time-consuming strain imaging sequences. FTI strain analysis provides important insight into the disturbed contraction in AL. Further investigations are necessary to analyze the impact of this new method on the prediction of clinical outcome in AL patients.None."}
+{"text": "Mycobacterium tuberculosis (Mtb) is one of the most successful human pathogens, and a key mechanism in its virulence arsenal is its ability to influence host immune responses to its advantage. In recent years it has become clear that one such mechanism pivots on bacterial-derived, secreted small molecules that are released from the intracellular phagosome of macrophages into the host cell cytosol where they interfere with host cell signaling and downstream cytokine responses. Using small molecules such as cyclic nucleotides, Mtb subverts the host's innate bactericidal responses to remodel the intracellular niche to an environment favorable for mycobacterial survival or growth . Upon infection Mtb produces a burst of cAMP within macrophages. Through a microbial adenylate cyclase gene, bacterial-derived cAMP is delivered to the macrophage cytoplasm increasing cytosolic cAMP levels 3\u20135-fold above baseline and triggering the PKA-CREB pathway to upregulate NF\u03baB transcription. One consequence of bacterial subversion of host cAMP signaling is the elevated TNF-\u03b1 secretion at the early stages of infection promoting necrosis and granuloma formation\u2014outcomes that foster bacterial survival .Mtb also interferes with immune signaling by secreting another bacterial-derived second messenger, cyclic-di-adenosine monophosphate (c-di-AMP) . This paThe failure to control the global TB epidemic despite the availability of curative drug regimens is partly driven by the inherent difficulties of maintaining continuous chemotherapy over at least six months . MoreoveSmall molecule phosphodiesterase (PDE) inhibitors \u2013 which raise levels of certain cytosolic cyclic nucleotides \u2013 have become important drugs in human medicine with the introduction of PDE3 inhibitors for intermittent claudication, PDE5 inhibitors for erectile dysfunction and pulmonary hypertension, and PDE4 inhibitors for chronic obstructive pulmonary disease. PDE4 inhibitors have been of particular interest for lung infections since they reduce pulmonary inflammation. Not surprisingly, the evaluation of FDA-approved human PDE inhibitors as well as those in the pipeline for FDA approval has emerged as an attractive strategy for adjunctive HDTs against TB.PDE inhibitors are isoenzyme-specific compounds of different binding affinities and potencies that also act according to the tissue distribution of the isozyme . SeveralIn this issue, Subbian et al. assess the adjunctive value of the PDE inhibitor CC-11050 when used in combination with isoniazid to treat TB . CC-1105The authors have no relevant conflicts of interest to disclose."}
+{"text": "The incidence of ocular surface squamous neoplasia (OSSN) is strongly associated with solar ultraviolet (UV) radiation, HIV and human papilloma virus (HPV). Africa has the highest incidence rates in the world. Most lesions occur at the limbus within the interpalpebral fissure particularly the nasal sector. The nasal limbus receives the highest intensity of sunlight. Limbal epithelial crypts are concentrated nasally and contain niches of limbal epithelial stem cells in the basal layer. It is possible that these are the progenitor cells in OSSN. OSSN arises in the basal epithelial cells spreading towards the surface which resembles the movement of corneo-limbal stem cell progeny before it later invades through the basement membrane below. UV radiation damages DNA producing pyrimidine dimers in the DNA chain. Specific CC\u00a0\u2192\u00a0TT base pair dimer transformations of the p53 tumour-suppressor gene occur in OSSN allowing cells with damaged DNA past the G1-S cell cycle checkpoint. UV radiation also causes local and systemic photoimmunosuppression and reactivates latent viruses such as HPV. The E7 proteins of HPV promote proliferation of infected epithelial cells via the retinoblastoma gene while E6 proteins prevent the p53 tumour suppressor gene from effecting cell-cycle arrest of DNA-damaged and infected cells. Immunosuppression from UV radiation, HIV and vitamin A deficiency impairs tumour immune surveillance allowing survival of aberrant cells. Tumour growth and metastases are enhanced by; telomerase reactivation which increases the number of cell divisions a cell can undergo; vascular endothelial growth factor for angiogenesis and matrix metalloproteinases (MMPs) that destroy the intercellular matrix between cells. Despite these potential triggers, the disease is usually unilateral. It is unclear how HPV reaches the conjunctiva. \u2022Limbal epithelial stem cells are the likely progenitor cells of OSSN.\u2022UV radiation causes DNA damage via dimers, photoimmunosuppression and reactivates latent HPV.\u2022HPV E6 inhibits p53 tumour suppressor gene allowing DNA-damaged cells past the G1-S checkpoint of the cell cycle.\u2022HPV E7 inhibits pRB gene antitranscription at G1 so infected cells keep replicating.\u2022HIV, photoimmunosuppression and vitamin A deficiency impair tumour surveillance. Early lOSSN occurs worldwide but the peak incidence is found at a latitude of 16\u00b0 South . The mea2The ocular surface consists of the cornea, limbus and conjunctiva but in a wider anatomical and embryological sense the mucosa of the ocular adnexa  is included. The epithelia of the cornea, conjunctiva and eyelid are formed from differentiation of the surface ectoderm during embryonic development. The corneal endothelium and the corneal stroma, conjunctiva and eyelids are formed when periocular mesenchymal cells of neural crest origin migrate and differentiate .The cornea has a stratified squamous non-keratinizing epithelium with five to seven cell layers. It is immunologically privileged due to its lack of blood vessels and lymphatics, with dendritic cells present usually only in the peripheral cornea .The limbal epithelium is 8\u201310 cells thick and is constantly being replenished from stem cells in the basal layer . The limThe conjunctiva consists of an epithelium on a basement membrane and underlying loose connective tissue called the lamina propria. The lamina propria is loosely anchored to the episclera and sclera making the conjunctiva easily mobile. The epithelium varies between 2\u20133 and 10\u201312 cell layers, depending on whether it is the bulbar, fornix or tarsal portion. Lymphocytes and plasma cells are abundant in the conjunctiva . They fo3Stem cell biology is a rapidly progressing field. A stem cell is a special undifferentiated progenitor cell capable of giving rise to many more cells of the same type, and from which other kinds of cells arise by differentiation. There are three types of stem cells. Embryonic stem cells originate from pre-implantation embryos and can develop into tissues that belong to one of the three germ layers . Non-embCorneo-limbal lineage is distinct from conjunctival lineage . EvidencLimbal stem cells are found in special niches in the basal region called limbal epithelial crypts which are cords of epithelial cells extending from the palisades of Vogt into the underlying stroma . The cryThe ocular surface is self-renewing. Superficial cells are constantly lost and are replaced by basal cells entering the differentiation pathway. To replenish the corneal epithelium, corneal epithelial stem cells undergo mitosis producing a progeny of fast-dividing transient amplifying cells (TAC) that make up the majority of the proliferating cell population in the epithelium . TAC mig4The term cancer stem cell is a relatively new one in cancer biology, though this is a concept known for many years . In maliCancer stem cells comprise less than 5% of the cell population in most tumours . They arTheir existence could help to explain the clinical observation of the inaction of conventional cancer chemotherapy and radiotherapy in some instances since these treatments target rapidly dividing cells yet stem cells by nature are slow-cycling. For example, treatment with fluorouracil (5-FU) selects and enriches the cancer stem cell population since the rapidly dividing cells would be killed while slow-cycling ones incorporate the drug at a lower rate . Potenti5The clinical presentation of ocular surface dysplastic and neoplastic diseases provides clues to the pathophysiology of OSSN. Firstly, OSSN, pterygium, pingueculae, climatic droplet keratopathy and actinic keratosis are usually located within the interpalpebral fissure, the space between the open upper and lower eyelid that is exposed to UV radiation . Secondl6\u03b8) and the corneal central radius of curvature (r0), is intensely focused onto the nasal limbus, lid margin or lens with up to a 20-fold increase in peak intensity  or epigenetic (variations in gene expression that do not involve changing the nucleotide sequence). DNA damage affects genome stability and stem cell function leading to cancer . Mutatio7.1.17.1.1.1Ambient UVR can be broadly divided into UVA  and UVB  wavebands . UVC (20UVB radiation causes direct DNA damage by crosslinking adjacent bases to form cyclobutane pyrimidine dimers (CPDs) and 6-4 photoproducts (6-4 PPs) . The mos\u2212OH , O2\u2212  or H2O2 (hydrogen peroxide) leading to DNA strand breaks (UVA causes indirect DNA damage via reactive oxygen species (ROS), like d breaks . No studd breaks .7.1.1.2Exposure to UVB reactivates latent HPV, HIVBre, varicelMuch of what is known about the pathophysiology of HPV in cancer is derived from cervical studies. HPV invades the basement membrane through micro abrasions where it initially binds to heparin sulphate proteoglycan (HSPG) . It doesHow HPV initially reaches the conjunctiva is not clear. The prevalence of HPV in OSSN tissue is heterogeneous, varying widely from zero to 100% .HPV infection is associated with an increased incidence of HIV acquisition  .7.2Several mechanisms prevent UV-induced DNA mutations from being incorporated into the genome and UV-damaged cells from establishing themselves. Cells can correct carcinogen-induced DNA damage; severely damaged cells are eliminated from healthy tissues by processes that trigger apoptosis; and abnormal cells are recognized, targeted and destroyed by immune surveillance .The cell-division cycle involves duplication of the genome and intracellular organelles . The staDNA damage activates checkpoint pathways that regulate specific DNA repair mechanisms in the different phases of the cell cycle . There aThe molecular mechanisms that repair UVR-induced DNA damage include excision repair, mismatch repair, strand break repair, and cross-link repair . During Base excision repair (BER) is the predominant pathway against lesions caused by ROS, ionizing radiation and strong alkylating agents . It proc7.2.1The p53 tumour-suppressor gene is found on the short arm of chromosome 17 (17p13.1) . P53 is 7.3Tumour immunology presumes that tumour cells express antigens such as mutp53 and HPV proteins that distinguish them from non-transformed cells. The immune system prevents tumour formation in 3 ways (i) elimination or suppression of viral infection (ii) preventing establishment of a pro-inflammatory environment and (iii) specifically identifying and eliminating cells that express tumour-specific antigens or molecular signals of cellular stress before they cause harm . The lat7.3.1Ambient UV radiation suppresses cell-mediated immunity . UVB is 7.3.2HIV preferentially infects helper T cells (CD4+), inducing their apoptosis . The virHIV potentiates the oncogenic action of other viruses such as HPV, Kaposi sarcoma-associated herpes virus (KSHV) and Epstein\u2013Barr virus (EBV) by enhancing their transmission to target cells . A reporLastly, HIV induces a state of persistent inflammation . Markers7.3.3Vitamin A helps to maintain the integrity of the ocular surface . Its defp\u00a0<\u00a00.001)  than HIV-negative women  .We hypothesize that vitamin A deficiency has three effects; it compromises the integrity of the surface epithelium creating micro-abrasions for HPV entry, it leads to cell-mediated immunodeficiency, and dysregulation of stem cell differentiation.88.1Human somatic cells can only undergo a limited number of cell divisions (50\u201370) then arrest, an event related to shortening of telomeres . In comp8.2Neovascularization occurs to meet the increased tumour metabolic demand. Tumours overproduce vascular growth factors such as vascular endothelial growth factor (VEGF) . In conj8.3Metastasis is considered a hallmark of malignancy. Cells loose adherence with each other and secrete proteolytic enzymes such as matrix metalloproteinases (MMPs) that degrade the extracellular matrix . UVB rad9The short lifespan of ocular surface cells means that epithelial cells with DNA mutations do not last long enough to have an effect, as they are constantly being shed from the surface. The longevity of stem cells however gives them enough time to accumulate mutagenic insults. Why tumours are heterogeneous yet originating from the same stem cells could partly be explained by ongoing mutagenesis .The location of stem cells on the ocular surface coincides with the position of OSSN tumours while the growth pattern of lesions (from base upwards) is consistent with the stem cell theory. A study in Australia described concurrent existence of features of OSSN and primary acquired melanosis and stem cells arranged in micro-clusters in the basal epithelium in 12% of pterygiums . Focus w10The known risk factors of OSSN \u2013 solar UV radiation, HIV and HPV are implicated in the aetiology. The pattern of distribution of OSSN lesions within the interpalpebral fissure of the ocular surface at the limbus, particularly the nasal side provides further clues. The site is highly vulnerable to solar UVR and has a high concentration of stem cells in the basal epithelium. Stem cells in the limbal epithelial crypts are the likely originators of this disease, and may take on cancer stem cell properties.Neoplasia is probably initiated when background solar UV radiation causes various forms of genetic and epigenetic DNA damage. UVB mainly creates pyrimidine dimers. Specific dimer CC\u00a0\u2192\u00a0TT transformation, a signature UV mutation, occurs at the p53 gene, a tumour suppressor that maintains cell-cycle arrest at the G1-S checkpoint. UV radiation also reactivates latent viruses such as HPV. HPV's E7 protein keeps infected cells in a proliferative state while E6 inhibits cell cycle arrest of DNA-damaged cells. Immunosuppression caused by UV radiation, HIV and vitamin A deficiency weakens the tumour surveillance system and allows DNA-damaged cells to proliferate into tumours. Vitamin A deficiency interferes with ocular surface integrity creating micro-abrasions through which HPV may invade the conjunctival basement membrane and epithelial cells. Cancer cells reactivate telomerase which maintains long telomeres increasing the number of cell divisions a cell can undergo. Further tumour expansion and metastasis is enhanced by angiogenesis and increased matrix metalloproteinases (MMPs) which destroy the intercellular matrix.Despite these advances in our understanding there remain gaps, which are areas for further research. For example, there is no explanation why the disease is mostly unilateral despite both eyes receiving equal sunlight exposure. Equally the route of transmission of HPV to the conjunctiva is unknown. The drivers on a molecular level which convert intraepithelial neoplasia to squamous cell cancer are also out with our current understanding of the disease."}
+{"text": "At UHCW Hospitals NHS Trust  the MRI guided breast biopsy service has been running since June 2011. Initially, the service was offered to patients imaged at UHCW NHS Trust. With increased experience and confidence the service is now offered to all the eight NHSBSP screening sites in the West Midlands. Here we present our experience regarding the outcomes.Since June 2011, 50 cases were referred for MRI guided breast biopsy of which 10 cases were referred from outside the UHCW NHS Trust diagnostic imaging cohort. There were three high-risk screening cases whilst the remaining cases already had diagnosis of cancer but MRI identified further lesions. All cases were graded B3 or above on diagnostic imaging. All images were reviewed (obtained via IEP) and biopsy performed within 10 days of the initial request. Biopsy samples were sent to local hospitals for pathological analysis.Forty-eight out of 50 cases were considered for biopsy. Two cases were deemed benign (one on review of diagnostic MRI and one case on second-look US). There were 24 malignancies . A follow-up MRI or surgical excision recommendation was made as necessary for non-malignant cases in the biopsy report.MRI guided breast biopsy has been successfully established at UHCW NHS Trust which currently serves as the regional referral centre in the West Midlands."}
+{"text": "Rituximab is an anti-CD20 monoclonal antibody that has proven to be effective in the treatment of ANCA-associated vasculitis (AAV) in adults. Standard treatments rely on corticosteroids and cyclophosphamide. Only isolated case reports of pediatric AAV treated by rituximab have been reported so far.Our objective was to collect clinical data and outcomes of children with AAV treated with rituximab in a multicenter retrospective study.We conducted a retrospective study within the French paediatric rheumatology society (SOFREMIP) in 2011-2012.2; one patient received only 3 infusions. Mean duration of follow-up was 2.65 yrs. All patients achieved clinical remission after 12 months. One patient presented several relapses associated with B cell increase and was dependent on rituximab infusions. No severe adverse event had been reported.We identified 6 children with AAV treated with rituximab . The age at onset ranged from 4 to 16 yrs. Treatment with rituximab consisted in 4 infusions of 375 mg/mFrom this multicenter retrospective series, short-term safety and efficicacy of rituximab in pediatric AAV is promising so that B cell depleting agents may represent an alternative to conventional treatment with cyclophosphamide but larger prospective studies are mandatory.None declared."}
+{"text": "Acute kidney injury (AKI) is a significant complication following cardiac surgery associated with an increase in morbidity, hospital stay and mortality. Although the estimated incidence of AKI following cardiac surgery is 30%, few studies have identified the incidence of AKI following cardiac surgery as defined by the Kidney Disease: Improving Global Outcomes (KDIGO) group . We condA prospective analysis was performed on 103 adult patients admitted to ICU post-cardiac surgery from September to October 2013. Data for perioperative risk factors and renal biochemical markers were collected up to the sixth postoperative day and are expressed as mean (SD).P = 0.03, P = 0.04 and P < 0.01 respectively) for developing postoperative AKI following cardiac surgery. See Table Ordered logistic regression was used to analyse the data. Thirty- three per cent of cardiac surgery patients at our institution developed AKI. Factors such as poor left ventricular (LV) function, low preoperative haematocrit and low preoperative glomerular filtration rate (GFR) were significant risk factors (Our results suggest that we should focus on LV function and GFR as predictors for developing AKI following cardiac surgery. Strategies to increase preoperative haematocrit should be investigated to reduce in the incidence and severity of postoperative AKI."}
+{"text": "Quadricuspid aortic valves are rare congenital anomalies which can bediagnosed by various imaging modalities. Described is the case of a 77year old female with a quadricuspid aortic valve diagnosed by cardiacCT.  A 77-year-old woman was referred for the investigation of atypical chest pain and exertional dyspnea. Cardiac CT demonstrated the following: (1) a quadricuspid aortic valve (QAV) with four equally sized cusps, mildly thickened leaflets and incomplete coaptation  . As wellThe authors declared that there is no conflict of interests.Movie 1: Gated images of the short-axis view of a quadricuspid aortic valve demonstrating motion of four equally sized cusps with incomplete coaptation.Movie 2: Axial images of the heart demonstrating a persistent left-sided superior vena cava and a left atrial appendage which is juxtaposed to the aorta.Click here for additional data file.Click here for additional data file."}
+{"text": "Toe deformities are highly prevalent in older people with up to 74% of older men and women having some degree of hallux valgus . DespiteForty-four older adults (60+ years) were recruited to participate in the study. Each participant had their feet assessed by the Chief Investigator (KJM), with hallux valgus severity rated using the Manchester Scale . The abdThe older women with moderate-severe hallux valgus were found to have a significantly reduced cross-sectional area of the abductor hallucis muscle (p < 0.05; Figure"}
+{"text": "A previously fit and well 37-year-old woman collapsed on her doorstep. Her next door neighbour started cardiopulmonary resuscitation (CPR). A police car arrived at the scene as first responder. An automated external defibrillator was connected and administered two shocks in between which CPR was continued by the police officers. When the ambulance arrived she had a return of spontaneous circulation. Due to massive aspiration she was not intubated. Upon arrival at the Accident and Emergencies Department, we saw this ECG Fig.\u00a0. After sWhat do you see?AnswerYou will find the answer elsewhere in this issue."}
+{"text": "Double strand break (DSB) repair is suppressed during mitosis because RNF8 and downstream DNA damage response (DDR) factors, including 53BP1, do not localize to mitotic chromatin. Discovery of the mitotic kinase-dependent mechanism that inhibits DSB repair during cell division was recently reported. It was shown that restoring mitotic DSB repair was detrimental, resulting in repair dependent genome instability and covalent telomere fusions. The telomere DDR that occurs naturally during cellular aging and in cancer is known to be refractory to G2/M checkpoint activation. Such DDR-positive telomeres, and those that occur as part of the telomere-dependent prolonged mitotic arrest checkpoint, normally pass through mitosis without covalent ligation, but result in cell growth arrest in G1 phase. The discovery that suppressing DSB repair during mitosis may function primarily to protect DDR-positive telomeres from fusing during cell division reinforces the unique cooperation between telomeres and the DDR to mediate tumor suppression. Genome integrity is constantly threatened by DNA lesions resulting from both endogenous stress and exogenous insult. Of the many types of genomic damage, double strand breaks (DSBs) present the greatest threat to genomic health. Left unrepaired, a DSB can result in the loss of substantial genetic material. Alternatively, if DSBs are repaired incorrectly this may result in chromosomal structural abnormalities; including dicentric chromosomes that drive further genome instability through a breakage-fusion-bridge cycle. Eukaryotic cells have thus evolved a sophisticated DNA damage response (DDR) that controls DNA repair and cell cycle arrest to cope with the dangers presented by genotoxic stress While it is critical that cells engage in efficient DSB repair, it is just as important that DSB repair is silenced under certain conditions. One such condition is at the naturally occurring chromosome ends where DSB repair is prevented by specialized nucleoprotein structures called telomeres Spatiotemporal localization of DDR factors during DSB repair is routinely analyzed through observation of cytological ionizing radiation induced foci IRIF, . In brieIn addition to regulating DSB repair, the DDR also controls interphase cell cycle arrest in response to genotoxic stress While there were indications that the DDR differed in mitotic and interphase cells Orthwein et al. Like RNF8 pT198, 53BP1 pT1609 and pS1618 are residues phosphorylated specifically during mitosis Both studies found that generating a double phosphomimetic allele (53BP1 T1609E S1618E or \u201c53BP1 TESE\u201d) resulted in the exclusion of 53BP1 TESE from mitotic and interphase IRIF Mitotic cells are sensitive to DSBs, presumably because DSB repair is silenced Discussed below is the current understanding of how the telomeres cooperate normally with the DDR to mediate cell cycle arrest and the implications of the findings by Orthwein et al. on telomere-dependent tumor suppression.DDR activity is modulated at chromosome ends by the telomere-specific \u201cshelterin\u201d protein complex However, an emerging theme in telomere biology is that telomere deprotection under physiological or pathological conditions is different from telomere dysfunction induced by genetically deleting shelterin subunits We now understand that human telomeres adopt three distinct protective states in relation to DDR activation and DSB repair Observation of spontaneous intermediate-state telomeres in immortalized or cancer cells indicated that TRF2 possessed independent protective functions which (1) inhibited DDR activation and (2) suppressed NHEJ Also reminiscent of the mitotic DDR, intermediate-state telomeres in asynchronous cultures induce muted ATM checkpoint signaling where ATM is activated but CHK2 and NBS1 are not phosphorylated In the recent study using TRF2 knockdown to induce intermediate- and uncapped-state telomeres it was observed that the telomere DDR is refractory to G2/M checkpoint activation The initial static observations of spontaneous telomere deprotection revealed that \u03b3-H2AX, MRE11 and MDC1, but not 53BP1, localized to metaphase-TIF  . For DSBWhy intermediate-state telomeres fuse when mitotic DSB repair is activated is not immediately clear, as some TRF2 remains bound at metaphase-TIF in aged cells and during prolonged mitotic arrest The passage of intermediate-state telomeres through mitosis is likely a critical feature of telomere-dependent tumor suppression Intermediate-state telomeres routinely pass through mitosis in increasing abundance during cellular aging, until sufficient numbers accumulate to induce senescence When DSB repair competent mitotic cells were irradiated to induce non-specific genome wide damage, this resulted in telomere-fusion-dependent genomic instability A potential answer is that Aurora B activation of the telomere DDR during prolonged mitosis is a general response to accumulating stress in mitotic cells. This is supported by the observation that increasing duration of mitotic arrest corresponds with increasing numbers of metaphase-TIF The recent discoveries described here highlight our emerging understanding of the complex relationship between telomeres, mitosis, and the DDR. Suppressing DSB repair during mitosis appears to ensure that intermediate-state telomeres pass through cell division to facilitate telomere-dependent growth arrest in stable diploid G1 phase cells without inducing genomic instability. However, much about the connectivity between mitosis, DSB repair and telomeres remains to be understood. For example, what is the molecular mechanism that facilitates telomere fusion in DSB repair competent mitotic cells? Also, what is the mechanism linking genomic breaks induced during mitosis to the Aurora B dependent mitotic telomere DDR, and how does this impact cells with silenced mitotic DSB repair? It is also unclear if 53BP1 dissociation from TIF at the G2/M boundary is controlled by the same mechanism that prevents 53BP1 from associating with mitotic IRIF or if there is another independent level of control regulating mitotic DSB repair that remains to be discovered.An appealing prospect raised by the discovery of the mechanism inhibiting mitotic DSB repair is that the spontaneous occurrence of abundant intermediate-state telomeres in many cancer cells may present a vulnerability to be exploited for therapeutic means. A combinatorial approach that arrests cancer cells in mitosis while simultaneously targeting mitotic kinases and/or the DDR may hold promise to induce telomere fusions that kill tumor cells. It will be exciting to unravel this surprising and complex relationship between telomeres, mitosis, and DSB repair and to identify the implications of this relationship on human aging and oncogenesis."}
+{"text": "Additionally, we have shown tumor suppression and a 30% decrease of PD-1 expression in tumor infiltrating lymphocytes in an in vivo B16 mouse melanoma model. This approach may not only reprogram local signaling within the tumor microenvironment, but also promote polyclonal cytotoxic T cell responses in the absence of defining the antigenic specificity of the infiltrating T cells.One of the largest obstacles in cancer immunotherapy involves overcoming the immunosuppressive tumor microenvironment . While m"}
+{"text": "P<0.001) and longer white matter path length (P<0.05) compared to healthy individuals. Higher HbA1c was associated with lower network efficiency  and longer network path length . A disruption in local microstructural integrity was found in the multiple white matter regions and associated with higher HbA1c and fasting plasma glucose levels (corrected P<0.05). Poorer glycemic control is associated with lower efficiency and longer connection paths of the global brain network in individuals with diabetes. Chronic hyperglycemia in people with diabetes may disrupt the brain\u2019s topological integration, and lead to mental slowing and cognitive impairment.Previous research has shown that the brain is an important target of diabetic complications. Since brain regions are interconnected to form a large-scale neural network, we investigated whether severe hyperglycemia affects the topology of the brain network in people with type 2 diabetes. Twenty middle-aged (average age: 54 years) individuals with poorly controlled diabetes  and 20 age-, sex-, and education-matched healthy volunteers were recruited. Graph theoretic network analysis was performed with axonal fiber tractography and tract-based spatial statistics (TBSS) using diffusion tensor imaging. Associations between the blood glucose level and white matter network characteristics were investigated. Individuals with diabetes had lower white matter network efficiency ( Furthermore, we did not examine cognitive/behavioral characteristics in our participants of the study.Some limitations of this study should be taken into account. The sample size for each group was relatively small (In summary, using DTI and graph theory, we found that poorly controlled hyperglycemia disrupts the topology of the brain network in T2DM. The measures of network integration showed decreased global efficiency and increased path length in patients with T2DM compared to those in healthy subjects and the measures had a correlation with the level of hyperglycemia. We suggest that disrupted network integration with widespread disruption of WM fiber integrity represent a manifestation of central neuropathy in diabetes, possibly contributing to mental slowing and cognitive impairments in individuals with diabetes."}
+{"text": "Wellens' syndrome, also known as LAD coronary T-wave inversion syndrome, is a characteristic ECG pattern that highly suggests critical stenosis of the proximal left anterior descending (LAD) coronary artery. 75% of patients with this finding go on to develop acute anterior wall myocardial infarction within one week unless prevented by early intervention on the culprit lesion. Most instances of ST-elevation occurring during cardiac stress testing have been observed with exercise, with only seven cases reported in the literature with pharmacologic stress. We present a case of a patient with no known cardiac disease who presented with chest pain and an ECG consistent with Wellens' syndrome that developed an acute anterior wall ST-elevation myocardial infarction after pharmacologic stress test. Wellens' syndrome typically presents with the characteristic ECG findings of biphasic T-waves or deep symmetrical T-wave inversions in the precordial leads (leads V1\u2013V4). This ECG finding usually occurs during a pain-free period and is highly suggestive of critical proximal LAD coronary artery stenosis. Given the significant number of patients that will go on to develop acute anterior wall myocardial infarctions, it is critical that all physicians recognize this classic ECG pattern and institute measures for the patient to undergo urgent coronary angiography and revascularization. If left untreated, managed medically, or further risk-stratified by cardiac stress testing, the patient may develop an extensive myocardial infarction or sudden death.A 72-year-old Hispanic male with a past medical history of hypertension, hyperlipidemia, end-stage kidney disease on hemodialysis, and cerebrovascular accident 5 years before presented to the emergency department with midsternal crushing chest pain that awoke him up from sleep at 7\u2009am in the morning. The pain radiated to his jaws bilaterally and was associated with diaphoresis. The pain continued for 30 minutes until EMS arrived and improved after sublingual nitroglycerin and chewable aspirin 325\u2009mg. Significant social history included a history of cigarette smoking. No additional pertinent history was appreciated including review of systems, family history, and social history. The patient's blood pressure on presentation was 137/70\u2009mmHg, heart rate was 102\u2009bpm, and physical exam was documented as essentially within normal limits.The patient's electrocardiogram upon presentation  showed aThroughout the hospitalization the patient remained chest-pain-free and subsequent cardiac markers remained normal. The patient was scheduled to undergo pharmacologic dipyridamole (Persantine) stress testing with nuclear imaging for further risk stratification. A repeat ECG taken before the test is displayed in Roughly sixty minutes after completion of the stress test the patient experienced severe retrosternal chest pain and diaphoresis. A subsequent electrocardiogram revealed sinus tachycardia at 102\u2009bpm  and ST-eA subgroup of unstable angina with high risk of progression to anterior wall myocardial infarction has been described early in the literature as \u201cleft anterior descending coronary T-wave syndrome\u201d . In earlECG patterns of Wellens' syndrome can be divided into variants. The larger group of patients (including our patient) demonstrate deep symmetrical T-wave inversion that can extend from V1 to V5. The other variant (24% of cases)  consistsOur case highlights several concerning features of Wellens' syndrome. At first the ECG changes developed during pain-free period. In Wellens' study, the characteristic pattern was seen in the first 24 hours in 60% of cases only (108 patients out of 180) .Despite the ominous ECG changes, our patient had limited myocardial injury as reflected by normal troponin levels. Baseline echocardiography and gated rest images were also normal. In the original series of patients, Wellens reported myocardial damage in 12% of cases only . We cameWellens' syndrome can progress to myocardial infarction over a course of days to weeks. STEMI has been precipitated in cases of Wellens' syndrome after regular exercise stress . Here, tRecognition of Wellens' syndrome and appropriate intervention prevent a potentially devastating myocardial infarction. It is prudent to recommend coronary angiography as the initial diagnostic modality in patients with ECG suspicious of Wellens' syndrome as stress tests including pharmacologic ones carry a risk of progression to myocardial infarction."}
+{"text": "Immunostaining data in IgA nephropathy patients needs more test to investigate its potential clinical significance, especially with regards to Oxford classification.Journal of Renal Injury Prevention. In this study on 114\u00a0biopsies of IgA nephropathy (IgAN) patients they found no significant association of IgG deposits with age. There was no correlation of IgG deposit with four morphologic variables of Oxford classification  group and IgA deposition alone (IgA) group. They found, proteinuria was greater in the IgA-IgG group than the IgA group. Capillary wall IgA deposits were noted more frequently in the IgA-IgG group than the IgA group. They concluded that mesangial IgG deposition is associated with more severe clinical features in patients with IgAN  have been completely observed by the authors.None."}
+{"text": "Tuberculosis (TB) remains a major killer amongst infectious diseases. Current treatment involves a four-drug regimen for at least six months. New drugs and regimens are required to shorten treatment duration, reduce toxicity and combat drug resistance however the optimal methodology to define the critical path for these regimens is not well-defined.We undertook a literature review to summarise outcomes reported in phase II trials of patients with newly-diagnosed pulmonary TB to determine the necessity for a core outcome set in TB.Relevant studies were identified by searching MEDLINE, EMBASE, LILACs and reference lists of included studies. All reported outcomes were considered.10 colony forming units (CFU) per ml sputum over various time points. Related outcomes such as CFU count were sometimes reported in preference (12 studies). Other popular outcomes included number of positive (20 studies) or negative cultures (4 studies) at selected time points while in others time to culture negativity was favoured (3 studies). In all cases there was disagreement as to which time points should be chosen with options ranging from two days to eight weeks. Results for novel drug combinations are currently being analysed and will be presented.49 included phase II studies presented data on 24 historic drug combinations. The most commonly reported outcome (35 studies) was early bactericidal activity (EBA) although there was disagreement regarding a definition. The majority of studies defined EBA as the fall (sometimes mean rate of change) in logThere is large variation in the outcomes reported across phase II studies in TB. To utilise results of multiple studies, and thus identify the best treatment regimens for TB, a core outcome set needs to be developed. This would enable trial results to be more easily compared and combined, potentially leading to improved treatment strategies for patients with TB."}
+{"text": "Sudden cardiac arrest has a significant global health burden with an estimated incidence of 95.9 per 100 000 person-years. The causal malignant ventricular arrhythmia may arise secondary to myocardial ischaemia, infarct, oedema, fibrosis or infiltration and survivors are at significant risk for recurrent events. Coronary revascularization procedures have a significant associated morbidity/mortaility in this patient popuation and hence identifying those patients who are most likely to benefit from therapeutic intervention is vital. The aim of this study was to evaluate the role and safety of cardiac MR (CMR) in the investigation of patients successfully resuscitated from out of hospital sudden cardiac arrest.A retrospective study was performed of all patients referred to our institution between July 2006 and July 2011 for CMR evaluation following successfully resuscitated out of hospital sudden cardiac arrest. Patients were defined as having a likely coronary disease aetiology vs non-coronary disease aetiology based on cardiac risk factors, echocardiography, post-resuscitation and admission ECG findings prior to CMR. CMR imaging was blindly interpreted to assign each patient to either a coronary disease aetiology or non-coronary disease aetiology groups based on CMR evaluation. The results were subsequently compared with the post event coronary angiogram.A total of 79 patients underwent CMR evaluation following successfully resuscitated cardiac arrest. In total 55.7% of patients had a coronary disease aetiology and 44.3% had a non-coronary disease aetiology. CMR changed the diagnosis in 20% of patients with a pre-CMR likely diagnosis of coronary disease and 13.3% of patients with a pre-CMR likely diagnosis of non-coronary disease. All our patients tolerated the entire CMR study with no adverse events.CMR is a safe technique in the investigation of patients successfully resuscitated following out of hospital sudden cardiac arrest and identifies a non-coronary cause in a significant number of cases.No external funding."}
+{"text": "Summary: Correlating disease mutations with clinical and phenotypic information such as drug response or patient survival is an important goal of personalized cancer genomics and a first step in biomarker discovery. HyperModules is a network search algorithm that finds frequently mutated gene modules with significant clinical or phenotypic signatures from biomolecular interaction networks.Availability and implementation: HyperModules is available in Cytoscape App Store and as a command line tool at www.baderlab.org/Sofware/HyperModules.Contact:Juri.Reimand@utoronto.ca or Gary.Bader@utoronto.caSupplementary information:Supplementary data are available at Bioinformatics online Establishing functional links between genetic variation and human disease is a key goal of cancer genome sequencing . ComplexDiscovery of modules (subnetworks) in biological networks helps isolate systems with disease-related properties and reduces interactome complexity. A growing number of methods are available for this purpose. A landmark paper combines gene expression signatures with protein\u2013protein interactions (PPI) to find predictive modules of cancer outcome . Net-CoxBecause clinical profiles of patients are increasingly available in cancer genomics efforts such as the The Cancer Genome Atlas (TCGA) pan-cancer project  based onP-value reflecting the fraction of seed-specific modules from shuffled networks exceeding the significance of the true module. This removes artifacts of the greedy strategy and corrects for topological features such as highly connected nodes.HyperModules assumes that clinically informative mutations of complex disease occur in systems of closely interacting genes. The greedy network search algorithm focuses on a local network area, defined by a central seed node (a mutated gene) and its surrounding subnetwork. All mutated genes are sequentially considered as seeds in module discovery. Search starts from the seed and grows the module toward increased benefit by adding connected genes that best improve clinical significance. This objective is driven by statistical tests where patients defined by the module are compared with other patients. Categorical clinical variables are studied with Fisher\u2019s exact test and survival times with log-rank test. Cox regression is currently not supported; however, we plan to add this feature in the future. To establish statistical significance of detected modules, we build a null distribution by searching networks with permuted gene names. Each module of the true network is quantified with an empirical Supplementary Fig. S1). For example, network analysis of 30 000 interactions with 121 liver cancer patients, 686 mutated genes and 10 000 permutations takes 10 min on an 8-core computer with 16 GB RAM. HyperModules is thus applicable to a range of networks and mutation datasets.The analysis pipeline is outlined in Supplementary File S1. It comprises 183 ovarian cancer patients from the TCGA study . Second, the categorical variable search with Fisher\u2019s exact test revealed fivemodules with significant enrichment of alive patients . The modules are also summarized in Supplementary Table S1.An example dataset is provided in GA study  and the GA study . The ovaHyperModules is a biological network-mining algorithm that reveals modules of interacting genes with clinically informative disease mutations. Diverse biomolecular interaction networks can be analyzed, including PPI networks, gene regulatory networks and curated biological pathways. Disease mutations are also broadly defined. Although we initially studied cancer point mutations, other types of alterations such as copy number and gene expression changes can be used. HyperModules finds correlations with groups of genes where mutations may be infrequent but the signature strengthens through network integration. Such modules are not often directly usable as biomarkers because of small sample size; however, we believe that our approach helps discover genes and pathways as potential multivariate biomarkers for further experiments."}
+{"text": "Genetic cystic kidney diseases, including autosomal recessive polycystic kidney disease (ARPKD), are among the most common causes of end stage renal disease in children and in adolescents. While the detailed biological events resulting in cyst formation remain incompletely understood, nowadays there is wide agreement that dysfunction of a specialized cellular organelle, the primary cilium, underlies genetic cystic kidney disease. In addition to cystic kidney disease, phenotypes resulting from impaired ciliary function can affect nearly every organ of the human body and are nowadays termed ciliopathies.Ruvbl1 in the renal tubule leads to a severe ARPKD-like cystic kidney phenotype in mice. RUVBL1 has previously been linked to regulation of cilia-associated signaling pathways.We recently identified the AAA ATPase RUVBL1 as part of various ciliopathy-associated renal protein complexes and could show that loss of in vivo data strongly supports this concept.To obtain novel insights into the cellular function of RUVBL1 and its partner protein RUVBL2, we generated stable murine cell lines with single genomic integration of coding sequences for fluorescence-tagged Ruvbl1 and Ruvbl2. Out of these cell lines we performed protein interaction screens by repetitive and independent immunoprecipitations followed by quantitative mass spectrometry. Along with multiple known interaction partners we identified novel candidates including proteins that had already been linked to ciliary function. In addition to the important role of RUVBL1 in the renal tubule our data point to a more general function of the RUVBL proteins and the RUVBLs-containing chaperone-like R2TP protein complex for ciliary function. Novel murine In summary, we obtained novel functional insights into the cell biological link of the AAA ATPases RUVBL1 and RUVBL2 to primary cilia. Our data suggest a role of the RUVBL proteins in the cytosolic pre-assembly of ciliary protein complexes."}
+{"text": "Ewing\u2019s sarcoma (ES) or primitive neuro-ectodermal tumor (PNET) typically occurs in long or flat bones, the chest wall, extra-skeletal soft tissue, and rarely in solid organs. Incidence of adrenal Ewing\u2019s sarcoma is very rare. Here we report a case of Ewing\u2019s sarcoma of the right adrenal gland in an 8-year-old girl who presented with an abdominal mass. The huge tumor was managed by preoperative neo-adjuvant chemotherapy followed by surgical resection. She died due to metastasis after five months of surgery. An 8-year-old girl presented with progressive pain and palpable lump in right flank for the last one month. Ultrasonography (USG) showed right retroperitoneal tumor, suprarenal in location. Contrast enhanced computed tomography (CECT) demonstrated 12.7 cm x 11.8 cm large variegated mass in right adrenal gland with retroperitoneal lymphadenopathy . A 24-hour urinary catecholamines, plasma metanephrine, aldosterone, and plasma renin levels were within normal range. CT-guided core biopsy revealed malignant small round cell tumor. Bone-marrow aspiration was unremarkable. Tumor was large and appeared unresectable thus neoadjuvant chemotherapy was planned and given for seven cycles using vincristine, doxorubicin and cyclophosphamide alternating with ifosfamide/etoposide with granulocyte colony stimulating factor (GCSF). Tumor regressed to one-fourth of its original size and lymph nodes appeared insignificant size . Patient also improved symptomatically. At operation the tumor was found densely adherent to surrounding tissues especially the upper pole of right kidney and inferior vena cava . The tumor was ultimately resected. Grossly the specimen was 8 cm x 6 cm with tan-yellow cut surface and areas of hemorrhage and necrosis. Histopathology showed adrenal medulla and cortex completely replaced by a small round blue cell tumor . Immunohistochemical (IHC) studies showed that tumor cells were positive for CD99 (membranous), synaptophysin and chromogranin . Postoperatively the patient was lost to follow up and admitted after five months with metastasis in lungs and liver and died within few days.Ewing\u2019s sarcoma/PNET of the adrenal gland is extremely rare.[1-3] Usually the patients present with flank pain and rapidly growing mass. USG should be done as an initial screening tool but CECT is essential to find out the relation with the surrounding structures. CECT imaging helps in distinguishing between benign and malignant adrenal tumors but exact nature.[4] Hormonal studies should be done to differentiate it from the functional adrenal tumors. It is difficult to make a definitive diagnosis of ES/PNET even on histopathology without IHC.[5] Our patient had very large tumor and considered non-resectable, so needle biopsy was done to find out the nature of the tumor. Final diagnosis was made after IHC. CD 99 is a highly sensitive marker for PNET/ES. Patients of ES/PNET show reciprocal translocation of t  involving the EWSR1 gene on chromosome 22 and the FLI1 gene on chromosome 11 in more than 90% of cases but this is not routinely assessed.[2] As per available literature these tumors are very rapidly growing with aggressive nature. As this is a rare tumor, there is no definite guideline for management but surgical resection is considered to be the mainstay for local disease control.[5-7] This tumor is considered as radio and chemo sensitive so adjuvant chemotherapy and radiotherapy are advocated for better disease control but there is no consensus on standard chemo-radiation regimen.[8] We initially tried chemotherapy which worked well in our patient. The outcome seems good in case of complete excision but the prognosis was poor in our case. Proper postoperative surveillance with imaging modalities and adjuvant chemotherapy might alter the outcome in index case.Source of Support: NilConflict of Interest: None declared"}
+{"text": "The case reported is a young \u201clight\u201d ex-smoker who initially had a localized adenosquamous carcinoma bearing an epidermal growth factor receptor (EGFR) sensitizing mutation. He first recurred six months after initial treatment within the brain with a pure squamous histology and the same EGFR mutation. Surgical resection and radiation rendered him disease-free. Subsequent isolated recurrence within the lung eighteen months later was a pure adenocarcinoma, again with the same identified EGFR mutation. These histologic changes (from adenosquamous to pure squamous to pure adenocarcinoma) have been described but not before in the absence of any selection pressure with EGFR tyrosine kinase inhibitors. This case points out the histologic \u201cflexibility\u201d of EGFR mutant lung cancers and the importance for appropriate molecular testing in nonsmokers with lung cancer of any histologic type. The identification of mutations within the epidermal growth factor receptor (EGFR), and the finding that these mutations make tumors exquisitely sensitive to EGFR tyrosine kinase inhibitors (TKIs), has revolutionized treatment of non-small-cell lung cancer (NSCLC). EGFR mutations are more common in never-smokers, in patients with Asian ethnicity, and in patients with adenocarcinoma histology . We presThe patient was a 43-year-old male who felt well until the onset of intermittent hemoptysis. A chest X-ray demonstrated a left upper lobe (LUL) mass. A Computed Tomography (CT) scan of the chest demonstrated a large LUL mass with satellite lesions and a 1\u2009cm left lower lobe (LLL) nodule . No mediSix months after completion of adjuvant chemotherapy, the patient experienced headaches and altered mental status. A brain MRI showed an irregular frontal lobe lesion measuring 7 by 5\u2009cm Figures . CraniotApproximately eighteen months following resection of the brain metastatic disease, surveillance imaging demonstrated new left lung and hilar nodules Figures . The patAdenosquamous carcinomas are uncommon primary lung tumors. A report in 25 Korean patients with adenosquamous tumors showed that if an EGFR mutation is present (in 44% of their patients), it is present in both components. This finding supports a monoclonal derivation of this tumor  .This report also helps inform the strategy for mutational analysis. While the incidence of \u201cactionable\u201d EGFR or other mutations is infrequent in heavy smokers or squamous histology, the exclusion of these patients from testing would exclude a large proportion of patients with actionable mutations . The NatThis case points out that all nonsmoking lung cancer patients should have molecular testing for \u201cactionable\u201d mutations, regardless of histologic type."}
+{"text": "Cerebrospinal fluid (CSF) contained within the brain ventricles contacts neuroepithelial progenitor cells during brain development. Dynamic properties of CSF movement may limit locally produced factors to specific regions of the developing brain. However, there is no study of in vivo CSF dynamics between ventricles in the embryonic brain. We address CSF movement using the zebrafish larva, during the major period of developmental neurogenesis.tnnt2a mutant fish (tnnt2a\u2212/\u2212) and chemical  treatment. Cilia motility was monitored at these stages using the Tg(\u03b2act:Arl13b\u2013GFP) transgenic fish line.CSF movement was monitored at two stages of zebrafish development: early larva  and late larva  using photoactivatable Kaede protein to calculate average maximum CSF velocity between ventricles. Potential roles for heartbeat in early CSF movement were investigated using tnnt2a\u2212/\u2212 fish and after BDM treatment. Brain cilia are immotile at the early larval stage.In wild-type early larva there is net CSF movement from the telencephalon to the combined diencephalic/mesencephalic superventricle. This movement directionality reverses at late larval stage. CSF moves directionally from diencephalic to rhombencephalic ventricles at both stages examined, with minimal movement from rhombencephalon to diencephalon. Directional movement is partially dependent on heartbeat, as indicated in assays of These data demonstrate directional movement of the embryonic CSF in the zebrafish model during the major period of developmental neurogenesis. A key conclusion is that CSF moves preferentially from the diencephalic into the rhombencephalic ventricle. In addition, the direction of CSF movement between telencephalic and diencephalic ventricles reverses between the early and late larval stages. CSF movement is partially dependent on heartbeat. At early larval stage, the absence of motile cilia indicates that cilia likely do not direct CSF movement. These data suggest that CSF components may be compartmentalized and could contribute to specialization of the early brain. In addition, CSF movement may also provide directional mechanical signaling.The online version of this article (doi:10.1186/s12987-016-0036-z) contains supplementary material, which is available to authorized users. Cerebrospinal fluid (CSF) is contained in the brain ventricles (chambers derived from the brain lumen) and contacts neuroepithelial progenitor cells during brain development and in adulthood. The CSF contains a unique composition of proteins (CSF proteome) \u20136, smallXenopus have investigated local intraventricular CSF dynamics in the developing brain  and late larva . Our study leads to four conclusions: (1) CSF moves preferentially anterior to posterior from the diencephalic (D) ) to rhombencephalic (R) ventricles. (2) Direction of CSF movement between the telencephalic (T) and diencephalic (D) ventricles reverses from early to late larval stages. (3) Directional CSF movement is partially dependent on heartbeat. (4) At early larval stages no motile cilia are present in the brain and therefore are not likely to direct the CSF movement observed. Together these data indicate that locally restricted CSF factors or physical signals associated with fluid movement may contribute to specialization of the early brain.max from D (D/M) to R ventricles. Reverse movement was present, but with about 25\u00a0% of the observed forward vmax. This raises two questions: (1) where does the excess volume of CSF entering the R ventricle go and (2) what mechanisms underlie directional CSF movement? First, with respect to CSF \u201cdestination\u201d, the brain-CSF barrier is quite tight at early developmental stages  to late  larval stages. CSF movement is partially dependent on heartbeat. At early larval stages, the absence of motile cilia indicates that cilia likely do not direct CSF movement. These data suggest that CSF components may be compartmentalized and could contribute to specialization of the early brain and CSF movement may also provide directional mechanical cues."}
+{"text": "Renal cell carcinoma (RCC) with rhabdoid features is a rare histology and exhibits clinically aggressive behavior. We report a case of a married couple in whom RCC with rhabdoid features concurrently occurred. The rarity of this event suggests that environmental factors may contribute to the etiology of RCC with rhabdoid features.A 76-year-old Japanese woman was diagnosed with a hypervascular mass in the right kidney and tumor thrombus extending into the right atrium by enhanced computed tomography (CT). She underwent radical nephrectomy and tumor thrombectomy following systemic therapy with the tyrosine kinase inhibitor sunitinib. The histological evaluation denoted clear cell RCC with rhabdoid features. The patient died of cancer 12 months postoperatively. A 76-year-old man, her husband, presented with gross hematuria 2 weeks after his wife had undergone surgery. He had a long history of asbestos exposure. An abdominal CT scan revealed a hypervascular mass in the right kidney and tumor thrombus extending into the inferior vena cava. He also underwent radical nephrectomy and tumor thrombectomy. The histological evaluation also showed clear cell RCC with rhabdoid features. Bone metastasis occurred 12 months postoperatively, but he died of an unrelated cause 18 months after surgery.Concurrent occurrence of RCC with rhabdoid features may not to be coincidental. Although further studies are warranted, asbestos exposure may contribute to the etiology of clear cell RCC with rhabdoid features. In large consecutive series of patients with malignant renal tumors, approximately 3\u20135% of RCCs showed rhabdoid features -4. GenerA 75-year-old womanwas referred to our hospital in May 2009 because enhanced computed tomography (CT) had confirmed the presence of a 70 mm mass on the upper pole of her right kidney and tumor thrombus extending into the right atrium Figure\u00a0a. Based Postoperatively, the patient developed acute renal failure secondary to circulatory insufficiency, and she received hemodialysis for about a month. The pathological diagnosis of the tumor was clear cell carcinoma with rhabdoid features and sarcomatoid change  for publication of this Case report and any accompanying images. A copy of the written consent is available for review by the Editor of this journal."}
+{"text": "Cellular non-coding RNA (ncRNA) transcription and regulation has only recently been systematically investigated. Studies have demonstrated abundant transcription of a set of ncRNAs preferentially within tumors as opposed to normal tissue. In some cases these tumor-associated ncRNAs also associate with inflammatory cytokine production suggesting potential immunostimulatory qualities. Using a novel approach from statistical physics we quantify global transcriptome-wide motif usage for the first time in human and murine ncRNAs determining that most have motif usage consistent with the coding genome. However an outlier subset of tumor-associated ncRNAs typically of recent evolutionary origin has motif usage more associated with pathogen RNA. Here we show that a human repeat enhances immunostimulatory motifs CpG dinucleotides in AU-rich contexts which most of the human genome and human adapted viruses have evolved to avoid. We demonstrate that a key subset of these ncRNA function as immunostimulatory \u201cself-agonists\u201d and directly activate cells of the mononuclear phagocytic system to produce pro-inflammatory cytokines. These ncRNAs arise from endogenous repetitive elements that are normally silenced, yet are often very highly expressed in cancers. We conclude that the innate response in tumors partially originates from direct interaction of immunogenic ncRNAs expressed in cancer cells with innate pattern recognition receptors and thereby assign a new danger-associated function to a set of dark matter repetitive elements, potentially reconciling several observations concerning the role of ncRNA expression in cancers. We consider the possible roles they may play in the tumor microenvironment."}
+{"text": "In patients with idiopathic intracranial hypertension (IIH) headache often persist as a disabling symptom even after intracranial pressure (ICP) has normalized. Yet very little is known about the mechanisms of chronification.To explore pain perception in patients with IIH in a controlled design at time of diagnosis and after 3 months of treatment.We explored pain perception in patients with newly diagnosed IIH by Quantitative Sensory Testing (QST) measuring cephalic and extra-cephalic supra-threshold pain ratings and pain thresholds for pressure and electrical stimulation. QST was performed at diagnosis and after one and three months. ICP was measured at baseline and at the 3-month follow-up. QST measurements from sex-matched controls were used for comparisons. Headache was assessed by monthly standardized interviews and headache diaries.At baseline IIH patients (n=28) showed no consistent abnormalities in pain sensitivity or thresholds . Although headache improved markedly and ICP normalized in 52%, there was no consistent change in pain sensitivity from baseline to follow-up . Patients with (54%) and without persistent chronic headache (46%) 3 months after diagnosis showed no different pain perception either at baseline or at the 3-month follow-up.Although headache persisted as a chronic symptom in half of the patients we found no evidence of increased central pain sensitivity suggesting that headache chronification in IIH is caused by mechanisms other than central sensitization."}
+{"text": "The MacIntyre strain originated from the brain of a patient with lethal HSV encephalitis and has a unique limitation in its neuronal spread, moving solely in the retrograde direction.We used paired-end Illumina deep sequencing and  The MacIntyre strain originated from the brain of a patient with lethal HSV encephalitis  , 31. HSV34\u2013KM222720.The HSV-1 MacIntyre strain genome sequence has been deposited at GenBank under the accession no."}
+{"text": "Solar UVB is carcinogenic. Nucleotide excision repair (NER) counteracts the carcinogenicity of UVB by excising potentially mutagenic UVB-induced DNA lesions. Despite this capacity for DNA repair, non-melanoma skin cancers and apparently normal sun-exposed skin contain huge numbers of mutations that are mostly attributable to unrepaired UVB-induced DNA lesions. UVA is about 20-times more abundant than UVB in incident sunlight. It does cause some DNA damage but this does not fully account for its biological impact. The effects of solar UVA are mediated by its interactions with cellular photosensitizers that generate reactive oxygen species (ROS) and induce oxidative stress. The proteome is a significant target for damage by UVA-induced ROS. In cultured human cells, UVA-induced oxidation of DNA repair proteins inhibits DNA repair. This article addresses the possible role of oxidative stress and protein oxidation in determining DNA repair efficiency \u2013 with particular reference to NER and skin cancer risk. It does not contain UVC. Germicidal UV is nevertheless a reasonable surrogate for some of the effects of sunlight on skin, including mutagenesis and carcinogenesis, because CPDs and 6:4 Py:Pys are also the predominant photoproducts of the shorter wavelengths of solar UVB. At longer wavelengths, the contribution of the canonical UV DNA photoproducts to cellular damage declines sharply. Biologically relevant UVA doses induce several orders of magnitude fewer CPDs (and effectively no 6:4 Py:Pys) 1.2CPDs and 6:4 Py:Pys are generated in oxygen-independent reactions whereas many of the biological effects of the longer UVA wavelengths are dependent on oxygen The canonical UV photoproducts appear not to be significant contributors to the biological effects of UVA. NER-defective XP cells that are extremely sensitive to UVC and UVB are not hypersensitive to UVA Taken together, the response of cells to UVA radiation and thorough analyses of UVA-damaged DNA suggest that damage to targets other than DNA is likely to be a significant contributor to the biological effects of UVA.1.3The oxygen dependence of the effects of UVA reflects the activation of endogenous photosensitizers to generate ROS. These cellular photosensitizers have not been fully characterized but candidates include porphyrins, flavins The thiopurine prodrug azathioprine  provides1O2) in a Type II photosensitized reaction. These ROS cause widespread DNA damage including oxidized bases The azathioprine metabolite 6-thioguanine (6-TG) replaces a small fraction of the patients\u2019 DNA guanine PTCHTP53 genes The expectation that a contribution of azathioprine/UVA-induced DNA lesions to skin cancer development would be evident from novel signature mutations in transplant-related skin tumors was not fulfilled. The mutational spectra of the frequently mutated Clinical photosensitivity similar to that caused by azathioprine is a common side effect of drug treatment and is often associated with an increased skin cancer risk Riboflavin  is anothb]carbazole (FICZ) is a naturally-occurring UVA chromophore. FICZ  was described almost 50 years ago More recent experiments provide direct evidence that UVA can compromise DNA repair in human cells and that it does this by damaging DNA repair proteins. UVA combined with 6-TG The extensive protein damage induced by photosensitized UVA Importantly, these photosensitizers simply exacerbate the effects of UVA and at higher doses, UVA alone induces sufficient protein oxidation to inhibit DNA repair These findings emphasize the vulnerability of human DNA repair to inhibition by protein damage by ROS induced by UVA either alone or in combination with an exogenous photosensitizer.1.6If ROS induced by UVA cause protein damage that inhibits DNA repair, it is appropriate to ask whether NER is vulnerable to other interventions that induce oxidative stress. The excess ROS that define oxidative stress results from an imbalance between their formation and removal. This can be induced experimentally by compromising cellular antioxidant defences. Treatment with the glutamylcysteine synthetase inhibitor buthionine sulfoximine (BSO) depletes cells of the important antioxidant glutathione (GSH). The oxidative stress associated with GSH depletion results in an increased steady-state level of protein oxidation and BSO treatment enhances UVA-induced protein oxidation in human keratinocytes. The increased levels of protein oxidation are associated with an inhibition of NER and cells treated with UVA and BSO do not excise UVB-induced photoproducts 2O2 and causes oxidative DNA damage 2O2 itself is widely used to induce oxidative stress. Although rather unreactive, it is converted into the much more reactive hydroxyl radical (OH\u2022) by the Fenton reaction. In addition to DNA damage, H2O2 also causes extensive protein oxidation and treatment of cultured human HaCaT keratinocytes with either H2O2 or high concentrations of ascorbate inhibits NER Pharmacologically active, high concentrations of ascorbate (vitamin C) sensitize cells to carboplatin, a cisplatin analog. At these high concentrations, ascorbate acts in a pro-oxidant fashion to induce oxidative stress. It generates HCells adapt to oxidative stress by diverting glucose metabolism from glycolysis to the pentose phosphate pathway (PPP). One outcome of this metabolic switch is a boost in the production of the NADPH that is required to maintain antioxidant defences by recycling oxidized GSH. By preserving reducing power, increased flux through the PPP protects against both DNA and protein oxidation. Silencing of glucose-6-phosphate dehydrogenase (G6PD), the first and rate-limiting step of the PPP, prevents this metabolic switch. G6PD silencing is associated with decreased NADPH levels, increased protein oxidation and inhibition of NER via the oxidative decarboxylation of isocitrate to \u03b1-ketoglutarate by isocitrate dehydrogenase (IDH). Heterozygous mutations in the IDH1 isoform are particularly common in gliomas, chondrosarcomas and some leukemias. Gain of function IDH1 mutations confer the ability to reduce \u03b1-ketoglutarate to \u03b1-hydroxyglutarate in a reaction that consumes NADPH The TCA cycle also supplies NADPH, in this case via increased protein oxidation.The therapeutic effectiveness of many anticancer agents is compromised by the removal of potentially lethal DNA lesions by NER and they are more effective against tumors in which NER is compromised. This is particularly evident with the platinum-based drugs and the spectacular success of cisplatin in treating testicular carcinomas is partly a reflection of their relatively low NER efficiency via its interaction with cellular photosensitizers, it seems pertinent to question the extent to which solar UVA affects the NER of UVB-induced DNA lesions in skin. How efficient is NER in sun-exposed skin? How good is the protection NER provides against mutation by solar UVB? DNA sequencing data from skin tumors suggests that the effectiveness of NER might be less than optimal.In summary, DNA repair proteins are susceptible to damage and inactivation by oxidation. Interventions that are known to induce oxidative stress damage DNA repair proteins and inhibit DNA repair. UVA inhibits NER 1.7A remarkable characteristic of tumors from sun-exposed skin is their high number of mutations. The mutational loads in BCCs and SCCs are more than an order of magnitude higher than those in tumors of other anatomical sites . Even mo2 UVC delivered to cultured cells. Despite this extensive UVB exposure, UVB phototherapy is not associated with a detectable cancer risk These huge mutational loads might simply reflect chronic sun exposure and the extremely powerful mutagenicity of UVB. In a different context, however, UVB is not a particularly potent carcinogen. UVB phototherapy is an effective treatment option for the management of chronic relapsing skin conditions such as psoriasis. It involves repeated  and escalating doses of narrowband UVB that produce levels of DNA damage roughly equivalent to those induced by two minimal erythema doses (MEDs) of solar radiation Skin cancer is common and available mutation data clearly implicate UVB photoproducts in its development. NER does protect against skin cancer and the extreme skin cancer susceptibility of NER-defective XP individuals testifies to the carcinogenicity of unrepaired UV-induced DNA damage. The topical application of liposomally-encapsulated DNA repair enzymes Most of us are and will remain unaffected by skin cancer. If oxidative protein damage by solar UVA does compromise NER and contribute to mutation and skin cancer risk, its effect is likely to be subtle and cumulative. In practical terms, the possibility that the long and short wavelengths of solar UV interact synergistically in cancer development dictates that truly effective skin cancer prevention requires protection against the whole solar spectrum with efficient screening of both UVA and UVB radiation.The authors declare no conflicts of interest."}
+{"text": "Salmonella induces the up-regulation of connexin 43 (Cx43), a ubiquitous protein that forms GJs. This up-regulation allows the transfer of antigens between tumour cells and dendritic cells (DC) licensing them to induce an efficient anti-tumour response in a mouse model of melanoma .Most cancer cells down-regulate gap junctions (GJ) resulting in loss of communication with their surrounding microenvironment. We have previously shown that infection of mouse tumour cell lines with Herein, we tested the idea that through the formation of intercellular communication channels in tumour cells, human autologous dendritic cells could be loaded with tumour antigens, preprocessed by cancer cells, and could be used to generate a cancer vaccine.Salmonella Ty21a (Vivotif) to induce up-regulation of Cx43 and formation of GJ channels. HLA matched DCs were differentiated in vitro by peripheral blood purified monocytes from healthy donors. Expression of surface molecules, cytokine release and cell proliferation was determined by cytofluorimetry. Cytotoxicity was determined either by Delfia cell cytotoxicity assay (PerkinElmer) and by a cytofluorimetry based CD107 assay.Human melanoma cell lines were infected with a vaccine strain of Vivotif-infected tumor cells established GJs in human melanoma cell lines. We show that tumour derived antigens could transit from 'donor' melanoma cells' cytoplasm to DC's cytoplasm through GJs, generate a tumour-specific CTL response and reactivate tumour infiltrating lymphocyte (TIL) in vitro. The transfer of tumor antigens was GJ-dependent because it was abolished in the presence of a GJ-specific inhibitor. In vitro generated tumour-specific human CTLs lysed also non-donor melanoma cell lines indicating that DCs were loaded with tumour-associated antigens shared among melanoma cell lines.Moreover, in vitro generated CTLs were melanoma specific because they were unable to lyse HLA matched colorectal adenocarcinoma cell lines.We exploited an antimicrobial response present in tumour cells to activate cytotoxic CD8 T cells specific for tumour-peptides, through a new pathway of antigen loading of human dendritic cells via intercellular communication channels. This unique and novel approach can be applied across a wide range of tumour cell types and can be used clinically as therapeutic vaccine alone or in combination with gold standard treatments."}
+{"text": "In new diagnoses of left ventricular (LV) systolic dysfunction it is important to exclude coronary artery disease (CAD) as the cause. Cardiac magnetic resonance imaging using late gadolinium enhancement (LGE CMR) highlights fibrosis from ischaemia or infarcts in a subendocardial distribution. Many consider that the absence of LGE indicates an absence of significant CAD. The evidence for this is debatable, with variable sensitivities depending upon the definition of CAD, the patient population, and the use of proximal coronary artery imaging (MRCA). We strived to ascertain the utility of LGE CMR to exclude prognostic CAD.2) on CMR or transthoracic echo were analysed. The presence and extent of subendocardial LGE was recorded with the 17 segment model. The degree of coronary stenosis at X-ray angiography was assessed visually and significant disease defined as stenosis of the LMS \u226550%, or proximal LAD \u226575%, or \u226570% in two main coronary vessels.We retrospectively reviewed a cohort of patients attending a district general hospital who underwent both X-ray angiography and LGE CMR since 2006. Records of those with European criteria for LV systolic dysfunction  with no false negative results.LGE CMR reliably excludes prognostic CAD in patients with LV systolic dysfunction.N/A."}
+{"text": "The tumoricidal effect of radioembolization is predominantly due to radioactivity and not ischemia. This article will present a comprehensive review of the side effects that have been associated with radioembolization using 90Y microspheres. Some of the described side effects are associated with all transarterial procedures. Side effects specific to radioembolization will also be discussed in detail. Methods to decrease the incidence of these potential side effects will also be discussed.Limited therapeutic options are available for hepatic malignancies. Image guided targeted therapies have established their role in management of primary and secondary hepatic malignancies. Radioembolization with yttrium-90 ( Hepatocellular carcinoma (HCC) and intra-hepatic cholangiocarcinoma (ICC) are primary liver malignancies. HCC is much more common than ICC , 2. SurgMalignancies commonly metastasize to the liver . Hepatic90Y microspheres are used in treatment of hepatic malignancies. The details of 90Y are beyond the scope of this manuscript. Table 90Y microsphere devices.\u00ae are FDA-PMA  approved for metastatic colorectal cancer to the liver (\u00ae are FDA approved under HDE (humanitarian device exemption) for radiation treatment or as neo-adjuvant to surgery or transplantation in patients with HCC who can have appropriately placed hepatic arterial catheters Serum bilirubinb)Serum albuminc)PT/INRd)Encephalopathye)AscitesAppropriate laboratory tests including but not limited to liver function tests and corresponding tumor markers should be performed to ascertain baseline values. For patients with cirrhosis, it is essential to classify patients. The Child-Pugh classification is commonly employed by multiple disciplines and includes the following variables:a)Extent of diseaseb)Location of diseasec)Relative tumor hypervascularityd)Variant vascular anatomyA triphasic liver CT or MRI is usually performed to evaluate the following:Angiography prior to radioembolization is essential. This provides the interventional radiologist with knowledge of the hepatic arterial anatomy and aberrant vasculature . Figure An aortogram assesses aortic atherosclerosis and tortuosity. A superior mesenteric angiogram is essential to determine variant vessels to the liver. Delayed images can assess the patency of the portal vein. A celiac angiogram determines hepatic vasculature and variants. Segment 1 tumors require special attention given various potential contributing feeders . More seCoil embolization of communicating vessels that may lead to aberrant microsphere deposition can be performed if necessary. The aberrant deposition of microspheres in the gastrointestinal tract (GIT) or pancreas can have grave consequences \u201318. SomeExperience of the treating physicianPlanned location of radio-microsphere deliverySize of vesselPre-treatment prophylactic coil embolization is dependent on the following variables , 20:ExpCollateral hepaticoenteric flow can develop following coil embolization. This may increase aberrant microsphere deposition on following repeat treatments. Theoretically, if the interval between coil embolization and radioembolization is long, this phenomenon can also occur during the initial treatment. Further research on this issue is needed.Appropriate tumor targeting is now routinely confirmed by using C-arm CT. This method aids in accurately recognizing non-tumor/non-hepatic contrast delivery.Variant hepatic artery and parasitized hepatic artery can be coil embolized prior to radioembolization. This leads to intra-hepatic collateralization in preparation for radioembolization.A systematic review concluded that Angiotensin II could increase tumor to non-tumor blood flow by approximately up to threefold . HoweverA five patient analysis on the use of degradable starch microspheres as an embolizate to normal hepatic parenchyma during radioembolization was performed. Post-radioembolization SPECT/CT demonstrated sparing of normal parenchyma . This is99mTc-MAA scan is performed to assess the lung shunt fraction (LSF) and splanchnic shunting. Figure A 99mTc-MAA resulted in effective avoidance of free 99mTc-pertechnetate concentration and decreased incidence of equivocal findings in the gastroduodenal region  and 99mTc-sulfur colloid (SC) , dual tracer SPECT/CT may provide more accurate dose calculations as this method provides a more accurate dose to functional liver (DFL)  . Researcer (DFL) .\u00ae using the following formula:\u00ae package insert, the upper limit of injected activity to the lungs is 0.61\u2009GBq  employed by the group showed no reportable events. In this analysis, planar scintigraphy was performed in 2\u2009h following administration of Tc-99m MAA and LSF was determined. Final dosimetry calculations were performed while the patient was being transferred back from nuclear medicine to interventional radiology. This method decreased the costs and time between initial clinical assessment and radioembolization . It shouAt our institution, cross-sectional contrast enhanced imaging (triphasic CT or MRI) is obtained at 1\u2009month following treatment and at 3\u2009month intervals following the first post-treatment imaging. This protocol evaluates response, or lack thereof, to treatment.90Y to the duodenum identified on PET/CT performed after radioembolization  may aid in assessing response to therapy.The complications occurring after radioembolization  are discPlease note that it is important to standardize recording and reporting toxicities. Clinical and laboratory toxicities may be classified according to the standard criteria such as the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0, whenever possible . Tables A post-radioembolization syndrome (PRS) includes fatigue, nausea/vomiting, abdominal pain/discomfort, and/or cachexia. PRS is less severe than that observed after embolic therapies. Hospitalization is rarely required \u201347. InciNausea and vomiting may occur following radioembolization. Based on this experience, antinauseants/antiemetics such as ondansetron are routinely administered prior to treatment. Antinauseants/antiemetics pro re nata (PRN) are usually sufficient to treat nausea/vomiting following treatment.Patients may experience right upper quadrant pain and/or generalized abdominal discomfort. Over the counter analgesics, PRN usually treat the discomfort/pain following radioembolization. Stronger analgesics such as opiates are rarely necessary.Pre-existing liver dysfunction is a significant confounding variable when assessing post-radioembolization liver toxicities in HCC patients . It is i\u00ae. The incidence of RILD after 90Y radioembolization ranges from 0 to 4% (Radiation-induced liver disease (RILD) is a potentially serious post-radioembolization complication . Given c 0 to 4% \u201332. RILDA recent article demonstrated repeated radioembolization to be a significant risk factor in development of radioembolization induced liver disease . Two of Prior exposure of the liver to external beam radiation therapy (EBRT) may lead to increased liver toxicity after radioembolization. This depends on fractional liver exposure and dose level. The authors concluded that radioembolization appears to be safe for the treatment of hepatic malignancies only in patients who have had limited hepatic exposure to prior EBRT .As biochemical aberrations may occur without clinical manifestations, follow-up liver function tests are routinely recommended 1\u2009month after treatment. In rare cases of clinically manifest RILD, a biopsy of the normal parenchyma may help confirm the diagnosis. A case of post-radioembolization fulminant hepatic failure has been reported .\u00ae, liver function toxicity (grades 1 through 4) was seen in 58% of infusions. The median duration of LFT toxicities was 20\u201329\u2009days. Grade 3 or greater toxicities occurred after 9% of infusions in their analysis. One patient died in 32\u2009days of treatment with signs and symptoms compatible with radiation-induced liver disease . An analysis by Memon et al.  in patiePost-radioembolization biliary complications are potential side effects of radioembolization. The incidence of these complications is less than 10% . These m90Y radioembolization in the setting of tumor-related biliary obstruction has an acceptable safety profile Obstructive jaundice due to biliary stricturesb)Biliary necrosisRadiation pneumonitis is very rare (less than 1% if standard dosimetry models are used) , 36. Thi\u00ae and SIR-Sphere\u00ae radioembolization of liver cancer based on 99mTc-MAA SPECT/CT. According to Yu et al., this method provides a more accurate estimate of radiation risk to the lungs (Delivery to the lungs of greater than 30 Gray (Gy) in one treatment or a cumulative dose of greater than 50\u2009Gy in multiple treatments is considered a relative contraindication. Planar scintigraphy is usually employed to calculate LSF. Yu et al. described a new method of calculating the mean lung dose for TheraSpherehe lungs . HoweverA restrictive ventilatory dysfunction following radioembolization has been reported . RadiatiSteroids may play a role in management. Other thoracic complications include atelectasis and/or pleural effusion.Diarrhea has been described following radioembolization. This is rarely significant enough to require hospitalization.Post-radioembolization GI complications occur secondary to hepaticoenteric arterial communications resulting in aberrant microsphere deposition . RecogniProphylactic coil embolization of the gastroduodenal and RGA may be considered. The left hepatic angiogram is performed to identify left gastric and inferior esophageal arteries. Delayed angiography of the left hepatic artery with opacification of the coronary vein confirms hepaticoenteric flow. The right hepatic angiogram is required to identify the supraduodenal and retroportal arteries .Prophylactic use of gastric acid suppressive agents (such as proton pump inhibitors) is recommended. If GI ulceration is clinically suspected, endoscopy is recommended to confirm the diagnosis , 61.p\u2009=\u20090.04), and proximal injection of the microspheres were also significant risk factors.A recent root cause analysis showed stasis during injection to be the strongest independent risk factor for development of gastroduodenal complications . Distal A potential complication of coil embolization of vessels, such as the GDA and RGA, is formation of collateral hepaticoenteric flow. This can result in increased enteric complications on repeat treatments.90Y Bremsstrahlung in the pancreas may be performed. Treatment is conservative.Acute pancreatitis is a potential but very rare complication of radioembolization . PatientPeriumbilical pain may occur due to aberrant microsphere deposition in the anterior abdominal wall via the falciform artery , 19, 20.Recognition of the falciform artery is essential. Prophylactic embolization of this vessel can be performed if needed to decrease the incidence of radiation dermatitis. Prophylactic topically applied ice prevents complications as it causes vasoconstriction which decreases cutaneous flow .Lymphopenia may be seen after glass microsphere radioembolization. Greater than 25% decrease in lymphocyte count after treatment is seen in the majority of patients , 64. HowA retrospective analysis demonstrated thrombocytopenia as a complication following radioembolization. Splenomegaly can be seen following radioembolization which was shown to be an independent risk factor for development of a low platelet count . No signa)Knowledge of prior anti-cancer therapyb)Stopping and resuming \u201cblood thinners\u201d appropriatelyc)Reviewing cross-sectional anatomy to determine vascular anatomy such as the furcation of the common femoral artery.The incidence of vascular injury may be prevented by the following:Newer anti-cancer drugs such as bevacizumab (Avastin) have been shown to make vasculature more friable and prone to injury, increasing the chances of dissection and vascular rupture. Abnormalities in vasculature and hepatic arterial flow in 12/16 (75%) patients who were on anti-cancer therapy has been reported. During angiography, a search for stenoses and abnormal flow should be undertaken . Murthy Dissection at the site of arteriotomy is rare but possible. A pre-closure common femoral angiogram assists in its diagnosis. However, this may not be routinely performed. The patient may present with a \u201ccold\u201d extremity and stenting/anti-platelet therapy may be required.Hematoma formation at the arteriotomy may be seen in radioembolization . StandarIf there is suspicion of pseudoaneurysm formation, ultrasound with Doppler may be needed. This is usually treated with ultrasound guided manual compression. Thrombin injection may be performed if necessary. Surgery is rarely necessary.It is important to know the patient\u2019s baseline renal function prior to performing transarterial therapies such as radioembolization. Adequate hydration pre- and post-radioembolization and stringent use of iodinated contrast limit contrast induced nephrotoxicity.Anticipation of possible allergic reactions is essential. Most patients being considered for radioembolization have received prior iodinated contrast media for CT scans. An allergic reaction can range from a minor reaction such as a pruritic rash to an anaphylactoid reaction. If there is a history of prior minor allergic reactions (such as hives) to iodinated contrast, the patient may still received iodinated contrast after receiving an allergy preparation prior to planned transarterial procedure .Acute chills may occur during treatment, which usually respond to anti-histamines .99mTc-MAA scintigraphic imaging) is necessary to minimize side effects of radioembolization. The incidence of complications that may require intervention is low. Grade 3 or higher complications following radioembolization occur in less than 9% of patients. Aberrant microsphere deposition may lead to various complications such as radiation cholecystitis. Surgical therapy may be required in severe cases. As radioembolization is a transarterial procedure, knowledge of general complications associated with transarterial therapies is also important.Radioembolization is being employed for treatment of various hepatic malignancies. As with any other common therapy, knowledge of potential complications of this therapy is essential. Selecting appropriate patients using a multidisciplinary approach can improve outcomes and decrease complications. Meticulous pre-treatment planning (angiography and Riad Salem receives research support from Nordion. The other co-authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "All but one of the linear models incorporating height-structured metrics showed significantly higher adjusted-r2 values than their counterparts without additional metrics. The interior forest guild richness showed a consistent low association with height-structured metrics. Our results suggest that height heterogeneity, beyond canopy height alone, supplements habitat characterization and richness models of forest bird species. The metrics and models derived in this study demonstrate practical examples of utilizing three-dimensional vegetation data for improved characterization of spatial patterns in species richness.Avian diversity is under increasing pressures. It is thus critical to understand the ecological variables that contribute to large scale spatial distribution of avian species diversity. Traditionally, studies have relied primarily on two-dimensional habitat structure to model broad scale species richness. Vegetation vertical structure is increasingly used at local scales. However, the spatial arrangement of vegetation height has never been taken into consideration. Our goal was to examine the efficacies of three-dimensional forest structure, particularly the spatial heterogeneity of vegetation height in improving avian richness models across forested ecoregions in the U.S. We developed novel habitat metrics to characterize the spatial arrangement of vegetation height using the National Biomass and Carbon Dataset for the year 2000 (NBCD). The height-structured metrics were compared with other habitat metrics for statistical association with richness of three forest breeding bird guilds across Breeding Bird Survey (BBS) routes: a broadly grouped woodland guild, and two forest breeding guilds with preferences for forest edge and for interior forest. Parametric and non-parametric models were built to examine the improvement of predictability. Height-structured metrics had the strongest associations with species richness, yielding improved predictive ability for the woodland guild richness models (r Avian diversity has been under increasing pressure from anthropogenic disturbances such as habitat loss and fragmentation Traditionally large scale habitat heterogeneity has been quantified mostly as topographical variability Until recently, there have been relatively few studies utilizing three-dimensional habitat information due to difficulties of acquiring measurements of vertical vegetation structure beyond the plot scale over extended geographical areas Related advances have been made in the development of statistical fusion models that provide a means to effectively combine remotely sensed data from radar, lidar, optical remote sensing systems and forest inventory data, yielding wall-to-wall high resolution vegetation structure maps at the continental scale The overall goal of our study is to examine the potential of three-dimensional habitat structure in improving avian richness models at broad geographical scales. In doing so we hope to expand our understanding of the relationship between habitat structure and the spatial distribution of avian species richness, and to lay the foundation for constructing habitat metrics that better utilize increasingly available three-dimensional habitat data. Specifically we address the following questions:How do the height-structured metrics compare with traditional habitat metrics in their ability to associate and predict forest bird richness in the forested ecoregion of the U.S.? Does incorporating the height-structured metrics improve the explanatory ability of avian richness models that use traditional habitat metrics?How do the predictive abilities of richness models vary among forest bird guilds with contrasting preferences to habitat edges?First, we introduce the conceptual similarities and differences between traditional habitat metrics and two types of height-structured metrics. Next, we describe the data and the methods we used to create the habitat metrics in this study. We then use correlation analysis and multivariate regression models to examine the relationships between different combinations of metrics and the species richness of three forest breeding bird guilds. Lastly, we examine the models\u2019 explanatory abilities and the importance of individual metrics in predicting the richness of the three guilds.Traditional habitat metrics are based primarily on two-dimensional habitat structure, such as land cover types, patch size and shape statistics. Developing such metrics generally depends on two steps: a) classifying scene space into binary habitat and non-habitat land cover types; b) delineating habitat patches based on the rule of contiguity  [38]. ThSome studies have applied three-dimensional habitat information in habitat quality and species diversity models To account for more height heterogeneity, we created two groups of height-structured habitat metrics, the first of which integrates vegetation height information into the habitat patch framework while the second one characterizes canopy height distribution directly using second-order texture algorithms.At the canopy level, vertical differences in vegetation create boundaries that segment contiguous habitats into smaller patches, each with similar height values . We firsBesides utilizing habitat patch and edge metrics to capture vegetation height heterogeneity, the second approach we introduce here involves calculation of the second-order (co-occurrence) texture statistics The study area includes 21 predominately forested ecological regions (provinces) Adjustments were made to take into account the detection probability bias The National Biomass and Carbon Database of the year 2000 (NBCD) 2 areas to characterize the surrounding habitat around BBS locations We adapted a method to use 19 km  radius buffers placed on the centroid of each BBS route, encompassing \u223c1100 kmAll the metrics created are listed in We first explored the statistical correlation between richness of the three avian guilds and the habitat metrics to evaluate the association between individual habitat metrics and the richness of different guilds. The woodland species richness models were based on data of all 21 forested ecoregions, and the interior forest and forest edge guild models were limited to data of the 10 forested ecoregions from Eastern U.S. as noted earlier .We selected 2 metrics from each of metric set (C) and (D) that on average had the best association with the richness of the three guilds as the best performing height-structured metrics (BPHMs). These four BPHMs were later combined with the traditional habitat metrics in multivariable models for comparisons of improvement. We limited our choice to only the four best metrics to avoid subsequent overfitting of our multivariate models while still maintaining enough representativeness.We next constructed 6 multivariate linear models to explain each guild\u2019s richness. The first 4 models were created using the complete list of metrics from set (A), (B), (C), and (D) respectively. They served to compare the explanatory abilities of models that characterize habitat condition with very different approaches. The two other models combined metric set (A) and (B) individually with the 4 BPHMs. We created the combined models to examine the impacts of adding spatial arrangement of height in richness models characterizing habitat in traditional ways.2 values and AIC values to assess models\u2019 explanatory ability and goodness of fit, as well as the variability of these measures. The bootstrap resampling was repeated 3000 times for each model. To examine the significance level of model improvements the 95% confidence interval of adjusted-r2 values and AIC values were obtained with the bias-corrected and accelerated (BCA) bootstrap algorithm We used a bootstrapping technique to provide the mean value and confidence intervals for the richness models\u2019 adjusted-rLastly we explored the effect of combining the 26 metrics from all four metric sets using a non-parametric Random Forest (RF) model. The RF model The predictor metrics that correlate best with bird species richness varied among guilds. For woodland species richness, (D) the second order texture metrics generally had the greatest predicative ability, followed by (B) the traditional patch-based metrics, and (C) the height-structured patch metrics. For forest edge bird richness, the metrics with the strongest correlation were (C) the height-structured patch-based metrics followed by (D) the second order texture metrics and (A) the summary height statistics . InterioThe direction of the correlation between metrics and the bird richness was generally consistent across three guild types except for metrics with weak correlation . Among tAfter incorporating vegetation height heterogeneity in patch-based metrics, the metrics characterizing patch number and area  showed a decreased correlation with the woodland guild richness. Conversely, the strength of the correlation between edge metrics  and the woodland guild richness increased. For the forest edge species both the patch and edge related metrics showed a prominent increase of correlation after incorporating vegetation height heterogeneity. The direction of the correlation for some patch-based metrics also changed. The NP metric showed an exceptionally large change for the woodland guild richness: from \u22120.45 to 0.25 after incorporating vertical patches .2\u200a=\u200a0.11), but the forest edge guild richness was predicted moderately well (r2\u200a=\u200a0.47) and the predictive model was strong for the woodland guild (r2\u200a=\u200a0.63)  from the four metric sets were the ones with greatest ability to predict species richness for each guild . Among t\u200a=\u200a0.63) . The mos\u200a=\u200a0.63) .For the RF models, our results consistently showed that adding height-structured metrics improved the model predictive ability. Specifically, the explained variance of the all-inclusive RF models for woodland and forest edge guild were up to 0.27 and 0.21 higher respectively than the RF models with only traditional habitat metrics. In addition for these two guilds, when the RF models were combined with the four BPHMs, the improvement for explained variance were up to 0.21 (woodland guild) and 0.13 (forest edge guild). The interior forest guild however showed only minor improvements when combined with any height-structured metrics. In general for woodland and forest edge guild, RF models\u2019 predictabilities were higher than the comparable linear models by a prominent margin. .The linear models had a lower explanatory ability than their RF counterparts. For a specific combination of habitat metrics, the linear models explained the most amount of variation in the woodland guild richness and the least in the interior forest guild richness. The one exception was the model using summary statistics of height (set A), which showed the highest predictability for forest edge guild richness, followed by woodland guild richness, and then the interior forest guild richness . In ever2 values in the woodland and forest edge models Click here for additional data file.Table S2Species list and guild classification.(XLSX)Click here for additional data file.Table S3Metric descriptions.(DOCX)Click here for additional data file.Table S4Metrics correlation with species richness.(XLSX)Click here for additional data file.Table S5Model performances for different multivariable models.(DOCX)Click here for additional data file.Supporting Information S1Contrast matrix for weighted-edge metrics.(PDF)Click here for additional data file."}
+{"text": "Truvada is licenced for HIV-1 prevention in the USA and is available in the private sector. Tenofovir performed as well as Truvada in the PARTNERS PrEP study and is used as HIV pre-exposure prophylaxis (PreP) in some settings. The clinical efficacy of Tenofovir for PrEP outside a clinical trial is unknown. Antiretroviral therapy (ART) at acute HIV-1 infection (AHI) limits the size of the reservoir, optimizing the chance of maintaining viral control off therapy. As such ART at acute HIV infection is proposed to offer a functional cure in a minority of subjects. We present two cases where Tenofovir PrEP failed to prevent HIV acquisition and failed to limit viral reservoir.Two individuals receiving tenofovir monotherapy for Hepatitis B monoinfection were diagnosed with AHI as defined by a negative HIV antibody test within three months of a positive HIV test following unsafe sex with casual male partners. In-depth histories were taken. Viral genotypes and Tenofovir drug levels were measured from samples taken as close to HIV seroconversion as possible and subsequent samples were analyzed for proviral Total HIV-1 DNA by qPCR.Patient A had received tenofovir for the preceding six years and always maintained an undetectable Hepatitis B viral load with no concerns about adherence. Two weeks preceding the positive HIV antibody test, he experienced mild symptoms  of HIV seroconversion. HIV status was confirmed by a repeat fourth generation HIV antibody test and by Western Blot and an HIV viral load was undetectable. Tenofovir trough level at HIV diagnosis was within normal limits. The regimen was intensified to Eviplera and a total HIV-1 DNA was 1381 copies/million CD4 T cells. Patient B received four regimens for hepatitis B treatment before starting tenofovir monotherapy in 2011 and subsequently maintained an undetectable hepatitis B viral load. After three years of tenofovir monotherapy he developed a severe symptomatic seroconversion illness and tested HIV antibody positive. The baseline HIV viral load was 103,306 copies/mL. The regimen was intensified and total HIV-1 DNA was 2746 copies/million CD4 T cells.Further investigation into the efficacy of tenofovir for PrEP outside a clinical trial is required. ART at AHI does not always lead to a low viral reservoir. To explore the possibility of replication incompetent virus, viral outgrowth assays are underway."}
+{"text": "Drug desensitization is the induction of temporary clinical unresponsiveness to drug antigens to which patients have presented severe hypersensitivity reactions (HSR). Rapid desensitization in patients suffering immediate hypersensitivity reactions with chemotherapeutic agents and monoclonal antibodies have been widely described and have shown to be successful. Non-immediate hypersensitivity reactions with other drugs have usually required desensitization with several days' protocols to achieve total doses.Forty three desensitization procedures were performed in 6 patients with a 12-13 step, 6-hour protocol. All patients had developed a delayed maculopapular rash with the use of chemotherapeutic and/or biological agents. Four patients were pretreated with corticosteroids, paracetamol and antihistamines before each desensitization procedure.All the 43 desensitizations undertaken were successfully completed . We observed HSR during 11 (25%) of desensitizations, including 5 inmediate exantema, 3 delayed local macular exantema and 3 delayed maculopapular lesions. Four patients were treated with corticosteroids and anti-histamines after the desensitization protocol to avoid more delayed HSR.Rapid desensitization protocols are safe and effective in getting over delayed HSR to chemotherapeutic and monoclonal antibodies and allow patients with severe diseases to continue their treatment."}
+{"text": "In the editorial \"Prophylactic Left Internal Mammary Artery Graft In Mildly-StenosedCoronary Lesions. Still An Open Discussion\", adjust the name of author Andr\u00e9Schmidit to Andr\u00e9 Schmidt.In the original article \"New Exercise-Dipyridamole Combined Test for NuclearCardiology in Insufficient Effort: Appropriate Diagnostic Sensitivity KeepingExercise Prognosis\", consider Vidal I as the correct form for the name of the authorIn\u00e9s Vidal Cortinas.Consider correct and use to citation the author's name Wojciech Wanha to the article\"First- Versus Second-Generation Drug-Eluting Stents in Acute Coronary Syndromes(Katowice-Zabrze Registry)\"."}
+{"text": "Immunity exhibits extraordinarily high levels of variation. Evolution of the immune system in response to host-pathogen interactions in particular ecological contexts appears to be frequently associated with diversifying selection increasing the genetic variability. Many studies have documented that immunologically relevant polymorphism observed today may be tens of millions years old and may predate the emergence of present species. This pattern can be explained by the concept of trans-species polymorphism (TSP) predicting the maintenance and sharing of favourable functionally important alleles of immune-related genes between species due to ongoing balancing selection. Despite the generality of this concept explaining the long-lasting adaptive variation inherited from ancestors, current research in TSP has vastly focused only on major histocompatibility complex (MHC). In this review we summarise the evidence available on TSP in human and animal immune genes to reveal that TSP is not a MHC-specific evolutionary pattern. Further research should clearly pay more attention to the investigation of TSP in innate immune genes and especially pattern recognition receptors which are promising candidates for this type of evolution. More effort should also be made to distinguish TSP from convergent evolution and adaptive introgression. Identification of balanced TSP variants may represent an accurate approach in evolutionary medicine to recognise disease-resistance alleles. Immune function is highly heritable \u20134, goverTrans-species polymorphism (TSP) refers to the occurrence of identical or similar alleles in related species, excluding instances where the similarity arose by convergence or introgression , 20. By http://dx.doi.org/10.1155/2015/838035). Surprisingly, our knowledge on TSP in other immune gene classes is only limited. Is TSP unique to MHC or does it represent a general evolutionary pattern masked by little endeavour paid to its investigation outside the MHC family? In the present review we compile present evidence on TSP in human and animal immune genes and outline main directions for further evolutionary immunogenetic research.The TSP concept was proposed three decades ago by Klein  who suppLong-lasting TSP in immune genes is dependent on balancing selection. This type of selection maintains genetic variation in populations for extensive periods of time based on three possible mechanisms: (1) heterozygote advantage , 30, (2)MHC groups several extremely polymorphic and dynamically evolving members of the immunoglobulin superfamily playing a crucial role in the adaptive immune defence against pathogens in jawed vertebrates , 37. MHC\u03b1-chain composed of \u03b11, \u03b12, \u03b13 domains and \u03b22-microglobulin . Articles dealing with TSP in blood group systems and serological allomorphs were not included into this survey."}
+{"text": "Lead extraction is becoming increasingly common as indications for pacing and ICD insertion expand. Periop management varies between extraction centers, and no clinical guidelines have addressed the need for perioperative anticoagulation. We report a case of massive thrombosis which occurred shortly after laser lead extraction and is undoubtedly related to the trauma of the extraction and ensuing hypercoagulabiilty. Routine post-operative anticoagulation has been advocated as a means to prevent access vein (subclavian) stenosis, but many centres do not employ a routine post-extraction anticoagulation strategy. Pulmonary embolism following lead extraction is a known complication of this procedure and late mortality following lead extraction is a significant and underappreciated problem. We propose that further research attention should be directed at addressing the issue of routine post-extraction anticoagulation. A 60 year-old man was referred to our center for lead extraction after developing a pocket infection following a routine generator change. His original dual-chamber device was implanted in 2002 for symptomatic bradycardia and standard right atrial appendage and right ventricular apical lead positions were confirmed on preoperative chest x-ray. A transesophageal echocardiogram was done to rule out any vegetations or thrombus on the leads and blood cultures drawn before the extraction were negative. The patient was not pacemaker dependent and underwent removal of his pulse generator prior to arriving to our center; swabs from the pocket done at this time showed methicillin-sensitive Staphylococcus aureus. Laser lead extraction was acutely successful and no immediate complications were noted. Post-operative anticoagulation was not administered. A routine transthoracic echocardiogram performed 30 hours following the procedure demonstrated extensive thrombosis extending from the right atrium all the way to the right ventricular outflow . AnticoaLead extraction has become increasingly important as more patients receive cardiac implantable electronic devices (CIEDs). Perioperative management protocols vary widely between centers, including concerning postoperative anticoagulation. The risk of postoperative subclavian vein occlusion, which occurs in at least 8% of cases , has bee"}
+{"text": "Fractional flow reserve (FFR) has been recognized as an effective tool to determine functional significance in intermediate coronary lesions and FFR-guided percutaneous coronary intervention (PCI) improves clinical outcomes. However, hemodynamic interaction between serial stenoses within one coronary artery complicates the assessment of functional severity of each individual lesion. We present a case in which FFR measurement by intracoronary bolus injection of adenosine helps to make appropriate revascularization decision in serial stenoses when the procedures are performed systemically and properly.  Fractional flow reserve (FFR) has been recognized as an effective tool to determine functional significance in intermediate coronary lesions. FFR is defined as the ratio between mean distal coronary pressure and mean aortic pressure at maximal hyperemia. A 0.014-inch wire with pressure sensor tip is introduced and advanced across the target lesions. The FFR value is measured after continuous intravenous infusion or intracoronary bolus injection of adenosine to induce maximal coronary artery vasodilatation. Several landmark outcome trials showed that FFR-guided PCI significantly reduced major adverse cardiac events including death and urgent revascularization in patients with stable coronary artery disease . Functio\u03bcg of intracoronary adenosine and FFR became 0.92 after 96\u2009\u03bcg of intracoronary adenosine when the pressure sensor was pulled back and positioned between the two lesions . Echocardiography showed left ventricular hypertrophy and normal systolic function with ejection fraction of 67%. Myocardial perfusion scan revealed a large area of myocardial ischemia at the lateral and inferior segments of left ventricle . Invasiv lesions . Percutadenosine . PCI usidenosine . The patThis case demonstrates that measurement of FFR in an intermediate lesion is critical in guiding PCI but can be easily misinterpreted in the presence of a serial lesion in the same artery.Pd \u2212 [(Pm/Pa)\u2217Pw])/((Pa \u2212 Pm)+(Pd \u2212 Pw)) [Pa), pressure between the two stenoses (Pm), distal pressure (Pd), and coronary occlusion wedge pressure (Pw) during maximum hyperemia. The higher coronary wedge pressure created by a more severe distal lesion results in an even more pronounced underestimation for the proximal lesion as our case evidently displayed. Nonetheless, FFR remains a helpful tool to improve PCI outcomes and reduce unnecessary intervention in these complex lesions. Kim et al. studied a total of 131 patients with multiple intermediate stenoses and 182 out of the 298 lesions were deferred according to FFR measurements. There were no events related to the deferred lesion at follow-up [When serial or multiple stenoses are present in the same coronary artery, hemodynamic interaction between stenoses complicates the assessment of functional severity of individual lesions. FFR value of each stenosis is usually underestimated and this influence is more pronounced for the proximal lesion than for the distal one. Individual FFR of each stenosis can be predicted by the following equation: FFR predicted = ( \u2212 Pw)) . The equollow-up .\u03bcg/kg/min [Most of the FFR studies were performed with a continuous intravenous administration of adenosine at a rate 140\u2009g/kg/min . Previou\u03bcg in the RCA and 200\u2009\u03bcg in the LCA induced maximum hyperemia while being associated with minimal side effects [Despite the recommended use of intravenous route of adenosine administration, intracoronary adenosine is still frequently used in clinical practice and published data . Intraco effects .A recent development in functional measurement of coronary stenosis using a hyperemia-free, pressure-derived hemodynamic index can potentially mitigate problems associated with hyperemic FFR in serial lesions. Instant wave-free ratio (iFR) is a resting index calculated as the ratio of distal coronary pressure to proximal aortic pressure over a specific wave-free period in diastole. During this cardiac cycle, resistance is naturally constant and minimized without administration of vasodilator drugs. This resting index measured at basal state can eliminate the flow interaction between stenoses under hyperemia. An iFR-pullback method can create a physiological map in complex serial stenoses and diffuse vessels and predict an expected iFR value for the treatment of selected stenosis , 13. MorThis case highlighted the importance of FFR in evaluating intermediate lesion and how it could be easily misinterpreted if operators are not familiar with this diagnostic tool. It also demonstrated that FFR measurement using intracoronary adenosine in serial lesions is a feasible and timesaving approach if correct and necessary procedures are performed systemically."}
+{"text": "Aminoglycosides are commonly used in tuberculosis treatment and are drugs of choice especially for MDR patients. They inhibit protein synthesis in susceptible bacteria by interacting with steps of translation. Several explanations have been put forward to explain the mechanism of aminoglycosides resistance but still our knowledge is fragmentary. Many culture filtrate proteins of pathogen represent potential targets for drugs, diagnostic probes and vaccine components; analysis of mycobacterial culture filtrate proteome in relation to aminoglycoside drug resistance is urgently required.M. tuberculosis sensitive and resistant clinical isolates were cultured in Sauton\u2019s medium. After four weeks, cells were removed by centrifugation; supernatant was filtered by 0.45 & 0.22\u00b5 filters and precipitated using SDS \u2013TCA precipitation method. Culture filtrate proteins were resolved by two dimensional gel electrophoresis and differentially expressed proteins (more than two fold) were selected for identification by matrix assisted LASER desorption/ionization time of flight mass spectrometry (MALDI TOF/MS) and characterization by bioinformatic tools (drug-protein docking).On comparing the protein profile of isolates, twelve proteins were found differentially expressed which were identified by MALDI TOF/MS. These proteins were not only involved in various metabolic pathways (site for drug targets) but also involved in survival of mycobacteria (various heat shock proteins).These results might help in new drug development through provision of new drug targets and in further revision of therapeutics & vaccines against aminoglycoside drug resistant tuberculosis."}
+{"text": "Endovascular therapy for iliac artery chronic total occlusions is nowadays associated with low rates of procedure-related complications and improved clinical outcomes, and it is predominantly used as first-line therapy prior to aortobifemoral bypass grafting. Herein, we describe the case of a patient presenting with an ischemic left foot digit ulcer and suffering complex aortoiliac lesions, who received common iliac arteries kissing stents, illustrating at final antegrade and retrograde angiograms the early recognition of a blood flow obstructing valve-like calcified intimal flap protruding through the stent struts, which was obstructing antegrade but not retrograde unilateral iliac arterial axis blood flow. The problem was resolved by reconstructing the aortic bifurcation at a more proximal level. Completion angiogram verified normal patency of aorta and iliac vessels. Additionally, a severe left femoral bifurcation stenosis was also corrected by endarterectomy-arterioplasty with a bovine patch. Postintervention ankle brachial pressure indices were significantly improved. At the 6-month and 2-year follow-up, normal peripheral pulses were still reported without intermittent claudication suggesting the durability of the procedure. Through stent-protruding calcified intimal flap, is a very rare, but existing source of antegrade blood flow obstruction after common iliac arteries kissing stents. Aortobifemoral bypass is still considered the gold standard treatment for chronic total occlusions (CTOs) of iliac arteries that belong to Transatlantic Intersociety Consensus (TASC II) guidelines C/D lesions . This prOccasionally, procedure-related complications may occur in both single- or kissing stent technique, necessitating various troubleshooting techniques or bailout procedures . We desc2). A clinical examination demonstrated an absent ipsilateral and a weak contralateral femoral pulse. His ankle brachial indexes were 0.32 and 0.64, respectively. Digital subtraction angiography revealed CTO of the left iliac axis and common femoral artery, and severe (~80%) right CIA stenosis  was placed percutaneously through the right femoral artery and advanced into the aorta. A similar, but through open femoral cut-down, guide wire was placed within the occluded left iliac axis, supported by a 5 \u00d7 6\u2009cm Optimed  percutaneous transluminal angioplasty dilatation catheter. This eventually crossed the lesion intraluminally, and was then advanced into the aorta. Balloon angioplasty was performed initially to predilate iliac arteries lesions before self-expandable stents (SEs) were implanted. Subsequently, primary CIA stenting was performed using standard techniques with a 10 \u00d7 40\u2009mm Complete SEs  on the right and a 10 \u00d7 100\u2009mm E-Luminexx SEs  on the left side, raising the aortic blood flow divider by 2-3\u2009mm. After stent deployment, concomitant postdilatation was performed using the kissing balloon technique. At a later stage, the left-sided SEs were extended up to the distal end of external iliac artery with a new E-Luminexx SEs (7 \u00d7 60\u2009mm), to fully cover the occluded lesion and completely recanalize the left iliac artery axis.Considering his severe comorbidities, the patient was scheduled for an endovascular approach. A Arrow catheter  placed into the aorta, 1-2\u2009cm above the kissing stents   inside the SEs (telescope technique), thus trapping the calcified intimal plaque. New angiograms (antegrade and retrograde) obtained after concomitant expansion of the stents verified normal aortoiliac blood flow  using new kissing balloon expandable stents  can be challenging. Treatment of iliac CTOs may initially be limited primarily by an inability to cross the occlusion and later by the failure of balloon angioplasty . HoweverCurrently, there is no consensus whether the kissing stents technique offers an advantage over the single-stent stenting strategy , 4. FurtTASC II C/D lesions are generally regarded as challenging targets to treat due to their high plaque burden and their anatomical proximity of the aorta and both CIAs. Occlusion of a contralateral CIA due to unfavorable plaque shift has a low incidence using the single-stent technique . HoweverIt has been shown also that patients in whom the proximal end of the kissing stents overlapped more than half of their angiographic width within the aorta had significantly lower primary and assisted primary patency rates at 2 years, compared to those in whom the proximal ends of the stents overlapped half of their width or less . In our The potential shortfall of retrograde completion angiography and the contrasting benefit of antegrade angiography in depicting neointimal flaps were shown recently in aortobifemoral grafts . As in oNovel minimally invasive techniques such as the single-stent procedure eventually result in the tacking of intimal calcified flaps or calcified plaques that protrude through prior stents and allow for normal antegrade blood flow without hemodynamic compromise. However, ostia CIA flaps require kissing stents to compress them between the stent and the arterial wall, simultaneously protecting the contralateral side. Similar stent-in-stent techniques have been used to treat plaque prolapse in stents placed in the coronary circulation . AlthougThrough bare metal stent-protruding heavily calcified intimal flap overcoming the radial force of the stent is a very rare but existing source of antegrade blood flow obstruction after CIA's kissing stents for aortoiliac occlusive disease. Interventionalists should remember this procedural complication and all effective ways to treat it endovascularly when treating complex aortic bifurcation lesions. As such, no clinical consequences for the patient will arise making the procedure extremely safe."}
+{"text": "Human leukocyte antigen (HLA) Class I and Class II antigens can be genetically extremely diverse, play a central role in immunity and are of primary importance in several branches of medicine. By presenting fragments of pathogens or altered \u2018self\u2019 proteins, HLA molecules activate T lymphocytes and are essential in adaptive immune responses against infection or cancer. Clinically, certain HLA types are associated with severity, treatment outcomes or risk of particular infections  . HLA areWith > 7000 alleles HLA is the most polymorphic region of the human genome . The comde novo each time they transmit. This hinders the adaptation of pathogens to the population of hosts as a whole and also favours in hosts many, rare HLA alleles [Each HLA type \u2018sees\u2019 a unique set of pathogen targets (epitopes). Individuals carrying different alleles at a given HLA locus (heterozygotes) produce both molecules thereby increasing the number of potentially targeted epitopes and so, on average enjoy broadened immunity and likely stronger protection . Such ad alleles . HLA div alleles . Such beStudies of HIV and Hepatitis C virus suggest that rapidly evolving RNA viruses are able to escape HLA-dependent defences in human populations . HLA is"}
+{"text": "This study was performed to establish the frequency of pre-hospital airway compromise in trauma patients attended by a UK physician-led pre-hospital service and the role of advanced airway interventions in the treatment of the compromise.Over a one year period (April 2012-March 2013) all pre-hospital trauma patients attended by the doctor-paramedic LAA team who were identified as having airway compromise or an indication for any airway intervention on scene were included in a prospective observational study. The doctor paramedic team recorded any airway compromise on arrival and prior interventions carried out by ambulance service personnel.472 patients met the inclusion criteria. Ambulance service personnel attended before the enhanced care team in 469/472 (99.4%) of cases. 200 patients had no evidence of compromise of which 134 (67%) had received airway interventions by the ambulance service. 269 (57%) had airway compromise at the point of arrival of the enhanced care team. Of the 269 with airway compromise, 174 had complete or partial airway obstruction and 145 had gross contamination with blood or vomit. Ninety-eight patients received paramedic advanced airway management interventions (intubation without drugs or supraglottic airway insertion). 48/50 (92%) supraglottic airway insertions and 29/45 (64%) intubations were successful. All patients had successful pre-hospital intubation by the enhanced care team before transport to hospital.The reported results suggest a requirement for on-scene advanced airway management in a relatively small number of severely injured trauma patients. Standard ambulance service interventions do not appear to adequately treat airway compromise in a small proportion of trauma patients. Intubation without drugs had a high failure rate. These results suggest that the airway management problems reported in the NCEPOD report: Trauma who cares? in 2007 still exist."}
+{"text": "A 9-year-old girl with grade 4-5 right vesico-ureteric reflux (VUR) into a solitary collecting system was initially treated with endoscopic Deflux injection. Micturition cystourethrogram (MCUG) performed after 6 months showed a grade 1-2 reflux. After 3 years, MCUG was repeated due to recurrent urinary tract infection (UTI) showed severe VUR. DMSA renal scan showed a non-functioning right kidney. The patient underwent a right nephrectomy by retroperitoneoscopic approach. A small distal ureteral stump (DUS) was left. One year after surgery, another MCUG was performed due to recurrent UTI showed an active VUR in the ureteral stump . The 5-cm long DUS  was surgically removed. The child is asymptomatic at follow-up of 5 years.The management of a poorly functioning kidney associated with primary VUR is nephrectomy with total or proximal ureterectomy. The retroperitoneal laparoscopic approach is particularly beneficial owing to a small residual distal ureteral stump (DUS) shorter than that achievable via a single flank incision. However, it does not allow the stump dissection down to the bladder base.[1] The transperitoneal laparoscopic approach is preferable for total removal of the ureter.[2]Reflux in DUS is a rare complication due to partial excision of ureter. Recurrent UTI after nephrectomy is a useful signal to suspect the presence of reflux in DUS which act as a reservoir resulting in stasis and infections.[4] A long stump could be a risk factor in the pathogenesis of ureteric stump syndrome. A long refluxing stump inevitably acts as a diverticulum from which the urine cannot be effectively drained thus leading to outbreaks of UTI.[3] In our case a short ureteral stump became symptomatic due to reflux into it. We recommend transperitoneal laparoscopic approach for the management of a poorly functioning kidney which allows nephrectomy and complete ureterectomy up till the bladder base thus avoids reflux into the DUS.Source of Support: NilConflict of Interest: None declared"}
+{"text": "We read with interest the study by Zhou and colleagues because it represents an important effort towards advancing the knowledge in current sedation strategies . HoweverRecent randomized trials demonstrate that sedation strategies with similar short-term mortality rates and ICU length of stay may still be associated with different short-term and long-term cognitive outcomes ,3. LimitMultiple studies demonstrate that ICU delirium is a prevalent syndrome that can be detected with simple validated diagnostic tools ,5. ICU-a"}
+{"text": "Persistent left superior vena cava (PLSVC) is a rare congenital anomaly of the superior venous system that may be discovered at the time of cardiac implantable electronic device (CIED) implantation.We present a subject who needed cardiac resynchronization therapy (CRT)-CIED implantation and was discovered to have PLSVC with absent innominate vein during the implant procedure. We were able to successfully implant a CRT-CIED using a right-sided approach via the right superior vena cava (SVC). We present a description of our implant technique and a brief review of the different aspects of CIED implantation in subjects with variants of PLSVC.Superior venous anomalies such as PLSVC can make CIED implantation technically challenging. However, with increasing operator experience, cardiac imaging and appropriate tools successful CIED implantation is possible in almost all cases. Persistent left superior vena cava (PLSVC) is a congenital venous developmental abnormality of the sinus venosus with an incidence of 0.47% in patients undergoing cardiac implantable electronic devices. The two variants include a double superior vena cava  or a single left sided SVC (without a right SVC) . ImplantA 59-years old gentleman with non-ischemic dilated cardiomyopathy, severe LV systolic dysfunction (left ventricular ejection fraction = 25%), LBBB (QRS width 180 ms), NYHA class III symptoms  and morbid obesity (body weight 160 kg) was referred to our service for CRT-CIED insertion. The procedure was performed under general anesthesia and full therapeutic anticoagulation as the subject had a history of paroxysmal atrial fibrillation with CHADS2 score of 3. A left superior venogram performed to guide left subclavian venous access revealed the presence of a PLSVC draining into the proximal segment of the coronary sinus (CS). The combined PLSVC and CS confluence drained into the right atrium. The venogram also revealed the absence of an innominate vein connecting the PLSVC to the right SVC. A venogram performed from the right side demonstrated the presence of a right SVC draining into the right atrium .The left subclavian vein was accessed using the Seldinger technique and a CS sub-selector catheter (Medtronic Attain Select soft-tipped guide catheterTM ) was introduced over a guide wire to cannulate the coronary sinus, distal to its confluence with the PLSVC. The selective coronary sinus venogram demonstrated a suitable lateral tributary for coronary sinus pacing lead insertion . HoweverWe were able to successfully implant a CRT-CIED system using a right-sided approach. A straight coronary sinus cannulation catheter (Medtronic 7F catheterTM) was introduced over a deflectable decapolar electrophysiological diagnostic catheter into the CS, distal to its confluence with the PLSVC. A venogram demonstrated the presence of a lateral CS tributary of adequate caliber for CS pacing lead placement. An endocardial bipolar pace-sense CS lead (Medtronic 6F 4194 leadTM) was introduced over a 0.014\" coronary guide wire  into this tributary  and 4. TOur case highlights a rare congenital venous anomaly that could potentially make CIED implantation technically challenging. The important factors increasing the complexity of lead placement from the left side include the tendency for the RV lead to be deflected away from the tricuspid annulus, torrential CS blood flow, acute angulation at the point where the PLSVC joins the CS and other anomalies making lead placement extremely difficult -5. In ouThe presence of PLSVC can be inferred from the presence of dilated CS on echocardiography. If the presence of PLSVC is suspected prior to CIED insertion cardiac imaging CT/MRI/3-D echo) can be used to understand superior venous anatomy. This will assist the operator in selecting the most appropriate approach and the necessary tools  for CIED implantation, possibly increasing the chance of success. In view of the very low incidence of PLSVC, in subjects without congenital heart disease, routine cardiac imaging to detect superior venous anomalies in patients may not be indicated. Given the higher incidence 10-15%) superior venous anomalies in subjects with congenital heart disease a case can be made for cardiac imaging prior to CIED insertion, especially in subjects needing CRT 0-15% sup. Torrent-D echo cThe variant of PLSVC without a right SVC or innominate vein connecting the PLSVC to the right atrium makes LV pacing lead insertion via the CS very difficult. In such subjects experienced operators have used a variety of special stylets, catheters and pacing leads to successfully implant CRT-CIED using an endovascular left-sided approach -4. OtherThe variant of PLSVC with right-sided SVC, with or without an innominate vein connecting the right and left SVC, makes it more likely that a CRT-CIED can be inserted exclusively using an endovascular approach. In this situation operators have used right or left sided approaches to insert all three pacing leads . Other operators have used a hybrid approach inserting the RA and RV pacing leads from the right side and the CS pacing lead from the left side using the PLSVC. The CS pacing lead was then tunneled through the subcutaneous plane to the right side . Very raSuperior venous anomalies such as PLSVC can make CIED implantation technically challenging. However, with increasing operator experience, cardiac imaging and appropriate tools successful CIED implantation is possible in almost all cases."}
+{"text": "GNAQ or GNA11 oncogenes, encoding persistently active G protein \u03b1 subunits of the Gq family [The core components of the Hippo pathway are conserved from flies to mammals . In humaq family . As the GNAQ was initially revealed by a systematic analysis of the transforming potential of G proteins and GPCRs [2+ levels and diacylglycerol (DAG) production, which stimulate classical PKCs and ERK . In seaOur study  and receThese YAP pools are likely dynamically regulated Fig. . AMOT reThese findings may have direct clinical relevance, as recent drug screens revealed that a family of porphyrin-related molecules can inhibit the interaction of YAP with TEAD transcription family members . Among t"}
+{"text": "Magnaporthe oryzae attack and drought stress enabled us to obtain insights about cross-talk among hormone biosynthesis pathways at the transcriptional level. We identified some master transcription regulators that co-ordinate different hormone biosynthesis pathways under stress. We found that Abscisic acid and Brassinosteroid regulate Cytokinin conjugation; conversely Brassinosteroid biosynthesis is affected by both Abscisic acid and Cytokinin. Jasmonic acid and Ethylene biosynthesis may be modulated by Abscisic acid through DREB transcription factors. Jasmonic acid or Salicylic acid biosynthesis pathways are co-regulated but they are unlikely to influence each others production directly. Thus, multiple hormones may modulate hormone biosynthesis pathways through a complex regulatory network, where biosynthesis of one hormone is affected by several other contributing hormones.Crosstalk among different hormone signaling pathways play an important role in modulating plant response to both biotic and abiotic stress. Hormone activity is controlled by its bio-availability, which is again influenced by its biosynthesis. Thus, independent hormone biosynthesis pathways must be regulated and co-ordinated to mount an integrated response. One of the possibilities is to use cis-regulatory elements to orchestrate expression of hormone biosynthesis genes. Analysis of CREs, associated with differentially expressed hormone biosynthesis related genes in rice leaf under  Plants being sessile creatures are forced to adapt to various adverse conditions to successfully complete their life-cycles. A repertoire of complex signaling systems was acquired by plants to respond to physiological and environmental cues. Phytohormones are one of the key mediators that afford plants the ability to rapidly respond to external cues by adjusting their metabolism. Previous research efforts have revealed importance of individual hormones in plant development and stress response  and jasmonic acid (JA) promote resistance against pathogens Figure . EthylenMagnaporthe oryzae attack  and drought stress. Results of this work allowed us to map the CRE-mediated regulation of differentially up-regulated rice hormone biosynthesis (HB) genes under blast and drought conditions. Through analysis of CREs associated with differentially expressed HB genes we were able to develop insights about effect of different hormones and stress conditions on regulation of all HB pathways. We were also able to identify key transcription factors for CRE elements that integrate and modulate these pathways.Regulation of hormone biosynthetic pathways at both transcriptional and post transcriptional level has been well documented  of rice loci is collected from Rice Genome Annotation Project, version 6.1  database   from each experiment (4 dpi of GSE7256 and panicle stage leaf of GSE26280) were considered for further analysis.Gene expression data were collected from Gene Expression Omnibus (GEO) . A series of filtering steps  separately. The locus-locus co-enriched CRE network was developed using the up-regulated HB genes and the over-represented CREs at their promoters. Each node of the network was specified by individual locus and two loci were interconnected if they have at least one common over-represented CRE.k) is interpreted as a complete (fully connected) subgraph having k number of nodes. In CRE co-occurrence network, a clique represents a combination of co-occurring CREs having statistically significant co-occurrence relationship with every other CREs of the same clique. CFinder , genes associated with Gibberellin biosynthesis were absent. Similarly Salicylic acid biosynthesis associated genes were absent from drought dataset (GSE26280) Table . This inOs07g05940.1 was associated with highest number of CREs, sixteen in number. This locus was common to both blast and drought datasets. Lowest number of CREs was associated with JA biosynthesis locus Os06g11210.1, it had a single CRE element  were over-represented in individual promoters. Promoter of ABA biosynthesis locus nt Table .The co-occurrence tendency for all possible CRE pairs present in the promoters of differentially up-regulated HB genes for each condition (37 for blast and 26 for drought) were calculated and significantly co-occurring pairs based on the filtering steps , whereas, number of common interacting edges were relatively small in number (24) Figure . This inThe locus-locus co-enriched CRE network was developed using the up-regulated HB genes having over-represented CREs at their promoters. Each node of the network represents individual locus and two loci are interconnected if they have at least one common over-represented CREs. Thus, the interacting edges represent the regulatory similarities among the promoters (loci) where the edge weight shows the number of common over-represented CREs among them. Interestingly we found that loci of same HB pathways as well as of different HB pathways share abundant edges. This indicates that different HB pathways may have common regulators Figures .k = 3\u20138) analysis was performed on CRE co-occurrence network for each condition. In case of blast and drought 76 and 29 cliques were observed, respectively. Twenty one cliques in case of blast and a single clique in case of drought were found to encompass all the HB pathways. Whereas 55 cliques in blast and 28 cliques in drought were found to be present only in loci of particular HB pathways. It was interesting to note that in case of Blast we did not find any clique which are exclusive to a single HB pathway; in case of drought we found two  exclusive to cytokinin biosynthesis genes. Under blast infection 7 cliques were associated with all 37 up-regulated HB loci, whereas under drought condition a single clique was associated with 25 (out of 26) up-regulated HB loci and another was associated with 22 up-regulated HB loci. These 9 cliques were composed of 10 CREs of which 6 were common to both blast and drought loci  followed by CK (93.7%), JA (85.5%) and SA (75.0%) Figure . In caseMagnaporthe oryzae infection and drought stress, demonstrates that some genes are differentially up-regulated under both conditions whereas some are exclusively up-regulated in either condition. These findings indicated that differential regulation of hormone biosynthesis may contribute to stress response. Analysis of CREs in promoters of these up-regulated HB genes allowed us to extract insights about regulation of HB pathways and CREs (and/or transcription factors) that may integrate and modulate hormone biosynthesis.Expression analysis of HB pathway associated genes under Role of cytokinins in regulating plant growth and development by promoting cell division and stimulating sink strength is well established. Recently evidence has accumulated demonstrating importance of CK in environmental stress response as well. Endogenous CK levels were reported to alter stress tolerance of plants and conversely stress conditions were found to change CK content in plants , a key gene of ABA biosynthesis  and 8 (out of 16) CK HB loci in drought and blast infected leaves were also associated with various ABA response CREs respectively Table . As all ET and JA interactions and their response play important role in abiotic and biotic stress management  functions are considered important under osmotic stress  and ZPF252 (Os12g39400.1) expression is known to be induced by salt and drought stress  and Os08g17500.1 (cinnamoyl-CoA reductase), CK  response elements were present. These loci are associated with initial steps of BR biosynthesis. Os08g17500.1 and another loci with similar annotation Os02g08420.1 were also associated with ABA responsive element DRE2COREZMRAB17. Therefore, our results indicate that in case of blast CK and ABA both may interact directly with BR HB loci likewise BR may also interact directly with CK HB loci  and CK  response elements. As BR-response elements are not present in PLACE database we scanned all the CK and BR HB up-regulated loci promoters for the presence of BR response element (CGTG[T/C]G) . These common CRE were associated with 72.4 % of cliques (combination of CREs) for blast infection. These observations indicate that JA and SA HB loci may be co-regulated under fungal attack. Previous research has shown that interactions between SA and JA are complex and condition specific . Os04g43800.1 is a phenylalanine ammonia-lyase which is also associated with secondary metabolite phenylpropanoid derivative synthesis. Analysis of CRE in up-regulated JA and SA HB genes under both drought and blast revealed no CRE (except one JA responsive CRE in SA loci) that can be tied to SA or JA response directly, so it is highly unlikely that these hormones directly affect each-other's biosynthesis.JA HB genes LOX and four OPR were found to be up-regulated but none of them had any SA-responsive CRE in their promoters. Similarly out of three only one SA HB gene Our investigations into CRE-mediated regulation of differentially up-regulated hormone biosynthesis associated loci under blast infection and drought stress revealed that hormone biosynthesis pathways are subjected to hormone cross-talk. Plant response to blast and drought is associated with transcriptional modulation of biosynthesis genes of several hormones and these hormones modulate bio-availability of each other through a complex regulatory network. Abscisic acid and Brassinosteroid regulates Cytokinin by modulating its conjugation. Conversely Brassinosteroid biosynthesis is effected by both Abscisic acid and Cytokinin. Through our analysis we found that DREB transcription factors may be important in modulation of both Jasmonic acid and Ethylene biosynthesis. Moreover we found that though DREB response are known to be ABA independent but at least DREB2A response may be regulated by ABA signaling through C2H2 zinc finger protein transcription factors. Interestingly we found no indication of direct interaction of Jasmonic acid or Salicylic acid with each other's biosynthesis pathways. Thus, multiple hormones may modulate several hormone biosynthesis pathways through a complex regulatory networks, where biosynthesis of one hormone is effected by several other contributing hormones.AD, RG, and SK conceived the idea and designed the study. AD and RG collected the data. AD developed and executed computational pipelines and took part in result analysis. RG performed literature survey and result analysis. AD and RG wrote the manuscript. SK edited the manuscript and supervised the study. AD and RG contributed equally to this study. All authors read and approved the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Modern human activity fueled by economic development is profoundly altering our relationship with microorganisms. This altered interaction with microbes is believed to be the major driving force behind the increased rate of emerging infectious diseases from animals. The spate of recent infectious disease outbreaks, including Ebola virus disease and Middle East respiratory syndrome, emphasize the need for development of new innovative tools to manage these emerging diseases. Disseminating vaccines are one such novel approach to potentially interrupt animal to human (zoonotic) transmission of these pathogens. If at first the idea is not absurd, then there is no hope for it.Modern human activity is profoundly and irreversibly changing our natural world. In additMicrobial movement into humans from animals (zoonotic transmission) has always been responsible for the majority of EIDs, including at one time EIDs that form such present day matrix diseases as malaria falciparum, measles The task of identifying and preventing zoonoses is daunting, particularly given that the emerging pathogen may be completely unknown. The availability of limited resources and allocation of these resources over short-term funding periods further compounds the problem.,9 RecentMycobacterium bovis to cattle has had some success in the control of bovine TB in Ireland and regions of the UK . Howeveiew, see  This unaiew, see  \u2013 with liew, see In non-temperate \u2018hotspot\u2019 regions of Africa, Asia and South America, the ability to contain even known EIDs such as Ebola virus in wildlife is currently not possible. Management of diseases that involve livestock in these regions, such as Rift Valley fever and Crimean Congo hemorrhagic fever, pose similar problems,,18 in thEven with programs such as EPT, prediction of which animal pathogens will become established as globally significant EIDs within the human population still remains beyond our capability. However, pathogens emerging from an animal source are often initially poorly adapted to their new human host in terms of sustained human to human transmission. MechanisThe earliest disseminating vaccine for animals was designed to target two highly lethal rabbit-specific EIDs in the European rabbit population, myxoma virus (MV) and rabbit hemorrhagic disease virus (RHDV). The vaccIn the above studies, MV was selected as the genetic basis for the disseminating vaccine due its ability to spread through rabbit populations. High species specificity of MV for rabbits also decreased the potential for spread to \u2018off-species\u2019 targets within the environment. However, use of a normally virulent pathogen for the host species being targeted as the self-disseminating vaccine platform necessarily required use of an attenuated MV strain. This requirement had a clear impact on the disseminating capacity of the MV6918-based vaccine. More recent self-disseminating vaccine approaches have used cytomegalovirus (CMV), which is a beta-herpesvirus, as the disseminating vaccine platform. Similar to MV, CMVs are immunogenic and spread efficiently through their host species.\u201327 HowevAlthough not targeting an EID, over a decade of work toward the use of a murine CMV (MCMV) as a viral vectored immunocontraceptive vaccine to control mouse plagues in Australia gives some insight into the application of disseminating vaccines to target high risk pathogens for EID control. Mice directly infected with MCMV strains expressing female mouse fertility antigens develop prolonged \u2013 essentially life-long \u2013 infertility. Immunocoin vitro combined with the lower anti-PCMV antibody levels suggested a level of attenuation. However, PCMV(\u0394P33:G1EGFP) was still able to induce G1-specific immunity in healthy deer mice previously infected with either PCMV(\u0394P33:G1EGFP) or wild-type PCMV.[The first studies using CMV as a disseminating vaccine targeting a human EID used CMV from deer mice (Peromyscus CMV (PCMV)) to target SNV in the wild deer mouse SNV transmission species. Using a PCMV expressing the SNV envelope glycoprotein G1, the PCMV(\u0394P33:G1EGFP) vaccine induced G1-specific antibodies following direct inoculation of deer mice. PCMV are also a known reservoir of Marburg virus [CTL) was shown to induce durable NP-specific immunity (>14 months).[CTL vaccinated mice showed no evidence of Ebola virus disease (EVD) following lethal Ebola virus challenge. Impressively, 5/8 mice completely controlled Ebola virus infection, with no detectable viremia; the remaining 3 mice showed a 2.8 log reduction in viremia relative to non-vaccinated controls. Protection was long-lived as mice vaccinated with a single dose of MCMV/ZEBOV-NPCTL were protected against EVD following lethal challenge 17 weeks post-vaccination \u2013 an attractive quality for a disseminating vaccine to be used in wildlife populations. Studies in the NHP Ebola virus challenge model were recently completed (manuscript under review). In this model, the key question of transmissibility of immunity in CMV seropositive animals (which cannot be assessed in the laboratory mouse model (see above)) can now be addressed in an experimental system more translatable to NHPs in the wild.A disseminating CMV-based approach is also being developed toward the control of Ebola virus in wildlife reservoir and transmission species in Africa.,39 Approrg virus ; a disserg virus ,39 In th months).,39 MCMV/Substantial evidence supports the ability of primate CMVs, including human CMV (HCMV), to superinfect the seropositive host. A 2008 study examining HCMV seropositive women showed the frequent presence of multiple glycoprotein N (gN) and/or gB variants within HCMV positive urine and blood samples suggesting that most individuals are infected with multiple HCMV strains. A subseqThe studies performed in the SIV:rhesus macaque model showed that the ability to superinfect was dependent on genes in the US2-11 region of the genome \u2013 a region which contains several genes involved in down-modulation of MHC class I antigen presentation. CD8+\u00a0T-cFurther studies are needed to ensure recombinant CMVs expressing heterologous target antigens can similarly maintain wild-type transmission and target-specific immune responses following transmission. Experience from studies exploring the use of disseminating vaccines targeting other pathogens (see above) are expected to prove invaluable for these studies, especially in regard to the importance of avoiding vaccine attenuation to maintain wild-type characteristics of CMV transmissibility. Where studied, frequencies of CMV infection from natural transmission in animal populations approach 100%. Consistent with epidemiological studies in humans, a major peak of infection occurs at an early host age, with essentially all US primate center rhesus macaques being RhCMV seropositive by the age of one year. Environmall countries has been raised to a level that enables identification and control of high-risk EIDs at source, we as a global community will be fated to reactive responses to EID outbreaks. Innovative strategies are therefore urgently required to identify and then pre-emptively control EIDs in these under-resourced \u2018hotspot\u2019 regions. Self-disseminating vaccination is one innovative approach that may potentially overcome the problems associated with use of conventional vaccines for pre-emptive pathogen control in \u2018high-value\u2019 animal populations within these challenging environments. Although still in relatively early stages, the nascent field of self-disseminating transmissible vaccines has the potential to solve many current intractable public health and conservation problems that cannot be addressed by conventional vaccines ; and UK applications No. 1508136.7, No. 1514005.6 and No. 1514034.6 (MA Jarvis and AA Murphy). The authors would like to acknowledge support by the School of Biomedical and Healthcare Sciences, Plymouth University (MA Jarvis and AA Murphy), The Marie Sk\u0142odowska-Curie Programme (MA Jarvis) and The Institute for Immunology and Infectious Diseases, Murdoch University (AJ Redwood). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.Emerging infectious diseases (EIDs) place an increasing burden on human health and infrastructure. The increasing rate of EID incidence can be directly linked to human activity.Current funding paradigms often focus on wealthy countries rather than developing countries which contain geographic EID \u2018hotspots\u2019. This funding paradigm leaves the world ill-prepared to detect and then control these diseases.Targeting zoonotic pathogens in wildlife populations by vaccination is a potentially powerful method for reducing transmission of EIDs. Direct vaccination of these animals may be hampered by a number of obstacles, including: poor infrastructure to support necessary cold chains, inaccessibility of animal species, inhospitable terrain and cost.Vaccines capable of self-dissemination may overcome many of the hurdles faced by direct administration of conventional vaccines. Self-disseminating vaccines will need to display species specificity, immunogenicity and normal transmission dynamics. Cytomegalovirus (CMV)-based viral vectors potentially fulfill many of these requirements, including being native to and endemic in target animal species.\u2018Proof of concept\u2019 studies using direct inoculation of CMV-based vaccine vectors have been performed for viral pathogens such as Sin Nombre hantavirus and Ebola virus. CMV-based vaccine vectors have also been used for successful \u2018proof of concept\u2019 of viral vectored immunocontraception.Production of CMV-based vaccines with proven capacity to transmit is the next step in the development of self-disseminating vaccines."}
+{"text": "A 15-year-old previously healthy boy was involved in a traffic accident and presented to our emergency department (ED) with complaints of chest pain and mild shortness of breath. On physical examination, he had complained for the last 2 hours of the right hemithorax pain in the fifth intercostal space radiating to the right midaxillary line. He had no past medical or surgical history. Chest x-ray demonstrated doubtful multiple thin-walled cystic lesions in the right lung (A). Computed tomography (CT) scan of thorax revealed a well- defined thin-walled, and 9.97 \u00d7 8.78 cm in diameter giant air cyst occupying the right upper lobe parenchyma with multiple air-space cysts (B). The patient was finally diagnosed as a multiple cystic lung disease and he underwent elective thoracic surgery for cyst removal. Cystic lung disease is defined as intrapulmonary air-containing multiple cysts surrounded by sharply demarcated thin walls. CT scanning of thorax is more sensitive than chest radiography in the detection and the distribution of lung cysts. Patients with cystic lung disease may be asymptomatic or present with nonspecific symptoms, such as chronic cough or shortness of breath. They are at increased risk for spontaneous pneumothorax. Surgical treatment of multiple cystic lung disease plays a crucial role in the prevention of pneumothorax."}
+{"text": "Spinal cord ischemia is a well-known potential complication of endovascular aneurysm repair (EVAR), and it is usually manifested by paraplegia or paraparesis. We describe a case in which spinal cord ischemia after EVAR presented by isolated bladder and rectal incontinence without other neurological deficits. A 63-year-old woman presented with intermittent claudication secondary to an infrarenal abdominal aortic aneurysm (AAA), and a left common iliac artery obstruction, for which she underwent EVAR using an aorto-uniiliac (AUI) device and ilio-femoral artery bypass. On postoperative day 3, she developed urinary and fecal incontinence without signs of paraplegia or paraparesis. Magnetic resonance imaging (MRI) showed a hyper-intense signal in the spinal cord. She received hyperbaric oxygen (HBO) therapy and was discharged after 18\u00a0days when her urinary and fecal incontinence were almost resolved. This report suggests that spinal cord ischemia after EVAR for aortoiliac occlusive disease might present as bladder and rectal incontinence without other neurological manifestations. Neurologic complications due to spinal cord ischemia (SCI) after elective infrarenal abdominal aortic aneurysm (AAA) repair, while catastrophic, rarely happen. Approximately 1 in 400 cases occur after open AAA repair while 1 in 5000 occur after arterial reconstruction of occlusive aortoiliac disease . ProlongWe describe a case of a woman who developed isolated bladder and rectal incontinence without paraparesis/paraplegia after endovascular aneurysm repair, treated with hyperbaric oxygen (HBO) therapy, and with significant clinical improvement after 3\u00a0weeks.A 63-year-old woman with a history of hypertension and chronic kidney disease presented with intermittent claudication. A computed tomography (CT) revealed a 41-mm infrarenal AAA with total obstruction of the left common iliac artery. The bilateral external and right internal iliac arteries were patent. The distal left internal iliac artery was occluded but filled through collateral circulation Fig.\u00a0. Given tAfter a thorough risk-benefit discussion with the patient, we performed an endovascular repair with an aorto-uniiliac (AUI) device  and ilio-femoral artery bypass using an 8-mm vascular graft (Goretex ePTFE graft) in a \u201chybrid\u201d operating room under general anesthesia. After bilateral groin incision to expose the right and left common femoral artery, a bifurcated stent graft  was placed just below the renal artery branch section to the right common iliac artery through the right external iliac artery, followed by placing a converter of 24\u00a0mm in a proximal diameter ESC-24-12-80) and an iliac extender of 16\u00a0mm in a distal diameter (TFLE-16-56-ZT) for the right common iliac artery. An arteriogram confirmed adequately positioned endografts, with patent bilateral renal arteries without evidence of proximal or distal endovascular leak. Subsequently, the right external iliac artery was cut longitudinally for the inflow for the bypass. The right external iliac artery and an 8-mm vascular graft (Goretex ePTFE graft) were anastomosed by using a parachute technique with a CV6 needle. The left common femoral artery was also identically anastomosed to the graft  showed a hyper-intense signal at the lower end of the conus medullaris visible in the T2-weighted image. Fig.\u00a0. CerebroSCI has been reported after endovascular aneurysm repair (EVAR) either as an immediate or a delayed finding . An analThe process leading to SCI after elective surgical management of an infrarenal AAA has not been fully understood. Factors that may contribute to it after EVAR include atheromatous embolization, interruption of the great radicular artery (artery of Adamkiewicz), or collateral circulation  , 4, 7. IAtheroembolization is a well-known complication of endovascular surgery and may lead to SCI. Rockman et al. reported two cases of paraplegia as a result of atheroembolization to the spinal cord after successful or attempted endovascular management of AAA . In the The patient\u2019s clinical presentation is explained by the anatomy of the conus medullaris. The conus medullaris is the lower end of the spinal cord, and it usually occurs at the level of the first lumbar vertebra. The segments of spinal cord that give origin to the nerves that control the bladder and bowel sphincters are located below the third sacral segment (S3). An injury to the conus medullaris below the third sacral segment (S3) will manifest with bladder and rectal incontinence and symmetric sensory loss around the anus and sexual organs. Motor dysfunction will not develop because most of the lower extremity motor nerves originate above the S2 segment of the spinal cord . AlthougThe goal of the treatment for SCI is to augment spinal cord perfusion pressure and reduce edema. The usefulness of the COPS protocol (CSF drainage to maintain a pressure of less than 5\u00a0mmHg without limit under CSF drain status/oxygen delivery/patient status) has been reported after delayed neurologic deficit in thoracoabdominal aortic aneurysm repair . Other tHBO therapy has sporadically demonstrated a decrease in the size of infarcts . In the We describe a case of a woman who developed isolated bladder and rectal incontinence without paraparesis/paraplegia after EVAR, and HBO might be beneficial for improving the symptoms.Written informed consent was obtained from the patient for publication of this case report and any accompanying images."}
+{"text": "The 11-year old girl presented a diagnosis of viral hepatitis A confirmed by anti-HVA IgM. Eight 8 weeks after, she developed hemorrhagic syndrome coupled with fever associated and persistent jaundice. The blood count showed aregenerative pancytopenia secondary to aplastic anemia confirmed by bone marrow biopsy. During conditioning for allogenic bone marrow grafts, the patient developed generalized seizures revealing disseminated intracerebral hemorrhage (pictures). There was a favorable outcome after blood transfusions and resuscitation. Hematological complications in hepatitis A are rare. Although intracerebral hemorrhage resulting from Hep A has never been reported in the literature; its occurrence is directly correlated with the degree of thrombocytopenia due to aplastic anemia. The prevalence of aplastic anemia in viral hepatitis is estimated at 0.1%. This complication implies systematic hematological evaluation in cases of viral hepatitis A; especially in severe forms or those associated with involving cholestasis."}
+{"text": "Double ventricular response is a rare arrhythmia that results from simultaneous antegrade conduction over the fast and slow pathways of AV node. Double ventricular responses may lead to arrhythmia-related cardiomyopathy. As far as we know, there is not any reported reversible cardiomyopathy development that resulted from double ventricular responses to one atrial impulse after slow pathway ablation. We report a unique case of double ventricular response cardiomyopathy that has been developed 5 years after slow pathway ablation. Double ventricular response is a rare arrhythmia that results from simultaneous antegrade conduction over the fast and slow pathways of AV node. Slow-pathway conduction must be slow enough to allow his-purkinje system to recover excitability after depolarization by the first excitation over the fast pathway. Double ventricular responses may lead to tachycardia-related cardiomyopathy. We report a unique case of double ventricular response cardiomyopathy that has been developed 5 years after slow-pathway ablation.A 69-year-old patient admitted to our ambulance with severe dyspnea. Five years ago a slow-pathway cryoablation due to typical atrioventricular nodal reentry tachycardia was performed. Transthoracic echocardiography performed at admission revealed severely reduced left ventricular ejection fraction (LVEF) (30%), which was reported normal 5 years ago. In the next step, haemodynamic relevant stenoses were excluded in coronary angiography. Cardiac MRI confirmed severely reduced LVEF without the presence of myocardial fibrosis. Electrocardiography (ECG) revealed an uncommon finding of two ventricular beats after one atrial beat . An elecTo the best of our knowledge, this is the first report of reversible cardiomyopathy due to double ventricular response to one atrial impulse that developed as a late complication of slow-pathway cryoablation.Atrioventricular nodal reentrant tachycardia (AVNRT) is one of the most common sustained supraventricular arrhythmia. Catheter ablation of the slow pathway is treatment of choice for patients with recurrent drug-refractory AVNRT . The risDouble ventricular response is a rare arrhythmia that results from simultaneous antegrade conduction over the fast and slow pathways of AV node . Slow-paThe presence of his electrograms before each QRS complex and a relatively stable interval between the fast- and slow-pathway his electrograms during electrophysiological study supports the concept. However, simple junctional extrabeats as bigeminus cannot fully be excluded. The termination of the tachycardia with slow-pathway ablation is the treatment of choice.Although double ventricular responses and tachycardia-related cardiomyopathy that reverses with slow-pathway ablation has been described in the literature, our case is unique in which double ventricular responses and related cardiomyopathy occurred 5 years after slow-pathway ablation.It is known that there may be late recovery of conduction after successful ablation . In our The normalization of LV function after ablation strongly supports that cardiomyopathy was related to the dual ventricular responses."}
+{"text": "The development of immune-based strategies for cancer for solid cancers is challenged by the scarcity of T cells with high receptor avidity for tumor-specific antigens within the patient\u00b4s lymphocyte repertoire, and by the failure of tumor cells to present antigen to T cells. Both obstacles can be bypassed by genetic modification of T cells with recombinant chimeric receptors (CARs) which redirect T cells towards a tumor surface antigen independent of antigen presentation. CAR reengineered T cells efficiently interact with tumor cells in vitro and have significant in vivo activity against tumor xenografts. Recently, first clinical trials have shown evidence for a potent antitumor activity of CD19-specific CAR T cells in leukemia. Current efforts focus on improving in vivo survival, functional persistence and potency of adoptively transferred anti-tumor T cells. The design of more effective strategies against both solid tumors and leukemias further depends on enhanced knowledge of specific mechanisms of immune escape. Moreover, rational combinations of targeted therapies with immunotherapies and optimal integration of cellular therapies into current treatment regimens may allow higher rates of durable responses."}
+{"text": "Septo-optic dysplasia (SOD) is a heterogeneous malformation condition consisting of optic nerve hypoplasia, various types of forebrain defects and hormonal deficiencies. This study aims to expand knowledge about endocrine abnormalities in patients with SOD in ASEAN countries.Forty-eight patients  who has been diagnosed as having SOD in ASEAN countries were clinically reviewed from medical records.Clinical manifestations and endocrine abnormalities of the patients are shown in Table 1This multicenter and multinational study shows that about 20-35 % of SOD patients have endocrine abnormalities. Hypothyroidism and GH insufficiency are the most common endocrine problems associated with this condition."}
+{"text": "Plasmodium berghei in inbred mouse strains [Babesia rossi causes cerebral disease in some cases [The favoured animal model of cerebral malaria is an artificial host-parasite combination caused by  strains . Canine me cases . This dime cases .Post mortem brains collected from 50 natural cases of canine babesiosis showing clinical signs of cerebral involvement were collected and evaluated grossly and using light and electron microscopy.Grossly visible lesions (seen in 31/50) were classified as global (16/50) or regional (34/50). Global lesions were diffuse swelling and diffuse cerebral congestion or pallor. Multifocal petechial haemorrhages and white matter malacia appeared more regional. There were 18/50 cases that had a grossly appreciable oedema. Histological lesions appeared in a spectrum of severity, and included very localized endothelial injury. Babesia-parasitised red cell sequestration was a feature in some sections. Early lesions were multifocal and strictly associated with the microvasculature. Intermediate lesions were characterized by perivascular haemorrhage and some neutrophil infiltration. Advanced lesions were locally extensive and similar in appearance to haemorrhagic infarction. Ultrastructural evidence of cytoadherence between erythrocytes and capillary endothelium was demonstrated. Endothelial cell necrosis occurred early in the development of the lesions before neuronal and glial changes.The endothelial injury, parasitized red cell packing and perivascular haemorrhage showed some similarities to the neuropathology of human CM. However the large haemorrhagic infarctions and clinical presentation with almost 100% mortality of dogs presenting with cerebral babesiosis were key differences."}
+{"text": "Acute respiratory distress syndrome (ARDS) and ventilator induced lung injury (VILI) are characterized by neutrophil recruitment in the lung, and human neutrophil peptides (HNP) are the most abundant cationic proteins that are released into the extracellular matrix upon neutrophil activation. We and others have previously shown that high concentrations of HNP can lead to capillary-epithelial barrier damage in a mouse model of ARDS. We also demonstrated that VILI can lead to lung fibrotic development. We now extended the studies to examine the effects of HNP in lung remodeling.Examine the role of HNP on lung remodeling in a mouse model of ARDS followed by mechanical ventilation.+/+) were generated using a human neutrophil elastase promoter. The HNP+/+and the FVB wild type mice received either HCl  intratracheally, or vehicle solution as a control. Respiratory system compliance, protein concentrations and differential cell counting in bronchoalveolar lavage fluid (BALF) were determined 48 h after HCl. In a parallel experiment, the mice were randomized into 3 different groups 48 h after HCl: 1) no mechanical ventilation; 2) low pressure mechanical ventilation for 2 h; and 3) high pressure mechanical ventilation for 2 h. The mice were then observed for 14 days for evaluation of epithelial damage, Ashcroft score for fibrosis and inflammation.Mice endogenously expressing HNP (HNP+/+ mice showed significantly body weight loss (Fig +/+ mice 14 days after HCl instillation followed by mechanical ventilation at either low pressure or high pressure (Fig The HNPloss Fig , increasloss Fig  and enhaloss Fig  in BALF loss Fig  at 48 h sure Fig .Figure 1HNP can accelerate inflammation at an early phase in a mouse model of HCl-induced ARDS, which may contribute to lung remodeling at late phases, magnifying the deleterious effects of ventilator-induced lung injury. We are hoping to present a full picture regarding lung remodeling 14 days after receiving HCl/mechanical ventilation at the ESICM conference in September."}
+{"text": "Acute Lymphoblastic Leukaemia (ALL) is the most common cancer in children. Over the past four decades, research has advanced the treatment of this cancer from a less than 60% chance of survival to over 85% today. The causal molecular mechanisms remain unclear. Here, we performed sequencing-based genomic DNA methylation profiling of eight paediatric ALL patients using archived bone marrow smear microscope slides.SOLiD\u2122 sequencing data was collected from Methyl-Binding Domain (MBD) enriched fractions of genomic DNA. The primary tumour and remission bone marrow sample was analysed from eight patients. Four patients relapsed and the relapsed tumour was analysed. Input and MBD-enriched DNA from each sample was sequenced, aligned to the hg19 reference genome and analysed for enrichment peaks using MACS  and HOMER (Hypergeometric Optimization of Motif EnRichment). In total, 3.67 gigabases (Gb) were sequenced, 2.74 Gb were aligned to the reference genome . This dataset enables the interrogation of differential DNA methylation associated with paediatric ALL. Preliminary results reveal concordant regions of enrichment indicative of a DNA methylation signature.Our dataset represents one of the first SOLiD\u2122MBD-Seq studies performed on paediatric ALL and is the first to utilise archival bone marrow smears. Differential DNA methylation between cancer and equivalent disease-free tissue can be identified and correlated with existing and published genomic studies. Given the rarity of paediatric haematopoietic malignancies, relative to adult counterparts, our demonstration of the utility of archived bone marrow smear samples to high-throughput methylation sequencing approaches offers tremendous potential to explore the role of DNA methylation in the aetiology of cancer. This project was approved by the Royal Children\u2019s Hospital Human Research Ethics Committee (RCH HREC# 29140C). We have performed Methyl-Binding Domain protein 2 (MBD2) enrichment and isolated fractions of DNA from 40 individuals for sequencing on the Sequencing by Oligonucleotide Ligation and Detection (SOLiD\u2122) sequencing platform . MBD2 has been shown to bind to double-stranded methylated DNA molecules and used to interrogate the human methylome [Genomic DNA from archived bone marrow smear microscope slides from ALL patients, cells and cell lines were extracted as previously described  and usedSingle and paired-end SOLiD\u2122 sequencing reads were aligned using LifeScope\u2122 Genomic Analysis Suite (Life Technologies) with default parameters against the hg19 reference genome. Alignment efficiency  ranged from 26.57% to 93.15% across all samples in this study   and HOMEThis study is unique in a number of ways. This is the first sequencing-based DNA methylation profiling study in childhood ALL using archived bone marrow samples of similar quality to formalin-fixed paraffin-embedded (FFPE) tissue samples . We have\u03bcg and 5 \u03bcg of starting genomic DNA to determine if 1 \u03bcg of starting material was sufficient for DNA methylation enrichment. This was less than the recommended quantity but a typical amount obtainable from our primary patient samples.We performed replicate DNA methylation enrichment analysis using the JWL cell line with 1 We isolated four haematopoietic cell populations  at major stages of development corresponding to the arrested stages of development in paediatric leukaemia. This was achieved by positive selection using fluorescent-labelled antibodies and Fluorescent Activated Cell Sorting (FACS) from four individuals. This would enable us to track changes in DNA methylation between cell lineages and contrast them with leukaemic cells. After MACS enrichment peak analysis, a large proportion of peaks were common between the CD19 cells from three individuals, confirming the premise of tissue-specific DNA methylation profiles in haematopoietic cells  from the same individual, distinct enrichment peaks are seen; these are likely to correlate to disease state Figure B. The nuFor each of the samples analysed in this study, we have generated track hubs that can be uploaded and visualised on the UCSC Genome Browser. This permits the immediate visualisation of regions of differential DNA methylation with potential biological significance. Moreover, we have performed Infinium analysis on these samples, and visualisation using the Genome Browser permits direct comparison to other publicly available data such as The Cancer Genome Atlas (TCGA)  and TARGIn summary, our data represent one of the first DNA methylation enrichment analyses using SOLiD\u2122MBD-Seq on archival bone marrow smears from children diagnosed with ALL. Such specimens are readily available in most pathology laboratories across the world and are amenable to genomic-scale analysis, as we have demonstrated here. These data should prove valuable for other DNA methylation studies in childhood ALL in haematopoeitic cell development.Supporting data is available from the GigaScience Database, GigaDB  and at NSRA Files included BioProject PRJNA272864MACS and HOMER output files of peaks and peak locationsTrack Hubs for UCSC Genome Browser"}
+{"text": "Central nervous system (CNS) injury, such as stroke, is known to increase susceptibility to infections that adversely affect clinical outcome. This impaired immune response to infection is termed CNS injury-induced immune deficiency syndrome (CIDS). Activation of the cannabinoid 2 receptor (CB2R) suppresses immune function suggesting that antagonism of this receptor may overcome CIDS. The main purpose of this study was to determine the impact of CB2R inhibition on leukocyte activation within the microcirculation following endotoxin challenge in an experimental stroke model.2). The CB2R antagonist was given 15 minutes prior to LPS administration. Intravital microscopy was carried out 2 hours after LPS administration. Brains were then extracted and stained with tetrazolium chloride to calculate the infarct volume. The primary outcome measurement in this study regarding the immune response after stroke was the quantification of leukocyte adhesion following endotoxin challenge in submucosal venules of the gut - an important organ in the development of multiorgan failure in endotoxemia and sepsis.This was a prospective, randomized animal study. Five experimental groups  were subjected to the following treatments: control; endotoxemia ; transient cerebral hypoxia-ischemia (HI) + endotoxemia; HI + endotoxemia + CB2R antagonist . HI was induced by unilateral carotid artery occlusion, followed by 50-minute exposure to a low oxygen atmosphere (8% OCompared with endotoxemic animals without CNS injury, mice subjected to HI displayed reduced leukocyte activation in intestinal submucosal venules indicative of CIDS. Administration of the CB2R antagonist in animals with CIDS challenged with endotoxin restored peripheral leukocyte recruitment without a detrimental impact on infarct size.CB2R-related modulation of leukocyte activation is involved in the impaired immune response following CNS injury. Future studies will explore the CB2R pathway in order to develop novel therapies to improve the immune response in CIDS."}
+{"text": "In vitro studies into the role of OPG produced by breast tumor cells have demonstrated that OPG can block TNF-related apoptosis inducing ligand (TRAIL)-mediated apoptosis. Furthermore, in vivo studies show that OPG expression by breast tumors can promote tumor growth and metastasis. In addition it has been shown that OPG stimulates endothelial cell survival and tube formation thus it may indirectly promote breast tumor progression through impacting angiogenesis. This article will present a summary of the data concerning the tumor-promoting effects of OPG in breast cancer.Osteoprotegerin (OPG) is a secreted protein and member of the Tumor Necrosis Factor (TNF) Receptor superfamily. OPG has been well characterized as a regulator of bone metabolism which acts by blocking osteoclast maturation and preventing bone breakdown. Given this role, early studies on OPG in breast cancer focused on the administration of OPG in order to prevent the osteolysis observed with bone metastases. However OPG is also produced by the breast tumor cells themselves. Research focusing on OPG produced by breast tumor cells has revealed actions of OPG which promote tumor progression.  Osteoprotegerin (OPG) is a secreted protein that acts in the bone to block the maturation of bone resorbing osteoclast cells and thus prevent bone breakdown , 2. ThisOPG was initially identified through sequence homology to the tumor necrosis factor (TNF) receptor superfamily. OPG contains the four cysteine-rich domain repeats characteristic of the TNF receptor family but lacks a transmembrane region and is therefore a secreted protein , 5, 2. Iin vitro osteoclast maturation studies demonstrate that OPG acts as a negative regulator of bone metabolism and blocks osteoclast maturation [Generation of transgenic mice has allowed elucidation of the major physiological role of OPG as a regulator of bone metabolism. OPG over-expression results in a lack of mature bone-resorbing osteoclasts and a pronounced increase in bone density known as osteopetrosis . Mice inturation , 2. Substuration , 10.Given the characterization of the role of OPG as a negative regulator of bone metabolism as described above, early studies on OPG and breast cancer focused on the bone microenvironment. Bone is the most common site of breast cancer metastasis. Breast tumors tend to form osteolytic metastases where the tumor is surrounded by osteoclasts which degrade the bone tissue -13. An iThese early studies focused on actions of exogenously added, truncated OPG within the bone microenvironment. However, subsequent studies that are described below demonstrate a more extensive and complex role for OPG in breast cancer.One of the first studies to characterize OPG revealed expression in two human breast cancer cell lines \u2013 MDA-MB-436 and MCF-7 . FurtherWhile there have been no investigations focusing on OPG in normal breast epithelium, OPG knockout mice are able to maintain litters which would suggest that OPG is not required for normal mammary gland development and lactation . It appeThe studies described above demonstrate a basal level of expression of OPG in breast cancer cells and tissue. Further investigation has revealed the potential for modulation of OPG expression levels within breast tumors. Immunohistochemical staining of human breast tumor samples showed that OPG expression correlated with the presence of the Estrogen and Progesterone receptors . Howeverin vitro using human breast cancer cell lines. TRAIL-induced apoptosis in MDA-MB-436 and MDA-MB-231 human breast cancer cells could be reduced by the addition of recombinant OPG (10-1000\u00a0ng/ml). MDA-MB-436 cells which had been incubated for 72 to 120\u00a0h to allow accumulation of endogenous OPG were less susceptible to TRAIL-induced apoptosis. This effect could be reversed by the addition of excess RANKL to compete for OPG binding [TNF-related apoptosis inducing ligand (TRAIL) is secreted by normal tissues and preferentially induces apoptosis in tumor cells , 26. The binding .in vitro studies clearly demonstrate effects of the OPG-TRAIL interaction, the relevance of this interaction for breast cancer cells has yet to be demonstrated in vivo. MDA-MB-231 human breast cancer cells were transfected to over-express full length OPG. Despite showing a significant increase in OPG expression along with a reduced sensitivity to TRAIL-mediated apoptosis in vitro, there was a lack of effect in vivo. Two weeks after intra-tibial injection in mice of cells the anti-tumor effect observed with TRAIL treatment was identical between empty vector and OPG over-expressing human breast tumor cells [While or cells .in vivo due to simultaneous presence of TRAIL and RANKL. An in vitro binding study demonstrated that OPG binds TRAIL and RANKL with equal affinity [The role of OPG produced by breast cancer cells may be more complex affinity . Howeveraffinity , 24. Thiin vivo studies that indicate tumor-promoting effects of OPG on breast cancer cells, potentially via TRAIL-independent mechanisms as described below. MCF-7 human breast cancer cells were engineered to express Parathyroid Hormone allowing them to form osteolytic metastases after intra-tibial injection in nude mice. Administration of truncated recombinant Fc-OPG reduced bone destruction in agreement with previous studies. In contrast, when the MCF-7 cells were transfected to over-express full length OPG and injected into mice tibias there was an increase in osteolysis. The intra-tibial tumors from the cells over-expressing OPG had an increase in cells staining positive for the proliferation marker Ki67. These MCF7 cells over-expressing OPG produced larger tumors compared to control cells after injection into the mammary fat pad although in this context there was no difference in Ki67 staining. The MCF-7 cells over-expressing OPG did not show any alteration in sensitivity to TRAIL treatment in vitro, suggesting that there must be additional mechanisms whereby OPG can have a tumor-promoting effect [There are now a number of g effect . The cong effect . Howeverg effect .in vivo study suggests that the tumor-promoting effects of the Estrogen-Related-Receptor-Alpha (ERR\u03b1) in breast cancer may be mediated in part via OPG. ERR\u03b1 expression in bone metastasizing MDA-MB-231 human breast cancer cell derivatives led to an increased expression of OPG. In agreement with this experimental observation, the analysis of 251 patient samples showed that OPG levels were significantly higher in ERR\u03b1-positive tumors compared with ERR\u03b1-negative tumors. High ERR\u03b1 and high OPG expression in breast tumor tissue from patients is associated with a greater increase in risk of recurrence than high expression of ERR\u03b1 only. An increase in tumor growth was observed when the ERR\u03b1 expressing cells were implanted in the mouse mammary fat pad however a reduction in osteolysis was observed when these cells formed bone metastases after intravenous injection in mice [Another  in mice . TherefoThis possibility that OPG can protect the bone microenvironment from tumor growth while promoting growth in other tissues is also evident in a recent study. MDA-MB-231 human breast cancer cells were stably transfected to express OPG and injected into the tibias of nude mice. Over-expression of OPG by injected breast cancer cells protected bone from destruction and inhibited growth of the tumors within the bone. However breast cancer cells over-expressing OPG persisted to grow in the space outside of the bone. In addition, OPG over-expressing breast tumor cells injected into the bone had an increased tendency to metastasize to lungs .in vivo model of breast cancer metastasis. Knockdown of OPG expression reduced metastasis formation in chick tissues both from a primary tumor and after direct introduction of cells by intravenous injection. Our in vitro mechanistic studies show that OPG knockdown cells express lower levels of Matrix Metalloproteinase-2 and have a reduced ability to invade through a collagen matrix. This would suggest that OPG can exert an autocrine effect and promote breast cancer cell invasion and metastasis [Despite the accumulating evidence that OPG produced by breast cancer cells may promote tumor growth in sites outside of the bone microenvironment, the mechanism behind this effect is unclear. We have recently performed a study using MDA-MB-231 human breast cancer cells transfected with sh- or siRNA to knock down OPG in a chick embryo tastasis .in vivo studies suggest that while the interaction between OPG and the bone microenvironment can lead to an inhibition of bone tumor growth, OPG can promote breast tumor formation and growth at other sites.The findings of these While OPG produced by breast cancer cells may exert effects directly on breast tumor cells it appears that OPG\u2019s interaction with other cells in the tumor microenvironment may also promote breast tumorigenesis. In particular, several studies have reported an impact of OPG on endothelial cells suggesting the potential role of OPG to regulate angiogenesis.v\u03b23 antibody in the co-culture medium [v\u03b23 signaling can promote OPG expression. This study also demonstrated that OPG (10\u00a0ng/ml) promoted tube formation by HuDMECs confirming the potential for OPG to exert pro-angiogenic effects.Human umbilical vein endothelial cells (HUVECs) and Human Dermal Microvascular Endothelial cells (HuDMECs) both express OPG. Treatment of endothelial cells with recombinant OPG (100\u00a0ng/ml) promotes cell survival and formation of cord-like structures. Analysis of human breast tumor tissues showed that OPG is expressed by endothelial cells in breast tumor tissue but not in normal surrounding tissue. There is a strong positive correlation between endothelial OPG expression and tumor grade, and a strong negative correlation between endothelial OPG expression and ER expression . Furthere medium . This woSeveral studies have investigated the mechanism whereby OPG could promote angiogenic behavior of endothelial cells. HuDMECs treated with OPG were elongated with extensive actin networks compared to untreated cells. OPG (0.5-2ug/ml) led to cytoskeletal reorganization and cell spreading; this may be mediated by Focal Adhesion Kinase (FAK) as phosphorylation of FAK Y397) was induced by treatment with OPG. OPG-mediated HuDMECs proliferation was blocked by the Erk 1/2 inhibitors U0126 and PD98059 while OPG-induced cell migration and cord-like structure formation was blocked by the Src inhibitor PP1 . The abi7 was indThe cumulative findings of these endothelial cell studies demonstrate the potential for OPG to exert tumor-promoting effects by stimulating angiogenesis in addition to the direct effects of OPG on breast cancer cells.A few studies have investigated links between OPG and breast cancer prognosis although conflicting findings have been reported. Real-time quantitative PCR was used to analyze the expression of OPG mRNA in 127 primary human breast cancer tissues. It was found patients with higher expression levels of OPG had significantly poorer overall survival as compared with patients who had lower OPG expression levels . HoweverIn addition to the expression of OPG, changes in the OPG gene have been reported in breast cancer. We analyzed the TCGA-2013 human breast invasive carcinoma data set, through the cBioPortal website, and found that OPG gene copy gain occurred in 182 out of 934 tumors in the set (19.4\u00a0%). The presence of an OPG copy number gain is a significant predictor of decreased overall survival in this cohort . The occSince its initial discovery and characterization, evidence has been accumulating that OPG plays a role in breast tumorigenesis. The reported actions of OPG in breast cancer are summarized in Fig.\u00a0While OPG clearly has potential to modulate breast tumor growth and progression, further investigation is required to fully determine the mechanism of effect and overall outcomes of the different types of interactions. The data available currently would suggest that OPG can no longer be considered solely in the bone microenvironment in breast cancer and caution must be exercised in the development of systemic treatment strategies aimed at increasing OPG levels. Localized delivery of OPG to the bone may be more appropriate to prevent osteolysis associated with metastatic breast cancer. Additional studies are required to determine whether strategies to block OPG signaling would be effective in blocking the growth and progression of primary breast tumors."}
+{"text": "Clinical examination revealed a loud continuous murmur with diastolic accentuation in the left precordium, noncollapsing pulse, and no differential pulses in the upper and lower limbs. The ECG showed normal sinus rhythm with PR interval of 220 milliseconds.A 40 year-old man with no significant past history except for asymptomatic 1Transthoracic echocardiogram Figure  showed ast degree atrioventricular (AV) block. Coronary arteriovenous fistula (CAVF) arises as a persistence of sinusoidal connections between the lumens of the primitive tubular heart in the early embryologic period. It is reported in 0.1%\u20130.2% of all cases of selective coronary angiography[st degree AV block in our case may reflect a flow limitation to atrioventricular (AV) node directly caused by the CAVF.This case illustrated a rare saccular aneurysm formation in a right coronary artery to right atrium  fistula associated with 1giography or penetCT angiogram has now emerged as an excellent imaging technique to delineate the lesion anatomy-6 CAVF g"}
+{"text": "Neurons of the cerebellar nuclei convey the final output of the cerebellum to their targets in various parts of the brain. Within the cerebellum their direct upstream connections originate from inhibitory Purkinje neurons. Purkinje neurons have a complex firing pattern of regular spikes interrupted by intermittent pauses of variable length. How can the cerebellar nucleus process this complex input pattern? In this modeling study, we investigate different forms of Purkinje neuron simple spike pause synchrony and its influence on candidate coding strategies in the cerebellar nuclei. That is, we investigate how different alignments of synchronous pauses in synthetic Purkinje neuron spike trains affect either time-locking or rate-changes in the downstream nuclei. We find that Purkinje neuron synchrony is mainly represented by changes in the firing rate of cerebellar nuclei neurons. Pause beginning synchronization produced a unique effect on nuclei neuron firing, while the effect of pause ending and pause overlapping synchronization could not be distinguished from each other. Pause beginning synchronization produced better time-locking of nuclear neurons for short length pauses. We also characterize the effect of pause length and spike jitter on the nuclear neuron firing. Additionally, we find that the rate of rebound responses in nuclear neurons after a synchronous pause is controlled by the firing rate of Purkinje neurons preceding it. Neurons can transmit information by two different coding strategies: Rate coding, where the firing rate of the neuron is vital, and time coding where timing of individual spikes carries relevant information. In this study we analyze the importance of brief cessations in firing of the presynaptic neuron (pauses) on the spiking of the postsynaptic neuron. We perform this analysis on the inhibitory synaptic connection between Purkinje neurons (presynaptic) and nuclear neurons (postsynaptic) of the cerebellum. We employ a computational model of nuclear neurons and \u201csynthetic\u201d Purkinje neuron spike trains to study the effect of synchronous pauses on the spiking responses of nuclear neurons. We find that synchronous pauses can cause both well-timed spikes and increased firing rate in the nuclear neuron. In addition, we characterize the effect of pause length, amount and type of pause synchrony, and spike jitter. As such, we conclude that nuclear cells use both rate and time coding to relay upstream spiking information. Cerebellar nucleus (CN) neurons are crucial to the olivo-cerebellar circuit as they provide the sole output of the entire cerebellum ,2. CN nePNs exhibit an elaborate firing pattern characterized by simple spikes and complex spikes . Simple Several coding strategies have been proposed for the CN neurons. Broadly, these strategies can be categorized as rate coding or time coding. For a long time it was assumed that CN neurons receive information from PNs by means of a rate code. In cats, CN neurons (recorded from the anterior interpositus nucleus) exhibited rate modulations during locomotion . SimultaSystematic analysis of simple spikes from neighboring PNs in anaesthetized rats revealed that spikes associated with pauses in firing are far more synchronized (\u00b12 ms precision) than regular firing simple spikes , which iBased on the experimental study of pause synchronization , we defiin vitro [In vivo, the firing of these neurons becomes irregular [in vivo data, we tuned both the gain of inhibitory and excitatory synapses impinging on the CN neurons so that the neurons fire spontaneously around 37\u201338 Hz, which is the observed mean firing rate in vivo of normal rats [The firing of deep CN neurons is highly regular in vitro . In vivorregular  mediatedmal rats . The anamal rats . The excin vivo [Synaptic input had maximum impact on the regularity firing of the neuron at the high gain condition . A CN nein vivo , the higIn order to analyze the influence of PN synchrony on the firing response of the CN neuron, we characterized the neuron\u2019s response to synchronous PN pauses see . SimulatWe quantified the increase in firing rate of the CN neuron during synchronous pauses with spikes synchronized at the beginning or ending, or overlapping pauses (where no spikes are synchronized), for different amount of synchronization. Synchronous pauses were generated by randomly selecting a pause greater than threshold and temporally aligning it with pauses from other Purkinje neuron spike trains according to the desired amount of synchronization. Pause ending and pause overlapping synchronization consistently mediated greater firing rate increases compared to pause beginning synchronization. This could be seen for both pause values of 20 and 40 ms . For allWe also simulated the effect of a mixed-type synchronization where PN pauses were synchronized with all three types of synchronization  in equal proportion. This resulted in increased firing rate modulation of CN neurons, which was greater than that of the pause beginning synchronization, but less than the pause overlapping condition.In order to elucidate the membrane mechanisms underlying increased firing of CN neurons during the synchronous PN pauses, we blocked the rebound conductances  in the CN neuron model. Next we investigated the effect of the amount of synchrony on the rate modulation of CN neurons. Increase in PN input synchronization resulted in an increased rate modulation for all pause synchrony conditions . We starWe observed similar results for the pause overlapping synchronization condition: a 40 ms pause represents the amount of presynaptic PN pause synchrony better . One notvivo and in vitro [According to Person and Raman, PN synchronization causes brief periods of relief from inhibition and this time-locks the CN neuron\u2019s response to the input synchronization . This noin vitro . By varySynchronous pause beginning spikes effectively time-locked the CN neuron\u2019s response to the synchronized event . For almIn the previous section we demonstrated how synchronous PN pauses elicit time-locked CN neuron spikes thereby transmitting the timing information in a reliable manner to downstream targets of CN neuron. We compared the degree of time-locking caused by pause beginning or pause overlapping synchronization by looking at their spike latency distributions in detail. This analysis revealed that time-locking by pause beginning spikes is more accurate than that of pause overlapping condition for a 20 ms  synchronIn order to elucidate membrane mechanisms causing the time-locking of CN neuron spiking to PN pause synchronization, we blocked the rebound conductances in CN neuron model and analyzed its effect on time-locking. Rebound conductances had an insignificant effect on the time-locking of the CN neuron . There wUp to this point, we used precise synchrony of spikes without any jitter. Because this is a rather idealized situation, we also investigated whether jittered pause spikes can still evoke time-locking of CN neuron\u2019s responses. Therefore, we quantified the time-locking behavior of the neuron when presented with synchronous pause differing in the amount of synchronization and pause beginning spikes jittered with various values of jitter. We generated synchronous PN pauses in the same way as described in previous sections but with jittered pause beginning spikes and a pause duration of 40 ms.When the CN neuron's input gain is high, the strong inhibition prevents the neuron to spike during the jitter period. This can be seen in For the low gain condition, the CN neuron often fired during the jitter period because the inhibition was too weak . We compSo far our analysis was limited to the effect of synchronous pauses on the firing modulation or time-locking within the pause. Our analysis has revealed that, on average, rebound conductances have no or little effect on this firing modulation or time-locking. CN neurons exhibit rebound firing when the membrane is hyperpolarized for a considerable amount of time and subsequently released from it . De SchuAverage PN firing rate  during a period of \u0394t before the synchronous pause was forced to a particular frequency 'fPN' see . We sampIn this study we investigated the effect of PN synchrony in the context of pauses on the spiking response of CN neurons. We stress the importance of pause synchrony in our simulations because the cerebellum is known to control the motor output pattern by transient disinhibition of CN neurons through corresponding pausing of PN firing ,24. A wiin vitro study [in vivo optogenetic study highlighted the importance of input synchrony through transient \u2018pausing\u2019 of PNs by photostimulation of molecular layer interneurons expressing channelrhodopsin [We find that pause overlapping and pause ending spike synchronies mediate greater firing rate modulation during the synchronous pause than their pause beginning counterparts. It is worth noting that the synchrony types are not uniquely encoded in the firing rate of these neurons as their standard deviations overlap . Similarro study , we alsohodopsin . They shCN neurons exhibit both rate and time coding, but it remains unclear how these neurons can switch between these two different coding schemes. We reasoned that synchronous pause length could play a vital role in controlling the coding strategy of CN neuron. Therefore we compared the effect of pause length, by measuring the effect of synchronous pauses of 20 or 40 ms. For pause beginning synchronization, a 40 ms pause sequence evoked greater firing rate increases than a similar 20 ms pause sequence . ConversWith respect to time-locking of CN neuron spikes to PN pause synchrony, we found that pause beginning synchronization cause more accurate time-locking than pause overlapping or pause ending type synchronies. A similar phenomenon was reported earlier by Person and Raman  where thThe amount of PN synchrony reaching a CN neuron is unknown . This isWe conclude that the multiplexed coding scheme  of the PThe CN neuron model used in our study is based on a previously published model . Three dCN neurons receive inhibitory inputs from PNs and excitatory inputs from mossy fibers. Both synaptic pathways are included in our model and described below. Climbing fiber inputs were not simulated.\u03c4rise and \u03c4decay are rise and decay time constant respectively. gmax is peak synaptic conductance, and N is a normalization factor that makes the maximum of Gsyn(t) equal to gmax.PNs inhibit CN neurons. The number of PN synapses on a single CN neuron is highly debated and values in the literature range from 40  to 860 ,6,31\u201333.max = 11.7 nS and synaptic reversal potential of -75 mV [10 values for synaptic current kinetics (Q10 = 2)[Rss) and time constant of depression (\u03c4) was fitted to experimental data [PN to CN neuron IPSCs time constants are based on published experimental data . IPSCs rf -75 mV . The syn(Q10 = 2),36. The (Q10 = 2),37. Syna(Q10 = 2) and steatal data . The equNMDA) that shows weak voltage dependence and much slower component (SNMDA) that shows strong voltage dependence. NMDA voltage dependence is modeled [NMDA, SNMDA time constants and peak synaptic conductance values, parameters s1 and s2 of voltage dependence were obtained from [10 values for synaptic current kinetics (Q10 = 2) [CN neurons are excited by mossy fibers . The mos modeled  accordinned from  (S1 Tablned from . AMPA anQ10 = 2) ,36.et al [PN simple spike trains contain highly regular inter-spike intervals (ISIs) and hence cannot be described accurately by a Poisson process . Shin etet al  showed tSynthetic PN simple spikes were generated based on the method described in  using spvivo [Pause synchrony is defined by either having the pause beginning or pause ending spike synchronized or no spikes (overlapping) synchronized across the population of PN inputs. We introduce synchrony by randomly selecting a pause that was longer than the threshold (either 20 or 40 ms) and temporally aligning it with pauses from other spike trains. The pause thresholds were selected so that they are greater than the spontaneous PN simple spike ISIs in vivo . We usedFor simulations where we tested the role of PN firing rate before the pause on CN neuron\u2019s firing rate post pause onset, average PN firing rate during each trial was forced to a particular frequency, \u2018fPN'. We used the same number of trials for each fPN. Average PN firing rate for a trial was forced to fPN in the following way: For each PN participating in the synchronous pause, a pause exceeding a threshold of 20 ms and whose preceding spiking for a time period of 100 ms has a firing frequency of fPN, was randomly selected. We then temporally aligned both the pause and preceding spiking with their corresponding counterparts from other PN spike trains. For certain PNs where no desired fPN could be found before a pause, a pause exceeding the threshold was randomly selected.Neuronal spike times were recorded from the simulated CN neurons. The firing rate during synchronous pauses was computed and compared to a control condition  to investigate changes in the firing rate caused by the release of inhibition. We measured the spike latency with respect to the onset of synchronous pause, the standard deviation/median absolute deviation of which was then used to further assess the degree of time-locking.To avoid the stochastic influences inherent to the synthetic spike trains, we performed 100 or more simulations for each input regime and computed the average change in firing rate, as well as the standard deviation/median absolute deviation of spike latency. We used standard deviation of latency to first spike within the synchronous pause if the distribution of spike latencies of both distributions followed the normal distribution. If either one of the distribution was not normal, the median absolute deviation was used. The normality of the distribution was established by Lilliefors test  using 99Vector strength ,42 quantcov is the covariance and \u03c3 the standard deviation.For simulations where we tested the role of PN firing rate before the synchronous pause on the CN neuron\u2019s firing rate following the immediate pause, the CN neuron\u2019s firing rate was computed for a period of 1s from synchronous pause onset and compared to a control condition (model run without synchronized spike and pause sequence). Linear regression was used to fit a straight line through the data points. Correlation was measured with Pearson\u2019s correlation asS1 FigAnalysis for 20 ms (A-D) and 40 ms (E-H) synchronous pauses. (A&E) Population spike timing histogram of all PNs projecting onto the CN neuron. (B&F) Increase in firing rate of CN neuron quantified for both pause ending and pause overlapping conditions and for low input gain. (C&G) Same for medium input gain. (D&H) Same for high input gain.(TIF)Click here for additional data file.S2 Fig(A&E) Population spike timing histogram of all Purkinje cells projecting onto CN neuron. Pause beginning type synchronization is illustrated in A and pause overlapping type is explained in E. (B&F) Increase in firing rate of the CN neuron during synchronous pause of length 20 ms and 40 ms and for low gain condition. (C&G) Same for medium gain condition. (D&H) Same for high gain condition. In all panels red color stands for 20 ms global pause period, blue for 40 ms global pause period. Error bars are represented by shaded region. (*) represents pairwise comparisons between results of different amount of input synchronization  that are significant (p<0.05) and (^) represents insignificant comparisons (p> = 0.05).(TIF)Click here for additional data file.S3 Fig(A&E) Population spike timing histogram of all PNs projecting onto the CN neuron. Note the presence of synchronous pause of length 20 ms (A) and 40 ms (E) for both types of synchronization. (B&F) Variability of latency calculated from 100 trials for pause ending and pause overlapping type synchronization and low gain condition. (C&G) Same for medium gain condition. (D&H) Same for high gain condition. In all panels red color stands for pause ending condition, blue for pause overlapping condition. (*) represents comparisons of variability in latency between pause ending and pause overlapping type synchronization that are significant (p<0.05) and (^) represents insignificant comparisons (p> = 0.05).(TIF)Click here for additional data file.S4 Fig(A&E) Population spike timing histogram of all Purkinje cells projecting onto the nuclear neuron. Note the presence of synchronous pause beginning spikes and pause length of 20 ms (or 40 ms). Plots B,C and D represents quantification of variability in latency of CN neuron\u2019s spiking for low (B), medium (C) and high input gain (D) condition respectively. Plots F,G and H represents quantification of increase in firing rate of the nuclear neuron for low gain (F), medium gain (G) and high gain (H) condition respectively. (*) represents appropriate comparisons that are significant (p<0.05) and (^) represents insignificant comparisons (p> = 0.05).(TIF)Click here for additional data file.S5 FigSynthetic PN spikes were generated using a three-step process: First we segregated the experimental ISIs into regular firing patterns  and pause ISIs (red) (step 1). For each regular firing pattern a corresponding synthetic regular firing pattern was generated based on gamma distribution statistics from  (step 2)(TIF)Click here for additional data file.S6 FigA-I: Distribution of experimental and synthetic PN ISIs for nine randomly selected PNs. The similarity between experimental and synthetic ISIs was determined by Kolmogorov-Smirnov test. None of the generated synthetic ISIs was significantly different from experimental ones .(TIF)Click here for additional data file.S1 Table(DOCX)Click here for additional data file."}
+{"text": "Oxidative stress can cause DNA breaks which induce activation of the DNA nick sensor enzyme poly(ADP-ribose) polymerase-1 (PARP-1), part of the 17 member PARP enzyme family. PARP-1 modifies target proteins by attaching to them several NAD-derived ADP-ribose units forming poly(ADP-ribose) (PAR) polymers. PARylation controls many cellular processes while intense PARylation may also lead to cell death by various mechanisms. Here we summarize the modes of activation, inhibitors and modulators of PARP-1 and review the cellular functions regulated by the enzyme. Poly(ADP-ribosyl)ation (PARylation) is a protein modification catalyzed by poly(ADP-ribose) polymerase (PARP) enzymes. The enzyme family was created based on database screening using the highly conserved PARP signature motif. Whereas the PARP enzyme family consists of 17 members Here we review the mechanisms by which activity of PARP-1 can be stimulated, inhibited or modulated. We also aim to summarize the cellular functions that are regulated by PARP-1.PARP-1 has originally been described as a DNA nick sensor enzyme activated by DNA single and double strand breaks The findings that stimuli other than broken DNA can also activate PARP-1  led to ai values remains to be determined.Several classes of compounds with PARP inhibitory properties have been developed and characterized. Their discussion would go way beyond the scope of this review so we only refer to excellent reviews on PARP inhibitors and their therapeutic potentials A much more interesting issue is the interference between certain signaling events and PARP activation . Above wUntil recently calcium was the only ion considered to serve a second messenger role. However, similar roles have later been assigned to magnesium and zinc ions The role of several metabolites connected to PARP-1 including its substrate (NAD), a key metabolite required for NAD synthesis (ATP) and a product (nicotinamide) should not be disregarded as they have also been shown to affect PARP activity The effects of PARP-1 and PARylation are translated to cellular responses in various different ways . On the The consequences of PARylation, PAR signaling, interaction of PARP-1 with partner proteins and substrate competition affect many cellular events ranging from genome organization + and ATP consumption has recently been challenged. Dawson's group has elegantly demonstrated [From these intertwining networks of molecular events and cellular functions here we would like to highlight one aspect bearing the highest relevance to oxidative stress: regulation of oxidative stress-induced cell death. The generally held view that in severe oxidative stress situations unrepairable DNA damage induces excessive PAR production and consequent NADnstrated  that PARAuthors declare no conflict of interest."}
+{"text": "The objectives of the research were to enhance our understanding of the phenotype (water holding capacity) and search for biomarkers of this economically significant pork quality attribute. Major changes in protein abundance across nine phenotype-by-time conditions were observed. Proteomic patterns were dominated by post mortem ageing timepoint. Using a machine learning algorithm (l1-regularized logistic regression), a model was derived with the ability to discriminate between high drip and low drip phenotypes using a subset of 25 proteins with an accuracy of 63%. Models discriminating between divergent phenotypes with accuracy of 72% and 73% were also derived comparing respectively, high drip plus intermediate phenotype (considered as one phenotype) versus low drip and comparing low drip plus intermediate phenotype (considered as one phenotype) versus high drip. In all comparisons, the general classes of discriminatory proteins identified include metabolic enzymes, stress response, transport and structural proteins. In this research we have enhanced our understanding of the protein related processes underpinning this phenotype and provided strong data to work toward development of protein biomarkers for water holding capacity.Two dimensional Difference Gel Electrophoresis (2-D DIGE) and mass spectrometry were applied to investigate the changes in metabolic proteins that occur over a seven day   Numerous proteomic studies have shown that very many of the observed post mortem proteome changes relate to these protein degradation processes  .puma.princeton.edu) . The oupost mortem respectively were identified. Details of the significant spots at day 3 and 7 post mortem  are presented in et al., .analysis . cCompar(DOC)Click here for additional data file."}
+{"text": "Heme peroxidases are found in all kingdoms of life and typically catalyze the one- and two-electron oxidation of a myriad of organic and inorganic substrates. In addition to this peroxidatic activity distinct (sub)families show pronounced catalase, cyclooxygenase, chlorite dismutase or peroxygenase activities. Here we describe the phylogeny of these four superfamilies and present the most important sequence signatures and active site architectures. The classification of families is described as well as important turning points in evolution. We show that at least three heme peroxidase superfamilies have ancient prokaryotic roots with several alternative ways of divergent evolution. In later evolutionary steps, they almost always produced highly evolved and specialized clades of peroxidases in eukaryotic kingdoms with a significant portion of such genes involved in coding various fusion proteins with novel physiological functions.Four heme peroxidase superfamilies  arose independently during evolution, which differ in overall fold, active site architecture and enzymatic activities. The redox cofactor is heme  During turnover H2O2 is reduced to water and one-electron donors (AH2) are oxidized to the respective radicals (\u2022AH) (\u2212) are oxidized to the corresponding hypohalous acids (HOX)   whereas ds (HOX) . Besidesreaction  and use reaction .(ReactioIn the last decade \u2013 due to the application of powerful sequencing techniques \u2013 an ever increasing amount of protein sequences (including numerous heme peroxidases) were automatically assigned to related protein families due to typical conserved motifs This review demonstrates the independent evolution of four heme peroxidase superfamilies, namely of the (1) peroxidase\u2013catalase superfamily, (2) peroxidase\u2013cyclooxygenase superfamily, (3) peroxidase\u2013chlorite dismutase superfamily and the (4) peroxidase\u2013peroxygenase superfamily. We present an update of their reconstructed phylogeny and introduce their representative sequence signatures and essential amino acids in the heme cavity. From http://pfam.xfam.org) this universally distributed superfamily is annotated as PF00141.The peroxidase\u2013catalase superfamily previously known as the \u201csuperfamily of bacterial, fungal and plant heme peroxidases\u201d families in analogy with all other heme peroxidase superfamilies (see below). Novel clades representing hybrid enzymes between the previously defined classes are well distinguishable in this reconstruction. R-XX-W/F-H-X- and the proximal triad His-Trp/Phe-Asp (these amino acids are not neighbored in the primary sequence). The typical overall globular fold of representatives of this superfamily consists of twelve \u03b1-helices and was already acquired from the beginning. It was only slightly modified in the later steps of ongoing divergent evolution. Generally, the level of structural conservation is higher than the conservation of amino acid sequences Here we have selected 500 representative full-length sequences that were used for an updated phylogenetic reconstruction based on the maximum likelihood (ML) method. c peroxidases catalatic activity according to c peroxidases are typical monofunctional peroxidases . The main function of Family I peroxidases seems to be scavenging of excess H2O2.Family I was previously defined to contain intracellular bacterial catalase\u2013peroxidases c peroxidases from Choanoflagellida predecessors of fungi and animals Family I is the most divergent one among the three structural classes. It contains eukaryotic intracellular A peculiar minor descendant clade containing yet putative secretable ascorbate peroxidases from Unikonts/Metazoan lineages represents another evolutionary turning point . A majorThe highest number of members are found in Family III that is comprised of numerous plant secretory peroxidases like horseradish peroxidase(s) (HRP) e.g.,  but alsoThe peroxidase\u2013cyclooxygenase superfamily has Pfam accession PF03098 and its members are widely distributed among all domains of life In contrast to the peroxidase\u2013catalase superfamily, in many cases members of the peroxidase\u2013cyclooxygenase superfamily are multidomain proteins with one heme peroxidase domain of predominantly \u03b1-helical fold with a central heme-containing core of five \u03b1-helices. Moreover, this superfamily is unique in having the prosthetic heme group posttranslationally modified Q-X-X-D-H-D-X- which includes the distal catalytic histidine that is neighbored by two aspartates, the first being involved in ester bond formation and the second in Ca2+-binding. The highly conserved glutamine seems to be involved in halide binding R-X-X-E-X-  the early evolved heme peroxidases to cope with reactive oxygen species produced by ancient oxygenic photosynthesis The ancestral clade of short bacterial peroxicins  is supposed to contain the oldest representatives of this superfamily , namely One evolutionary trend led to the emergence of the well known animal peroxidases like myeloperoxidase (MPO), eosinophil peroxidase (EPO), lactoperoxidase (LPO) and thyroid peroxidase (TPO) and started with bacterial peroxidockerins (Family 6). The cyanobacterial LspPOX is a typical representative of early stage in this direction and it was already investigated on protein level The second evolutionary direction leads towards bacterial and animal cyclooxygenases (Family 4) . AlthougThe alternative evolutionary trend leading from long peroxicins towards Families 3\u20131 occurred stepwise. First steps led over  peroxidockerins (Family 6). It is important to note that evolutionary descendants of variable length emerged not only in eubacteria but can be also found in genomes of eukaryotic Amoebozoa, Heterolobosea and Chromalveolata . This fa2O2 but the function of the modified peroxidase domain in this large multidomain protein remains obscure Dual oxidases (Family 7) were segregated from peroxidockerins at the level of primitive eukaryotes as stated before . These mIn a further step peroxinectins (Family 3) evolved. They were shown to exhibit cell adhesion function(s) and to be involved in invertebrate immune response by production of hypohalous acids according to Next evolutionary event led to division in peroxidasins (Family 2) and a sister family of Chordata peroxidases (Family 1). They diverged in several Chordata subfamilies including the separated subfamily of thyroid peroxidases, minor subfamilies of fish peroxidases and three closely connected subfamilies of mammalian lactoperoxidases (LPO), myeloperoxidases (MPO) and eosinophil peroxidases (EPO)  that areIn contrast, we can observe a broad and rather abundant distribution of peroxidasin isozymes in various Eumetazoan phyla . They weThis superfamily was first constituted by Goblirsch et al. I-P-V/I-K/R-K-X- that includes proximal residues  and PF06778 (for Cld), they are classified in a common protein clan CL0032 (SCOP 54909) that comprises up to 18 member families, but most of them without the ability to bind the prosthetic heme group. It is important to note that in contrast to the two previously described heme peroxidase superfamilies, the peroxidase\u2013chlorite dismutase family appears to cover only a small part of a very large dimeric \u03b1/\u03b2 barrel structural superfamily . The modification of such a fold to acquire the ability to bind the heme group and exploit it evolved probably only in one evolutionary event. The whole dimeric \u03b1/\u03b2 barrel structural superfamily is outside of the scope of this issue.2, whereas Cld-like enzymes neither exhibit a peroxidase nor a chlorite degrading activity. Moreover, Cld-like proteins show a diminished affinity for the prosthetic group.DyP heme peroxidases are abundant not only in many bacterial phyla Mucor circinelloides  did not yield any output for DyP peroxidase genes. This supports the theory of HGT from autotrophic prokaryotes to heterotrophic eukaryotes. Anyway, upcoming new genomes of early diverging fungi must be also screened with blast in this respect. Their codon usage has to be analyzed and compared.The ancestral clade of the whole superfamily is probably located in DyP-subfamily A, namely among sequences from thermophilic facultatively anaerobic bacteria of the division Firmicutes . This woDictyostelium discoideum or Naegleria gruberi DyP-peroxidases occur. Most of here presented protein sequences from this subfamily stem from Proteobacteria therefore also in subfamily B HGT events appeared probably several times during the evolution. Even more surprising is the occurrence of DyP-type B genes in the Trematode parasite Schistosoma mansoni. Also in this multicellular flatworm DyP genes were acquired by HGT from lower eukaryotes but their functionality must be proven experimentally. Thus it appears that subfamily B is the most divergent one of all four described DyP subfamilies leading to unique evolution of DyP peroxidases within Unicont genomes. Turning points in this superfamily\u2019s evolution lie unequivocally in this subfamily clades that besides several HGT events enabled also further evolution towards chlorite-dismutase like proteins.Fungal DyP sequences occur not only in subfamily D but also in subfamily B, where also several other sequences from lower eukaryotes like b prosthetic group are segregated in two distinct clades (6). Clade 1 is almost completely formed by proteobacterial penta- or hexameric representatives whereas Clade 2 contains dimeric proteobacterial as well as numerous cyanobacterial enzymes. The N-terminus of Clade 2 proteins is truncated  efficiently incorporate peroxide-derived oxygen into substrate molecules. Additionally their proximal heme ligand is cysteine instead of histidine  fumago has been in the focus of research only. In the last decade other members of this superfamily (Pfam accession number PF01328) were found and started to be analyzed.This heme peroxidase superfamily is unique since its members can  \u2013 included in the genomes of ancestral, primitive fungi already from the beginning of the evolution of the fungal kingdom. The monophyletic clade of Stramenopiles enzymes diverged apparently very early in parallel with the evolution of \u201cclassical\u201d but minor fungal enzymes represented by CfuHalPrx from the ascomycete Caldariomyces fumago with known 3D structure Auricularia delicata or Coprinellus radians are results of later evolutionary events from Mucor peroxidases via repeated gene duplication and speciation events (Auricularia heme-thiolate peroxidase (AaeAPO) reveal slight differences in the heme pocket if compared to CfumagHTP Mucor clade no sequences from phyla other than dikaryotic fungal subkingdom are known in the four above mentioned abundant clades yet. As most here presented sequences are only putative, the future research shall uncover their peculiar enzymatic properties not only for their peroxidatic activity but for oxyfunctionalization of organic molecules in general The ancestral clade appears to contain n events . The dev"}
+{"text": "The correlation between headache and cocaine is controversial and still understimated.As many as 14-21 million people worldwide  use cocaine , seems eWritten informed consent to publish was obtained from the patient(s).None."}
+{"text": "Simultaneous PET and MR acquisitions have now become possible with the new hybrid Biograph Molecular MR (mMR) scanner from Siemens. The purpose of this work is to create a platform for mMR 3D and 4D PET image reconstruction which would be freely accessible to the community as well as fully adjustable in order to obtain optimal images for a given research task in PET imaging. The proposed platform is envisaged to prove useful in developing novel and robust image bio-markers which could then be adapted for use on the mMR scanner.STIR (Software for Tomographic Image Reconstruction ), an opeConversion of the Siemens Dicom files to the STIR interfile format.Histogramming the emission data.Component-based normalisation.\u00b5-maps [Estimation and correction for attenuation and scatter using atlas based \u00b5-maps .Correction for randoms.Iterative image reconstruction \u20135)..5]).The reconstruction pipeline involves the following:\u00b5-map including the bed component (bottom).Two datasets were used: uniform cylinder phantom and FDG-PET human brain scan. Figure The reconstruction of the FDG human brain dataset is presented in Figure It was demonstrated that STIR image reconstruction of PET mMR data is possible paving the way to more advanced models included in the pipeline of 4D PET reconstruction."}
+{"text": "Postoperative new-onset atrial fibrillation (PNAF) is the most common complication after cardiac surgery. Inflammation as an underlying mechanism has been studied by various inflammatory markers, and white blood cell count (WBC) is the only present consequent inflammatory marker predicting PNAF . This stpost-hoc cohort study. The WBC was prospectively measured preoperatively and once during each of the first four postoperative days. Development of PNAF was evaluated with continuous 12-lead ECG monitoring the first 5 days postoperatively.Patients >18 years undergoing elective cardiac surgery with a sinus rhythm preoperatively were recruited from the Dexamethasone for Cardiac Surgery-PNAF trial for this P < 0.001), CABG plus valve surgery , single valve surgery  and other surgery  were correlated with the occurrence of PNAF.A total of 657 patients were included in this trial, 277 developed PNAF. The WBC was significantly higher in the PNAF group on day 2 and day 4 Figure . HoweverPreoperative and postoperative WBC were not associated with development of PNAF."}
+{"text": "Patients previously prescribed one epinephrine auto-injector device may be switched to an alternative device by their pharmacist or physician - sometimes without training on the new device. It is unclear whether \u201cdevice switches\u201d without retraining compromise the ability to deliver epinephrine.TM. ISRCTN29175528We evaluated mothers of food-allergic children participating in a UK study of epinephrine auto-injectors (EAI), 1 year after they were first trained to use an EAI, either Anapen or Epipen (old design). Participants' ability to deliver epinephrine using their device was assessed using a simulated anaphylaxis scenario. Participants then underwent repeat assessment using a different EAI device, randomly allocated, without training on the new device. The UK-approved EAIs Epipen (new/old designs), JEXT or Anapen were used, or Intelliject, an EAI with audio/visual prompts approved in North America as AuviQ(tm) and AllerjectWe evaluated ability to deliver epinephrine in 108 participants. Overall success rates were similar using their original EAI 68/108 (63%) to the new device 65/108 . However the outcome differed significantly for different types of device switch. Success rates were lower when switching between Anapen and either old Epipen, new Epipen or JEXT  compared with switching from old Epipen to either new Epipen or JEXT . Success rates were highest when switching from Anapen or old Epipen to Intelliject  compared with switching to other EAIs .The safety of EAI device switches varies according to the specific device. Switches to Intelliject appear to be safer than other forms of device switch."}
+{"text": "Rheumatology key messageUS-guided injection improves patients\u2019 experience with this intervention, which may contribute to improved response rates.ir, US-guided intra-articular and soft tissue steroid injections are common procedures in rheumatology and are taking the place of fluoroscopic and CT-guided injections. Little is known about patients\u2019 views about US-guided steroid injections despite several efficacy studies comparing blind to US-guided injections [Sjections . In the jections . We condRheumatology Online).Fifty questionnaires that included balanced Likert scale questions were distributed to rheumatology patients who underwent a US-guided procedure between January 2011 and January 2012. Survey receipt was concluded in April 2012 relating to a post-injection period ranging from 4 to 16 months. Of the 50 questionnaires distributed, 30 (60%) were returned and 26 (50%) were completed and included for data analysis  performed all the procedures. During the procedure the sonographer explained to the patient the anatomical features of the diseased target site, power Doppler activity and dynamic needle progression through the superficial tissues into the target site. A total of 34 joints/tendon regions were injected in 26 patients . All procedures were part of the patients\u2019 normal care pathways.All patients felt that seeing the US images was very helpful or helpful in understanding the procedure A. EightyThis pilot study has some limitations. No validated psychometric questionnaire was available for this specialized purpose, therefore we used a non-validated questionnaire to obtain retrospective views of patients. Furthermore, such a retrospective survey is vulnerable to response bias, potentially enhancing the number of overtly positive or negative responses.Observing US images during the procedure improved the overall experience of this intervention. Observing the US images in real-time improved patients\u2019 understanding and tolerability of the procedure and reduced patients\u2019 anxiety. This is consistent with a randomised controlled study that suggested US guidance improved pain scores (p < 0.001) and overall response rate (p < 0.01) compared with traditional palpation-guided injection . AnxietyA larger study is required to confirm our preliminary findings that US-guided injection improves the tolerability of the procedure and reduces patients\u2019 anxiety during the procedure. Further issues that require investigation include whether visualising real-time images during US scanning improves patients\u2019 understanding of disease pathology, which could lead to indirect benefits such as improving therapy adherence and improved pain management strategy.Funding: Arthritis Research UK (Grant 17767) provided funding for the US Unit.Disclosure statement: The authors have declared no conflicts of interest.Supplementary data are available at Rheumatology Online."}
+{"text": "Rituximab (RTX) is a monoclonal antibody; recently it has been use as a new treatment strategy in patients with high-degree steroid-dependent nephrotic syndrome. It provokes a lymphocyte B depletion in some cases that interacts with Immunoglobulins creating decreased plasma IgG levels and hypogammaglobulinemia.2. Baseline analysis before RTX treatment evidenced low IgG levels, although these values are not conclusive because they were taken during nephrotic state. Twenty days later, the patient presented severe hypogammaglobulinemia with IgG levels of 149 mg/dL, without nephrotic proteinuria. We decided to start intravenous gammaglobulin (IVIG) every 4-6 weeks. Analysis showed low levels of lymphocytes (predominantly B type) four days after initiated the treatment. Follow up demonstrated complete recovery of lymphocyte count two years later. After 3 years of RTX administration the patient continues to have hypogammaglobulimenia, requiring IVIG until now.We report the case of a 2.5 year old male diagnosed of idiopathic nephrotic syndrome. He presented resistance to systemic steroids as well as second line treatments (cyclophosphamide and mycophenolate). Patient started with intravenous infussion of rituximab at 375mg/mThe cause of immunodeficiency in this patient has not yet been established. Is it because of the nephrotic syndrome itself? An adverse effect of the drug? Maybe a pre-existing primary immunodeficiency?Use of RTX has reported cases of hypogammaglobulinemia values usually normalizing after 11 months; persistent hypogammaglobulinemia is not a common side effect. We only found one series describing the association of persistent hypogammaglobulinemia in nephrotic patients treated with RTX, suggesting a certain predisposition in patients with low baseline IgG levels previous to the treatment with this monoclonal antibody.Starting a full immune panel previous to treatment with RTX could be a good way to predict possible persistent hypogammaglobulinemia and to rule out immunologic pathology before making any therapeutic decision."}
+{"text": "Extensive DNA damage and inefficient DNA repair might be responsible for some of the pathogenic features in patients suffering from asthma. To determine whether DNA adducts can be used as a \u201cdosimeter\u201d for asthma disease severity, we measured the DNA adducts level in lung of mouse with house dust mite (HDM)-induced allergic airway inflammation, as the disease progresses. Apoptosis of airway epithelial cells is one of the most critical pathophysiological factors in the development of chronic asthma. As repairing of DNA lesions is important in preventing apoptosis, we propose that DNA repair plays an important pathophysiologic role in regulating lung epithelial cell DNA damage response.We immunofluorescence-stained mice asthmatic lung tissue sections and observed an increase in DNA double strand break (DBS) markers, \u03b3H2AX and 53BP1 as compared to control. Level of DNA repair proteins that involved in homologous recombination and non-homologous end joining, were up-regulated substantially as early as 1 day-post last challenge. TUNEL assay revealed high level of DNA strand breaks in bronchial epithelium. DNA damage signaling pathway PCR array showed a reproducible increase in expression of multiple genes involved in DNA damage and repair. Treatment with glucocorticoid significantly reduced cell infiltration into airway as well as DNA damage and repair markers. To elucidate the role of DNA repair in regulating disease outcome, we treated mice with NU7441, a DNA-dependent protein kinases inhibitor, and had observed an increased DNA damage makers expression in lung and increased apoptotic level in bronchial epithelium as compare to no-drug treatment control. When DNA repair was obstructed, apoptosis of airway epithelium cells was enhanced. This indicates the important role of DNA repair in airway inflammation."}
+{"text": "Significant abnormal hemispheric cerebral physiology resulting in neurological injury can occur without knowing because the current monitoring system could not detect the abnormal hemispheric abnormality. Cerebral oximetry can provide a rapid, non-invasive detection of each hemisphere's cerebral physiologic changes during ictal/post-ictal phases. The aim was to study left and right rSO2 values in patients in the pre and post seizure periods and in nonseizing controls.During ictal/post-ictal events, altered cerebral physiology occurs: increased neuronal activity causes significant increase in cerebral metabolism with changes in ipsilateral cerebral blood flow. Standard PED seizure monitoring is by O2 readings compared with nonseizure patients.An observational study of seizing and nonseizing patient's left and right rSO2 readings across ages. See Figure No difference for ictal left and right rSO2 values were significantly decreased. In patients with focal seizures, the ipsilateral rSO2 values were significantly different from the contralateral rSO2 readings and correlated to the hemisphere experiencing the focal seizure. In certain patients, during the ictal phase their rSO2 readings rose and stayed or rose then dropped. Overall, cerebral oximetry has shown great monitoring potential for actively seizing patients in the emergency department.We have demonstrated abnormal hemispheric cerebral physiology during focal or generalized ictal activity. In patients with generalized seizures, the left and right rSO"}
+{"text": "We hypothesized that the region of latest mechanical contraction would correspond to the region of latest electrical activation but the time between mechanical and electrical activation would vary between patients.Numerous studies have shown that placing the left ventricular (LV) pacing lead in the latest contracting region  or the latest activated region  of the LV improves patient response to Cardiac Resynchronization Therapy (CRT). However, no studies have examined electrical and mechanical dyssynchrony Mechanical dyssynchrony: High temporal resolution steady-state free precession (SSFP) cine images were acquired with 60 frames per cardiac cycle in ten patients enrolled for CRT. The endocardial boundary was delineated in a stack of short-axis images. Radial contraction curves (RDCs) were generated for 100 locations on the endocardial boundary for each slice. The delay between each RDC and a patient-specific reference was determined using cross-correlation analysis. Mechanical delay times throughout the LV were mapped to the AHA 17-segment model. Electrical dyssynchrony: Regional electrical delay times were determined from local electrograms (EGMs) acquired during CRT device implantation. EGMs were acquired simultaneously from the RV lead (placed in the apex of the RV) and LV lead . 35 EGM recordings were obtained at several potential pacing sites in the 10 patients. The electrical delay was defined as the peak-to-peak difference between the EGMs from the RV and LV leads. Lead localization: Dual-plane fluoroscopic projection images were acquired at each LV lead recording site and was mapped onto the AHA 17-segment model. Mechanical delay times within a region the size of an AHA segment centered at the LV pacing location were averaged to obtain a corresponding mechanical delay time. Analysis: Mechanical delays (from MRI bullseye) and electrical delays (from EGM) were correlated on a patient-by-patient basis.2=0.85 \u00b1 0.21). The linear best fit in each patient yielded a positive slope (1.7 \u00b1 1.3) and the slope varied greatly between patients (Range: 0.06-4.11). The site that exhibited the largest electrical delay always corresponded to the site of latest mechanical delay. The location of this latest activated/contracting site varied significantly between patients .There was a strong linear relationship between electrical and mechanical delay times over all patients (RThe latest electrically activated site always corresponded to the latest mechanically contracting site; therefore either mechanical or electrically dyssynchronous regions can be targeted in an attempt to improve patient response to CRT.This study was funded in part by the National Science Foundation Graduate Research Fellowship Program."}
+{"text": "A 36-year old man presents to the emergency room five days after undergoing extracorporeal shock wave lithotripsy (ESWL) for a symptomatic 11mm left renal pelvis stone. The patient has persistent symptoms of severe left flank pain at presentation.steinstrassen)  .1 This pFor asymptomatic cases of steinstrasse, conservative management is preferred with observation and serial imaging with plain radiography to follow progression of the stones and ultrasonography to evaluate for hydronephrosis. Sixty-five percent of steinstrassen will pass spontaneously over days to weeks.This particular patient underwent urgent ureteroscopy with stent placement the following day and had an uneventful recovery thereafter."}
+{"text": "The adoptive transfer of tumor infiltrating lymphocytes (TIL) can mediate the regression of metastatic melanoma. In addition, the adoptive transfer of lymphocytes genetically modified to express tumor reactive T cell receptors (TCRs) can mediate tumor regression. Many T cells from TIL recognize mutated antigens expressed only on the autologous patient's tumors. Therefore, we attempted to isolate TCRs reactive with unique mutated antigens so that we might eventually be able to treat patients with autologous T cells genetically modified to express those TCRs.in vitro transcribed and electroporated into autologous dendritic cells (DCs). Recognition of TMGs by TIL was evaluated on the basis of IFN-\u03b3 secretion and CD137 expression after overnight coculture with the electroporated DCs. Subsequently, mutation reactive T cells were enriched from TIL by sorting for CD137+ T cells after overnight coculture with the electroporated DCs and were expanded in vitro with anti-CD3 and IL-2. Dominant TCR \u03b1 and \u03b2 chain sequences were identified in the enriched mutation reactive populations, and retroviruses encoding those TCRs were used to transduce human PBL to determine if they mediated recognition of the mutated antigen.Mutations in tumors were identified using whole exome sequencing and/or RNA sequencing. Tandem minigene (TMG) constructs containing 12-24 minigenes were synthesized, each encoding the mutated amino acid flanked by 12 amino acids on both sides. RNAs encoding the TMGs were Thus far, using these techniques we have isolated mutation reactive TCRs from 6 different patients with metastatic melanoma as described in the attached table. We are currently extending these techniques to identify mutation reactive TCRs for patients with other cancers including those of the gastrointestinal tract, breast, and ovaries. We are also developing clinical reagents to treat patients with TCRs that recognize unique mutations on autologous tumor cells."}
+{"text": "Benefits of early reperfusion in patients presenting with acute ST elevation myocardial infarction (STEMI) are well known. The American College of Cardiology / American Heart Association guidelines recommend triage decisions are made within 10 minutes of performing initial electrocardiogram (ECG). Since many patients presenting with ischemic symptoms may have ST elevation (STE) at baseline, not all STE signify transmural ischemia. Benign patterns can be easy to find in some cases. However, patients with benign STE at baseline  may have ongoing ischemia and present with Non-ST elevation myocardial infarction (NSTEMI) or even STEMI superimposed on the benign pattern. The ability of clinicians to distinguish between ischemic and non ischemic STE varies widely and is affected by prevalence of such changes in patient population. More studies need to be done to delineate the criteria to clearly distinguish between ischemic and non ischemic ST elevation. The electrocardiogram (ECG) plays an important part in appropriate management of patients presenting with chest pain. Patients diagnosed with acute STEMI are triaged to receive urgent reperfusion therapy with either primary percutaneous coronary intervention (pPCI) or thrombolytic therapy and those judged not to have ST elevation receive conservative treatment early on . The AmeReperfusion decisions should be made within 10 minutes of initial ECG in patients presenting with suspected STEMI according to ACC/AHA STEMI guidelines . TherefoThe ST segment is at the same horizontal level as that of adjacent T- P or P- R segments or iso-electric in the majority of individuals  and deviNormally, the ST segment is iso-electric with the TR and TP segments and reflects ventricular depolarization. It is a classic teaching that STE with upwardly convex or straight is consistent with STEMI and STE which is concave is morphology is consistent with NISTE. The ACC/AHA guidelines also mention that STEMI is less likely if associated ST elevations are concave versus convex . DifficuEarly repolarization usually manifests as STE of 0.1- 0.4 mV in the lateral leads (mainly V5- V6), accompanied with a characteristic notch at J point . InvolveProminent J point notching- also known as Osborne waves may be seen transiently in hypothermia , and shoLeads V1- V3 most commonly demonstrate the normal variant pattern  Figure . It is oIt is observed most commonly in leads V1 \u2013 V3  . Common Diffuse STE with reciprocal ST depressions in leads AVR and V1 are hallmark features of stage 1 pericarditis . DiffuseLBBB is associated with secondary ST- T wave abnormality which leads to deviation of ST segment in the opposite direction to major QRS deflection . It is iSecondary repolarization changes, as seen with LBBB, may also be seen with non specific IVCD . CompariThe Brugada syndrome associated NISTE manifests as RBBB-like pattern and STE in anterior leads  Antzele. There iTakotsubo\u2019s syndrome is a form of reversible myocardial dysfunction which is preceded by intense physical or emotional stress and is more commonly seen in post menopausal women. Presenting features may include chest pain or dyspnea and ECG shows STE in precordial leads in up to 80% of patients  along wiThe ACC/AHA STEMI guidelines recommend urgent reperfusion therapy in patients presenting within 12 hours of symptoms suggestive of myocardial ischemia and STE in \u2265 2 adjacent precordial leads (> 0.1 mV at J point) . No menthttp://hqmeded-ecg.blogspot.com/2008/11/65-yo-male-with-recent-rule-out.html). The magnitude of STE may change over time and is highly dependent on the heart rate, increasing with tachycardia and decreasing with slow heart rate . These dynamic changes should be differentiated from evolving changes of STEMI. The ACC/AHA guidelines  recommenIn clinical practice, many cases of true STEMI are easily identified. In those patients where differentiation is difficult, combining clinical presentation with interpretation of ECG by a skilled electrocardiographer who has access to previous tracings and occasionally, repeating ECG can increase the yield of interpretation."}
+{"text": "The purpose of this retrospective study is to examine the incidence and imaging appearance of pelvic malignancies in a symptomatic patient population being screened for MRgFUS treatment.373 women with symptomatic uterine fibroids were screened with MRI exams with and without contrast utilizing T2 coronal and axial, T2 fat suppressed sagittal, T1 axial precontrast images, and post contrast fat saturated images in 3 planes. Uterine masses were classified by their intensity on T2 weighted images relative to normal myometrium . The enhancement pattern was also categorized as homogenous or inhomogeneous. Any extra-uterine masses were also noted as well as any other incidental pelvic findings.Results: Of the 373 patients (ages 26-61) that underwent pelvic screening for MRgFUS treatment, 19 presented with findings suspicious for cancer and after further evaluation, 7 of these patients (1.9 %) were confirmed to have a pelvic malignancy. 5 patients had a uterine sarcoma, 1 had endometrial carcinoma and 1 had ovarian carcinoma. Three out of the five sarcomas appeared markedly heterogeneous on T2 weighted images with ill-defined dark areas and bright fluid components and demonstrated heterogeneous, poorly defined areas of enhancement throughout. The remaining 2 sarcomas appeared more fluid in nature with eccentric, enhancing soft tissue components and multiple septations.vs. minimally invasive procedures). It is equally important to avoid delayed diagnosis and unintended treatment of malignant diseases with non-excisional approaches at this time. MRI pelvis exams may also help direct patients with more typical benign uterine fibroids to both non-invasive treatments (MRgFUS or uterine artery embolization (UAE)) or surgery . The more liberal use of MRI pelvis exams to screen and characterize pelvic pathology in symptomatic women can help avoid recent deleterious outcomes with morcellation procedures of unsuspected malignancies. With increasing familiarity with the MR appearance of uterine pathology and attentive evaluation of screening studies, early diagnosis of pelvic malignancy may be achieved.The endometrial carcinoma appeared as an intra-cavitary mass with ill-defined margins with a blood clot in the endometrium. This finding is highly unusual, as a large endometrial clot is not typically seen in cases where irregular bleeding was noted for fibroids. The ovarian carcinoma appeared as an extra-uterine mass with metastatic spread to the pelvic lymph nodes. Malignancy was considered in the remaining 12 patients due to the MRI imaging characteristics listed in Table"}
+{"text": "In Table 2 of the manuscript originally published online, the waist-difference values for women were incorrect. They have been corrected here."}
+{"text": "Nonlabens ulvanivorans, which was recently isolated. To our knowledge, this is the first published genome of a characterized ulvan-degrading bacterium. Revealing the ulvan utilization pathways may provide access to a vast marine biomass source that has yet to be exploited.Here we report the draft genome sequence of the bacterium  Ulvales (Chlorophyta) are worldwide-distributed green seaweeds   paired-end sequencing. Four samples were loaded into one lane to receive 58 million passed filter reads for each sample. Data were analyzed using the de-novo assemblers AbySS (Flavobacteriaceae (between 1 and 6 copies) (rs AbySS  and Velvrs AbySS . The finUlva degradation and Ulvales cell wall polysaccharide utilization. Furthermore, it may allow for better characterization and even modification of these untapped polysaccharides in the near future.The first draft genome sequence of an ulvan-degrading bacterium provides a major step toward the unveiling of other enzymes that participate in JPJI00000000. The version described in this paper is version JPJI01000000This whole-genome shotgun project has been deposited at DDBJ/EMBL/GenBank under the accession number"}
+{"text": "A focused bedside ultrasound over the patient\u2019s region of maximal discomfort revealed a thickened bowel wall and several small contiguous hypoechoic projections surrounding a hyperechoic center, suggestive of diverticulitis (A 72-year-old otherwise healthy female presented to the emergency department with two weeks of worsening abdominal pain. She was afebrile with normal vital signs. Her physical examination was notable for moderate abdominal tenderness without rebound to the left and suprapubic regions of the abdomen. Laboratory studies were remarkable for a white blood cell count of 13,000/mmiculitis . She wasiculitis .Acute diverticulitis resulting from inflammation of colonic diverticulum affects over half the population greater 65 years of age.5Particularly in cases of suspected uncomplicated diverticulitis, abdominal ultrasound may reach the diagnostic reliability of CT.2"}
+{"text": "To build a detailed circuit diagram in the brain, one needs to measure functional synaptic connections between specific types of neurons. A high-resolution circuit diagram should provide detailed information at subcellular levels such as soma, distal and basal dendrites. However, a limitation lies in the difficulty of studying long-range connections between brain areas separated by millimeters. Brain slice preparations have been widely used to help understand circuit wiring within specific brain regions. The challenge exists because long-range connections are likely to be cut in a brain slice. The optogenetic approach overcomes these limitations, as channelrhodopsin 2 (ChR2) is efficiently transported to axon terminals that can be stimulated in brain slices. Here, we developed a novel fiber optic based simple method of optogenetic stimulation: the laserspritzer approach. This method facilitates the study of both long-range and local circuits within brain slice preparations. This is a convenient and low cost approach that can be easily integrated with a slice electrophysiology setup, and repeatedly used upon initial validation. Our data with direct ChR2 mediated-current recordings demonstrates that the spatial resolution of the laserspritzer is correlated with the size of the laserspritzer, and the resolution lies within the 30 \u00b5m range for the 5 micrometer laserspritzer. Using olfactory cortical slices, we demonstrated that the laserspritzer approach can be applied to selectively activate monosynaptic perisomatic GABAergic basket synapses, or long-range intracortical glutamatergic inputs formed on different subcellular domains within the same cell . We discuss significant advantages of the laserspritzer approach over the widely used collimated LED whole-field illumination method in brain slice electrophysiological research. The modular design of molecular optogenetic components enables bidirectional and cell-specific control of neuronal excitabilities in vivoin vivoin vitroOptogenetic approaches have become the method of choice to manipulate neuronal excitability Brain slice preparations have been used extensively to help understand circuit wiring within specific brain regions. To build a detailed circuit diagram, one needs to measure functional synaptic connections between specific types of neurons. A high-resolution circuit diagram should provide detailed information at the subcellular levels . During the past few decades, electrophysiological recordings from connected cortical neurons in brain slices have demonstrated many intra- and inter- laminar connections between specific neuronal subtypes 1) subcellular resolution such that synaptic currents formed on specific cellular compartments can be selectively interrogated [e.g. sCRACM method, 2) a high degree of cell or synaptic specificity; and 3) ease of use with existing electrophysiology setups. So far, the two photon ChR2 activation approach retains the best spatial resolutions (<10 \u00b5m). However, this approach requires genetically modified opsin tools and an expensive two photon setup http://www.ephus.org)For brain slice neural circuit interrogations, ideal optogenetic tools should have the following features To combat these limitations, a simple and low-cost novel approach is described below. This is a straight forward fiber optic based local light delivery method that we named laserspritzer; analogous to the picospritzer used by many electrophysiology labs for locally delivering drugs within a small area. We provide experimental data to demonstrate its spatial properties and its application in circuit investigations using olfactory cortical slices. We also discuss the advantages of the laserspritzer over the widely used collimated LED whole-field illumination method.The laserspritzer was made from a multi-mode fiber optic patch cable  with appropriate mating ends (e.g. SMA) to the light source . Step 1. We trimmed and stripped the fiber optic patch cable to expose the cladding and core (250 \u00b5m) by about 2\u20134 cm 1. Step 22 laser power) was collected for further experimentation. Prior to electrophysiology experimentation, we recommend that laser scattering properties be measured in testing brain slices. 2, at physiologically relevant laser intensities , laserspritzers with different tip sizes were used e.g. 1 v. B2. ensities 3. An advThe spatial resolution of the laserspritzer was examined by making whole-cell recordings from ChR2-expressing cells in brain slices from VGAT-ChR2 mice A potential shortfall associated with the laserspritzer is that it does not specifically limit the light scattering within the tissue unlike the two photon stimulation method. We typically minimize light scattering with the laserspritzer by decreasing its tip size 3 and utiOptogenetic methods have been widely used to evoke synaptic releases. Expression of ChR2 within specific presynaptic neurons are achieved by means of virus delivery We sought to compare GABAergic inhibitory synaptic currents induced by the laserspritzer to collimated LED whole-field illuminations. Mice used in this study were vesicular \u03b3-aminobutyric acid transporter-channelrhodopsin2 (H134R)-enhanced yellow fluorescence protein mice . In this line of mice, the ChR2-YFP fusion protein was selectively expressed under the control of a VGAT promoter A potential issue with collimated LED whole-field illumination is that all monosynaptic inputs formed on different cellular compartments are stimulated simultaneously. Thus, the recorded evoked whole-cell ChR2-EPSCs result from the temporal and spatial summation of multiple EPSCs arriving at different subcellular domains (dendrites and soma). This problem is more prominent in cells with large dendritic arbors, such as neocortical pyramidal neurons. To test that our laserspritzer approach can help overcome this issue, we studied long-range intracortical projections formed on different dendritic sites. We chose the olfactory cortex slice because intracortical glutamatergic inputs are formed on specific subcellular domains on distal dendrites in layer IB As shown in Assuming the distribution of synapses is uniform along all distal dendritic arbors in the aPc (which appears to be true, e.g. in vitro.Described here is a fiber optic based simple method of optogenetic stimulation: the laserspritzer approach. This is a convenient and low cost approach that can achieve high spatial resolutions of stimulation and can be easily implemented with an existing slice electrophysiology setup and repeatedly used upon initial validation. Our data, composed of direct ChR2 mediated-current recordings, demonstrates that spatial resolutions created by the laserspritzer lie in the 30 \u00b5m range. Using olfactory cortical slices, our data demonstrates that the laserspritzer approach conveys significant advantages over the widely used collimated LED illuminations for both spatial resolutions, and also reduces ChR2 desensitization in brain slices. We provide examples to apply this approach in studying monosynaptic perisomatic GABAergic basket synapses or long-range intracortical glutamatergic inputs formed on different dendritic and somatic domains within the olfactory cortical slices"}
+{"text": "Chemotherapy-induced liver injury is a well-known phenomenon after neoadjuvant therapy of liver metastasis and contributes to postoperative morbidity and mortality. Still there is no suitable test available to reliably determine functional impairment and hepatic regeneration after chemotherapy.We report two cases of caucasian patients who underwent repeated liver function assessments using LiMAx (maximum liver function capacity), Indocyanine plasma disappearance rate and biochemical liver function parameters in the course of adjuvant oxaliplatin-based chemotherapy.Both patients yielded a decrease from their initial liver function determined by LiMAx. Liver regeneration assessed functional recovery within 4 weeks in case of mild functional impairment after cessation of chemotherapy or within 8 weeks in case of major functional deterioration. Indocyanine plasma disappearance rate and biochemical parameters remained stable or without a clear trend in case of minor functional impairment. This is the first report using a dynamic liver function test to evaluate the impact and recovery from chemotherapy associated liver injury.The LiMAx test might be a sensitive tool to diagnose mild functional impairment after chemotherapy when standard liver function tests have remained within normal ranges and might be capable to assess the course of regeneration after chemotherapy. This could be useful to optimize individual chemotherapy-free interval before liver surgery can be carried out safely. Chemotherapy-induced liver injury (CALI) after receiving potent chemotherapy is a considerable problem in patients undergoing partial liver resection since increased perioperative mortality and morbidity have been reported -3. HowevWhereas previous studies were based on the clinical course and histology of resected liver parenchyma after surgery, less is known about the impact on actual liver function and the course of regeneration after cessation of chemotherapy ,10.Clinical biochemistry usually fail to diagnose reduced liver function after neoadjuvant therapy as standard parameters remain within normal ranges . The freConcerning the chemotherapy-free interval from cessation of chemotherapy to a safe partial liver resection only statistical figures are known in the literature and suggest an interval of six to eight weeks . There iHere we report two cases of patients that both received adjuvant oxaliplatin-based chemotherapy as a consequence of colorectal surgery due to adenocarcinoma. All patients underwent assessment of liver function using common biochemical liver tests, ICG-PDR and LiMAx (maximum liver function capacity) test before, directly after withdrawal as well as 4 and 8 weeks after cessation of chemotherapy. Both patients did not have additional regular drug intake during the study period and did not suffer from any marked comorbidities known to impair liver function.13C-labeled methacetin bolus injection and continuous measurement of 13CO2/12CO2 concentration ratio using a special device  as previously described by Stockmann and colleagues [LiMAx (maximum liver function capacity) reflects the actual enzymatic liver function capacity. The test is based on a bodyweight-adjusted intravenous lleagues . The LiMlleagues -21. LiMAIndocyanine green plasma disappearance rate (ICG-PDR) evaluates hepatic clearance and is suggested to provide additional information on liver function. The test is based on bodyweight-adjusted intravenous injection of ICG followed by pulse spectrophotometry to assess hepatic excretion via a special device . ICG-PDR is considered to be normal over 18%/min ,23.Case 1 reports a 56-year-old male caucasian patient that received 8 cycles of XELOX chemotherapy substituting 5-FU for the oral drug Xeloda. The patient started XELOX chemotherapy with a LiMAx value of 463 \u03bcg/kg/h and showed a decrease of functional liver capacity by 56% to 204 \u03bcg/kg/h after withdrawal of chemotherapy. ICG-PDR also declined from physiological 19.3%/min prior to chemotherapy to 16.6%/min , however ICG-PDR results in case 2 are inconclusive. This might be explained by general limitations of this testing procedure. ICG-PDR is strongly dependent on blood flow to the liver and the absence of cholestasis -26. Sincet al. .Both LiMAx and ICG-PDR have shown superior prognostic relevance for perioperative mortality and morbidity in patients undergoing partial liver resection compared to standard liver function tests ,20,28,29Certainly we present cases in patients without liver metastases and without indication for liver surgery. However our workgroup has already shown that the sole presence of liver metastasis which is usually advanced in patients that undergo neoadjuvant treatment can also impair liver function making it impossible to discriminate between reduction of liver function by chemotherapy or multiple metastasis in a proof of principle report .This is the first report using a dynamic liver function test in a controlled prospective setting to assess chemotherapy induced liver injury. It suggests an impairment of liver function, which might not be recognised by standard liver function tests and a defined course of regeneration after chemotherapy measurable with dynamic liver function tests. This might help to optimize the chemotherapy-free interval prior to liver surgery and therefore needs to be addressed in a larger cohort.Written informed consent was obtained from both patients for publication of this Case Report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal."}
+{"text": "A concise synthetic route leading to highly functional erythrina alkaloid skeletons has been developed. The key process is an oxidative carbon-carbon coupling followed by a conjugated addition. Based on this new strategy, a formal synthesis of demethoxyerythratidinone was completed in only 6 steps from 4-aminophenol."}
+{"text": "Monoclonal antibody based vaccines are effective and highly specific in disease targeting. Presently, most of the existing broadly neutralizing antibodies are generated against non subtype c viruses. HIV-1 subtype c accounts for more than 90% of infection in India. The disease progression in children is faster than adults.Nine ART drug na\u00efve HIV-1 subtype c infected children were recruited. PBMCs were isolated from all the subjects and pooled. RNA was isolated and cDNA was synthesized followed by amplification of VH and VL chain genes and scFv construction. A human recombinant scFv phage display library of 108 clones was constructed. Diversity of the phage library was checked by DNA sequencing and biopanned with RSC3 core antigen. 60 random clones were screened by phage ELISA. Expression of the scFvs was assessed by SDS-PAGE and Western blotting.The diversity of the phage library was more than 90%. Eight scFv monoclonals showed positive binding in phage ELISA and two best binders were further characterized. Both scFvs didn\u2019t show any reactivity with unrelated antigens. DNA fingerprinting analysis showed both scFvs were distinct. A 32kDa band was obtained in SDS-PAGE and Western blot. Both scFvs showed cross neutralizing activity against a standard panel of pseudoviruses.Here, we have for the first time generated a human recombinant scFv phage display library containing neutralizing clones from HIV-1 infected children. Further characterization of these scFvs generated against CD4 binding site for their epitope mapping would be helpful in the development of an effective HIV-1 vaccine."}
+{"text": "Plants maximize their chances to survive adversities by reprogramming their development according to environmental conditions. Adaptive variations in the timing to flowering reflect the need for plants to set seeds under the most favorable conditions. A complex network of genetic pathways allows plants to detect and integrate external  and/or internal  information to initiate the floral transition. Furthermore different types of environmental stresses play an important role in the floral transition. The emerging picture is that stress conditions often affect flowering through modulation of the photoperiodic pathway. In this review we will discuss different modes of cross talk between stress signaling and photoperiodic flowering, highlighting the central role of the florigen genes in this process. Arabidopsis ecotypes, the transition to flowering is strongly promoted by variations in day length (photoperiod). The photoperiodic pathway promotes flowering when Arabidopsis plants are exposed to long days (LDs) conditions . Photoperiodic flowering is the result of complex interactions between the circadian clock (an endogenous timekeeping mechanism) and external cues, which ultimately results in the activation of a set of floral genes.-CO expression is regulated transcriptionally by the circadian clock through the GIGANTEA (GI)-FLAVIN-BINDING, KELCH REPEAT, F-BOX (FKF1) complex.,FLOWERING LOCUS T (FT) and TWIN SISTER OF FT (TSF) in the phloem companion cells.--SUPPRESSOR OF OVEREXPRESSION OF CONSTANS 1 (SOC1), APETALA1, and FRUITFUL, responsible for triggering the floral transition.,After the floral transition the shoot apical meristem (SAM) changes its identity switching from vegetative to reproductive. In annual Arabidopsis, a facultative LD plant and Rice (Oryza sativa), a facultative short day (SD) plant.Solanum lycopersicum).Florigen gene expression has been demonstrated to play a pivotal role in photoperiodic flowering in different plants including Arabidopsis. However, it is now apparent that the FT promoter conveys several environmental information, in some cases independent of day length. Many plant species are induced to flower following drought stress which results in a drought escape response - DE -.-Arabidopsis DE occurs under LDs but not SDs, thus revealing a strong interdependence of certain drought responses on photoperiod. Genetic screens showed that photoperiod-stimulated GI activity is necessary and sufficient to trigger a drought dependent activation of the florigen genes FT and TSF.LDs promote flowering via activation of the florigen genes in aba1 mutants are impaired in ABA biosynthesis and display reduced accumulations of FT and TSF transcripts, especially under drought conditions. In addition to FT and TSF another FT-like genes MOTHER OF FT AND TFL1 (MFT) all appear to be positively regulated by ABA.,The phytohormone ABA plays a pivotal role in mediating several drought adaptive mechanisms although its precise role in flowering is still poorly understood.Shorea beccariana.SbFT transcript accumulations early in bud development, preceding flower morphological changes. Shorea beccariana grows at the equator where day length and temperature are constant throughout the year. It is thus plausible that drought spells could represent a major external cue to trigger mass flowering in this species via direct activation of FT independent of photoperiod. Photoperiod-independent modes of activation of FT exist also in Arabidopsis where an increase in ambient temperature is reflected in augmented FT transcript accumulation.FT expression largely independent of CO.Some plants use drought stress as a primary cue to flowering. Recent studies suggest that drought stress is involved in the upregulation of the florigen genes in the tropical tree FT activation is unknown. Drought stress results in an increase in FT expression with no evident effect on the physiological circadian oscillation of FT.,FT transcript accumulation depends on variations in CO protein, drought might directly affect CO expression. FLOWERING BHLH 1 (FBH1), a CO positive activator, is phosphorylated in vivo following ABA signaling activation.,CO transcription under drought conditions. Also, EID1-like protein 3 (EDL3), a positive regulator of ABA signaling is an activator of CO. EDL3 transcript is upregulated following ABA applications.CO transcript accumulations we could find only minor variations in CO transcript in wild-type or aba1 mutant plants subjected to drought stress  domain involved in the recruitment of the CO protein to the promoter of FT.,abi3 mutants display high levels of TSF, suggesting a repressive role for ABI3 on TSF expression.MFT is downregulated by ABI3.Drought (via ABA) could affect CO protein activity or stability. For example, besides the well-established role in seed germination the ABA signaling protein ABA INSENSITIVE 3 (ABI3) is involved in the control of flowering time. FT, FT upregulation may occur independently of either CO or GI. For example, warm temperatures results in an acceleration of flowering in the absence of GI and CO activities.co but not gi mutants, although it is unknown whether drought can stimulate FT upregulation in the absence of CO activity.FT activation have been described.,-FT promoter. Other pathways could facilitate the responsiveness of FT to photoperiod-stimulated GI. For example, similarly to gi, cry2 mutants have a defective DE response, despite constitutively accumulating increased ABA levels compared with wild type.,FT.Despite the GI-CO module being responsible for most of the activation of Arabidopsis has 3 florigen genes, of which 2 (FT and TSF) act redundantly to mediate photoperiodic flowering.,,FT and TSF transcripts are found in a non-overlapping pattern of expression.TSF expression (but not FT) can be activated under SDs following exogenous applications of a synthetic Cytokinin (CK).TSF. Because of this reduced dependence on photoperiod, TSF upregulation might also occur in the absence of CO  under drought conditions and contribute to the DE response observed in co mutants. In conclusion, more work is needed to clarify the mode of FT and FT-like genes activations under drought conditions and their specific interdependence with the photoperiodic pathway machinery.FT expression even under inductive photoperiodic conditions. It has been shown that cold temperatures induce the degradation of CO protein via an ubiquitin/proteasome pathway that involves the E3 ubiquitin ligase HIGH EXPRESSION OF OSMOTICALLY RESPONSIVE GENE 1 (HOS1).Not all abiotic stresses are interpreted as an escape signal. For example, cold stress delays flowering and alters the diurnal oscillation of Arabidopsis by interfering with the photoperiodic pathway. Interestingly salt affects FT at 2 different levels, transcriptional and post-transcriptional. Salt stress promotes GI protein degradation through an unknown ubiquitin/proteasome pathway.CO and FT transcripts accumulation. Salt stress delays flowering by activating the floral repressor BROTHER OF FT (BFT), a florigen-like protein with opposite function to FT.BFT is strongly responsive to drought stress and ABA.BFT can be transcriptionally activated under drought conditions in an ABA dependent manner and this regulation is dependent on GI  clearly prevails over BFT. One could hypothesize that the balance between florigen and anti-florigen proteins is necessary to generate an optimal duration of reproductive development according to environmental stress. In this sense BFT may buffer FT action and prevent a premature interruption of inflorescence development. Deciphering the regulatory logic of the different florigen genes is thus an important goal to gain insights into the different flowering adaptations to stress as well as the mechanisms that govern crop seed yield under adverse conditions.A different osmotic stress, salinity, delays flowering in nt on GI . Thus, Bgi mutants display different phenotypes including an increased salt tolerance.,-A question arise as to how plants might coordinate flowering networks with tolerance responses, which allow individual cells to survive under stress conditions. GI is emerging as a key node connecting different abiotic responses with flowering time. Arabidopsis the escape strategy requires a positive integration between photoperiodic and drought-dependent signals. A floral delay strategy takes place upon conditions where growth restraint provides an adaptive advantage over an escape, namely on salt.In conclusion, plant adaptation to stress is complex and involves different strategies. In"}
+{"text": "The End-Cretaceous Impact Winter Killed Off Slow-Growing Plants The end-Cretaceous mass extinction caused the selective extinction of plant species with slow-growth strategies, consistent with an impact winter hypothesis. The Chicxulub bolide impact caused the end-Cretaceous mass extinction of plants, but the associated selectivity and ecological effects are poorly known. Using a unique set of North Dakota leaf fossil assemblages spanning 2.2 Myr across the event, we show among angiosperms a reduction of ecological strategies and selection for fast-growth strategies consistent with a hypothesized recovery from an impact winter. Leaf mass per area (carbon investment) decreased in both mean and variance, while vein density (carbon assimilation rate) increased in mean, consistent with a shift towards \u201cfast\u201d growth strategies. Plant extinction from the bolide impact resulted in a shift in functional trait space that likely had broad consequences for ecosystem functioning. Sixty-six million years ago the Chicxulub bolide impacted the Earth, marking the Cretaceous\u2013Paleogene boundary (KPB). This event caused the planet's most recent mass extinction, but the selectivity and functional consequences of the extinction on terrestrial plants has been largely unknown. A key untested hypothesis has been that a subsequent impact winter would have selected against slow-growing evergreen species, a possible cause of the modern dominance of high-productivity deciduous angiosperm forests. We tested this hypothesis using fossil leaf assemblages across a 2-million-year interval spanning the KPB. We assess two key ecological strategy axes\u2014carbon assimilation rate and carbon investment\u2014using leaf minor vein density and leaf mass per area as proxies, respectively. We show that species that survive the KPB have fast-growth ecological strategies corresponding to high assimilation rates and low carbon investment. This finding is consistent with impact winter leading to the nonrandom loss of slow-growing evergreen species. Our study reveals a dramatic example of the effect of rapid catastrophic environmental change on biodiversity. The Cretaceous\u2013Paleogene boundary (KPB) is marked by the Chicxulub bolide impact and mass extinction Here we test if the extinction event was selective for functional traits related to plant ecological strategies. We measure functional traits from fossil leaf assemblages spanning a 2.2 Myr interval across the KPB and assess four differing selection scenarios for functional traits: (i) directional selection\u2014a shift in phenotype space, caused by novel postboundary environments replacing preboundary environments; (ii) stabilizing selection\u2014a reduction in phenotype space caused by postboundary conditions making some strategies temporarily nonviable; (iii) diversifying selection\u2014an increase in phenotype space due to a wider range of postboundary conditions; or (iv) a lack of selection, because previous adaptations were unrelated to survival after major catastrophe.We assess evidence for these selection scenarios using functional traits 2]) Alternatively, longer-term temperature change may also have selected for certain traits across the KPB. Multiple proxies show a brief warming during the latest Cretaceous, starting approximately 300,000 y before the boundary near the base of Chron 29r, followed by a rapid return to cooler temperatures approximately 50,000 y before the boundary, which were then maintained through the earliest Paleogene 2 leaf area (LA)], and leaf minor vein density . Variation in these traits reflects a tradeoff between the transport of water and carbon We evaluate the causes and consequences of ecological change across the KPB by producing records of two central leaf functional traits that reflect variation in ecological strategies: leaf mass per area , because lower carbon dioxide availability could select for higher hydraulic capacity to maintain productivity 2] 2] decrease across the KPB therefore could be a key driver to our findings of an observed shift in VD. One hypothetical driver of lower [CO2] could be enhanced chemical weathering, via late-Cretaceous Deccan volcanism 2] dynamics within the time interval of interest. More detailed assessments of atmospheric composition and temperature across the KPB would be needed before this prediction could be tested.The increase in VD from the late Cretaceous to the early Paleogene in our data parallels the increases in VD seen across angiosperm taxa in the early-mid Cretaceous and then again across the KPB 2]. Although selection against low hydraulic capacity in low [CO2] environments should occur for all plants, for nonangiosperms and shade species, low values of VD appear to have successfully persisted in the fossil record across the Cretaceous There is an important criticism of the proposed mechanism coupling between VD and [COObserved trait dynamics across the KPB likely ramify to influence ecosystem functioning. Because of the close linkage between leaf economic traits and ecosystem resource fluxes We analyzed fossils of nonaquatic nonmonocot angiosperm taxa from sites previously collected from the Hell Creek and Fort Union Formations, now located in southwestern North Dakota. The stratigraphy of these sites and the identification of specimens has been described previously During the summer of 2013, we examined all appropriate specimens at the Denver Museum of Nature and Science (DMNH) and Yale Peabody Museum (YPM). We digitally photographed specimens with (1) intact petioles at the point of insertion with the leaf blade and (2) LAs that could be directly measured or confidently reconstructed. For each image, leaves were separated from their rock matrix using the lasso tool in Adobe Photoshop; LA and petiole width (PW) were then measured using ImageJ following the protocol of During June 2012, we examined all appropriate specimens at DMNH, including holomorphotypes on loan from YPM . We selected specimens that appeared to have complete preservation of the minor venation network in at least one region of the fossil, discarding all others . In specimens containing more than one leaf, we made a measurement for each leaf. We captured a digital image of each leaf fossil centered on the region of interest using a dissecting microscope coupled to a digital camera . Illumination was provided by ring-light. Image resolution was 243 pixels per millimeter.\u22121) and intervein distance  are related as:We then estimated VD using a line-counting program Each specimen was originally assigned a facies type by the original collector (table 3 in n\u200a=\u200a40).We calculated time series of VD and LMA using a binning approach. We first assigned each specimen to a 1-m depth interval defined by integer-rounding the measured stratigraphic depth. Within each bin we calculated species-at-site mean trait values, then used these to compute site means. We used these site-means to infer the distribution  of trait values within each bin. Because VD and LMA data were not always available within the same bin, we used piecewise linear interpolation to infer LMA values at each bin for which VD values were available  was obtained from a leaf margin analysis of the same fossil floras using the range-through mean annual temperature values corresponding to the supplementary table 8 of c using the error estimates provided in the original source, using the mean plus (minus) one standard deviation as the upper (lower) quartile. When no standard deviations were available, we assigned a standard deviation equivalent to the mean of all other standard deviations (2.8\u00b0C).An index of temperature Click here for additional data file.Figure S2LMA data, broken out by stratigraphy and facies. Symbols indicate species at-site means. Black points, data for each category; gray points, all other data.(PDF)Click here for additional data file.Figure S3LMA of species with different stratigraphic ranges and abundances. High LMA leaves are common in species that are found only in the Cretaceous but drop out at all abundances in species that cross the KPB or are found only in the Paleogene. Each point represents a species. Abundance data come from the quantitative census of Wilf and Johnson (PDF)Click here for additional data file.Figure S4Correlations between traits for time series data shown in (PDF)Click here for additional data file.Data S1VD data for all measured specimens.(CSV)Click here for additional data file.Data S2LMA data for all measured specimens.(CSV)Click here for additional data file.Data S3Temporally binned VD and LMA values, paired with proxy temperature values.(CSV)Click here for additional data file."}
+{"text": "Anal. Biochem. 474 (2015) 69\u201379].This data article contains three benchmark datasets for training and testing iDNA-Methyl, a web-server predictor for identifying DNA methylation sites [Liu et al.  Specifications table1\u2022DNA methylation plays an important role in regulating a variety of biological processes and is very important for basic research and drug development as well.\u2022The datasets presented here are good for testing DNA methylation site identifying algorithms because of their realistic, highly unbalanced nature.\u2022For the first dataset , users c2http://www.jci-bioinfo.cn/iDNA-Methyl, a web-server predictor for identifying DNA methylation sites. The DNA sample was formulated by combining its trinucleotide composition (TNC) and the pseudo amino acid components (PseAAC) of the sequence translated from the DNA sample according to its genetic codons. Sliding a window of nucleotides along each of the DNA sequences taken from MethDB (http://www.methdb.de/), and DNA sample was formulated by combining its trinucleotide composition (TNC) and the pseudo amino acid components (PseAAC) of the sequence translated from the DNA sample according to its genetic codons. In real world, the data very unbalanced. Target-jackknife was used to optimize the unbalanced benchmark dataset and minimize the consequence of this kind of mis-prediction.I.The first dataset  containsII.The 2nd dataset  is the oIII.The 3rd dataset  is the oThe data presented here are three benchmark datasets for training and testing iDNA-Methyl"}
+{"text": "Arterial stiffness is an independent predictor of cardiovascular mortality and can be assessed by CMR measurement of aortic distensibility (AD) and pulse wave velocity (PWV). We sought to determine AD and PWV in patients with severe symptomatic aortic stenosis and identify changes following TAVI compared to SAVR.Forty-eight patients underwent identical paired 1.5T CMR scans . Brachial artery blood pressure was recorded by Dinamap . Multi-phase steady state free precession (SSFP) cine imaging (50 phases) was acquired in a axial plane to the thoracic aorta at the level of the pulmonary artery bifurcation (Ascending aorta (AA) and proximal descending aorta (PDA)). AD (mmHg-1) was calculated following the contouring of the aortic region of interest, Figure 27 SAVR patients  and 21 TAVI patients  were studied before and 6 months following valve replacement. Arterial pulse pressure significantly increased following SAVR  but not after TAVI . AD significantly decreased post SAVR  whereas there was no change observed in the TAVI group . PWV significantly increased post-SAVR  whereas there was no change observed in the TAVI group .In patients with severe aortic stenosis, SAVR but not TAVI is associated with a significant increase in PWV and decrease in AD at 6 months. This increase in aortic stiffness may be a consequence of the different techniques of valve replacement and has potential long-term implications on cardiovascular mortality.This study was part-funded by the British Heart Foundation (BHF) (PG/11/126/29321). GP McCann and CD Steadman have received support from the NIHR Leicester Cardiovascular BRU."}
+{"text": "Epidemiologic data indicates that Asian diets, which are high in soy protein, reduce a women\u2019s risk of developing breast cancer. However, it has been difficult to dissociate the benefits of soy from other variables including environmental and lifestyle factors. Since prospective studies in humans would take decades to complete, rodent models provide a valuable research alternative.In this study, MTB-IGFIR transgenic mice, which develop mammary tumors resulting from overexpression of the type I insulin-like growth factor receptor (IGF-IR), were utilized. MTB-IGFIR mice were fed a soy-based or casein-based diet throughout all stages of development to reflect soy exposure in Asian cultures. Mammary tumors were initiated at 2 different developmental stages by commencing IGF-IR transgene expression either during puberty or in adult mice.Pgr and Areg, were elevated in mammary tissue from mice fed the soy diet compared to mice fed the casein diet suggesting that high levels of soy may promote mammary tumor development through acting as an estrogen receptor agonist. Mammary tumors from mice fed a soy diet more frequently expressed metaplastic markers such as cytokeratins 5 and 14 as well as p63 and displayed reduced lung metastases compared to mammary tumors from mice fed a casein diet.MTB-IGFIR mice fed a soy-based diet displayed increased tumor incidence and accelerated tumor onset compared to MTB-IGFIR mice fed a casein diet. Two markers of estrogen receptor signaling, Diets consisting of very high levels of soy protein promote mammary tumor development and decrease tumor latency possibly through activating estrogen receptor signaling. Additional studies are required to determine whether a more moderate amount of dietary soy can inhibit oncogene-induced mammary tumorigenesis.The online version of this article (doi:10.1186/s12885-015-1037-z) contains supplementary material, which is available to authorized users. Breast cancer rates vary depending on geographical location with the incidence of breast cancer being relatively high in North America and Western Europe compared to Asian countries such as Japan and China . One facSoy has been shown to contain several putative chemopreventative agents including isoflavones . IsoflavThe protective effects of soy have been demonstrated in case\u2013control and cohort studies in Asian populations in that soy consumption was inversely associated with breast cancer risk -13. ReduSince it is difficult to design studies to assess the causal association between dietary soy and mammary tumor risk as well as the mechanism through which soy modifies mammary tumorigenesis in humans, animal models have also been employed. Most of the animal studies performed to date have explored the impact of soy or specific isoflavones on chemically induced mammary tumors in rodents. Using these models, it has been shown that soy or specific isoflavones inhibit mammary tumor development induced by chemicals such as 7,12-dimethylbenz(a)anthracene (DMBA) and nitrosomethylurea (NMU) -22. It sMore recently, transgenic mice have been used to determine whether dietary soy protects against mammary tumor development. MMTV-Wnt1 mice fed a soy diet after weaning exhibited reduced mammary tumor incidence but significantly shorter tumor latency compared to mice fed a casein diet . In a stThe animal studies performed to date do suffer from some limitations. First, diets high in soy or isoflavones are often initiated during postnatal development while Asian populations presumably consume high levels of soy throughout their lives and thus Asian women are exposed to soy isoflavones during embryonic and postnatal development. Data from human studies suggest that although soy intake at any age decreases breast cancer risk, the greatest decrease in risk was associated with high dietary soy intake during childhood ,29-31. AOur study was designed to minimize the limitations of other animal models. To accomplish this, soy or casein diets were administered to female mice prior to mating and the females were maintained on the same soy or casein diet during lactation. Upon weaning the offspring were also maintained on the soy or casein diet to ensure female MTB-IGFIR transgenic mice were exposed to the soy or casein diet throughout all stages of development. Since it remains unclear when breast cancer initiation occurs, the IGF-IR transgene was induced at two different developmental stages, during puberty and in young, post-pubertal mice. Induction of the IGF-IR transgene at these two stages would simulate a spontaneous genetic alteration acquired in pubertal or young adult women.Pgr and Areg were expressed at higher levels in mammary glands of soy-fed mice suggesting a stimulatory effect of soy on estrogen receptor signaling.Using this experimental design, mice fed a soy-based diet had a significant increase in tumor incidence and shorter tumor latency than mice fed a casein-based diet. Mammary tumors from mice fed a soy diet more frequently expressed markers associated with metaplastic breast cancer including cytokeratin 5, cytokeratin 14, p63 and the presence of osseous matrix. The soy diet appeared to have a protective effect against tumor progression as lung metastases were more frequent in casein-fed mice. Although it is unclear how dietary soy promotes mammary tumorigenesis, two estrogen regulated genes, Animals were housed and cared for following guidelines established by the Central Animal Facility at the University of Guelph and the guidelines established by the Canadian Council of Animal Care. This study was approved by the Animal Care Committee at the University of Guelph (AUP# 1695) and all efforts were made to minimize suffering.MTB-IGFIR transgenic mice were generated in our lab and have been previously described . At the volume\u2009=\u2009length x width2/2. Tumor specific growth rate (SGR) was estimated using the formula: SGR\u2009=\u2009ln(V2/V1)/(t2-t1)  found at datam.i2r.a-star.edu.sg/ergdbV2/). Areg is a member of the epidermal growth factor family (EGFR) and is expressed at higher levels than any other EGF family member in the pubertal mammary gland [Areg expression in mammary glands and thus provides a potential mechanism through which dietary soy can influence mammary epithelial proliferation and potentially transformation.The mechanism through which soy isoflavones regulate mammary tumorigenesis remains unclear but most likely involves signaling through ERs. Estrogen is one of the main regulators of mammary epithelial proliferation -54 and sry gland . The AREry gland ,58. Our Fgf10, Fgfr1, Fgfr2, and Tgf\u03b1 [A number of other genes implicated in mammary gland development were evaluated in the mammary tissue of mice fed soy and casein diets including and Tgf\u03b1 -61. NoneOne potential protective effect of soy observed in our study was a 3-fold reduction in the percentage of soy-fed mice with metastatic lesions compared to the casein-fed mice when the IGF-IR transgene was induced at 100 days of age. The difference in metastatic incidence however, was not significant due to the small number of casein-fed mice that developed mammary tumors. A decrease in the percentage of soy-fed mice with lung mestatases is consistent with most of the studies in the literature that demonstrate that soy or isoflavones inhibit mammary tumor migration and metastasis -66, howeThe consumption of high levels of dietary soy also appears to impact mammary tumor morphology. Mammary tumors from soy-fed mice more frequently contained a mixture of luminal and basal/mesenchymal cells than mammary tumors from casein fed mice. Tumors expressing luminal and basal cell types have been described in humans and classified as metaplastic breast cancers. This is a rare subtype of breast cancer representing 0.2-5% of all breast cancers and was the focus of a recent commentary in Nature Reviews Cancer . MetaplaAreg. Future studies should examine the impact of different levels of dietary soy on mammary tumor development and whether soy regulates Areg expression. Determining whether lower levels of dietary soy can inhibit mammary tumorigenesis and whether Areg expression has potential as a biomarker for predicting breast cancer risk may have important implications for prevention and treatment of this disease.In conclusion, our study indicates that extremely high levels of dietary soy can promote mammary tumor development induced by overexpression of the tyrosine kinase receptor, IGF-IR. This increased susceptibility to transformation in the soy-fed mice appears to be associated with increased expression of"}
+{"text": "Cancer cell transformation entails significant alterations in intracellular metabolic pathways one of which is the aerobic glycolysis phenotype . The oriin vitro and in vivo) of the parental and modified cancer cells was carried out.We used two human breast cancer cell lines (MDA-MB-231 & MDA-MB-453) in this study where we cultured these cell lines in the presence of mitochondrial complex I inhibitor (rotenone) inhibitor for 25 generations thereby creating metabolically adapted cell lines counterparts. Metabolic analysis (In vivo analysis of tumor xenografts revealed that metabolically modified MDA231 cells displayed a ~50% reduction in tumor growth/volume accompanied by a reduced in vivo proliferation rate in comparison with the parental MDA231 cells thereby confirming the physiological relevance of metabolic adaptation in preclinical animal models. In conclusion, long-term metabolic adaptation to mitochondrial complex I modulators can be a unique and novel strategy for achieving tumor control in vitro and in vivo.Analysis of metabolic status in the isogenic parental and metabolically modified adaptive breast cancer cells show an overall improvement in mitochondrial function and a reduction in metabolic switch phenotype."}
+{"text": "Rice stripe virus (RSV) rice plants were examined by small RNA high-throughput sequencing. Our research confirms that the newly generated siRNAs, which are derived from the engineered inverted repeat construct, is the major contributor of the viral resistance in rice. Further analysis suggests the accuracy of siRNA biogenesis might be affected when siRNAs machinery is excessively used in the transgenic plants. In addition, the expression levels of many known miRNAs are dramatically changed due to RSV infection on both wild type and transgenic rice plants, indicating potential function of those miRNAs involved in plant-virus interacting process.RNA-mediated gene silencing has been demonstrated to serve as a defensive mechanism against viral pathogens by plants. It is known that specifically expressed endogenous siRNAs and miRNAs are involved in the self-defense process during viral infection. However, research has been rarely devoted to the endogenous siRNA and miRNA expression changes under viral infection if the resistance has already been genetically engineered in plants. Aiming to gain a deeper understanding of the RNA-mediated gene silencing defense process in plants, the expression profiles of siRNAs and miRNAs before and after viral infection in both wild type and transgenic anti- TheyCaenorhabditis elegans or Drosophila melanogaster with mutation affecting RNAi machinery have been reported to be more susceptible to viral infections [RNA-mediated gene silencing is known to serve as a self-defensive mechanism against viral pathogens by host cells. Individuals of fections , 12. Furfections \u201316. Thusfections , 18. Besfections , 20. Durfections \u201325. Somefections \u201328. Howefections , 30. Witfections .The usage of ihpRNA-based transgenic plants raises an interesting and important biological question: how does the plant natural defensive system react to virus infection when the viral resistance has been already transgenically introduced? Meanwhile, the fact that miRNAs and siRNAs could interact with each other adds another layer of complexity to this issue. Specifically, the altered expression levels of one might disrupt the existing miRNA-siRNA balance in cells and cause changes in the expression levels of the other by saturating the sRNA-induced silencing machinery since both miRNAs and siRNAs are utilizing an overlapped pathway in their biogenesis and metabolism processes \u201333.To further explore the underlying mechanisms of viral resistance in plants, our study offers a new perspective as the first study that compares changes of siRNAs and miRNAs expression profiles between wild type and transgenic viral resistant plants. Illumina small RNA deep sequencing is applied onto both wild type and ihpRNA transgenic rice plants before and after RSV infection. Those siRNAs derived from ihpRNA insertion, novel miRNAs and known miRNAs are identified and compared. Our analyses suggest the accuracy of siRNA biogenesis is reduced in transgenic plants. We also find many known miRNAs involved in the antiviral process and their putative gene targets are predicted. Lastly, we discuss the potential mutual impact and interaction between siRNAs and miRNAs for future research.Oryza sativa cv. Aichiasahi (AiA) as the background . To trigger viral defensive processes in plants, each experimental seedling was inoculated with approximately five planthoppers. The viruliferous and virus-free planthoppers (mock group) were introduced respectively into the plant growth chambers at the three-leaf stage of rice for virus inoculation. After 48 h, the planthoppers were removed, and the inoculated seedlings were maintained under 14-h/10-h light/dark cycle at 25\u00b0C greenhouse condition until the total RNA was isolated. The leaf materials for the total RNA extraction were obtained from one young leaf per treatment. The young leaves were collected one week after the virus-induced syndromes appeared  and the total RNAs were isolated subsequently.Our RSV resistant transgenic rice plants (T4B1) were engineered with the ihpRNA strategy using 5 of transgenic plants inoculated by virus-free and viruliferous insects respectively. Small RNA-Seq was conducted in Beijing Genomics Institute (BGI) by single-end sequencing. The four sRNA FASTQ files have been deposited in the NCBI Sequence Read Archive (study accession ID: SRP049382). The clean reads were obtained after trimming the sequencing adapters and filtering out the low quality reads. Clean reads ranging from 18\u201330 nucleotides in length  were used for downstream analyses. Small RNA reads were then mapped to the rice genome to study their genomic origins and small RNA annotation by using SOAP [Small RNA libraries were prepared with Illumina Small RNA library kit by following manufacturer\u2019s protocol. Four libraries were obtained: AiA_VF and AiA_V represented wild type plants inoculated by virus-free insects and viruliferous insects respectively; similarly, T4B1_VF and T4B1_V represented the Ting SOAP  and custing SOAP . All clehttp://www.phytozome.net/) to determine the origin of siRNAs. Varied mismatch settings of mapping were used for biogenesis accruracy analysis.siRNA duplex sequences were identified by Tag2siRNA . After nhttp://sourceforge.net/projects/mireap). To annotate known miRNA reads, all the clean reads are aligned to the rice miRNA precursor database (downloaded from www.mirbase.org). To study the known miRNA expression profiling, annotated miRNA species sequences with at least 3 supported reads were selected. The expression level changes for miRNAs were analyzed using DESeq [The novel miRNA and known miRNA were identified by Mireap (BGI: ng DESeq .http://plantgrn.noble.org/psRNATarget/) was used to predict the putative targets for specific siRNA and miRNA [psRNATaget web server  that are described to be highly expressed (>1000 reads supported) in Du\u2019s paper [Although RSV-derived siRNAs might be the vital reason for this viral resistance in our case, the contribution of miRNA for RSV resistance cannot be ignored. In order to examine the expression profile changes of known miRNAs and to study the possible connection between miRNA profiling with the viral resistance, DESeq was used to compare miRNA expression levels among four libraries , 41. Bei\u2019s paper  presenteThe changes of known miRNA expression profiling were studied using DESeq from three aspects: the impact on expression profiling of known miRNA caused by the engineered ihpRNA construct was studied by comparing AiA_VF and T4B1_VF, the impact caused by viral infection in wild type plants was studied by comparing AiA_VF and AiA_V, and the impact caused by viral infection in transgenic plants was studied by comparing T4B1_VF and T4B1_V respectively. As described in To study the effect of novel miRNAs in transgenic rice plants, putative novel miRNAs see  were preTo study the impact of RSV-derived siRNAs in transgenic rice plants besides their original function of silencing RSV-CP genes, the top 50 highly expressed RSV-derived siRNAs from T4B1_VF were selected as input query sequences for psRNAtarget web server  to prediAs shown in Previous research claims the possible role miRNA plays in the process of self-defensive response to virus . RegardiArabidopsis [The crosstalk of siRNA and miRNA is also briefly examined in our study. Liang et al have reported that manually induced siRNAs can alter the expression level of many miRNA through competing Ago2 loading site . Limitedbidopsis . On the bidopsis . In our Collectively, our results provide the first research of the siRNA and known miRNA profiling changes in an ihpRNA engineered viral-resistant plant using high-throughput sequencing. The siRNA derived from ihpRNA construct is determined as an important contributor to the antivirual resistance in plants. The accuracy of siRNA biogenesis machinery might be influenced if excessively used, but the accuracy of miRNA biogenesis machinery seems not to be affected. In addition, our data analysis does not suggest any novel miRNAs involved in the process of RSV infection. We have also assessed the potential impact of differentially expressed miRNAs due to the insertion of ihpRNA construct or the RSV infection by predicting their targeting genes. In sum, this research will facilitate our understanding of the regulation and function of miRNAs and siRNAs in transgenic plants.S1 Fig(DOCX)Click here for additional data file.S1 Table(DOCX)Click here for additional data file.S2 Table(DOCX)Click here for additional data file.S3 Table(DOCX)Click here for additional data file.S4 TableNormal count represents the population of miRNA reads without SNP. SNP count presents the population of miRNA reads with SNP (mismatches) from their miRNA precursors. The ratio is calculated by dividing SNP count with normal count.(DOCX)Click here for additional data file."}
+{"text": "A 15-year-old adolescent presented to us with mild headache, progressive dizziness and recent vomiting since 2 weeks without seizures. There was a history of head injury (neglected) following a stone-throwing incident 2 months earlier. On examination, he was conscious with a left cerebellar syndrome but without other neurologic deficit. Routine biologic data were normal. CT-scan revealed left posterior fossa extradural lesion with hypodensity in the center and calcified wall (A). MRI showed that the lesion was liquid with homogeneous ring enhancement following gadolinium injection and cerebellar compression (B and C). A sub-occipital craniotomy was done and a chronic liquefied hematoma was removed. There was a thick hard calcified wall relatively adherent to the duramater (D). Postoperative period was uneventful and the patient was discharged symptoms free. Histologically, the wall contains large areas of ossification. Ossified chronic epidural hematoma is a very rare complication following head injury. The blood accumulates slowly from a venous source becomes chronic extradural hematoma and becomes calcified or ossified due to an inflammatory reaction of the dura especially in children. This rare phenomenon should be considered in the differential diagnosis of other traumatic epidural and subdural hematomas."}
+{"text": "Prone positioning is a therapeutic maneuver to improve arterial oxygenation in patients with acute lung injury that is not implemented in most centers performing adult cardiac surgery. The aim of this study was to review our experience with prone positioning, which has become increasingly used at our center over the last years.From 2010 to 2014, 127 adult patients with postoperative acute respiratory failure were treated with prone positioning in addition to supportive therapy. Preoperative and intensive care unit data obtained from medical records were retrospectively reviewed. Univariate and multivariate logistic regression analyses were performed to identify independent risk factors associated with in-hospital mortality.2/FiO2 ratio were significantly different between groups , but only pre-pronation FiO2 remained highly significant at multivariate analysis . Patients who died showed a higher improvement of the PaO2/FiO2 ratio immediately after pronation compared with survivors . Patients who died had higher pea k white blood cell counts than survivors  and a higher rate of low output syndrome prior to prone positioning . Both variables were found to be independent predictors of mortality at multivariate analysis .In-hospital mortality was 22.8% (n = 29). No complications related to the proning maneuver were recorded. No significant differences were observed in preoperative risk factors between patients who survived (group S) and those who died (group D), except for age  and EuroSCORE II . Age retained statistical significance at multivariate analysis . Pre-pronation values of the PaO2/FiO2 ratio.Prone positioning is a safe treatment option for adult patients with postoperative acute respiratory failure. Its efficacy seems to be closely related to two factors: the optimal timing of application of the procedure and a noncardiogenic etiology as the cause of low PaO"}
+{"text": "A subset of patients with cancer have evidence of a spontaneous anti-tumor immune response and T cell infiltration into tumor sites. This has prognostic significance and is associated with clinical response to immunotherapeutics in multiple cancers. It has been observed that high mutational load in a tumor also correlates with response to modern immunotherapies though definitive mechanistic data has yet to be shown. Molecular mechanisms underpinning the absence of a T cell response are beginning to be understood with identification specifically of the WNT/\u03b2-catenin pathway playing a major role in melanoma.in silico analysis of The Cancer Genome Atlas (TCGA), sorting gene expression profiling and DNA sequencing data across all tumor types included. For each tumor, RNAseq data was subjected to unsupervised clustering on ~15,000 genes expressed in at least 50% of the samples.To better understand the genetic landscape of T cell-inflamed human solid tumors and to investigate molecular pathways that may mediate immune-exclusion, we performed an We discovered 160 genes concordantly clustered with a previously identified 13 gene immune signature across all cancers. Subsequent consensus sample clustering using the concordant genes facilitated division of each tumor into either a high, medium or low T cell-inflamed status. Simultaneously, non-synonymous exonic somatic mutations were retrieved from DNA sequencing data allowing mutational load to be associated with the presence or absence of a T cell-inflamed phenotype in individual samples. Pathway analysis was performed to identify molecular signaling pathways showing activation in low versus high T cell-inflamed tumors.Overall the analysis identified the T cell-inflamed phenotype as being present in approximately 33% of all samples within TCGA with clear cell kidney cancer demonstrating the highest median score and uveal melanoma demonstrating the lowest score. While there was some trend between tumors known to have high mutational load and higher incidence of the T cell-inflamed tumor microenvironment, this correlation was imperfect, and within individual tumors there was no difference in mutational load between high T cell-inflamed tumors and low T cell-inflamed tumors. Pathways analysis again confirmed WNT/\u03b2-catenin pathway activation in non-T cell-inflamed melanomas as well as other non-T cell-inflamed cancers. Pathways of interest by individual tumor type are under further investigation.These data suggest that spontaneous anti-tumor immune priming is not driven by mutational load alone. Additionally, it appears likely that tumor-intrinsic molecular pathways will be identified in many tumor types which may suggest rational combination therapy approaches for the future."}
+{"text": "Daam1), which is important for the morphogenesis of the eye and other organs. In this study, Patricia Ybot-Gonz\u00e1lez\u2019s group sought to further explore the role of the Wnt-PCP pathway in diabetic embryopathies. They induced experimental diabetes in pregnant mice and found that maternal hyperglycaemia induced eye malformations in mouse embryos. In vitro studies confirmed sensibility of eye development to hyperglycaemia and showed reduced expression of Wnt-PCP pathway genes. Notably, Daam1-mutant embryos displayed similar eye malformations, which were worsened by environmental hyperglycaemia. These results show that maternal diabetes can affect embryogenesis by altering Wnt-PCP signalling. Modulating this pathway might thus represent a potential strategy to reduce the impact of diabetic embryopathies. 157Page Congenital malformations in diabetic pregnancy are still a major health concern despite the improvements in glycaemic control strategies. Advancing our understanding of the mechanisms responsible for diabetic embryopathies could help develop strategies to prevent this condition. It is known that maternal hyperglycaemia affects components of the Wnt-PCP signalling pathway, including the dishevelled-associated activator of morphogenesis 1 gene ("}
+{"text": "Our results clearly indicate that combining Bortezomib with adoptive T cell therapy can sustain T cell activation and function and, thus, enhances tumor immune surveillance. We are also elucidating a microRNA signature regulating immune Notch signaling. Our preliminary data suggest the role of miR-155 and miR-34a in Bortezomib induced regulation of T cell activation. The potential of Bortezomib to modulate anti-tumor Notch signaling and to enhance T cell activity presents exciting opportunities. Therapeutic restoration of immune Notch signaling by Bortezomib could help to break tumor resistance, enhance immune surveillance and sustain robust anti-tumor immunity.The immunosuppressive tumor microenvironment perturbs numerous immune regulatory networks and usurps host antitumor immunity. We discovered that tumor interferes with host hematopoietic Notch system in lung cancer patients. The resultant decrease in immune Notch signaling could be a major causative link in the adequate induction of antitumor immunity. Interestingly, we observed that administration of the FDA- approved proteasome inhibitor drug Bortezomib  to tumor bearing mice can restore Notch signaling in lymphoid cells without increasing tumor cell proliferation or clonogenicity. Moreover, Bortezomib administration altered Notch receptor and ligand expression pattern and increased the expression of Notch target genes Hes1, Hey1 and deltex1 in thymus, lymph node and spleen. Bortezomib administration in tumor bearing mice increased IFN-g production by T cells while the proportion of regulatory T cells was decreased. Our results indicate that the activation of Hes1 and Hey1 is mediated via inhibition of NFkB pathway while deltex1 activation is mediated by PI3K pathway. In another set of experiment, we observed that administration of Bortezomib along with adoptive CD8"}
+{"text": "Our previous work has demonstrated that Notch signalling modulates cilia length in the zebrafish left-right organizer (LRO) . Howeverdnah7.To link Notch signalling to the regulation of cilia motility genes that may be upstream of Gene expression of potential motility-mediator targets were validated by qPCR in deltaD mutants. Whole mount in situ hybridization was performed to assess dnah7 gene expression in zebrafish embryos at various stages of development. We used high-speed videomicroscopy to study olfactory pit and LRO cilia motility in dnah7 zebrafish morphants. The ultrastructure of static cilia was analysed from embryos injected with dnah7-MO.dnah7.Dnah7 is upregulated in deltaD mutants. Dnah7 is expressed in other organs with motile cilia, such as the olfactory pits, brain ventricles and pronephros. Down-regulation of dnah7 showed also to affect motility in olfactory pits and pronephros. We are validating microarray data by qPCR and will present a model on how Notch signalling may affect the expression of Dnah7 knock-down affects cilia motility in various ciliated organs during zebrafish development. We found specific target genes from the foxj1 and rfx families, which encode regulatory factors that may be involved in a Notch signalling transduction pathway linked to cilia motility.Supported by FCT-ANR/BEX-BID/0153/2012 grant."}
+{"text": "We present a method based on minute-by-minute ICP monitoring and outcome (GOS) to visualize in a clinically useful way the dynamic aspects of secondary injury.A retrospective analysis of data from 165 adult patients from the Brain-IT database [Figure Secondary injury is dynamic such that not only thresholds but also insult duration are relevant. The proposed visualization goes beyond the static 20 mmHg ICP threshold introduced in ["}
+{"text": "Purpose. To report an unknown complication of laser in situ keratomileusis (LASIK) surgery. Case Presentation. A 28-year-old female presented with photophobia and glare to our eye service. She stated in her medical history that she had undergone femtosecond assisted LASIK surgery in both eyes 15 months ago and her symptoms started just after this surgery. On admission, her best-corrected visual acuity was 10/10 in both eyes. She had mydriatic pupils with no direct light reflex. Examination of the anterior segment revealed bilateral iris atrophy projecting within the LASIK ablation zone and a transillumination defect was remarkable on the slit lamp examination. Conclusion. We hypothesized that this condition may have been caused by the abnormally increased IOP that resulted in ischemia in the iris vascular plexus during the suction process of surgery. Refractive surgery has undergone significant progress and evolution during the past two decades with the advent of the excimer laser. Excimer laser refractive surgical options mainly include photorefractive keratectomy (PRK) and laser in situ keratomileusis (LASIK) . Since FA 28-year-old female presented with photophobia and glare to our eye service. She stated in her medical history that she had undergone femtosecond assisted LASIK surgery in both eyes 15 months ago and her symptoms started just after this surgery. Preoperative medical records of the patient revealed \u22124.75 (\u22121.00 \u00d7 175) in the right eye and \u22124.50 (\u22120.50 \u00d7 180) in the left eye and otherwise a normal ophthalmological examination. On admission, her best-corrected visual acuity was 10/10 in both eyes. She had mydriatic pupils with no direct light reflex. Visual fields were full to confrontation in both eyes. Examination of the anterior segment revealed bilateral iris atrophy projecting within the LASIK ablation zone  and a trSeveral flap-related or intraoperative complications of femtosecond assisted LASIK surgery are reported in the literature . HoweverAll these studies show the significant effects of LASIK surgery on intraocular pressure and ocular hemodynamics. In the literature optic neuropathy cases have been reported following LASIK surgery and it has been considered that this complication might be a result of barotrauma or ischemia related to extremely elevated intraocular pressure during a portion of the LASIK procedure \u201311. Ther"}
+{"text": "Echocardiography is currently the gold standard for cardiac tissue velocity measurement . Phase cEighteen healthy volunteers underwent cardiac MRI examination on a Signa HDxt 3T scanner . A phase contrast sequence modified to acquire only the central k-space line was used in a mid-ventricular small axis scan plane with through-plane velocity encoding during 128 heartbeats. The frequency encoding direction was angulated to encompass the projection of the left ventricular outflow tract plane . One subject was manually post processed due to failure of automatic detection and a total of 360 heart beats were also discarded. For eleven subjects, velocity curves similar to echocardiographic ones were obtained  as well as MPI were well correlated. This paves the way for the observation of beat to beat intra-subject variability of cardiac indices.None."}
+{"text": "There is a suspected link between Brazilian babies born with microcephaly and Zika virus (ZIKV) infection. However, little is know about the brain cell targets and the mechanisms that Zika virus may cause microcephaly. A recent report demonstrated that Zika virus infection increases cell death and dysregulates cell-cycle, resulting in attenuated human neural progenitor cells growth. This study fills a major gap and serves as an entry point to establish a mechanistic link between Zika infection and microcephaly. The recent dramatic rise of infant microcephaly in Brazil has drawn globe attention . There hA recent study from Dr. Guo-li Ming and colleagues of Johns Hopkins School of Medicine has filled a major gap in ZIKV biology. This new research may serve as an entry point to establish a mechanistic link between ZIKV and microcephaly .By using a laboratory protocol of differentiating induced pluripotent stem cells (iPSCs) into forebrain-specific human neural progenitor cells (hNPCs) , Ming anZIKV infection was also found to lead to cell death by activating Cas3. The virus can dysregulate cell-cycle, resulting in attenuated hNPC growth. This is also consistent with the hypothesis that Zika infection may cause microcephaly.This new study provides a tractable experiment system for modeling the impact of ZIKV on neural development. The in vitro hNPC model provides a new tool for investigating the underlying cellular and molecular mechanisms. The robust hNPC cellular phenotype comprises a readily scalable platform for high-throughout screens to anti-ZIKV drugs."}
+{"text": "The 2009 outbreak of H1N1 caught many off guard-not least those responsible for tracking the emergence of new influenza strains and outbreaks [Acute lung infection and inflammation such as in influenza pneumonia are associated with the \u201ccytokine storm\u201d that recruits excessive immune cells to infiltrate lung tissue. The infiltrated immune cells clear pathogens by various means such as generating reactive oxygen species that exacerbates tissue damage. Influenza infection also impairs pulmonary functions partially by inducing vascular leakage that facilitates further infiltration of immune cells and pulmonary edema. These phenomena raise the possibility that enhancing lung endothelial barrier integrity during infection and inflammation may ameliorate lung tissue damage, and may be therapeutically useful for acute lung injury \u20134.Recent studies reveal that angiopoietin-like 4 (ANGPTL4) is upregulated during influenza pneumonia . High-thBacterial pneumonia may present as a primary disease process, or as the final terminal event in individuals who are already debilitated. A historical review of the 1918 influenza pandemic suggests that the majority of deaths were not directly attributed to the influenza virus; rather the mortalities were due to bacterial co-infections. While the objective of anti-inflammatory approaches against influenza pneumonia is to mitigate the devastating impact of hypercytokinemia, such therapies also render the host more susceptible to secondary infections. In contrast, direct regulation on vascular or tissue leakiness may attenuate excessive inflammation without compromising host immune defenses. Although the role of ANGPTL4 in inflammation remains to be fully elucidated, our interrogation of microarray gene expression data of lungs from influenza-infected mice treated with neutralizing ANGPTL4 antibody did not reveal significant diminution of host defenses against bacterial infections. Hence, improving vascular integrity may offer a more effective and probably safer alternative to combat lung infection. Furthermore, ANGPTL4 also shows great potential as a biomarker for pneumonia.Vascular leakage is a hallmark of many infectious diseases, including those caused by dengue virus, severe acute respiratory syndrome (SARS) coronavirus, and Middle East respiratory syndrome (MERS) coronavirus. The roles of ANGPTL4 in these infections are unclear, and certainly warrant future investigations. Importantly, the recent studies on host response factors such as ANGPTL4 provide a new level of understanding with respect to vascular integrity in pulmonary infection and inflammation."}
+{"text": "Insulin independence is a realistic therapeutic goal in feline diabetes. Remission is dependent on achieving fast glycemic control. However, without intensive monitoring high insulin doses increase the risk of hypoglycemia. An 11-year old spayed Burmese cat presented with diabetes after steroid treatment for skin allergy. Control of blood glucose was not achieved using low carbohydrate diet plus the recommended q12h treatment with either insulin lente or glargine, with the total dose limited by the risk of hypoglycaemia.The aim was to achieve euglycaemia and insulin-independence.A more frequent insulin treatment was tried. Seven weeks from start of q12h treatment, the total daily dose of insulin glargine was divided across three injections. One week later the frequency of injection was increased to q6h. There was intensive monitoring of capillary blood glucose (Accu-Chek Aviva).There was a prominent glucose nadir after approximately 4h regardless of insulin type. Within four weeks on insulin q8h and q6h blood glucose levels were within the normal range. Weight gain was noted and within one week of caloric restriction insulin was withdrawn completely. One month later fructosamine had normalized and after more than three years the cat remains off insulin with blood glucose levels at the upper limit of the reference range.More frequent insulin injections than recommended in literature may be necessary to achieve glycemic control. Owners are important collaborators in feline diabetes care and with intensive home monitoring more frequent insulin treatment may lead to remission without hypoglycemia."}
+{"text": "Mycobacterium tuberculosis.Tuberculous aortitis is an unusual presentation of a common disease in Sri Lanka. There were no reported cases of tuberculous aortitis from Sri Lanka. Here we report a case of a 40-year-old woman who developed an ascending aortic aneurysm with severe aortic regurgitation caused by A 40-year-old Sri Lankan female who presented with exertional breathlessness (NYHA II) and weight loss for 4\u00a0weeks duration was found to have collapsing pulse and early diastolic murmur at left sternal edge. Transthoracic and transesophageal echocardiogram showed ascending aortic aneurysm with severe aortic regurgitation. Computed tomographic aortography confirmed the diagnosis of aneurysmal dilatation of the ascending aorta. She underwent successful aortic valve replacement and aortic root replacement. The final diagnosis of tuberculous aortitis was made on the basis of macroscopic appearance of inflammation and microscopic confirmation of caseating granuloma. She made a good clinical recovery with category 1 antituberculous chemotherapy.Although most cases of aortitis are non-infectious in Sri Lanka, an infectious etiology must be considered in the differential diagnosis because therapeutic approaches differ widely. Tuberculous aortitis may be under diagnosed in Sri Lanka, a country with intermediate tuberculosis burden, as the histological or microbiological diagnosis is not possible in most cases. The clinical and radiological diagnostic criteria for tuberculous aortitis need to be set out in case of aneurysmal aortic disease in the absence of apparent etiology. Staphylococcal species and Streptococcus pneumoniae which seed the aortic wall with preexisting pathology via the vasa vasorum [Mycobacterium tuberculosis is a rare disease entity, with involvement of the aortic root being exceedingly rare [The diagnosis of rare infectious aortitis should be made accurately as the treatment strategy differ from that of more common non-infectious aortitis such as giant cell arteritis (GCA) and Takayasu arteritis. Bacterial aortitis is most commonly associated with Salmonella,  vasorum . Mycoticgly rare . Aortic gly rare . The diaA 40-year-old Sri Lankan female presented with exertional breathlessness (NYHA II) and weight loss for 4\u00a0weeks duration. There was no cough, hemoptysis, evening pyrexia or night sweats and no history of limb claudication. Her past history was negative for connective tissue disorders, vasculitis or tuberculosis. The family history was unremarkable. General examination did not reveal any abnormal physical signs. She had collapsing pulse and blood pressure of 110/40\u00a0mmHg in both arms. Early diastolic murmur was heard in both left and right sternal edge. The lung bases were clear and rest of the systemic examination was normal.Chest x-ray showed smooth dilatation of the ascending aorta and walls of it are not parallel to each other. Transthoracic and transeseophageal echocardiogram showed ascending aortic aneurysm (maximum diameter of 54\u00a0mm) with severe aortic regurgitation. Cardiac chamber dimensions were within normal limits and left ventricular ejection fraction was normal. Computed tomographic (CT) aortography confirmed the dilatation of aortic root and ascending aorta without dissection or leaking. Acute phase reactants were slightly elevated . Venereal Disease Research Laboratory test (VDRL) was non-reactive. Antinuclear antibody was negative.Cardiology team proceeded their further evaluation with pre-operative coronary angiogram which showed normal epicardial coronary arteries. Aortic valve and root replacement was recommended by the cardiologist. Cardiothoracic surgical team carried out the aortic valve replacement (AVR) with 19\u00a0mm bileaflet St Jude Medical mechanical valve and aortic root replacement with 30\u00a0mm Albo graft. Surgeon noted evidence of aortitis with external inflammatory adhesions during the surgery. Post-operative period was uneventful. Warfarin therapy was started while closely monitoring the INR and it was kept between 2 and 3. Histological examination of aortic wall revealed granulomatous aortitis with caseous necrosis  consisting of 3 fixed dose combination tablets per day each containing rifampicin 150\u00a0mg, isoniazid 75\u00a0mg, pyrazinamide 400\u00a0mg and ethambutol 275\u00a0mg (RHZE). Frequent dose adjustment of warfarin was required during ATT. Continuation phase of ATT was extended for up to 10\u00a0months with rifampicin and isoniazid as in the case of disseminated tuberculosis. She made a good clinical recovery with improvement of her symptoms and follow up image showed functioning aortic prosthesis while maintaining INR in therapeutic range.Tuberculous aortitis is a very rare form of extra-pulmonary tuberculosis. It can be caused by direct extension of Mycobacterium tuberculosis from an adjacent focus of infection or by hematogenous spread. Close proximity of distal aortic arch and the descending aorta to a specific group of mediastinal lymph nodes may explain it being the commonest site for tuberculous aortitis, but exceptionally ascending aorta is affected as in this case . The speMany infectious and non-infectious etiologies are associated with aortitis. Negative VDRL test makes the syphilitic aortitis less likely as a cause for ascending aortic aneurysm in this patient. She did not have any typical clinical features or radiological criteria of Takayasu arteritis. Giant cell arteritis was not a consideration in this case as it affects individuals older than 50\u00a0years of age . AbsenceTuberculous arteritis is an important consideration in this case as new case finding rate of all tuberculous diseases (pulmonary and extra-pulmonary) are 9000\u201310,000 in Sri Lankan annually . The diaThe definitive diagnosis was ultimately established by histology of the surgical specimen which confirmed it as granulomatous aortitis with evidence of caseous necrosis. Although positive AFB on ZNS strongly favor the diagnosis of tuberculous aortitis, negative test does not exclude the diagnosis as the sensitivity of this test is very low. Granulomatous aortitis with caseous necrosis more favor the diagnosis of tuberculous aortitis even though no evidence of tuberculosis in another site.She complied with Category one ATT without any drug induced complications, but warfarin therapy to maintain INR in therapeutic range (2\u20133) needed frequent monitoring and dose adjustments as some of the anti-tuberculous drugs are known liver enzyme inducers. Since this form of tuberculosis is indicative of disseminated disease , we deciInfectious aortitis like tuberculosis should be considered as an etiology for aortic aneurysm. Diagnostic criteria without histological specimens are defined for non-infectious aortitis like Takayasu arteritis and GCA. Surgical biopsy or specimens are often needed for the confirmation of infectious etiology such as tuberculous aortitis though it is not possible in all cases. Noninvasive imaging techniques like MRA are emerging investigation modalities to detect aortic wall inflammation and peri-aortitis. High degree of suspicion in an appropriate clinical setting in combination with imaging may justify the treatment with ATT. Development of diagnostic criteria for tuberculous aortitis based on the clinical findings and imaging may be a future research area.Written informed consent was obtained from the patient for publication of this case report and any accompanying images."}
+{"text": "After completing a successful quality improvement (QI) initiative to decrease non-medically indicated scheduled births <39 weeks in 20 large maternity hospitals, the Ohio Perinatal Quality Collaborative (OPQC) aimed to expand this work across Ohio. Our objective was to evaluate the effectiveness of the QI intervention used by OPQC to rapidly spread the 39 week initiative.Participating hospitals were exposed to an 8-month QI intervention to reduce non-medically indicated scheduled deliveries <39 weeks and reflect those improvements in accurate state vital statistics data. The intervention was implemented using a step-wedge design with hospitals divided into three balanced waves. Effectiveness was assessed using interrupted time-series analysis. Interviews with a sample of participants and project call recordings were analyzed using qualitative methods to understand implementation.Seventy of the 72 (97%) eligible hospitals agreed to participate. Hospitals actively participated as evidenced by 95.7% attending the in-person learning session and 80% attending at least three of four monthly group calls. Based on birth registry data, rates of non-medically indicated inductions <39 weeks declined in all waves concurrent with the start of the intervention. Changes related to reducing deliveries <39 weeks were variably implemented--some hospitals described extensive changes as a result of their participation while others who had previously begun work in this area described either small changes or no changes. Participants implemented multiple changes to improve birth registry accuracy.We describe a QI intervention enabling state-wide spread of effective change strategies over 12 months. This intervention could support a model where a network of innovator hospitals develops and tests change strategies and then rapidly spreads successful approaches to a broader population. Such a model has the potential to advance dissemination and implementation science.AHRQ U19HS02114, CDC 31-90000-553005-130488, and Ohio Government Resource Center."}
+{"text": "Peroneal artery arteriovenous fistulas and pseudoaneurysms are extremely rare with the majority of reported cases due to penetrating, orthopedic, or iatrogenic trauma. Failure to diagnose this unusual vascular pathology may lead to massive hemorrhage or limb threatening ischemia. We report an interesting case of a 14-year-old male who presented with acute musculoskeletal pain of his lower extremity. Initial radiographs were negative. Further imaging workup revealed a peroneal arteriovenous fistula with a large pseudoaneurysm. After initial endovascular intervention was unsuccessful, the vessels were surgically ligated in the operating room. Pathology revealed papillary endothelial hyperplasia consistent with an aneurysm and later genetic testing was consistent with Ehlers-Danlos syndrome Type IV. This case illustrates an unusual cause of acute atraumatic musculoskeletal pain and uncommon presentation of Ehlers-Danlos syndrome. Arteriovenous fistulas often result from iatrogenic trauma while gaining percutaneous vascular access. Turbulent blood flow and endothelial damage may eventually lead to pseudoaneurysm formation with resulting mass effect and risk of massive hemorrhage. While several case reports have documented peroneal pseudoaneurysms resulting from iatrogenic and orthopedic trauma, there are no known reports of both an arteriovenous fistula and pseudoaneurysm presenting in a patient with an undiagnosed connective tissue disorder. Utilizing multiple imaging modalities, this case nicely documents the unique vascular findings in this interesting case.A healthy 14-year-old male presented with acute onset lower extremity calf pain and swelling that began while playing soccer. He denied trauma to the limb and on physical exam was neurovascularly intact. An MRI to evaluate possible ligamentous injury revealed a large abnormal flow void adjacent to the peroneal artery and vein thought to represent a pseudoaneurysm or arteriovenous malformation . CT angiUltrasound showed a 2.0 \u00d7 1.5\u2009cm pseudoaneurysm with swirling of blood flow in the pseudoaneurysm sac giving the characteristic \u201cYin-Yang\u201d appearance on Color Doppler . Both pePercutaneous intervention was attempted; however, a wire could not be successfully placed distally in the peroneal artery to traverse the pseudoaneurysm neck. The patient subsequently underwent open ligation of the pseudoaneurysm and arteriovenous fistula. Postoperatively his symptoms resolved and genetic analysis revealed a collagen mutation compatible with Vascular Ehlers-Danlos syndrome Type IV.Arteriovenous fistulas (AVF) and pseudoaneurysms (PSA) of the peroneal artery are uncommonly reported in the literature and are extremely rare presenting together. Most pseudoaneurysms result from orthopedic, penetrating, or iatrogenic trauma with the latter often seen after Fogarty balloon embolectomy or percutaneous vascular access , 2. CongWhile the pseudoaneurysm and arteriovenous fistula in this patient were initially thought to be traumatic in origin, genetic testing later revealed a mutation in the COL3A1 gene of collagen 3 compatible with a diagnosis of the Vascular Type 4) Ehlers-Danlos syndrome. Of the 6 major types of Ehlers-Danlos syndrome, Type 4 is one of the most serious types and is most often associated with major vascular complications  Ehlers-D. While vPeroneal artery pseudoaneurysms have been successfully treated by coil embolization of the pseudoaneurysm sac or, alternatively, embolization of the peroneal artery proximally and distally to the pseudoaneurysm neck , 7. Whil"}
+{"text": "A set of standard clinical chemistry and hematology parameters are usually measured during clinical studies. The major outcome of these standard tests is to control that the drug investigated does not lead to pathophysiological changes in respective organs or blood. In some cases based on scientific rationale such tests may not be needed.In this paper we report on a standard set of clinical chemistry and hematology laboratory parameters measured before and after treatment in three different immunotherapy studies, representing different routes of administration and different formulations.Thirteen hematological laboratory parameters and eight clinical chemistry parameters were evaluated from three double-blind, placebo-controlled, randomized, multi-centre, phase III studies. The three studies include one with sublingual immunotherapy (n\u2009=\u2009185), one subcutaneous immunotherapy trial with an aluminium hydroxide-adsorbed recombinant hypoallergenic Bet v1-FV (n\u2009=\u2009211) and one with pre-seasonal subcutaneous immunotherapy with a 6-grass pollen allergoid (n\u2009=\u2009154).Allergen specific immunotherapy with both administration forms and formulations respectively did not show any influence on any of the 21 laboratory parameters analyzed. Few patients had a change in laboratory parameters from within normal range at baseline to either below or above at end-of-treatment. No differences between active and placebo were seen with respect to number of patients with such a change.This study with different preparations and routes of application indicates that the value of repeated measurements of standard clinical chemistry and hematology parameters during allergen immunotherapy should be discussed further. As a routine analysis for evaluation of safety in clinical development programs for new drugs, a set of standard clinical chemistry and hematology parameters are measured. The major outcome of these standard tests is to control that the drug investigated does not lead to pathophysiological changes in respective organs or blood. Guidelines from EMA on safety pharmacology studies discuss such a pharmacology core battery for investigation of vital functions and that in some cases based on scientific rationale such tests may not be needed . In the Allergen specific immunotherapy is known to be an efficient treatment for respiratory allergic diseases and based on clinical investigations also shown to have a good safety profile including only potential allergic side effects in patients already allergic to the allergen they are treated with . In receIn this paper we report on a standard set of clinical chemistry and hematology laboratory tests measured before and after treatment in three different immunotherapy studies, representing different routes of administration and different formulations.Thirteen hematological laboratory parameters and eight clinical chemistry parameters Table\u00a0 were evaThe first study was performed with sublingual immunotherapy (SLIT) of the high dose grass pollen preparation (ALLERSLIT\u00ae forte) (SLIT 6-grass study) and included 185 patients . Mean agAll patients had a history of IgE-mediated seasonal allergic rhinitis/conjunctivitis with or without asthma (GINA stage I and II) caused by grass pollen (grass studies) or birch pollen (birch study), positive skin prick test result to grass pollen extract (grass studies) or birch pollen extract (birch study), and positive conjunctival provocation test with grass pollen allergens (grass studies) or birch pollen allergens (birch study). Only patients with moderate to severe allergic symptoms to grass or birch pollen were included in the clinical trials. Patients were excluded if they previously had undergone grass or birch pollen immunotherapy or suffered from other seasonal allergies in the same period as the relevant grass or birch pollen, or had a history of cardiovascular or other immunological or medically relevant diseases.Holcus lanatus, Dactylis glomerata, Lolium perenne, Phleum pratense, Poa pratensis, and Festuca elatior) or placebo from January 2004 until end of grass pollen season in 2005. The group 5 allergen content of the active maintenance dose corresponded to 40\u00a0\u03bcg. Patients in the SCIT rBirch study were treated with subcutaneous injections of recombinant hypoallergenic variant of the major birch pollen allergen  or placebo from October 2004 until end of birch pollen season in 2006. Treatment of patients in the SCIT 6-grass study included pre-seasonal weekly injections with either 6-grass pollen  allergoid or placebo until the expected onset of the grass pollen season 2001 and 2002.After up-dosing patients in the SLIT 6-grass study were treated daily with high-dose sublingual 6-grass pollen preparation ; SLIT: Sublingual immunotherapy; SLIT 6-grass study: Sublingual immunotherapy study with a high dose 6-grass pollen preparation.All authors are employees of Allergopharma GmbH & Co. KG. The authors declare that they have no competing interests.DH, VG and AN were involved in the design of the studies, data interpretation and drafting, revising and final approval of the manuscript. All authors read and approved the final manuscript.A list of all participating ethics committees.Click here for file"}
+{"text": "Respiratory and cardiac motion in PET/MR imaging leads to reduced quantitative and qualitative image accuracy. Correction methodologies involve the use of double gated acquisitions which lead to low signal-to-noise ratio (SNR) and to issues concerning the combination of cardiac and respiratory frames. The objective of this work is to use a generalized reconstruction by inversion of coupled systems (GRICS) approach, previously used for PET/MR respiratory motion correction, combined with a cardiac phase signal and a reconstruction incorporated PET motion correction approach in order to reconstruct motion free images from dual gated PET acquisitions. The GRICS method consists of formulating parallel MRI in the presence of patient motion as a coupled inverse problem. Its resolution, using a fixed-point method, allows the reconstructed image to be improved using a motion model constructed from the raw MR data and two respiratory belts. GRICS obtained respiratory displacements are interpolated using the cardiac phase derived from an ECG to model simultaneous cardiac and respiratory motion. Three different volunteer datasets (4DMR acquisitions) were used for evaluation. GATE was used to simulate 4DPET datasets corresponding to the acquired 4DMR images. Simulated data were subsequently binned using 16 cardiac phases (M1) vs diastole only (M2), in combination with 8 respiratory amplitude gates. Respiratory and cardiac motion corrected PET images using either M1 or M2 were compared to respiratory only corrected images and evaluated in terms of SNR and contrast improvement. Significant visual improvements were obtained when correcting simultaneously for respiratory and cardiac motion (using 16 cardiac phase or diastole only) compared to respiratory motion only compensation. Results were confirmed by an associated increased SNR and contrast. Results indicate that using GRICS is an efficient tool for respiratory and cardiac motion correction in dual gated PET/MR imaging."}
+{"text": "MicroRNAs have emerged in recent years as important regulators of cell function in both normal and diseased cells. MiRNAs coordinately regulate large suites of target genes by mRNA degradation and/or translational inhibition. The mRNA target specificities of miRNAs in animals are primarily encoded within a 7 nt \u201cseed region\u201d mapping to positions 2\u20138 at the molecule's 5\u2032 end. We here combine computational analyses with experimental studies to explore the functional significance of sequence variation within the seed region of human miRNAs. The results indicate that a substitution of even a single nucleotide within the seed region changes the spectrum of mRNA targets by >50%. The high functional cost of even single nucleotide changes within seed regions is consistent with their high sequence conservation among miRNA families both within and between species and suggests processes that may underlie the evolution of miRNA regulatory control. RNA-induced silencing complex (RISC) recognize their regulatory targets by Watson-Crick base pairing to compatible sequences  in target mRNAs.MicroRNAs (miRNAs) are small 20\u201322 nucleotide (nt) RNA molecules that play important regulatory roles in cell function It is estimated that there are >1000 sequentially distinct miRNAs in the human genome, each being present in a few to hundreds of copies To determine the mRNA targets of the 249 conserved miRNAs, we utilized three online target prediction programs, miRanda-mirSVR We determined the distance between two sequences by calculating the Hamming distance 2. The transfection protocol was as described previously HEY RNA was extracted from transfected cells using the RNeasy Mini RNA isolation kit . Microarray experiments were performed as previously described http://www.ncbi.nlm.nih.gov) SuperSeries number GSE56973.To determine differentially expressed genes in triplicates of experimental miRNA and negative control treated cells, the following procedure was followed. Quality control was first assessed using all raw CEL files as implemented in Array Analysis Homo sapiens genes were selected on BioMart and filtered to remove the genes with no mouse orthologs. The output file included the mouse orthologs for all the resulting genes. These genes were then used for our comparison of miR-429 and miR-200b predictions across human and mouse species.Orthologous genes in human and mouse were identified using the BioMart data-mining tool The functional consequence or \u201ccost\u201d of seed region nucleotide changes involves the loss of regulatory control over previously targeted mRNAs and/or the acquisition of novel regulatory control over previously untargeted mRNAs. To systematically explore this phenomenon computationally, we first determined the number of nucleotide changes needed to transform one seed region into another (Hamming distance) for each of the 249 miRNAs analyzed in this study. We then calculated the percent overlap (cosine similarity) of predicted targets for all pairs of miRNAs having identical seeds. For example, the percent target gene overlap for miR-25 and miR-32 (both having the seed sequence: 5\u2032AUUGCAC) predicted by miRanda-mirSVR is 81% . The 19%We next independently computed the average percent overlap of predicted mRNA targets for pairs of miRNAs having seeds that differ by 1 to 7 nucleotides. The results  indicatein vivo because they ignore the myriad of indirect regulatory effects induced by miRNAs While informative in their own right, functional predictions based on target prediction algorithms alone are often inaccurate 2\u200a=\u200a1511; p<0.0001) and consistent with the prediction that a substantial functional cost is associated with even a single nucleotide change within miRNA seed regions. Differences in overlap between the miR-429 vs M12 and miR-429 vs M14 comparisons were not found to differ significantly  indicating that, in this experimental context, position of the single nucleotide change is not significant with respect to functional cost.As mentioned above, the functional cost associated with nucleotide changes within seed regions is reflective of the loss of regulatory control over previously targeted mRNAs and/or the acquisition of novel regulatory control over previously untargeted mRNAs. We experimentally estimated these parameters by comparing all significantly differentially expressed genes in cells transfected by miRNAs with seeds differing by 0 (miR-429 vs miR-429), 1 (miR-429 vs M12 and miR-429 vs M14) or 5 (miR-429 vs M5) nucleotides. Presented in 2\u200a=\u200a1535; p<0.0001) but not significantly different from the changes induced by miRNAs with only a single nucleotide difference from miR-429 .Changes in the percent overlap of significantly differentially expressed genes between cells transfected by miR-429 vs those transfected by the miRNA differing at 5 nucleotide positions within the seed region  were alsCollectively, the above results indicate that even a single nucleotide substitution within the seed regions of miRNAs is associated with substantial functional cost and suggests an evolutionary model whereby strong stabilizing selection is maintaining rigid conservation of miRNA seed sequences both within and between species. Individual target genes, on the other hand, may acquire and/or lose miRNA regulatory control(s) through even single nucleotide substitutions in miRNA target sequences complimentary to miRNA seeds  . Any funAs an initial test of this prediction, we selected two miRNAs (miR-429 and miR-200b) that have identical seed regions in both humans and mice . We emplCollectively, our findings support an evolutionary model whereby miRNAs initially evolve to regulate large suites of target genes. Thereafter, the sequential integrity of miRNA seed regions is maintained by strong stabilizing selection due to the high functional cost of even a single nucleotide mutation within miRNAs. In contrast, nucleotide mutations in the target sequences of individual genes, being, on average, of substantially lower functional cost, allow for a relatively rapid repositioning of miRNA-target gene associations. Indeed, a variety of scenarios might arise to buffer the possible negative effects of target sequence mutations in regulated genes. For example, duplication of specific target sequences within regulated genes could serve to mask the impact of the sudden loss of existing miRNA regulatory controls while still permitting genes to explore the potential adaptive benefits of acquiring new miRNA regulatory controls.S1 FigureOne nucleotide difference or 7 nucleotide differences in the seed regions of miRNAs is predicted to be associated with equivalent levels of change in regulated target genes. (a) miRNAs with identical seeds, miR-195 and miR-16, are predicted to share 91% of their target genes; (b) miRNAs with a single nucleotide change in their seed regions, miR-195 and miR-29a, are predicted to share only 21% of their target genes; (c) miRNAs with no sequence similarity in their seed regions, miR-195 and miR-205, are predicted to share only 18% of their target genes. These results are consistent with the hypothesis that as little as a single nucleotide difference within miRNA seed regions has a major effect on miRNA regulatory control.(PDF)Click here for additional data file.S2 FigureDistribution of percent overlap of miRanda-mirSVR predicted targets of miRNAs having 0 through 7 seed mismatches. Insets show distribution according to two other popular prediction algorithms: a) TargetScan, and b) PicTar. The results are uniformly consistent with the prediction that even a single nucleotide mismatch within miRNA seed regions results in a large change in targeted mRNAs.(PDF)Click here for additional data file.S1 TableTarget overlap for miRNAs with identical seeds. Predicted (miRanda-mirSVR) overlap (cosine similarity) in target genes for all pairs of miRNAs with identical seed regions.(XLSX)Click here for additional data file.S2 TableTarget overlap for miRNAs with non-identical seeds. Predicted (miRanda-mirSVR) overlap (cosine similarity) in target genes for all pairs of miRNAs with non-identical seed regions.(XLSX)Click here for additional data file.S3 TableFold-change for all (5229) significantly differentially expressed genes after ectopic expression of miR-429 in HEY cells.(XLS)Click here for additional data file.S4 TableFold-change for all  significantly differentially expressed genes after ectopic expression of M12 in HEY cells.(XLS)Click here for additional data file.S5 TableFold-change for all  significantly differentially expressed genes after ectopic expression of M14 in HEY cells.(XLS)Click here for additional data file.S6 TableFold-change for all  significantly differentially expressed genes after ectopic expression of M5 in HEY cells.(XLS)Click here for additional data file."}
+{"text": "Plakin repeat domains mediate the interactions of these proteins with the cell cytoskeleton and are critical for the maintenance of tissue integrity. Despite their biological importance, no solution state resonance assignments are available for any homologue. Here we report the essentially complete  Envoplakin is a member of the plakin family of cytolinkers. Plakin proteins connect elements of the cell cytoskeleton to each other and to junctional complexes at the cell membrane. The plakin proteins play a vital role in the maintenance of tissue integrity, particularly in tissues such as the heart and skin that are subjected to high levels of mechanical stress  and resuspended in phosphate buffered saline with complete EDTA-free protease inhibitors (Roche). The cells were lysed using an EmulsiFlex-C3 (Avestin) and the lysate cleared by centrifugation . The envoplakin PRD was purified from the supernatant by nickel affinity chromatography using HisTrap HP columns (GE Life Sciences). The poly-His tag was cleaved using Tobacco Etch Virus protease, leaving 8 exogenous residues. The PRD was further purified by size exclusion chromatography using a Superdex-75 column (GE Life Sciences).A construct comprising the complete human envoplakin PRD module (residues 1822\u20132014) was expressed with a cleavable N-terminal His-tag using the pProEx HTc vector (Life Technologies) in BL21 (DE3) NMR experiments were performed at 298\u00a0K on Agilent NMR spectrometers equipped with cryogenic Z-axis pulse field gradient probes. Backbone assignments were made using BEST versions of the HNCA, HNCACB, HNCOCA, HNCO and HNCACO experiments  under accession number 26642.The own Fig.\u00a0 indicateown Fig.\u00a0 and the"}
+{"text": "Mucinous cystic neoplasm (MCN) occurs predominantly in women (>95%) with a mean age of approximately 45 years and most commonly is located in the pancreatic body or tail. The mass is lined by mucin-producing columnar epithelium with a fibrous ovarian-type stroma. The epithelial lining can contain various degrees of atypia, ranging from adenoma to invasive carcinoma. The CT and MR appearance is that of a thick walled cystic mass with septa and/or mural nodules. The contour of the mass is smooth, and the wall or septa may contain calcification. Endoscopic ultrasound with fine needle aspiration of the cyst fluid to assess CEA level may be helpful in distinguishing MCN from serous cystadenoma. CEA <5 ng/mL favors serous cystadenoma, whereas CEA >192 ng/mL favors MCN, with an accuracy of approximately 80% [Serous cystadenoma (SCA) also occurs predominantly in women (approximately 75%), but the mean age is older (mid 50s to early 60s). It is lined by glycogen-rich cuboidal epithelium and is considered a benign neoplasm, although rare cases of malignant SCA have been reported. The typical appearance is that of a lobulated mass consisting of numerous tiny cysts which give it a honeycomb appearance. Larger lesions may contain a central stellate scar and calcifications. Oligocystic or macrocystic SCA is an uncommon variant comprised of a small number of larger cysts. Distinction between macrocystic SCA and MCN can be made based on the lobulated contour of SCA, its multiple clustered cyst configuration and homogeneity of each locule on T1 weighted MR images [R images . SurgicaR images .Solid pseudopapillary neoplasm (SPN) is a rare low-grade malignancy that predominantly affects younger women (>80%), with a median age 30-38 years [38 years ,6. It isCystic neuroendocrine neoplasm of the pancreas most commonly occurs in patients with multiple endocrine neoplasia type I and usually is nonfunctional [nctional . It genenctional ."}
+{"text": "TN usually leads to paroxysms of short lasting but very severe pain. Between the attacks the patient is usually asymptomatic, but a constant dull background pain may persist. Carbamazepine is currently the drug of first choice in the treatment of TN. It is efficient in 70-80% of patients but often associated with severe adverse effects such as drowsiness, confusion, nausea and ataxia, which may require discontinuation of medication. Surgical interventions may not be suitable for all patients and waiting for the procedure can be agonizing. Therefore different non-invasive treatment options are indispensable.To investigate the efficacy of transcranial direct current stimulation (tDCS) of the primary motor cortex on pain and trigeminal nociceptive processing in subjects with classical trigeminal neuralgia (TN).Seventeen subjects with TN were recruited in the study. Patients stimulated daily for 20 minutes over two weeks using anodal (1mA) or sham tDCS in a randomized cross-over design. Primary outcome variable was pain intensity on a verbal rating scale (VRS). VRS and attack frequency were assessed daily for one month before and after tDCS using an individual patient diary. The impact on trigeminal pain processing was assessed with pain-related evoked potentials (PREP) and the nociceptive blink reflex (nBR) following electrical stimulation on both sides of the forehead (V1) before and after tDCS. All patients gave written informed consent prior to study inclusion. The study was approved by the Ethics committee of University of Duisburg-Essen medical faculty.Anodal tDCS reduced pain intensity more effectively than sham stimulation after two weeks of treatment. The attack frequency reduction was not significant. PREP showed an increased N2 latency and decreased peak-to-peak amplitude after anodal tDCS. No severe adverse events were reported. Patients with concomitant chronic background pain do not seem to benefit from tDCS as described previously for medical therapy and surgical intervention.Daily anodal tDCS over two weeks ameliorates trigeminal pain in TN. It may become a valuable treatment option for patients unresponsive to conventional medical treatment or on wait for surgical procedures. International, multicenter, randomized controlled trials are needed with higher patient numbers before a definite recommendation can be proposed.No conflict of interest."}
+{"text": "Antibody engineering allows proper design of improved properties in antibody products such as a high binding affinity, stable biophysical properties and low immunogenicity. Besides these obvious features improved by elegant design the primary amino acid sequence also has tremendous effects on the performance of the expression host itself influencing cell culture parameters including specific productivities and growth rates therefore having major impact on the finally obtained antibody expression titers . By undeMany different antibody variants were expressed in our group in different projects based on various isotypes. For several antibody variable regions we could observe a direct correlation of advantageous cell performance and a high degree of similarity to the closest human germline sequence of the respective mature antibody leading to higher specific productivities. However, the fundamental principles of these consistent observations and the correlation of cell behavior and biophysical product properties remain quite elusive. Therefore, in this project we aim to set the proper foundations to investigate the generalization of a concept to improve cell performance and antibody expression based on the primary sequence at a high germinality degree Figure . To haveAll cell lines  were grown under serum- and protein-free conditions in chemically defined media in suspension using shaker flasks. Transfections were performed with the cationic 25kDa linear polymer polyethylenimine (PEI). Stable subclones were either generated by limited dilution subcloning or fluorescence-activated cell sorting (FACS).Germline antibody sequences were identified by the IgBlast program. Variable antibody sequences were synthesized and cloned into vectors containing leader and constant antibody regions.For recombinase-mediated cassette exchange a CMV (for DUKX-B11) or CAGGS (for CHO-K1) promoter was placed 5' upstream of the first flippase recognition target site to establish a promoter trap in the parental RMCE-cassette. A selection/reporter marker was placed in-between two heterospecific FRT sites harboring a gfp/thymidine-kinase/neomycin-phosphotransferase fusion protein. Antibody producing cells were developed after recombination with the reporter marker by negative selection with ganciclovir. Antibody product was purified by protein A chromatography.The observed expression levels in cell cultures are influenced by many different parameters that should be controlled for a valid comparison of different antibody variable sequences. Besides different host cell lines and media formulations our group also has standardized fermentation process protocols and biophysical analytical tools for in-depth investigations of possible correlation between cell culture performance, product quality attributes and expression levels. Recently, we also engineered a CHO DUKX-B11 host cell line suitable for recombinase-mediated cassette exchange (RMCE)  to contrAn improved RMCE host cell line and an antibody panel consisting of versatile variable regions including mature antibodies and respective germline antibody sequences were constructed for in-depth analysis of cell culture parameters and biophysical properties evoked by different degrees of germinality. By understanding the underlying principles it should be possible to improve antibody cell culture processes and biophysical features by means of proper antibody engineering to optimize the primary antibody sequence."}
+{"text": "Calciphylaxis following acute renal failure is rare.We report A 57-year-old male with an acute renal failure associated with necrotizing fasciitis. We also review the cases of calciphylaxis due to acute renal disorder further.It should be kept in mind that calciphylaxis is observed in patient with not only chronic renal disease but also acute renal failure. Calciphylaxis is a disease of cutaneous vessel calcification-induced skin ulceration Hayashi . AlthougA 57-year-old male with an acute renal failure associated with necrotizing fasciitis underwent hemodialysis. He had no history of diabetes mellitus or heavy smoking. Six weeks after the hemodialysis, he noticed painful skin ulcers on both of his legs, which gradually enlarged without any rubbing or other outer physical stimuli. Physical examination revealed a skin ulcer covered with black-yellowish necrotic tissue Fig.\u00a0a. DorsalAlthough almost all cases with calciphylaxis have been described in patients with end-stage renal disease on hemodialysis, this patient exhibited calciphylaxis following hemodialysis due to acute renal failure. To clarify the detail characteristics, we review the cases of calciphylaxis associated with acute renal failure. There have been three reported cases including our case Table\u00a0 Honda e. All casIt should be kept in mind that calciphylaxis is observed in patient with not only chronic renal disease but also acute renal failure. Because of limited number of cases, further investigation is necessary to clarify the detail mechanism of calciphylaxis due to acute renal failure."}
+{"text": "Toxoplasma gondii. Toxoplasmosis is considered one of the most common cerebral opportunistic infections in HIV-AIDS patients. It develops when CD4 count falls below 100 cells/cmm, either from acute exposure to the parasite or from reactivation of latent infection. These patients may also develop extra-cerebral toxoplasmosis such as ocular toxoplasmosis and pulmonary diseases. Another clinical manifestation described in HIV-infected patients is disseminated toxoplasmosis which consists of fever, pulmonary infiltrates and sepsis-like syndrome.Toxoplasmosis is a disease caused by the intracellular parasite T. gondii, CMV and fungal infection. We noticed also an extensive ulcerated esophagitis of HSV and fungal etiology.We present a case of a 22 years old female patient diagnosed with HIV since her childhood. Over the years she was uncompliant to combined antiretroviral therapy (cART). After 16 years from her HIV diagnosis she presented an acute hepatitis type C with severe prolonged evolution, from which she slowly recover after a period of 3 months. After discharge she was well for about one month but came back with left hemiparesis difficulties in speech and visual disturbances. Also during this last hospitalization she presented a severe bronchopneumonia. After 20 days of hospitalization she died. Postmortem histopathological examinations revealed a disseminated toxoplasmosis involving multiple organ systems: central nervous system, lung, liver, spleen and lymph nodes. Lung examinations revealed bronchopneumonia due to multiple opportunistic coinfections with In immunosuppressed patients disseminated toxoplasmosis has a polymorphic clinical presentation requiring a more attentive investigation because it may hide also an involvement with other opportunistic infections. The syndrome of disseminated toxoplasmosis is affecting more than two organs and it is highly lethal in HIV positive patients."}
+{"text": "While cutaneous metastases are already extremely rare in primary metastatic prostatic adenocarcinoma, cutaneous manifestations in recurrent prostate cancer have rarely been described prior to this report. Here we present the case report of a 93-year-old male who underwent radical prostatectomy but eventually suffered from a previously undescribed recurrence of prostatic adenocarcinoma with distant cutaneous metastases to proximal right lower leg. Adenocarcinoma of the prostate is the most commonly diagnosed nondermatological malignancy among men and a leading cause of cancer-related mortality, second only to lung cancer. Despite the high incidence and prevalence of prostate cancer in society, distant cutaneous metastases tend to occur exceptionally infrequently\u2014reported at <0.1% in primary disease \u20134. Of noA 93-year-old man presented with gross hematuria and a red, translucent papule on his proximal right lower leg . Twenty Next to early-stage primary dermatological neoplasms, prostate cancer remains one of the most curable malignancies, with encouraging recurrence-free five-year survival rates greater than 80% . Most paCutaneous manifestations are associated with a poor prognosis because of the presumed systemic involvement required to develop such overt metastatic disease. The mean survival time after diagnosis of cutaneous metastasis has been calculated at 7 months . Because"}
+{"text": "Segmentectomy is an anatomic sublobar resection that has recently been introduced for small lesions in cases of lung cancer.In completion lobectomy after segmentectomy, pleural adhesion in the hilar vessels and inter-segmental plane makes the procedure most difficult. Preventing adhesion could reduce intraoperative bleeding and operation time in cases of reoperation.Here, we present a case of right S9+10 segmentectomy followed by completion lobectomy for unanticipated nodal metastasis of cT1N0/pN1 lung cancer, in which pleural adhesion was prevented by coating with fibrin glue.We describe the case of a 54-year-old man who underwent completion lobectomy for unanticipated hilar nodal metastasis reported on postoperative pathologic examination 1 month after right S8+9 segmentectomy for clinical T1N0 lung cancer. In the initial surgery, we used electrocautery without a stapler to divide the inter-segmental plane. The entire dissected inter-segmental plane was covered with absorbable mesh and fibrin glue. At re-thoracotomy, pleural adhesion at the inter-segmental plane was never observed although there were adhesions at parietal pleura not covered with fibrin glue.Covering the inter-segmental plane with fibrin glue may be useful not only for preventing air leakage but also for preventing pleural adhesion.Written informed consent was obtained from the patient for publication of this abstract and any accompanying images. A copy of the written consent is available for review by the Editor of this journal."}
+{"text": "Isolated thoracic spinous process fractures involving multiple adjacent vertebral segments are a rare occurrence in the setting of high-energy trauma. These findings should prompt further investigation to exclude other concomitant osseous or ligamentous injuries. Evaluation by computed tomography is often most useful to detect these fractures. Proper treatment of extensive multilevel injury is poorly defined in the literature. In our experience, conservative management consisting of initial bracing with graduated lifting restrictions has produced excellent functional results. The term \u201cClay-Shoveler's fracture\u201d was originally coined in 1940 to describe isolated spinous process fractures occurring from C6-T3 in Western Australian laborers \u20136. ThereA 53-year-old male was involved in a motorcycle collision at a speed of approximately 40\u2009mph. Physical exam was significant for right-sided paraspinal tenderness in the thoracic region. He had no neurologic deficits. Computed tomography (CT) revealed thoracic spinous process fractures within T5\u2013T10 without evidence of vertebral body injury, extension into the lamina, or ligamentous compromise . He alsoA 53-year-old man without a helmet lost control of his motorcycle and collided with a guardrail. He had loss of consciousness and an initial Glasgow coma scale score of 12. Physical exam revealed no gross abnormalities of the spine; however he expressed significant left-sided paraspinal tenderness in the thoracic region. CT of his spine revealed isolated fractures of the thoracic spinous processes within T6\u2013T10 without any other evidence of spine pathology . He alsoIsolated thoracic spinous process fractures involving five or more contiguous vertebrae are rarely encountered in the orthopaedic literature. These fractures often occur in conjunction with other bony or soft tissue injuries of the vertebral column. The two aforementioned cases almost double the reported literature on this specific fracture pattern. Although this pattern of injury has been referred to elsewhere as \u201cClay-Shoveler's fracture,\u201d it should be considered a different entity based on the energy mechanism, level, and extent of contiguous segment involvement. Meyer et al.  describeOther authors have recently reported cases of extensive multilevel spinous process fractures involving the cervicothoracic junction , 10. HowIsolated thoracic spinous process fractures are stable injuries, which are routinely treated with conservative therapy. Even in the setting of multilevel contiguous fractures, excellent functional outcomes are commonplace with nonoperative therapy. Conservative treatment with a TLSO brace for 6 weeks with graduated lifting restrictions for up to 10 weeks has produced great results in our experience, with both patients going on to pain-free full recovery. Persistent and focal pain over the spinous processes beyond this time period should raise concern for a symptomatic pseudoarthrosis. It is well documented that spinous process fractures infrequently achieve osseous union ; howeverIsolated thoracic spinous process fractures in the setting of high-energy trauma are a rare occurrence. Involvement of five or more contiguous thoracic vertebral segments has been reported only three times previously in the literature , 5, 7. I"}
+{"text": "NK cells contribute to melanoma cell recognition and anti-tumor immunity, which is traditionally analyzed using human peripheral blood NK cells. An important checkpoint in the progression of malignant melanoma is the metastasis to lymph nodes.To investigate the role of lymph node NK cells in disease progression, we analyzed frequency, phenotype and functions of NK cells purified from either tumor infiltrated lymph nodes or tumor-free ipsilateral lymph nodes of the same patients. Lymph node NK cells were compared to peripheral blood NK cells from either melanoma patients or healthy donors.dimCD57+CD69+CCR7+KIR+ NK cells in tumor infiltrated lymph nodes. This phenotype corresponds to a recently described fully mature and highly cytotoxic NK cell population, and indeed we found that these lymph node NK cells displayed robust anti-tumor activity against autologous melanoma cells. The NK cells trafficking from periphery to the tumor draining lymph nodes have been investigated and the chemokines pattern identified. Moreover, the presence of a high proportion of KIR+CD57+CD56dim in the infiltrated lymph nodes was associated with an improved patients\u2019 survival.The data showed an expansion of CD56Our data suggest that NK cells from tumor infiltrated lymph nodes are attractive candidates to improve current NK cell-based immunotherapy of melanoma."}
+{"text": "While current breast cancer staging includes lymph node involvement as a key indicator of prognosis, little is known about how healthy tissue surrounding the immediate tumor microenvironment contributes to the loco-regional spread of disease. Previous studies of the role of the immune microenvironment in breast cancer have focused on the study of intratumoral T cells, reporting that increased intratumoral CD8+ T cell proportions with decreased CD4+ T cell proportions are associated with lymph node metastasis and rapid tumor progression. We hypothesized that T cells within the unaffected breast tissue  near the tumor (2-5 cm away from the tumor margin) may influence the local/regional spread of tumor cells. Since the amount of tissue available for study from the excision of primary tumors is limited, we utilized a previously established three-dimensional explant method to expand resident T cells from fresh breast cancer and healthy-adjacent breast tissue to investigate their phenotypic and functional qualities. We compared tissues from patients with LN metastasis (n = 8) and those without LN involvement (n = 7). We defined the surface phenotype of T cells derived from breast cancer and healthy-adjacent tissue using multiparameter flow cytometry. We found that healthy-adjacent tissue from patients with LN metastases exhibited a 1.6 fold lower percentage of CD4 T cells (p < 0.01) and 3.7 fold higher percentage of CD8 T cells (p < 0.05) than patients with no LN involvement. In contrast, we did not find any statistically significant differences in the number of intratumoral CD4 and CD8 T cells in patients with LN metastases versus those with no LN involvement. We hypothesized that qualitative T cell cytokine response from the surrounding healthy adjacent tissue may also be associated with LN metastases. Our preliminary data from the study of breast cancer patients (n = 6) showed some trends of increased Th2 cytokine and decreased pro-inflammatory cytokine associated with nodal metastases. These data suggest that the tissue extending beyond the tumor microenvironment  may contribute to immune surveillance and regional metastases. While this study size is small, it demonstrates the feasibility of using the explant method to interrogate healthy-appearing tumor adjacent tissue to investigate the surrounding breast tissue environment. Our preliminary findings also indicate the potential relevance of investigating the role of T cells in tumor adjacent healthy-appearing breast tissue to provide tumor immune surveillance. Further analysis of the T cells present in healthy adjacent breast tissue is warranted.Written informed consent was obtained from the patient for publication of this abstract and any accompanying images. A copy of the written consent is available for review by the Editor of this journal."}
+{"text": "Combining focused ultrasound (FUS) with real time MRI guidance and monitoring enables a new non-invasive treatment of brain disorders. In this technique multisource ultrasound waves are focused at a single point raising the temperature gradually until ablation occurs. Lesions as small as 2-4 mm can be made, without impact on surrounding tissue or remote brain tissue.Our aim was to assess MR guided focused ultrasound (MRgFUS) as a new non-invasive surgical tool for treating essential and parkinsonian tremor by thalamotomy of the ventral-intermediate nucleus.Eight patients with severe medically refractory tremor, 4 essential tremor and 4 with Parkinsonian tremor, underwent unilateral ventral-intermediate nucleus thalamotomy using MRgFUS. Following the preoperative planning using 3D CT and 3D 3T MRI, patients lay in the MRI scanner while awake with their head immobilized in a stereotactic frame. The transducers helmet was mechanically positioned and a silicone membrane sealed the space between the patient\u2019s head and the helmet.MRI scans was performed with the helmet and frame in place, the target identified and accuracy verified at low temperatures. Treatment consisted of multiple sonications at gradually increased temperatures. MRI thermal scan provided feedback on the temperature achieved and the target accuracy. Between sonications patients provided information concerning side effects and neurological examinations were performed to verify effect.Tremor stopped in the contralateral upper extremity in all patients immediately following the procedure. In two Parkinson disease patients ipsilateral rigidity was decreased as well. Immediate side effects included during sonications: vomiting (n=1), and transient forehead pain (2), transient vertigo (2) and following the procedure: scalp numbness , subjective transient gait unsteadiness  Clinical assessment of the examiner and patient changed from severe disability to no functional disability from tremor immediately following the procedure. Follow-up of up to 10 months show sustained effect. No late side effects were noted.Thalamotomy of the VIM using MRIgFUS is safe and effective in both Parkinson disease tremor and essential tremor with minimal mostly transient side effects. Large randomized studies and longer follow up are needed in order to assess safety and efficacy."}
+{"text": "Delirium is frequent in the critically ill and is associated with long-term morbidity . CurrentTo investigate whether systemic corticosteroids increase the probability of transitioning to delirium in a mixed medical-surgical ICU population.We conducted a prospective cohort study in a 32bed mixed medical-surgical ICU. Critically ill adults who stayed in the ICU for more than 24hours, without acute neurological disorders or other conditions hampering delirium assessment were included. Systemic corticosteroid administration was measured daily. Dosage were converted in milligrams (mg) prednisone equivalents. Daily mental status was classified as 'coma', 'delirium', or an 'awake without delirium' state using a previously described algorithm based on the CAM-ICU score . The priA total of 1112 patients accounted for 9867 ICU days. The transition from being 'awake without delirium' to 'delirium' occurred 562 times (6%). On 3483 days (35%) systemic corticosteroids were administered, with a median dosage of 50 (interquartile range 25-75) mg prednisone equivalents. Administration of systemic corticosteroids was not significantly associated with the transition to delirium . Increasing dosage on days patients received corticosteroids was not associated with an increased odds of transitioning to delirium either .Our findings suggest that exposure to systemic corticosteroids is not a risk factor for the transition to delirium."}
+{"text": "Human parvovirus B19 is considered an important trigger of aplastic crisis in patients with chronic congenital hemolytic disorders.We describe the case of a young adult known with hereditary microspherocytosis who presented with fever, marked agitation and confusion and a slight left hemiparesis. The cerebral imaging revealed multiple giant cystic Virchow-Robin spaces, but no other abnormalities. The complete blood counts showed pancytopenia and the peripheral blood smear revealed reticulocytopenia, confirming the diagnosis of aplastic crisis. Human parvovirus B19 infection was proven by the detection of serum DNA using PCR technique. After the initiation of packed red cells transfusion a favorable outcome was seen and his neurologic symptoms fully remitted.Direct invasion of human parvovirus B19 may induce both aplastic crisis and acute encephalopathy in patients with hereditary spherocytosis. Human parvovirus B19 may induce aplastic crisis but also acute encephalopathy through direct invasion, although in our case the transient neurological symptoms were rather an effect of hypoxia."}
+{"text": "Differences in the relative abundance of dinucleotides, if any may provide important clues on host-driven evolution of viruses. We studied dinucleotide frequencies of large DNA viruses infecting vertebrates  and invertebrates . We have identified systematic depletion of CpT(ApG) dinucleotides and over-representation of CpG dinucleotides as the unique genomic signature of large DNA viruses infecting invertebrates. Detailed investigation of this unique genomic signature suggests the existence of invertebrate host-induced pressures specifically targeting CpT(ApG) and CpG dinucleotides. The depletion of CpT dinucleotides among large DNA viruses infecting invertebrates is at least in part, explained by non-canonical DNA methylation by the infected host. Our findings highlight the role of invertebrate host-related factors in shaping virus evolution and they also provide the necessary framework for future studies on evolution, epigenetics and molecular biology of viruses infecting this group of hosts. Differences in the relative abundance of dinucleotides provide interesting insights on virus evolution. CpG dinucleotides in particular have received a lot of attention. Depletion of CpG dinucleotides among viruses has been linked to selective mutational pressure Mutational pressure at specific dinucleotides is a critical parameter for understanding evolution of viruses. CpG dinucleotides are heavily methylated (80%\u201390%) in vertebrate host genomes as opposed to low levels of methylation in invertebrate host genomes Codon usage bias is an important determinant of virus evolution. Both mutational pressure and translational selection may contribute to codon usage bias In this study, we investigate the differences in the relative abundance of dinucleotides, mutational pressure and codon usage bias between large DNA viruses infecting vertebrate- and invertebrate hosts. Well documented differences between the two host groups include (a) Depletion of CpG dinucleotides in the vertebrate host genomes http://www.ncbi.nlm.nih.gov/genomes/GenomesGroup.cgi?taxid=35237) or http://www.ncbi.nlm.nih.gov/nucleotide). When multiple full-length sequences were available for a virus, only one full-length sequence was used for analysis. The genomes with annotated tRNAs were excluded from analysis. A total of 193 sequences were used in this study; this includes 88 sequences of large DNA viruses infecting invertebrates  and 105 sequences of large DNA viruses infecting vertebrates   as compared to the large DNA viruses included in the study (average genome size 164 kb). In addition, viruses belonging to the family Iridoviridae and Polydnaviridae were also excluded from the study. The genomes of iridoviruses are known to encode DNA methyltransferases leading to heavy methylation of the cytosine residues of CpG dinucleotides Polydnaviridae are composed of multiple segments of DNA including wasp genes and wasp non-coding DNA The available full-length sequences of large double-stranded DNA (ds-DNA) viruses infecting vertebrates and invertebrates were retrieved from NCBI virus genome resources , the frequencies of the mononucleotides f(X) and f(Y) and the length of the genome G. In other words, pY of one strand will be equal to the frequency of dinucleotide Y\u2032pX\u2032 in the complementary strand, where Y\u2032 and X\u2032 are complementary nucleotides to Y and X respectively.The observed/expected ratios for the dinucleotide XpY [(O/E)Hence, the dinucleotide frequencies in a double-stranded sequence can be calculated using the following formula:http://bioweb.pasteur.fr/seqanal/interfaces/codonw.html) was used to determine the effective number of codon (ENC), total GC content and the nucleotide composition at the third codon position. The values of ENC range from 20\u201361, with a value of 20 representing maximum codon bias i.e one codon is used for one amino acid and a value of 61 represents no codon bias i.e. all the codons are equally used for each amino acid. ENC values of 35 or less are suggestive of significant codon usage bias.A freely available and widely used web tool, CodonW  was calculated by using the following formula: http://www.cbs.dtu.dk/services/FeatureExtract/). The observed/expected ratios for the CDS (XpY -CDSO/E) were calculated.The coding DNA sequences (CDS) as annotated in Genbank files were extracted using a web tool (3) was plotted against the GC content at the first and second codon positions . The GC1,2 values were plotted against GC3 values in a scatter plot.For each virus, total GC content and the frequency of nucleotides at the third (silent) codon position was calculated. In order to determine the relative effects of translational selection and mutation pressure, GC content at the third codon position  as appropriate. Box plots, scatter plots and column (bar) graphs were made using MS-Excel or using the software Graph pad. On each box, the central horizontal line represents the median, the edges represent lower (Q1) and upper quartiles (Q3). Scatter plots were used to compare two parameters. Results were considered statistically significant at a P value of <0.05.Data were analyzed using Student\u2019s P<0.0001; Wilcoxon signed rank test) and the CpG dinucleotide was the most overrepresented dinucleotide  among large DNA viruses infecting invertebrate hosts.The relative abundance of dinucleotides among large DNA viruses infecting invertebrates and vertebrates are summarized in O/E ratios than those infecting vertebrates . Large DNA viruses infecting invertebrates had a significantly higher CpGO/E ratios than those infecting vertebrates  dinucleotides in large DNA viruses infecting invertebrates and vertebrates is shown in O/E ratios and GC content .The GC content ranged from 19\u201358% in large DNA viruses infecting invertebrate hosts and between 26\u201377% in those infecting vertebrate hosts. A positive correlation between GC content and CpG dinucleotide frequencies has been demonstrated in previous studies 3) and ENC values using ENC-GC3 plots. This relationship was then compared to the expected ENC value (ENC*) that would result if GC content primarily accounts for codon usage biases. In other words, ENC-GC3 plots will help assess the relative role of mutational pressure  and translational selection . Interestingly, the actual values of ENC for both the groups of viruses lie on, or just below the expected ENC curve  NC curve , indicatThe ENC statistic does not take into account the variation in nucleotide composition of the sequences studied 3) with GC content at non-synonymous first and second codon position   . The corO/E ratio will be lower than the CDS CpTO/E-CDS ratio. On the contrary, if translational selection were the major driving force for CpT depletion, one would expect that the depletion of CDS (CpTO/E-CDS) ratio will be more pronounced than the depletion of genome-wide CpTO/E ratio. Among viruses infecting invertebrates, the genome-wide depletion of CpT dinucleotides was more pronounced as compared to that within the CDS    is the major driving force leading to CpT(ApG) depletion and CpG excess among large DNA viruses infecting invertebrates we sought to investigate the difference between genome-wide dinucleotide O/E ratios and dinucleotide O/E ratios in the coding DNA sequence for a given dinucleotide. If CpT depletion is primarily driven by pressures other than translational selection , one would expect that the genome-wide CpTnk test) . Similarnk test) .O/E/TpCO/E ratios for the viruses studied. The CpTO/E/TpCO/E ratios were significantly lower in large DNA viruses infecting invertebrates as compared to those infecting vertebrates . There was no correlation between the relative abundance of CpT (ApG) dinucleotides and TpT(ApA) dinucleotides among large DNA viruses infecting vertebrate hosts . In addition, TpTO/E ratios was significantly higher among the large DNA viruses infecting invertebrates as compared to those infecting vertebrates  (Deamination of methylated cytosines results in C to T transitions <0.0001) .2r\u200a=\u200a0.335; P<0.0001). However, there was no correlation between the relative abundance of CpT(ApG) and CpG dinucleotides among the large DNA viruses infecting vertebrate hosts .The loss of CpT(ApG) dinucleotides correlated with a gain in CpG dinucleotides among large DNA viruses infecting invertebrate hosts (O/E ratios were significantly lower among the large DNA viruses infecting invertebrates as compared to those infecting vertebrates (P<0.0001). The CpGO/E ratios were significantly higher among the large DNA viruses infecting invertebrates as compared to those infecting vertebrates (P<0.0001). Depletion of TpA dinucleotides was a common feature among both the groups of viruses (We investigated the relative abundance of dinucleotides among large DNA viruses infecting a wide range of invertebrates and vertebrates hosts. We found systematic CpT(ApG) depletion and CpG excess among large DNA viruses infecting invertebrate hosts . In cont viruses . AvoidanThe depletion of CpT dinucleotides and the presence of CpG excess appears to be a unique genomic signature of large DNA viruses infecting invertebrate hosts. To the best of our knowledge, neither CpT depletion nor CpG excess have been described among any group of viruses. Intrigued by this finding, we went on to investigate the underlying mechanisms that could potentially contribute to this unique genomic signature of large DNA viruses infecting invertebrates.O/E ratios and GC content O/E ratios . Despite their high CpGO/E ratios, large DNA viruses infecting invertebrates had lower GC content as compared to those infecting vertebrates . Thus, it is clear that higher CpGO/E ratios among large DNA viruses infecting invertebrates are not linked to higher GC content.Several studies have demonstrated a positive correlation between CpGAfter having demonstrated CpT depletion and CpG excess among large DNA viruses infecting invertebrates we asked the question if these differences arose because of translational selection or host-induced pressures other than translational selection.3 plot  is observed it suggests a major role for translational pressure; while a good correlation between GC3 and GC1,2 supports the role of mutational pressure  in shaping the nucleotide composition of the genome. We found significant correlation between GC3 and GC1,2 among viruses infecting invertebrate hosts  O/E ratios for CpT and CpG dinucleotides. The genome-wide depletion of CpT dinucleotides and the genome-wide over-representation of CpG dinucleotides were more pronounced as compared to that with the CDS .Taken together, these findings unambiguously support the role of genome-wide substitutions as the major driving force leading to CpT depletion and CpG excess among large DNA viruses infecting invertebrates. Our finding that genome-wide substitutions dominate translational selection of specific codons is in keeping with previous reports on other viruses Having demonstrated that host-induced pressures other than translational pressure contribute to CpT(ApG) depletion and CpG excess among large DNA viruses infecting invertebrate hosts we investigated if the TpC dinucleotide is also under a similar pressure. The TpC(GpA) dinucleotide has the same mononucleotide composition (C and T or A and G ) as CpT(ApG) dinucleotides.O/E ratios O/E ratios were significantly lower in large DNA viruses infecting invertebrates host as compared to those infecting vertebrate hosts  <0.0001) . This fiO/E/GpCO/E ratios among large DNA viruses infecting invertebrates are significantly higher than those infecting vertebrates (P\u200a=\u200a0.01), suggesting that mechanisms linked to increasing or maintaining CpG dinucleotide content do not influence the GpC dinucleotide content. The CpT (and not TpC) and CpG (and not GpC) dinucleotides of large DNA viruses infecting the invertebrates represent unique targets for substitution, implying that the underlying invertebrate host-induced pressure is likely to be linked to methylation of 5-methylcytosine within the dinucleotides.Similarly, the CpGP<0.0001); but there was no such correlation among large DNA viruses infecting vertebrate hosts (P\u200a=\u200a0.503). This finding suggests that deamination of 5-methylcytosine in CpT dinucleotides may, at least in part explain the depletion of CpT dinucleotides among large DNA viruses infecting invertebrates. In addition, higher TpTO/E ratios among the large DNA viruses infecting invertebrates as compared to those infecting vertebrates  between vertebrate and invertebrate hosts are well known 2r\u200a=\u200a0.335; P<0.0001); but there was no such correlation among the large DNA viruses infecting vertebrates . The inverse correlation between the relative abundance of CpT and CpG dinucleotides among large DNA viruses infecting invertebrates is in keeping with finding from earlier studies on animal genomes An earlier study investigating dinucleotide frequencies among completely sequenced vertebrate and invertebrate animal genomes found a correlation between loss of CpG dinucleotides and the gain of CpT dinucleotides Despite major differences in genome organization, replication and host range among DNA viruses infecting invertebrates, CpT depletion and CpG excess have emerged to be the unifying theme across this group of viruses. This finding clearly links host-related factors to CpT depletion and CpG excess. Apart from the potential link between host methylation and the depletion of CpT dinucleotides, our findings do not elucidate specific host-related factors linked to CpT depletion or CpG excess. Two possible explanations are summarized below:The depletion of CpG dinucleotides has been linked to evasion of host immune response via stimulation of Toll-like receptor 9 (TLR9) by unmethylated CpG dinucleotides The complete genome sequence of most invertebrate and vertebrate hosts of viruses included in our study is currently unavailable. Nonetheless, data from studies analysing a limited number of complete and partial genomes indicate marginal CpT depletion in invertebrate hosts Apis mellifera (honeybee), a social insect, revealed that genes with a low CpG content (mean CpGO/E\u200a=\u200a0.55) were linked to hypermethylation of germline DNA, while those with a high CpG content (mean CpGO/E\u200a=\u200a1.5) were linked to hypomethylation of germline DNA The absence of TLR9 in invertebrates may potentially allow the maintenance of CpG dinucleotides in invertebrates DNA viruses. A study analysing the CpG content of genes in the In our study, the presence of excess CpG among large DNA viruses infecting invertebrates suggests that a mechanism to conserve CpGs against depletion of CpGs may exist in this group of hosts. Alternatively, large DNA viruses with increased CpG dinucleotide content may have a survival advantage in invertebrate hosts leading to a positive selection of these strains.Our findings shed new light on evolutionary differences between large DNA viruses infecting invertebrate hosts and those infecting vertebrate hosts. We have identified depletion of CpT(ApG) dinucleotides and over-representation of CpG dinucleotides as the unique genomic signature for large DNA viruses infecting invertebrates. Our data provides evidence that supports the existence of invertebrate host-induced pressures specifically acting on CpT(ApG) and CpG dinucleotides of the infecting large DNA viruses. We believe that our findings provide a framework to understand invertebrate host-related factors and their role in shaping virus evolution and perhaps virus pathogenesis.Figure S1Distribution pattern of CpT and CpG dinucleotides in large DNA viruses. The distribution pattern of CpT dinucleotides in viruses infecting (a) invertebrates and (b) vertebrates. The distribution pattern of CpG dinucleotides in viruses infecting (a) invertebrates and (b) vertebrates.(TIF)Click here for additional data file.Dataset S1Accession numbers of virus sequences and host type.(XLSX)Click here for additional data file."}
+{"text": "A 59-year-old man with a history of chronic ankylosing spondylitis for many years, developed neck pain and left cervico-brachial neuralgia following a road traffic accident sustained one week before. Plain radiographs of cervical spine were initially misinterpreted. On examination, he had severe neck pain on mobilization without any neurological deficits. Delayed cervical computed tomography scan showed ossification of the anterior longitudinal ligament, calcification of the intervertebral discs and complete vertebral fusion  with transversal fracture at C5-C6 disc level  causing a luxation of the cervical spine with significant compromise in canal space (A and B). A transcranial spinal traction was performed followed by anterior decompression and stabilization via an anterolateral cervical approach. The outcome was favourable. Transverse fractures of the spine are rare in patients with ankylosing spondylitis and diagnosis should be considered following even minor trauma. These atypical unstable fractures occur because of the loss of flexibility and fragility of the osteoporotic spine. Early diagnosis for possible intervention is important because of the high mortality rate."}
+{"text": "The following information is missing from the Acknowledgements section: The research leading to these results has partly received funding from the EU-FP7-SOCIOEC project under grant agreement No. 289192."}
+{"text": "Measuring patterns of volatile organic compounds ('VOCs') in exhaled breath  is a novel metabolomic non-invasive approach to study molecular signatures of respiratory disease.to study whether controlled and uncontrolled asthmatic children treated with inhaled corticosteroids (ICS) can be identified according to their breathprint.VOCs were measured in thirty-three asthmatic children  who participated in the PACMAN2 study. All children were current users of ICS. Current asthma control was assessed using the Asthma Control Questionnaire. Long-term asthma control was based on reported symptoms in the four seasons preceding baseline and follow-up visit. A single vital capacity volume of exhaled air was collected upon 5 minutes of normal breathing through a three-way non-re-breathing valve with a VOC filter in a Tedlar bag. The VOCs in the breath sample were subsequently captured on Tenax GR Tubes and analyzed offline on a validated panel of four eNoses with different sensor technologies . Breathprints were analysed per eNose using principal component analyses (PCA). ROC curves and cross-validated accuracy values of significant (t-test) principal components were used to assess the accuracy of the devices to discriminate between controlled and uncontrolled patients. Additionally, the fraction of exhaled nitric oxide (FeNO) was measured with a NIOX Mino and an expiration time of 6 seconds.Two eNoses in the panel were able to discriminate current uncontrolled asthmatic children and controlled asthmatic children according to their breathprint . Three eNoses were able to identify long-term uncontrolled asthmatic children and long-term controlled asthmatic children . For both outcomes the Comon Invent, a metal oxide sensor, was most accurate in separating both groups. In contrast, FeNO was a poor marker to discriminate between controlled and uncontrolled asthmatic children .Breathprint analyses can accurately distinguish uncontrolled from controlled asthmatic children. In contrast, a single FeNO measurement cannot. These preliminary results suggest that breathprints might be able to identify distinct childhood asthma phenotypes."}
+{"text": "Precision medicine utilising biomarkers to identify those patients likely to obtain a benefit from receiving a particular treatment has the potential to deliver benefit across multiple stakeholders. These are dependent upon having a well-defined biomarker positive population, which for continuous biomarkers such as gene or protein expression includes defining a threshold or cut-off based upon observed clinical data. To obtain the desired precision in estimating such a cut-off frequently requires larger sample sizes than typically used in early phase studies.A popular approach for investigating biomarker thresholds is the \u2018minimum interaction p-value\u2019 method . While this approach is flexible and relatively easy to implement, it operates independently of an efficacy target considered to be clinically meaningful.We propose an approach that anchors the biomarker threshold to a clinically meaningful treatment effect. p-splines are used to flexibly model the efficacy-biomarker relationship in order to identify the threshold defining a biomarker positive population meeting a pre-defined efficacy target. The significance of this population is tested through permutation. The method is placed within a hierarchical split-alpha testing structure also permitting the selection of an all-comers population.This innovative approach builds upon existing methods to define a biomarker cut-off and confirm efficacy within the same phase 3 trial. This method may lead to a viable path for more efficient clinical development programs and increased precision in threshold determination."}
+{"text": "HGPS skin fibroblasts are characterized by multiple nuclear defects: nuclear shape abnormalities chromatin structure alterations, increased DNA damage and cell cycle alterations.Hutchinson-Gilford Progeria Syndrome (HGPS) is caused by a LMNA gene transcription, due to the presence of a retinoic acid responsive element (L-RARE) in the LMNA promoter. Based on this knowledge, we investigated if all trans retinoic acid (ATRA) could lower progerin levels in HGPS fibroblasts. We also evaluated the effects of a combined treatment with rapamycin, a drug known to promote autophagy and reduce both farnesylated prelamin A and progerin amount.Retinoic acid may modulate We demonstrate a surprising effect of ATRA to repress Lamin A/C gene transcription and we show that the combined treatment with ATRA and rapamycin has a synergistic effect: it dramatically lowers progerin levels, restores both heterochromatin organization and nuclear shape, reduces DNA damage markers and improves cell viability. These promising results could open the way to a new therapeutic approach for HGPS."}
+{"text": "The simulated optical response (absorption and responsivity) of Au nanoislands integrated in CdS films confirms the strong dependence of NIR sensitivity on the size and shape of Au nanoislands. The demonstration of plasmon enhanced IR sensitivity along with the cost-effective device fabrication method using CdS film enables the possibility of economical light harvesting applications which can be implemented in future technological applications.We report the use of random Au nanoislands to enhance the absorption of CdS photodetectors at wavelengths beyond its intrinsic absorption properties from visible to NIR spectrum enabling a high performance visible-NIR photodetector. The temperature dependent annealing method was employed to form random sized Au nanoparticles on CdS films. The hot electron induced NIR photo-detection shows high responsivity of ~780\u2009mA/W for an area of ~57\u2009\u03bcm The next generation photodetector based devices most likely, would be made up of hybrid nanostructures improving the intrinsic properties of the base material to new and interesting functionalities. CdS is one of the cost effective materials and photodetectors made from films or nanostructures of this material have been investigated extensively for their photosensing applications12et al. showed strong coupling between plasmons (hot electrons) and semiconductor facilitating additional optical functionality. Here, the incident NIR light (1500\u2009nm) on metallic nanoantenna excites resonant plasmons and hot electrons injection takes place at the nanoantenna-semiconductor interfaceet al. have demonstrated plasmon-induced hot electron photocurrent generation in a grating based device patterned on a silicon substrate12et al. demonstrated the hot electron injection from Au tip into CdS nano rods and indicated the use of plasmon induced hot electron transfer for potential light harvesting applicationsThe present research advances on plasmonically enhanced hot electron photodetection enable materials to exhibit new optical functionalities for the wavelengths beyond their detection limit. The pioneering work of Knight IR light 00\u2009nm on Here we show the use of random sized Au nanoantennas generating hot electrons arising due to surface plasmon resonance phenomena and upon its decay collecting at the interface of the CdS semiconductor which eventually increases the photocurrent. We use a simple straightforward annealing temperature dependent method of random Au nano islands formation on ultra-low cost effective CdS films made by chemical bath deposition technique. The rapid annealing of thin gold film on CdS yields the formation of Au nanoislands. Different annealing temperatures resulted in random nanoisland formation having different sizes and density of particles. The absorption enhancement in CdS layer due to integration of gold nanoislands has been investigated by using FDTD software. The photoresponse of these devices is studied for visible and NIR wavelengths. The fabricated devices clearly demonstrate that the photoconductivity response shows sensitivity to visible-NIR region with high responsivity (780\u2009mA/W), reproducibility and stability.2 and CdS substrates. A thin layer of gold (Au) was sputtered coated on CdS film. The same sputtering chamber was used to anneal the Au films by increasing the temperature of the stage to 450\u00b0, 600\u00b0 and 700\u2009\u00b0C. The annealing temperature parameter was tuned to get the different sizes of Au nanoislands on CdS films and best photoconductivity results were obtained for 600\u2009\u00b0C (FESEM image 19Iph) was calculated by subtracting the current values (Iph\u2009=\u2009Ilight\u2009\u2212\u2009Idark). The stable and reproducible photocurrent response of the device was observed under different light illuminations . The device\u2019s photocurrent and its dependency on the applied bias voltage for the device have been plotted in To know the photoconductive response of the CdS -Au nanoislands fabricated devices under white light illumination, we have performed current-voltage (I\u2013V) and constant bias voltage dependent measurements . First, P) for 1064\u2009nm has been shown in I\u2009\u2248\u2009PN) where exponent N determines the response of photocurrent to laser power density which we have found \u2248\u20090.86 i.e. close to unity and the sublinear increase in photocurrent was observed as we increase the power of the laser from 1.5 to 29\u2009mW/cm2 at a constant bias voltage of 500\u2009mV. The reason behind sublinear response could be due to the contribution in photocurrent coming from bolometeric effects and such effects have been reported in materials like carbon nanotubesThe performance of a CdS_Au nanoislands based integrated device for NIR light illumination is shown in 2), CdS and Au materials. The observed simulation results (R) can be understood through the relation of Fowler function (S) which is B is the Schottky barrier height, CF is the Fowler emission coefficient, hv is the energy of the incident photons). The CdS films with Au electrodes junction have been studied previously and their potential barrier height is reported as ~0.76\u2009eVTo understand the optical properties of Au nanostructures formed on CdS films we have employed here FDTD (finite-difference time domain) method. The absorption profiles were calculated by modelling the glass (SiO results  show enh results  show tha2 (The best photoresponsivity of ~780\u2009mA/W is observed for the devices (CdS-Au nanoislands) fabricated in this study at annealing conditions 600\u2009\u00b0C and measurements were carried out on the smaller area ~57\u2009\u03bcm2 . The inc2 . The cro2  shows th2 which is far better compared to CdS thin films investigated here and thus triggers the possibility of Au nanoislands formation on CdS nanoblets for investigating ultrafast photodetection. However our work enables the potential use of Au nanoislands_CdS devices converting incident light into electrical signals which is backbone of the many photodetecting applications. Moreover, we have also used a very simple cost effective approach using glass as a substrate for CdS film deposition. The deposition of CdS films by CBD technique is well established, economical and known for an effective ultra-cost, large area production. The optimized procedure for Au nanoislands formation on CdS films is also simple and reproducible. The simplicity, high responsivity and large area fabrication make these devices more suitable candidate for ultra-low-cost Visible-NIR photodetectors. To the best of our knowledge, integrating random Au islands in CdS films and showing broadspectral (visible to NIR) region is new approach which was not attempted previously and further can be exploited in hot electron induced light harvesting or high performance photodetector applications.In summary, the CdS _Au nanoisland based integrated devices demonstrate hot electron generation and their transfer in CdS films contributing to photocurrent detection. They possess very attractive optoelectronic properties such as very high responsivity (780\u2009mA/W) and broadspectral photoresponse extending photodetection in CdS films from visible to NIR spectrum. The work on crystalline CdS nanobelt has shown ultrafast response time (~20\u2009\u03bcs)The CdS films were deposited by chemical bath deposition method as described in earlier reports. The metal pads needed for the electrical connection on CdS films were sputtered coated through shadow masking procedure. The shadow masks were custom designed and made by the Tecan ltd, UK. Thin films of Au (6\u2009nm) were also sputter coated and annealing was performed immediately after the deposition. The FESEM characterization  was performed to know the Au nanoislands size distributions. The CdS-Au nanoisland devices were mounted in the probe station setup [Cascade Microtech EPS150TRIAX with shield enclosure (EPS-ACC-SE750) and triax connections] which was further custom designed for photo conductivity and low signal measurements. All the electrical measurements were carried out by Keithley 2634B source measure unit (SMU).How to cite this article: Sharma, A. et al. Hot electron induced NIR detection in CdS films. Sci. Rep.6, 22939; doi: 10.1038/srep22939 (2016)."}
+{"text": "Transient left ventricular apical ballooning syndrome is characterized by transient akinesis of the left ventricular apex with basal wall hyperkinesis; this is also known as Takotsubo cardiomyopathy. There are three distinct contractile LV patterns described in the literature: apical, midventricular, and basal ballooning. The apical ballooning pattern is the most frequent pattern. We describe the case of a transient anterolateral left ventricular ballooning fulfilling the definition of Takotsubo cardiomyopathy except for the contractile LV pattern. The diagnosis was supported by cardiac magnetic resonance imaging and by the fact that the anterolateral ballooning resolved completely after 6 weeks. Transient left ventricular apical ballooning syndrome characterized by transient akinesis of the left ventricular apex with basal wall hyperkinesis was first described as Takotsubo-type cardiomyopathy in 1990 . The majWe report the case of a stress-induced left ventricular anterolateral ballooning in a 61-year-old female patient matching the diagnostic criteria of TTC but with a distinct pattern of ballooning/dyskinesia. The 61 year old female patient presented the day after new years eve with typical anginal chest pain at rest with radiation to the jaw. The ECG at presentation showed minimal ST-elevation (0.5\u2009mm) in I and aVL and poor R wave progression V1\u2013V4. Regarding cardiovascular risk factors the patient had mild hypertension and dyslipidemia (currently not treated). Troponin test was positive with normal values vor CK/CK-MB. An emergency coronary angiography was performed which revealed normal coronary arteries. The left ventricular angiogram showed anterolateral ballooning with globally preserved ejection fraction . 24\u2009h laThe patient was diagnosed with an atypical form of takotsubo cardiomyopathy and discharged one day later with an ACE-inhibitor and a betablocker. 6 weeks later, the patient was seen as an outpatient. She was asymptomatic and LV function was completely normal on echo.Our case fulfills the current diagnostic criteria of stress-induced cardiomyopathy or takotsubo cardiomyopathy except for the contractile LV pattern . In formCardiovascular magnetic resonance (CMR) imaging is uniquely suited for the evaluation of patients with TTC. In addition to accurate visualization of regional wall motion abnormalities, it allows for precise quantification of right ventricular (RV) and LV function and the assessment of additional abnormalities . Importantly, CMR imaging also provides markers for reversible  and irreversible (necrosis/fibrosis) injury, which may be particularly important to verify TTC and exclude similar acute cardiac diseases such as myocardial infarction or myocarditis . In conclusion we suggest that TTC can present not only with the classical LV ballooning patterns  but also with segmental  ballooning, and CMR is a useful tool in the diagnosis of TTC."}
+{"text": "Oral food inmunotherapy is a promising therapeutic aproach in patients with persistent cow's milk allergy (CMA). Although it seems that these protocols show a better outcome in patients with \"milder\" symptoms (i.e. non anaphylactic reactions) there are controversial results in highly sensitized subjects.We select patients with persistent CMA and severe uncontrolled anaphylactic symptoms despite a correct restrictive diet. We performed a two-day desensitization procedure at the Pediatric Critical Care Unit in our Institution. The second phase was weekly scheduled in the Outpatient clinic to reach a final cumulative dose of 250 ml of undiluted milk. Clinical and serological date were collected every six month for a five-year period.Fifteen children (2-16 y.o.) were included. All children reached the final dose of 250 ml of undiluted milk in less than ten weeks. Clinical follow-up every 6 months remained during 5 years to register all adverse reactions and possible factors involved. Serological changes were obtained every six months during the subsequent five years, including specific IgE and IgG4.Anaphylactic CMA patients may benefit from rush oral Cow's Milk immunotherapy. Clinical and serological changes have been found both at early and long-term follow-up. Several factors were involved in reactions for temporary loss of tolerance."}
+{"text": "Early extubation post coronary artery bypass grafting does not increase perioperative morbidity and reduces the length of stay (LOS) in the ICU and in hospital . Use of A prospective analysis was performed on all patients post adult cardiac surgery from 14 May 2013 to 10 July 2013. Emergency surgical patients and those with intraoperative complications were excluded.t test was used to analyse the data. Patient demographics are presented in Table P = 0.0184) (Table A two-sample 4) Table . There wAdministering morphine prior to extubation causes significant delays in weaning from mechanical ventilation. We plan to introduce intraoperative and postoperative protocols to facilitate rapid weaning from mechanical ventilation for elective cardiac surgical patients."}
+{"text": "Juvenile idiopathic arthritis (JIA) is a chronic inflammatory disease which commonly shows a remitting-relapsing course. Monitoring disease activity and adaptation of immune-suppressive therapy is still a challenge in clinical practice. In previous work our group has shown that members of the S100-protein family are reliable biomarkers for monitoring arthritis in JIA patients on medication and that these proteins may even predict risk of relapses in these patients. In my talk I will present novel data regarding the local release mechanism of these proteins during joint inflammation, use of serum concentrations of these S100-proteins for monitoring JIA as well as novel molecular imaging methods based on local S100-protein expression in preclinical models of inflammation and arthritis.None declared."}
+{"text": "A 37-year-old previously healthy man presented with a localized headache and a progressive enlarging mass in the left frontal area for more than 8 months. He also reported a history of head injury in the same area sustained two years before. On physical examination, the mass (about 28 mm in diameter) was hard to pressure with freely mobile skin above the lesion in the left frontal sus-orbital region. Ophthalmologic and neurologic examinations were normal. Cranial computed tomography scan showed an osteolytic intradiploic lesion with poorly defined margins (A and B). Magnetic resonance imaging showed hyperintense lesion on T2-weighted image and hypointense on T1-weighted image with gadolinium enhancement (C). The lesion was extradural with slight brain mass effect. Surgery consisted of total resection of the bony bluish lesion (D) and cranioplasty. The postoperative course was uneventful. Histological study revealed a cavernous hemangioma of the diploe. Bone hemangioma is a vascular hemartoma: a benign tumor arising from the intrinsic vasculature of the bone, commonly seen in long bones and vertebrae. Skull cavernous hemangiomas are rare tumors for which the origin is not yet clear. We suspected that in our case head injury may have been the cause of cavernous hemangioma in the cranial vault."}
+{"text": "Growing evidence suggests that, as long as the total lung capacity is not overcome, dynamic  is more injurious than static  lung deformation . BecauseIn eight healthy piglets we measured total hysteresis and the peak inspiratory pressure (Ppeak) while randomly increasing VT (with no PEEP) or PEEP (with fixed VT). P1 was extrapolated from the drop in airway pressure during an end-inspiratory pause . HystereP values refer to oneway repeated-measures analysis of variance.The main findings are shown in Figure Lung hysteresis increases with VT, but not with PEEP Further studies are needed to prospectively evaluate the role of lung hysteresis in the pathogenesis of ventilator-induced lung injury."}
+{"text": "An anomalous origin of a coronary artery (AOCA) is the second most common cause of non-traumatic sudden cardiac death in young athletes. Patients with a malignant course of an AOCA of the right coronary artery only need surgical correction when myocardial ischaemia is detected. An AOCA and its malignant or benign course can be detected by coronary angiography, coronary computed tomography or cardiac magnetic resonance imaging. Detection of ischaemia can be more difficult since even a negative maximal-effort stress ECG does not exclude a potential lethal coronary anomaly. Also, there are no case series or trials showing sensitivity or specificity for any form of ischaemia detection for AOCA in the literature. Although not described previously in adults, dobutamine stress echocardiography was previously described in a paediatric population with AOCA. We are the first to describe ischaemia detection by dobutamine stress echocardiography in three adult patients with an AOCA of the right coronary artery who were subsequently referred for surgery.The online version of this article (doi: 10.1007/s12471-014-0648-3) contains supplementary material, which is available to authorized users. An anomalous origin of a coronary artery (AOCA) is the second most common cause of non-traumatic sudden cardiac death in young athletes . PatientAn AOCA and its malignant or benign course can be detected by coronary angiography (best including a right oblique view), coronary computed tomography or cardiac magnetic resonance imaging . DetectiSince normal routine exercise electrocardiography test does not exclude ischaemia in patients with AOCA, we suggest the use of dobutamine stress echocardiography in patients with AOCA.(DOCX 1493 kb)"}
+{"text": "High-grade  gliomas are undifferentiated or anaplastic, are highly infiltrating and termed as malignant. The overall prognosis and survival rate is very low. Only few highly sensitive and specific biomarkers for Glioma have been identified, but are yet to be put for routine use due to challenges in their clinical validation for early disease detection, diagnosis and monitoring to improve long-term survival of patients. The inefficacy of currently available chemotherapeutic and radio-therapeutic agents largely depends on a number of resistance mechanisms among which DNA repair plays an important role. Hence bio-molecules involved in DNA repair mechanisms will be promising biomarkers. Current status in the validation of DNA repair genes include, studying the promoter methylation of the only direct DNA repair gene O6-methylguanine-DNA methyltransferase (MGMT). MGMT is epigenetically inactivated via hypermethylation of the 5\u2032-CpG islands located in promoter region. It is associated with prediction of successful alkylating agent therapy with temozolomide in combination with radiotherapy and also longer overall survival in patients. The silenced MGMT gene possibly enhances radiation effects by inducing radiation-mediated double stranded DNA (dsDNA) breaks and suppression of dsDNA repair pathways after radiation exposure.Post surgery excised tumor samples from 20 patients diagnosed histopathologically with high grade glioma were tested for MGMT promoter region methylation status. DNA extraction and bisulphate conversion using suitable commercially available kits (Qiagen) followed by Methylation specific PCR using specific methylated and unmethylated primers was carried out. Correlations are underway with clinical profile and treatment regimen.Hypermethylation of the promoter region was observed in about 60%, (12) samples. The other samples only demonstrated unmethylated regions.Assessment of promoter methylation of the MGMT gene helps in the therapeutic choice of the patients. It has gained importance not only as a prognostic but also as a predictive biomarker in molecular profiling of high grade gliomas."}
+{"text": "This report illustrates an unusual case of asymptomatic late cardiac perforation by an atrial pacemaker lead into the right lung. In the present case, the lead was explanted by simple manual traction through the device pocket without any complications. A 33-year-old patient with no evidence of underlying cardiomyopathy was implanted with a dual-chamber pacemaker  Zephyr XL DR; active fixation atrial lead SJM Tendril ST 1882T/52; passive ventricular lead SJM Tendril ST 1888T/58) for symptomatic complete atrioventricular (AV) block. The implantation procedure was uneventful and usual follow-up including device interrogation and chest radiography remained normal until the 8-month follow-up visit. During this last consultation, although the patient remained totally asymptomatic, both atrial sensing and capture were lost. Chest radiography revealed a clear migration of the atrial lead into the right lung . ContrasPacemaker implantation is a very common procedure that usually carries a low risk of complications. Acute perforation of a cardiac cavity by a pacemaker lead occurs in about 1% of the patients at time of the implantation . HoweverThis case report illustrates a rare case of asymptomatic late cardiac perforation of an atrial pacemaker lead into the right lung. In such situation, simple manual lead extraction through the device pocket is worth trying and allows for avoiding an invasive surgical approach."}
+{"text": "A 2-year-old male with Poland-Moebius syndrome was transferred from a local hospital to the Pediatric ICU at Children's Hospital of Georgia for suspected postobstructive pulmonary edema (POPE) after tonsillectomy/adenoidectomy (T&A). The patient's respiratory status ultimately declined and he developed respiratory failure. Imaging suggested pulmonary edema as well as a left-sided pneumonia. Echocardiogram showed pulmonary hypertension and airway exam via direct fiberoptic bronchoscopy revealed tracheomalacia and bronchomalacia. He developed acute respiratory distress syndrome (ARDS) and remained intubated for ten days. This case highlights the association between congenital upper body abnormalities with cranial nerve dysfunction and the development of POPE with delayed resolution of symptoms. Patients with upper body abnormalities as above are at great risk of postoperative complications and should therefore be managed in a tertiary-care facility. We present a case of postobstructive pulmonary edema after T&A in a child with Poland-Moebius syndrome. These relatively uncommon anomalies likely contributed to postoperative complications for this child including POPE and ARDS. Patients with similar upper body abnormalities should be recognized as high risk of development of postoperative complications following T&A.A 2-year-old male with Poland-Moebius syndrome had tonsillectomy/adenoidectomy (T&A) performed at a local general hospital due to snoring and apnea-hypopnea index (AHI) of 10\u201315 on multiple prior polysomnograms . Details of his anesthetic management during surgery are not available; however no immediate perioperative complications such as laryngospasm or retained pack were reported. While in recovery, he exhibited increased work of breathing, coarse breath sounds, and lethargy. He was admitted to an adult ICU and treated with IV diuretics and oxygen with continuous positive airway pressure (CPAP). He improved briefly and CPAP was stopped, but he had an episode of vomiting after administration of oral Percocet and oxygen saturation acutely dropped to the upper 60s. CPAP was restarted and saturation increased to 90%. A chest X-ray showed peribronchial and perihilar interstitial thickening and known left lateral rib deformities. Due to unstable respiratory status, he was transferred to the Pediatric ICU at the Children's Hospital of Georgia within 12 hours of surgery.2 80% to maintain sats in the 90s. Repeat chest X-rays and chest CT showed persistent, diffuse opacities. Clinical picture suggested acute respiratory distress syndrome (ARDS) and diuretic therapy was started for fluid management. Tracheal aspirate grew methicillin-susceptible staph aureus (MSSA). Direct fiberoptic bronchoscopy done on day 8 showed significant tracheomalacia and bronchomalacia. An echocardiogram on day 10 showed mildly dilated right ventricle and elevated right ventricular systolic pressure at 3/4 systemic pressure consistent with a diagnosis of pulmonary hypertension; these findings differed significantly from previous normal echocardiogram done at 14 months of age. Sildenafil was started for treatment of pulmonary hypertension and subsequent echocardiograms showed improvement in right ventricular systolic pressure. He remained intubated for ten days but eventually was extubated to noninvasive ventilatory support with BiPAP. He was weaned to room air with continued use of BiPaP at night and later discharged to a rehabilitation facility after a total inpatient stay of 30 days.On admission to our PICU he was noted to be in moderate respiratory distress with respiratory rate 56; subcostal and intercostal retractions were present. The patient's clinical picture was concerning for postobstructive pulmonary edema (POPE) although the differential diagnosis also included aspiration pneumonia. Repeat chest X-ray showed patchy infiltrates consistent with pulmonary edema. He was started on high-flow oxygen. Diuretic therapy was initiated and intravenous fluids were restricted. Pulmonary toilet was maintained with hypertonic saline and chest physiotherapy. IV dexamethasone was given to decrease airway swelling. He was noted to have poor swallowing of secretions, and a modified barium swallow done later in the course of his hospital stay confirmed dysphagia. On day 5, he developed fever and was treated empirically with ceftriaxone for pneumonia. His respiratory status continued to decline and he ultimately developed respiratory failure, requiring intubation on day 7 of hospital stay. Ventilator settings included respiratory rate 30, PEEP +9, and PC 27 with FiOWe present a case of POPE Type II after T&A in a child with Poland-Moebius syndrome. POPE (or negative pressure pulmonary edema) is a potentially fatal complication typically seen after relief of upper airway obstruction. POPE Type I develops immediately after relief of an acute airway obstruction whereas POPE Type II typically occurs after relief of chronic obstruction (as seen with obstructive sleep apnea caused by adenotonsillar hypertrophy). Patients with chronic obstruction appear to exhibit a level of autopositive end expiratory pressure (PEEP) with a concomitant increase in end expiratory lung volume. When the obstruction is relieved, lung volumes and pressures return to normal, creating a negative intrapulmonary pressure which may result in interstitial fluid transudation and pulmonary edema . POPE usIn addition to standard risk factors for post-T&A complications, including young age and AHI >5, our patient's Poland syndrome  and Moebius syndrome  undoubtedly impacted his clinical course. Poland syndrome occurs in 1 in 20,000 live births; Poland syndrome combined with Moebius syndrome has an estimated prevalence of 1\u2009:\u2009500,000 . DelayedThis case highlights the association between congenital upper body abnormalities with cranial nerve defects (as in Poland-Moebius syndrome) and the development of POPE with delayed resolution. This should be anticipated following surgery in any child with similar risk factors. These patients should have surgical procedures performed in a tertiary-care facility with admission to a Pediatric ICU postoperatively for optimal management of these complications."}
+{"text": "Left ventricular rotation is an important part of myocardial mechanics during the cardiac cycle. Understanding the mechanisms of LV rotation in different cardiac diseases could play an important role for diagnosis, risk stratification and prediction of heart failure. We sought to analyze LV rotation using the feature tracking technique in patients with dilated cardiomyopathy (DCM) included in the European CMR Registry.82 Patients diagnosed with DCM and a control group consisting of 30 healthy volunteers were analyzed using dedicated feature tracking imaging software . An apical, midventricular and basal slice in short axis orientation were tracked to analyze the peak rotation of each slice. LV twist  and LV torsion (defined as the LV twist per ventricular length) were calculated.DCM patients and controls with normally directed rotation  were compared to each other table : DCM patAmongst the DCM patients an inversed rotational pattern was frequently observed Table : 57.3% oDCM is associated with an inverted direction of rotation in a significant amount of cases, predominantly affecting the LV apex. Patients with a normal direction of rotation exhibit significant lower torsion. These findings warrant further investigation including clinical follow-up data in order to analyze their impact on clinical outcome in patients with DCM.N/A."}
+{"text": "Uganda poultry production is still faced with frequent outbreaks of Newcastle disease (ND) in the backyard free-range systems despite the accessibility of cross protective vaccines. Live bird markets and waterfowl has long been reported as a major source of disease spread as well as potential sources of avirulent strains\u00a0that may mutate to virulent strains. ND-virus has been reported enzootic in Ugandan poultry but limited studies have been conducted to ascertain thermostability phenotypes of the Ugandan ND-virus strains and to understand how these relate to vaccine strains.2 and LaSota) by standard thermostability procedures and Hemagglutinin-Neuraminidase (HN) gene domains. The known pathotypes with thermostability profiles were compared at HN amino acid sequences.This study evaluated thermostability of 168 ND-virus field isolates recovered from live bird markets and waterfowls in Uganda compared to two live commercial vaccine strains (I2 heamaglutinin (HA) titers during heat treatment and the infectivity of 9.8 geometric mean of log10 EID50 % in embryonated eggs. One isolate from this study exhibited a comparable thermostability and stable infectivity titers after serial passages, to that of reference commercial vaccine was recommended for immunogenicity and protection studies.Field isolates displayed disparate heat stability and HN gene domains. Thermolabile isolates were inactivated within 15\u00a0min, while the most thermostable isolates were inactivated in 120\u00a0min. Four thermostable isolates had more than 2 logThe occurrence of ND-virus strains in waterfowl and live bird markets with disparate thermostability and varying HN gene domains indicate circulation of different thermostable and thermolabile ND-virus pathotypes in\u00a0the country. Newcastle disease (ND) is a contagious poultry infection that usually invokes trade barriers and exerting great economic threats . NewcastGreat importance is attached to the thermostability of live vaccinates because of their retained potency in areas with poor transport, storage facilities, human error and power shortages. Studies in search of new thermostable isolates assess virulence of pathotypes by determining the amino acid sequences at the F protein cleavage site (FPCS), mean death time (MDT) and Intracerebral pathogenicity indices (ICPI). In areas where there is frequent use of vaccines, selective pressure leading to new strains or failed vaccination has been recorded due to the use of phylogenetically divergent vaccine strains from the circulating local ND-viruses , 28. BesHN gene is known to play crucial multifunctions in infectivity , 42. It 2 strain with well-defined genotypes. However, the recent ND-virus isolates from Ugandan live bird markets indicate a high pathogenicity and low evolution , vaccinates ."}
+{"text": "The most robust DTI associations were identified in white matter tracts linking cognitive and evaluative processing with emotional responses: anterior thalamic radiation, fornix (emotion identification) and uncinate fasciculus (sarcasm identification). DTI associations of impaired social cognition were more consistent than corresponding grey matter associations. These findings delineate a brain network substrate for the social impairment that characterises FTLD syndromes. The findings further suggest that DTI can generate sensitive and functionally relevant indexes of white matter damage in FTLD, with potential to transcend conventional syndrome boundaries.Impairments of social cognition are often leading features in frontotemporal lobar degeneration (FTLD) and likely to reflect large-scale brain network disintegration. However, the neuroanatomical basis of impaired social cognition in FTLD and the role of white matter connections have not been defined. Here we assessed social cognition in a cohort of patients representing two core syndromes of FTLD, behavioural variant frontotemporal dementia  and semantic variant primary progressive aphasia , relative to healthy older individuals (n\u00a0=\u00a037) using two components of the Awareness of Social Inference Test, canonical emotion identification and sarcasm identification. Diffusion tensor imaging (DTI) was used to derive white matter tract correlates of social cognition performance and compared with the distribution of grey matter atrophy on voxel-based morphometry. The bvFTD and svPPA groups showed comparably severe deficits for identification of canonical emotions and sarcasm, and these deficits were correlated with distributed and overlapping white matter tract alterations particularly affecting frontotemporal connections in the right cerebral hemisphere \u2022Social cognition deficits define frontotemporal dementias but are poorly understood.\u2022We studied brain network correlates of sarcasm processing in these dementias with DTI.\u2022Sarcasm deficits were particularly linked to right frontotemporal tract changes.\u2022DTI generates functionally relevant metrics of white matter damage in these dementias. These dThese challenges are well illustrated by the canonical FTLD syndromes of behavioural variant frontotemporal dementia (bvFTD) and the semantic variant of primary progressive aphasia . Clinically, bvFTD characteristically manifests with progressive behavioural deterioration leading to severe social dysfunction that may be misdiagnosed as a primary psychiatric disorder , while sSocial cognition is a multi-dimensional and still poorly understood aspect of human brain function ; it typiThe processing of sarcasm is an attractive model for probing component processes of social cognition that are vulnerable in FTLD syndromes . SarcasmThis work contributes to a growing body of evidence associating particular social cognition deficits with regional brain damage in FTLD . To dateHere we investigated white matter correlates of social cognition impairment in bvFTD and svPPA using DTI. We correlated DTI metrics with indices of canonical emotion identification  and sarcasm identification  in naturalistic vignettes. DTI data were analysed using a tract-based spatial statistics (TBSS) processing pipeline that makes minimal prior assumptions about key sites of disease involvement and is therefore relatively anatomically unbiased. White matter alterations were correlated with the distribution of grey matter atrophy assessed using voxel-based morphometry (VBM). We hypothesised that white matter alterations would target pathways binding the distributed fronto-temporal and limbic networks previously implicated in neuroimaging studies of social cognition in the healthy brain and in neurodegenerative disease. We further hypothesised that white matter signatures of impaired social cognition would constitute \u2018trans-syndromic\u2019 substrates for the overlapping behavioural deficits that characterise the bvFTD and svPPA syndromes clinically. DTI measures of axial (AX), radial (RD) and total  diffusivity and fractional anisotropy (FA) were assessed in parallel, given previous work suggesting that different DTI measures may constitute relatively specific indices of structural or functional integrity in white matter pathways .22.1Twenty-nine patients fulfilling consensus criteria for probable or definite bvFTD  and 15 p2.2The Awareness of Social Inference Test (TASIT)  was usedSocial cognition measures, general neuropsychological data and general demographic characteristics  were compared between participant groups using Stata12\u00a9. Repeated-measures analysis of variance regression models were used to assess group differences in performance scores, age and gender. British Picture Vocabulary Scale , augmented with parallel imaging acceleration to reduce susceptibility artefact. Nine sequences without diffusion weighting were also acquired (b\u00a0=\u00a00\u00a0s/mm2). Multiple diffusion and non-diffusion weighted scans were acquired to improve signal to noise and to provide multiple independent observations, improving the fit of the tensor model and robustness of the data. In addition a sagittal 3-D magnetisation-prepared rapid gradient echo T1-weighted volumetric MRI  and a coronal fluid-attenuated inversion recovery (FLAIR) MRI were acquired. For all participants, volumetric MRI, DTI and FLAIR sequences were assessed visually in all planes to ensure adequate coverage and to exclude artefacts, unexpected pathology or significant motion.Brain MR images were acquired on a Siemens Trio 3\u00a0T MRI scanner using a 32-channel phased array head-coil . Two 64-direction DTI sequences were acquired with a single shot, spin-echo echo planar imaging sequence  and FA and other DTI metrics at each voxel derived from the tensor eigenvalues /2), TR\u00a0=\u00a0(\u03bb1\u00a0+\u00a0\u03bb2\u00a0+\u00a0\u03bb3) and FA is given by:Raw diffusion weighted images were affine-aligned to the first corresponding b0 image using a linear image registration tool (FLIRTv5.5) within the FMRIB Software Library (FSLv4.1.5), in order to correct for motion and eddy currents. The weighting vectors were adjusted to correct for any rigid body motion. DTI volumes were then combined for tensor fitting using Camino  .http://www.fil.ion.ucl.ac.uk/spm) running under Matlab 7.14\u00ae. Pre-processing steps were carried out in accordance with current guidelines  and disease group membership included as covariates. To minimise confounding effects from correlated general semantic, executive or disease severity factors, raw scores on the BPVS and a Stroop ink colour naming test (a standard executive measure) were included as additional nuisance covariates in the model design. In the DTI analyses, FA, AX, RD and TR metrics were analysed separately. In each case, relationships between the behavioural and neuroimaging metrics were assessed across the two syndromic groups, in each syndromic group separately, and contrasting the two syndromic groups. In the grey matter analysis an additional step was applied to minimise voxel drop-out due to marked local regional atrophy in particular scans. The analysis was performed within a customised brain mask based on a specified voxel threshold intensity criterion  whereby cluster\u2019 to determine if multiple anatomical clusters of white matter alteration occurred within each contrast and to extract information on the statistical significance and spatial extent of each anatomical cluster. To determine involvement of specific white matter tracts the JHU ICBM-DTI-81 DTI white matter atlas was registered to the study specific mean FA image  randomise tool within FSL with 5000 permutations generated for each test. For all analyses, a significance threshold (p\u00a0=\u00a00.05) was applied following correction for multiple comparisons using family-wise error correction with threshold-free cluster enhancement  over theFA image . The peaMaps of disease-associated grey and white matter alteration were generated for each syndromic group relative to a historical age- and gender-matched cohort of healthy individuals  for which brain MR images were previously obtained using the same scanner and acquisition parameters. Grey and white matter disease maps were generated using the same parameters as previously specified.33.1General characteristics of participants are summarised in 3.2Social cognition data are summarised in 3.3As anticipated, compared with healthy controls both syndromic groups showed extensive profiles of grey matter atrophy and changes in cerebral white matter integrity. The bvFTD group showed distributed bi-hemispheric atrophy involving the anterior temporal lobes, mesial temporal structures, insular, prefrontal and orbitofrontal cortices; while the svPPA group showed an overlapping but distinctive profile of bi-hemispheric atrophy involving the anterior inferior temporal lobes (more marked on the left) extending into the posterior inferior temporal and orbitofrontal cortices . White matter alterations were evident bi-hemispherically but with a fronto-temporal gradient . The bvFTD group had both dorsal and ventral white matter alterations, most extensive in the bilateral uncinate fasciculus, corpus callosum and cingulum bundle, with less marked changes posteriorly including the parieto-occipital inferior longitudinal fasciculus. The svPPA group had a more ventral profile of white matter alterations most prominent in the uncinate fasciculus bilaterally and also involving the corpus callosum and bilateral cingulum bundle.3.4Maps of DTI metric alterations associated with performance on social cognition tasks are shown in Across both patient groups, TASIT emotion identification score was inversely correlated with AX, RD and TR and positively correlated with FA extensively over the dorsal, ventral and commissural white matter tracts in both cerebral hemispheres ; the larAcross both patient groups, TASIT total sarcasm  identification score was inversely correlated with AX, RD and TR in bi-hemispheric but predominantly right temporal and inferior frontal white matter tracts; the largest effects in terms of statistical significance and extent  were demAcross both syndromic groups , white m3.5Statistical parametric maps of regional grey matter volume associated with performance on social cognition tasks are shown in These grey matter correlates of social cognition performance from the VBM analysis were only partly convergent with the white matter correlates identified in the DTI analysis . Converg4Here we have used an anatomically unbiased DTI protocol to delineate white matter tract associations of cognitive processes relevant to social signal encoding  and interpretation (sarcasm identification) in two canonical FTLD syndromes with prominent social difficulties. In line with previous work , both thWhite matter correlates of emotion and sarcasm processing here were identified after adjusting for generic cognitive (semantic and executive) indexes, suggesting a relatively specific association with social cognitive operations rather than a more general association with disease severity. Attempts to define neuroanatomical correlates of behaviour in disease states are potentially biased by the brain topography of particular diseases, which tend to limit the associations that can be observed. In the present study, this was addressed by adjusting DTI regression analyses for disease group membership, allowing us to identify associations extending across syndromes in the combined patient cohort as well as syndrome-specific associations. Together this evidence suggests that bvFTD and svPPA involve common large-scale networks mediating social cognition, albeit with a regional emphasis that is modulated by syndrome; and that social cognition processes may constitute \u2018trans-syndromic\u2019 signatures of brain dysfunction in FTLD. Moreover, white matter tract correlates of social cognition impairment here were only partly convergent with (and more consistent than) the grey matter correlates identified in the corresponding VBM analyses: this underlines both the potential of DTI to reveal disease signatures that may not be fully delineated using grey matter imaging techniques, and the critical role of white matter pathway integrity in maintaining normal brain network function.The most robust white matter associations of emotion and sarcasm processing here were identified within tracts previously implicated in linking cognitive and evaluative processing with emotional responses, as part of a broad repertoire of cognitive operations supported by these tracts. Abnormal diffusivity in the anterior thalamic radiation was identified as a correlate of emotion identification in the combined group and within the svPPA group; and a correlate of sarcasm identification within the bvFTD group. The anterior thalamic radiation participates in thalamo\u2013fronto\u2013striatal re-entrant circuits and has widespread projections to the prefrontal cortex and basal forebrain regions. Both in the healthy brain and in a range of neuropsychiatric disorders, this tract has been implicated in various cognitive operations that mediate the social context of emotional signals, including reward and punishment potential, gating and cognitive meaning of affective signals and pervasive induced mood states that may promote evaluation of emotional experiences .Impaired emotion identification in the combined cohort and within the bvFTD group was strongly associated with altered diffusivity in the fornix, consistent with other work in FTLD syndromes . The forImpaired sarcasm detection in the combined cohort and within the bvFTD group was strongly associated with abnormal diffusivity in the uncinate fasciculus: this tract is part of the \u2018extended limbic system\u2019  and playThe grey matter (VBM) and white matter (DTI) correlates identified here together support previous evidence implicating the right temporal lobe in sarcasm detection  and furtOf note, primary correlates of social cognition here did not include fronto-insular connections within the salience network previously implicated as central both to the pathogenesis of bvFTD and to processes supporting human social cognition . The preOur findings illustrate the potential value of DTI as a functional and disease metric in FTLD. Neuroanatomical data derived from DTI and VBM should be compared with caution, given the different properties and technical bases of these modalities; with these caveats in mind, we analysed the present DTI and VBM data in a common pre-processing and statistical framework. Considering both social cognition metrics here, white matter associations were extensive and more consistent than regional grey matter associations, in line with other neuroimaging and neuropathological evidence for extensive white matter pathology in FTLD syndromes . The datWhite matter signatures based on the FA metric were substantially less extensive than for other diffusivity metrics here . InformaTaken together, these findings further define neurobiological signatures for the social impairment that characterises FTLD syndromes, grounded in the emerging neural network paradigm of neurodegenerative disease . The finThe present study has several limitations that suggest directions for future work. The findings should be corroborated in larger cohort studies comparing other neurodegenerative diseases and mimic syndromes such as autism, schizophrenia and other primary psychiatric disorders . These v"}
+{"text": "The neurological hallmark of TTR-FAP is a length-dependent axonal neuropathy that initially involves the unmyelinated and small myelinated nerve fibers that mediate pain and temperature sensation, causing sensory disturbances that typically start in lower limbs. Subsequent degeneration of larger myelinated fibers results in large fiber sensory deficit and muscle weakness.The disease can be difficult to recognize due to extreme phenotypic heterogeneity and nonspecific clinical symptoms even within the same mutation.In TTR-FAP related to Val30Met mutation, different neuropathy phenotypes have been reported mainly in patients from non endemic areas as well in late onset cases.We described 3 TTR-FAP Val30Met early onset cases from endemic areas with a different neuropathy phenotype that can be easily misdiagnosed as a different entity. One case presented as a bilateral carpal tunnel syndrome without neuropathy; another with a demyelinating neuropathy with predominant upper limb involvement and other with a demyelinating neuropathy with conduction blocks mimicking a CIDP.TTR-FAP is frequently misdiagnosed, e.g. as idiopathic polyneuropathy or chronic inflammatory demyelinating polyneuropathy, and may be greatly under diagnosed. However, early accurate diagnosis of TTR-FAP is crucial for effective disease control."}
+{"text": "Lobar torsion is a fatal but fortunately rare occurrence following lung resection. Early clinical signs and radiographic features may be nonspecific resulting in diagnostic delay. A high index of suspicion is vital for early diagnosis and intervention to avoid further parenchymal necrosis and deadly gangrene. We report a case of left lower lobe torsion in a 76-year-old female following elective upper lobectomy for underlying lung adenocarcinoma. Diagnosis was made following highly suggestive radiographic findings prompting bronchoscopy and revision thoracotomy. An emergency detorsion failed to restore lung viability and was followed by completion pneumonectomy. The patient recovered and was discharged on the seventh postoperative day. Lobar torsion is a very rare but potentially fatal postlobectomy complication. It represents a diagnostic dilemma in the early postoperative period and a high index of suspicion is crucial for lung salvage. Torsion most commonly involves the middle lobe following ipsilateral lobectomy with only few cases describing left sided involvement. We will present a case of left lower lobe torsion, followed by a review of the medical literature on this topic.Our patient is a 76-year-old lady with chronic obstructive pulmonary disease, peripheral vascular disease, and smoking as past medical history, presenting with 2 months of a nonproductive cough. The patient was found to have a left upper lobe nodule on a plain chest radiograph and further evaluation with a computed tomography (CT) of the chest delineating a 1.2\u2009cm spiculated nodule . FollowiThe immediate postoperative course was uncomplicated and the patient was transferred to the cardiothoracic unit for observation. Follow-up chest radiography on postoperative day-1 showed a small left lower lobe opacity with the patient complaining of mild pain at the surgical site. On postoperative day-2 the patient developed atrial fibrillation with rapid ventricular rate associated with hemoptysis and worsening left sided pleuritic chest pain. Plain chest radiography showed worsening left lung opacity with bronchial cutoff . A CT ofLung torsion is the rotation of a pulmonary lobe around the hilar pedicle resulting in bronchovascular compromise. It is a rare event seen mainly in the postoperative setting following thoracic surgery , 2. FeweThe underlying pathophysiology remains controversial with reports delineating few predisposing factors , 2, 10: The clinical picture of lung torsion varies depending on whether the torsion is partial or complete. Partial torsion has an insidious course presenting with partial collapse or obstructive pneumonia . On the Recognition of early imaging features is vital for prompt diagnosis and management. Plain radiography can raise early suspicion for postoperative torsion if certain findings are delineated including inappropriate hilar displacement away from the collapsed lobe, collapsed lobe in an unusual location, ipsilateral lobe opacification following surgery, and bronchial cutoff  10]. CT. CT10]. Following suspicion of torsion, an emergent surgical intervention is vital. The optimal type of intervention remains controversial depending on the lung status visualized by thoracotomy. If the involved lobe demonstrates viability, detorsion may offer the possibility for lung salvage . HoweverProphylactic lung fixation has been proposed as a successful method to prevent lung torsion using various surgical techniques including parenchymal suturing, adhesive membranes, and pleural flaps , 13, 18.In regard to our patient, she was at higher risk for a very rare complication of left lower lobe torsion secondary to surgical inferior pulmonary ligament transection and pedicle skeletonisation, a complete left longitudinal fissure, and a longer left lobar pedicle. Initially she presented with atrial arrhythmia and hemoptysis with no significant hypoxemia or respiratory distress. Early diagnosis in the first 24 hours was made possible with highly suggestive radiographic features; however the lung did not appear viable at the time of intervention. Lung detorsion performed within 24 hours did not result in clinical deterioration; however lung viability also did not improve and the patient eventually underwent complete pneumonectomy.Lung torsion remains a fatal but fortunately rare complication after lobectomy. A low threshold should be present in at risk patients for prompt investigation and intervention that is vital for lung salvage. Patients with multiple predisposing factors should be considered for prophylactic lung fixation."}
+{"text": "Previous studies using transcranial Doppler sonography have suggested that cerebral circulation is preserved relative to cardiac output during normotensive hypovolaemia (NTH). We have further investigated the cerebral autoregulatory responses to hypovolaemia using using MRI measurements of total cerebral blood flow combined with graded levels of lower body negative pressure (LBNP) to induce steady state central hypovolaemia.11 healthy male volunteers (21-24 years) underwent MRI scanning with their legs and torso within a LBNP chamber; phase contrast angiography based flow measurements (MRI-PCA) were acquired at 10mmHg increments from baseline, to -50 mmHg . Measurements were made through the carotid and vertebral arteries to measure total cerebral volume flow (CBVF) and through the ascending and proximal descending aorta to measure cardiac output (CO).At low levels of LBNP (\u2264 -20mmHg) decrease in CBVF was directly proportional to the decrease in CO Figure . Between1. This difference is likely to reflect the different methods of cerebral blood flow measurement. MRI-PCA allows direct volume flow measurements from the carotid and basilar arteries whereas TCD uses flow velocity in the middle cerebral arteries as a surrogate of volume flow. This potentially important discrepancy requires further investigation to elucidate the mechanisms controlling CBF responses to nth.These findings demonstrate a correlation between decreases in CO and CBVF during normotensive hypovolaemia (NTH), which is in disagreement with previous studies using transcranial Doppler to measure CBVF. The findings do not support previous descriptions of relative sparing of CBVF due to compensatory reductions in cerebrovascular resistance in response to NTH"}
+{"text": "Mycobacterium abscessus subsp. abscessus (MAB) is a highly drug resistant mycobacterium and the most common respiratory pathogen among the rapidly growing non-tuberculous mycobacteria. MAB is also one of the most deadly of the emerging cystic fibrosis (CF) pathogens requiring prolonged treatment with multiple antibiotics. In addition to its \u201cmycobacterial\u201d virulence genes, the genome of MAB harbours a large accessory genome, presumably acquired via lateral gene transfer including homologs shared with the CF pathogens Pseudomonas aeruginosa and Burkholderia cepacia. While multiple genome sequences are available there is little functional genomics data available for this important pathogen.We report here the first multi-omics approach to characterize the primary transcriptome, coding potential and potential regulatory regions of the MAB genome utilizing differential RNA sequencing (dRNA-seq), RNA-seq, Ribosome profiling and LC-MS proteomics. In addition we attempt to address the genomes contribution to the molecular systems that underlie MAB\u2019s adaptation and persistence in the human host through an examination of MABs transcriptional response to a number of clinically relevant conditions. These include hypoxia, exposure to sub-inhibitory concentrations of antibiotics and growth in an artificial sputum designed to mimic the conditions within the cystic fibrosis lung.P. aeruginosa and mirrors the transcriptional responses that lead to persistence in mycobacteria. These strategies include an increased reliance on amino acid metabolism, and fatty acid catabolism and highlights the relevance of the glyoxylate shunt to growth in the CF lung. Our data suggests that, similar to what is seen in chronically persisting P. aeruginosa, progression towards a biofilm mode of growth would play a more prominent role in a longer-term MAB infection. Finally, MAB\u2019s transcriptional response to antibiotics highlights the role of antibiotic modifications enzymes, active transport and the evolutionarily conserved WhiB7 driven antibiotic resistance regulon.Our integrated map provides the first comprehensive view of the primary transcriptome of MAB and evidence for the translation of over one hundred new short open reading frames (sORFs). Our map will act as a resource for ongoing functional genomics characterization of MAB and our transcriptome data from clinically relevant stresses informs our understanding of MAB\u2019s adaptation to life in the CF lung. MAB\u2019s adaptation to growth in artificial CF sputum highlights shared metabolic strategies with other CF pathogens including The online version of this article (doi:10.1186/s12864-016-2868-y) contains supplementary material, which is available to authorized users. Mycobacterium abscessus (MAB) is increasing and it is emerging as an important cystic fibrosis (CF) pathogen with a high innate antibiotic resistance rendering it refractory to most antimicrobial therapies .Fig.Fig35].FM. tuberculosis is thought to confer an adaptive advantage for growth in microaerophilic or anaerobic environments [devR & devS from the DosR regulon are up-regulated indicating short exposure to SCFM2 does not induce the hypoxic response and that devR & devS may be induced for reasons other than hypoxia. This is in keeping with our findings that points towards a metabolic adaptation to a restriction in the diversity of carbon sources upon SCFM2 exposure but missing a clear signature of anaerobic growth. Both antibiotic exposures included induction of the transcriptional regulator whiB7 (MAB_3508c) alongside the alleviation of a number of TetR transcriptional repressors (MAB_4647/MAB_4687/MAB_2957c). In MTB WhiB7 is induced by both antibiotics and acts in conjunction with the primary sigma factor SigA to activate a discreet regulon of 12 genes controlling intrinsic antibiotic resistance [erm41 (MAB_2297), a homolog of the multidrug efflux pump tap (MAB_1409c) and a putative macrolide transporter (MAB_1846). In addition to whib7 up-regulation, erythromycin exposure induced a large majority (7/8) of the MAB homologs of the WhiB7 regulon indicative of an evolutionarily conserved WhiB7 driven response to macrolides. whiB7 in MAB is also induced in response to sub-inhibitory concentrations of the aminoglycoside amikacin [whib7 and the putative macrolide transporter MAB_1846 were induced. This uncoupling of WhiB7 induction from upregulation of its predicted regulon was also evident in response to SCFM2 where, despite the large number of differentially expressed genes and a strong induction of whiB7, MAB homologs of its regulon were largely unaffected. One of the strongest induced operons in response to both antibiotics MAB_0357c & MAB_0356c encodes a delta-aminolevulinic acid dehydratase (ALAD) and a S-isoprenylcysteine methyltransferase (mddA), respectively. MddA has been shown to catalyze production of the volatile compound dimethyl sulphide (DMS) which has been used as a volatile biomarker for differentiating between the growth of different mycobacterial species [Our comparisons reveal some significant overlaps and number of interesting sub-networks that span differing conditions. We find 43\u00a0% (22 of 51) of the hypoxic response including the entire DosR regulon is up-regulated in MAB strains with a Rough morphotype, a link that is pronounced in clinical strains with the potential for persistence . Constitronments . In contsistance . MAB hasamikacin  and is t species .whiB7, which is up-regulated in response to all conditions tested except hypoxia.We looked at expression patterns for the novel sORFs identified by ribosomal profiling across the different conditions . Therefore we profiled MAB response to a number of biologically relevant exposures that have either been experimentally characterized or for which some comparable data is available from other species [M. abscessus hypoxic response and the role of the evolutionarily conserved DosR regulon therein. Our data lends greater weight to DosR regulon\u2019s constitutive up-regulation in strains of the Rough morphotype as it may confer an adaptive advantage for survival in the hypoxic CF lung environment. We identify for the first time numerous antibiotic resistance genes up-regulated in response to erythromycin and kanamycin exposure including antibiotic modification enzymes, efflux pumps and the redox sensitive WhiB7 transcriptional regulator. Unexpectedly we find that although whiB7 and its predicted regulon in MAB are both induced in response to erythromycin this link appears clearly uncoupled in response to other antibiotics and stresses. Given the diversity of WhiB7 activators and its important role in inducible antibiotic resistance this deserves further study. Comparison with transcriptional data from other CF pathogens clearly indicates a convergence in metabolic strategies towards adaption to the CF lung [Central to understanding the functional networks that contribute to adaptation and persistence in MAB is a well-characterized genome coupled with rich genome-wide functional genomics datasets. It\u2019s clear from our data that the complexity of the MAB genome is only modestly represented by current automated annotations of its coding regions. We demonstrate the presence of many novel sORFs with coding and regulatory potential and identify internal TSS as a potential source of protein isoforms. Our Ribo-seq data illustrates that many non-coding RNAs, including regulatory and antisense RNAs, are ribosomally protected. As they lack clear evidence of translation their presence means that these antisense RNAs are competing kinetically with the ribosome for access to the same region of the nascent target RNA. Functional regulatory RNAs are difficult to detect in mycobacteria due to the pervasiveness of transcription initiation  and iden species , 16, 22. CF lung , 23, 32.Detailed experimental procedures are provided in Additional file As the work was carried out on bacterial cultures the authors state that no ethical approval was required for any aspect of this study.M. abscessus ATCC19977 cultures were grown in Middlebrook 7H9 medium . When indicated, diethylenetriamine/nitric oxide (DETA/NO) adduct , kanamycin or erythromycin  were added to the culture media. For growth in an enhanced artificial sputum medium (SCFM2) bacterial cultures were washed with phosphate buffered saline solution (PBS) and then transferred to SCFM2 medium.RNA was isolated as described earlier using Qiagen miRNeasy kit with double DNase treatment . Sample Mycobacterium abscessus ATCC 19977 genome sequence  using Bowtie 1.1.1. Ribosome profiling and RNA-seq datasets were deposited into NCBI\u2019s Gene Expression Omnibus (GEO) (accession numbers: GSE78787 and GSE72996).Following removal of sequencing adapters and quality control, all ribosome profiling and RNA-seq reads were mapped to the Recovered bacterial pellets were washed with ice-cold PBS, suspended in protein lysis buffer  and physically disrupted. Clarified total cell lysate was reduced with dithiothreitol (DTT), alkylated with iodoacetamide and subjected to overnight trypsin digestion (Pierce Biotechnology Inc.). Resulting tryptic peptides were desalted by solid phase extraction with C18 ZipTips (Millipore Corporation) and analysed on a Thermo Scientic Q Exactive mass spectrometer connected to a Dionex Ultimate 3000 (RSLCnano) chromatography system.Mycobacterium abscessus ATCC 19977 genome sequence  using a database search approach implemented in PEAKS 6.0 proteomics software. A parent mass error tolerance of 6.0\u00a0ppm was used in conjunction with a maximum of 2 missed cleavages along with one non-specific cleavage.Tryptic peptides were aligned to the Mycobacterium abscessus; SCFM, synthetic cystic fibrosis sputum; TSS, transcriptional start siteDE, differentially expressed; MAB,"}
+{"text": "ICOS (inducible co-stimulator molecule) is a T cell encoded member of the extended B7/CD28 superfamily that is up-regulated upon early T cell activation. Previous studies have shown that higher ICOS expression on circulating T cells, post treatment with ipilimumab, is associated with better clinical outcome. In complementary pre-clinical studies, efficacy observed with a whole cell vaccine consisting of ICOS-L expressing B16 melanoma (IVAX) suggests that agonism of this pathway could provide therapeutic benefit in the cancer setting.We have generated a panel of anti-ICOS monoclonal antibodies with in vitro agonist properties. These lead agonist mAbs have been shown to be efficacious both as monotherapies in multiple syngeneic tumor models and in combination with an anti-PD1 antibody. Mechanistic studies that demonstrate tumor regression is associated with enhanced ratios of cytotoxic CD8/regulatory T (Tregs) cells as well as preferential reduction in ICOS high Tregs in the tumor microenvironment have informed the selection of optimal Fc regions for clinical development.Jounce is now developing a high affinity humanized agonist monoclonal antibody to be tested as both a monotherapy as well as in combination with other T cell checkpoints in solid tumor indications."}
+{"text": "In selected patients, our Unit has recently moved from handheld ultrasound-guided vacuum-assisted core biopsy (VACB) piecemeal acquisition of tissue to the handheld Intact Breast Lesion Excision System (Intact). Intact removes a single piece of tissue, potentially allowing radiologists to excise the entire lesion as well as allowing pathologists to visualise lesion architecture more easily and to calculate margins. We evaluated our early experience of excising benign or likely benign breast lesions using the 20 mm Intact.Prospective data collection was performed on all patients undergoing handheld ultrasound-guided Intact excision under local anaesthetic in 2014 and 2015, which comprised 19 lesions in 18 female patients aged 29\u221273.The device was technically straightforward to operate and well-tolerated by patients with no significant complications. Handheld needle orientation was difficult within dense glandular tissue (only one acquisition is possible per needle), but improved with increased operator experience. Achieving adequate analgesia required higher quantities of local anaesthetic than for the equivalent VACB. Pathologists found specimens easier to interpret than VACB samples. In all cases adequate excision was completed sonographically at one outpatient appointment, but in six cases a second Intact biopsy and/or a VACB was required to complete that excision, with extra cost implications. In two patients with M3 microcalcification the Intact pathology demonstrated ductal carcinoma in situ, leading to surgical wide local excision.Our early experience shows Intact as a reliable and effective tool for handheld diagnostic and/or therapeutic excision of selected breast lesions."}
+{"text": "Synchronous bilateral ovarian torsion is an uncommon entity of which both ovaries twist at the same time or observed twisted during the surgical intervention. Herein, we present a neonate with bilateral ovarian torsion, which successfully managed by laparoscopic approach.  A neonate born at term to a 26-year-old primigravida by elective cesarean delivery was diagnosed with an intra-abdominal cystic mass at 35th week of pregnancy. A conservative management plan was undertaken with repeated ultrasonographic evaluations every two weeks. The pregnancy, medical history of the patient and birth were unremarkable. A female full-term infant of 39+5 week of gestation was delivered with a birth weight of 4160 gram. Physical examination was unremarkable. Post-delivery ultrasonography revealed an anechoic uncomplicated cystic mass measuring 5x3.5 cm located in the right pelvis and another semi-solid complicated cystic mass was located in the left pelvis with a measure of 5.4x3.8 cm, without any vascular signal. Both ovaries were not identified. Laparoscopy revealed brown round smooth cystic mass with a tiny stalk nearly amputated from the left fallopian tube in the left pelvis. A loop of intestinal segment also twisted around this calcified tiny stalk of the mass . Right ovary was also twisted with the cystic mass . The right ovary was untwisted 2 times (360 degree) and left in the pelvis after cyst aspiration without excision and ovarian fixation. Then the left ovary examined and seemed to be nearly amputated from the adnexa. It was removed after cyst aspiration. The calcified stalk was separated from the bowel. The post-operative period was uneventful and the patient was discharged on the 2nd post-operative day. Follow-up at 1 month with ultrasonographic evaluations showed an18 mm right ovary and no cyst. The differential diagnosis of a prenatal cystic abdominal mass includes omental cyst, mesenteric cyst, intestinal duplication, urachal cysts, renal cysts and ovarian cysts [1]. Preoperative diagnosis of ovarian torsion is difficult not only in newborns or infants but also in pre pubertal girls. The etiology of the ovarian cysts during pregnancy is related to the immature hypothalamus-pituitary-ovarian feedback that results gonadal hyperstimulation or placental insufficiency with incomplete maturation of the gonadostat. There are few reported patients of asynchronous bilateral adnexal torsion in children in the literature . Synchronous bilateral ovarian torsion has also been reported which was successfully managed by laparoscopic detorsion [4]. When a post-natal radiological evaluation reveals a complicated ovarian cyst, irrespective of the size, surgical management recommended either by laparoscopy or laparotomy [5]. Uncomplicated cysts, smaller than 5 cm diameter usually resolve spontaneously while the cysts exceeding 5 cm should be decompress via aspiration to prevent complications [6]. This case highlights the importance of high index of suspicion and early diagnosis of bilateral ovarian torsion in the newborn with bilateral pelvic cysts detected on the pre-natal and post-natal scans.Source of Support: NilConflict of Interest: Nil"}
+{"text": "Transmembrane efflux pumps play an increasing role in the success of ART. The occurrence of increasing mRNA levels of the efflux pump proteins P-gp and MRP subtypes has been associated with ART therapeutics like PIs and NNRTIs. Moreover, a relation has been suggested of MRP subtypes and CD4 cell counts. So there is a challenge to find selective MRP inhibitors which may reduce MRP-induced drug resistances as well as discussed effects on CD4 cells. We developed novel nonpeptidic inhibitors of important MRP subtypes related to both MRP-mediated resistances as well as reduced cell counts.The molecular structures of the various efflux pumps guided the development of both symmetric and nonsymmetric inhibitors dedicated to selectively inhibit the relevant MRP-subtypes. Inhibiting properties were evaluated in exclusively P-gp as well as MRP-overexpressing cell lines in comparison to nonexpressing parental cell lines with fluorescent substrates using flow cytometry.Our inhibitors with allover symmetric substitution patterns are excellent P-gp inhibitors, while a reduction of those symmetric elements concerning their number and exact positioning significantly lowers the P-gp inhibition whereas the MRP1 inhibition is found mainly increased. So selective inhibitors are demonstrated to influence the efflux pump type-related antiretroviral drug resistance.The success of ART may be mainly increased by selective MRP inhibitors which reduce the MRP-related effects on drug resistance as well as on discussed cell counts. Structure-guided studies of the efflux pump inhibition helped to design novel selective inhibitors with structure-reasoned effects of the nonsymmetric substitution patterns. So far only nonselective inhibitors have been used in ART with undesired effects on transporter-related pharmacokinetics. Selective inhibitors will mean a progress in ART especially with less limiting side effects."}
+{"text": "Conventional anti retroviral treatment (ART) has been a core treatment for HIV over the past three decades. Despite the effectiveness of these drugs, most of them abide significant drawbacks such as poor bioavailability and undesirable side effects; thus reducing patient compliance and rendering treatment regime ineffective. This research work is an attempt to develop a dual pronged carrier system using gold nanoparticles (GNP) for increasing effectiveness and sustained drug release of saquinavir.Azadirachta indica was used as an efficient sink for synthesis of GNPs by microwave assistance. Saquinavir (Saq) was attached onto GNPs that were pre functionalized by capping polypeptide linkers of A.indica and characterized by FTIR. Percentage drug loading efficiency (%DLE) and release kinetics were studied by statistical model dependent method. Biocompatibility of drug nanoparticle conjugate was studied by MTT assay. Antiviral efficacy was assessed by quantifying aspartic protease of HIV by fluorescence (FRET) method.Leaf extract of Mono dispersed GNPs (30-40 nm) were synthesized and found to carry high payloads of saquinavir with %DLE of 93.6% as analyzed by Transmission electron microscopy and UV Vis spectroscopy respectively. GNP-saq conjugate demonstrated 16.7% increase in anti viral efficacy as compared to saquinavir alone. The conjugate showed sustained drug release and followed 1st order release kinetics at physiological pH (7.2).Biogenic GNPs serve as a potent candidate for ferrying high payloads of anti retroviral drugs with increased efficacy and reduced side effects. This approach can help reduce dosage frequency and improvise treatment strategy against HIV."}
+{"text": "Traumatic brain injury can trigger chronic neuroinflammation, which may predispose to neurodegeneration. Animal models and human pathological studies demonstrate persistent inflammation in the thalamus associated with axonal injury, but this relationship has never been shown in vivo.11C]-PK11195 positron emission tomography, a marker of microglial activation, we previously demonstrated thalamic inflammation up to 17\u00a0years after traumatic brain injury. Here, we use diffusion MRI to estimate axonal injury and show that thalamic inflammation is correlated with thalamo-cortical tract damage.Using [These findings support a link between axonal damage and persistent inflammation after brain injury. Why thaThe spatial pattern of microglial activation following brain injury may relate to the white matter architecture of the CNS , 6. ExpeDiffusion tensor imaging (DTI) can map the structure of thalamo-cortical white matter tracts using probabilistic tractography , but TBIHere, we combine this approach with PK PET to test the hypothesis that chronic thalamic inflammation after TBI can be explained by thalamo-cortical white matter damage.Ten patients with a history of moderate-severe TBI (Mayo classification)  had PK PET and structural MRI scans including DTI (see [Standard MRI T1 and DTI protocols were used (see ). For DTTo test whether thalamic PK binding is more strongly correlated to proximal than distal thalamo-cortical damage, FA was sampled from a series of non-overlapping ring-shaped ROIs extending centripetally from the thalamus from 2 to 60-mm diameter and intersected with the thalamo-cortical tract mask. ROIs were created by repeatedly dilating a thalamic mask by two voxels (2\u00a0mm). Ring-shaped ROIs were produced by subtracting the previous mask from each step.ND), we used a supervised clustering procedure to identify reference clusters of voxels in grey matter having PK time activity curves mirroring those of controls [ND was sampled in the bilateral thalamus as well as the cortical grey matter regions that were used to define the thalamo-cortical tracts [PK PET acquisition and analysis are described in . To prodcontrols . PK BPNDl tracts .ND was compared between groups using independent sample t tests. Mean FA values were similarly compared. Bonferroni multiple comparisons correction was used. In TBI, we tested for a relationship between regional PK BPND and thalamo-cortical FA using linear partial correlations, controlling for age and time since injury as both factors potentially influence DTI [Regional PK BPence DTI  and PK bence DTI .ND in TBI patients versus controls , the corpus callosum  and the white matter skeleton   Fig.\u00a0.ND and mean thalamo-cortical tract FA . The strength of this correlation decreased with the distance at which FA was sampled from thalamo-cortical tracts (Fig.\u00a0In TBI, we found a significant negative correlation between thalamic PK BPcts Fig.\u00a0. Thalamicts Fig.\u00a0. There wcts Fig.\u00a0. We alsoAxonal injury underlies many long-term problems after TBI . Glia beSeveral mechanisms might underlie persistent thalamic inflammation after TBI Fig.\u00a0. It may Following experimental axotomy, microglial activation is seen in both anterograde and retrograde projection areas . Hence, An anterograde evolution of microglial activation is seen in other conditions. After stroke, microglial activation spreads in an anterograde fashion along damaged tracts , 9, and Whether chronic thalamic inflammation is harmful or restorative is uncertain. This question is challenging partly because the relationship between activated microglial phenotype and TSPO expression is not clear . It may An important limitation of the study is that it involved a small sample of patients and with a history of a single moderate-severe TBI. There is a need to replicate these preliminary findings in larger cohorts, which might benefit from investigating a wider range of diffusion metrics. Studies from animal models of repetitive mild TBI show persistent inflammation both at sites of axonal injury and locations remote from the site of focal lesions, suggesting a similar microglial response in cases of lower injury severity , 27.Evidence of persistent neuroinflammation suggests that the window of opportunity for therapeutic intervention following TBI may be longer than is usually considered. Inflammatory PET imaging provides a biomarker to investigate this prolonged inflammatory reaction and potentially the effects of interventions targeting glial activation. Our findings emphasise the need for large multi-modal longitudinal studies combining inflammatory PET with diffusion MRI to image axonal injury."}
+{"text": "Familial Mediterranean fever (FMF) is an autosomal recessive disease characterized by recurring self-limited fever, abdominal pain and chest pain caused by serositis. FMF mainly affects Middle-East populations with a high prevalence in Sephardic Jews, Turkish, Arabs and Armenians. Carnitine is an important molecule in cellular energy metabolism. Secondary carnitine deficiency can be detected in chronic diseases by either renal loss or increased needs.Our hypothesis was that FMF patients would have lower free carnitine levels than their healthy age and gender matched controls due to increased need of carnitine because of recurrent auto-inflammation. The present study was conducted to determine the patterns of free carnitine and acyl-carnitine esters in FMF patients.This is a cross-sectional study of 205 FMF patients who were attending the outpatient Pediatric Rheumatology clinic of Cerrahpasa Medical Faculty Children's Hospital. The patients were selected by random sampling and FMF diagnosis was confirmed by a pediatric rheumatologist according to Yalc\u0131nkaya criteria. 50 healthy subsects were enrolled to the present study. A fasting died blood sample was taken for studying free carnitine and acyl-carnitine esters with tandem mass spectrometry from children in both groups.Acyl-carnitine analyses in spot dried blood samples with ESI-MS/MS were performed in all patients and control group. Screening of acyl-carnitine profile revealed free carnitine, C16-OH and C18:2 carnitine levels were higher , while C4-OH and C4DC carnitine levels were lower  in FMF patients than the control group.In the present study we were not able to define secondary carnitine deficiency in FMF patients, therefore usage of carnitine in all patients with FMF is not recommended."}
+{"text": "AA amyloidosis may develop as a consequence of chronic inflammatory conditions including autoinflammatory diseases(AID). Mevalonate-kinase(MVK) deficiency(MKD) appears to be the least frequent underlying condition among monogenic periodic syndromes. Moreover, amyloidosis rarely manifests during childhood. We report a case of a small child in whom renal biopsy performed because of the cortico-resistant nephrotic syndrome revealed amyloid A.To describe clinical manifestations, laboratory features and disease outcome in a patient referred for suspected periodic fever syndrome.Case report.A 4-years old Caucasian girl with negative family history presented with features of nephrotic syndrome in 1/2011. Over the previous 2 years she has been suffering with recurrent episodes of unexplained fever with pharyngitis and lymphadenitis lasting 3 days in 2-4 weekly intervals and received a putative diagnosis of PFAPA  syndrome. Despite the increasing frequency of febrile episodes over the last year investigations aimed at excluding monogenic fevers were not performed. In early 2011 her IgD was normal, IgA mildly elevated, serum amyoid A (SAA) fluctuated from normal to 200 mg/l. After the standard corticosteroid (CS) treatment of nephrotic syndrome had failed to induce remission after 6 wks, a renal biopsy was performed revealing amyloid A deposits in about 30% glomeruli. While genetic analysis was pending, Colchicine was added to the CS treatment followed by daily anakinra injections with good clinical response. After a laborious genetic screening to exclude mutations causing monogenic AID, following heterozygous variants in MVK gene were identified: Mutation V377I and a novel deletion in exon 5 C152WfsX6 (c.450_453delGGTG). The latter terminates the protein six amino acids after the deletion occurs, effectively making the protein shorter. Within 6 months of the treatment her proteinuria stabilised and there have been no signs of other organ involvement. Despite ongoing anakinra therapy she continues to have occasional febrile episodes with temporary increase of inflammatory parameters including SAA.MKD/HyperIgD-syndrome has been so far reported in only a few cases of AA-amyloidosis. Our patient has been the youngest one to develop this severe complication. The only other child reported so far was also a compound heterozygote carrying the genotype G326R/V377I. The long-term follow-up with careful SAA serial measurements will tell us more about the prognostic significance of the newly described MVK gene deletion. This case report also underlines the importance of careful differential diagnostic re-evaluation of children presenting with PFAPA phenotype in whom febrile episodes do not show a typical prolongation of afebrile intervals over the time.None declared."}
+{"text": "Serious thromboembolic events connected with rFVIIa therapy in hemophilia patients are rare. Only three cases are reported in children, all of them with hemophilia A.We present unique case of patient with hemophilia B and high titer inhibitors to coagulation FIX, who developed severe renal damage due to thromboembolic event during rFVIIa therapy, associated with unsuspected renovascular anomalies.Caution is necessary if hematuria B requires administration of rFVIIa. US color doppler renal imaging before and after drug administration should be sufficient as an early warning. Recombinant factor VIIa  has been shown to induce hemostasis in hemophilia patients with inhibitors against factor VIII or factor IX independent of factor VIII/factor IX. rFVIIa initiates hemostasis by forming a complex with tissue factor (TF) exposed as a result of vessel wall injury. Pharmacologic doses of rFVIIa can enhance thrombin generation. Recombinant activated factor VII  is in regular clinical use in haemophilia B patients with high-titer inhibitors to coagulation factor IX (FIX) since 1996 -4.We present the patient with hemophilia B and high titer inhibitors to coagulation FIX who was treated with rFVIIa for severe life-threatening hematuria. Although hematuria was successfully treated, renal thromboembolic adverse event associated with unsuspected vascular anomalies resulted in severe renal damage. To our knowledge, this is the first case of tromboembolic event connected with rFVIIa therapy with this set of symptoms presented exclusively on kidney with underlying vascular anomalies. The second normal kidney was fully spared.99mTc-DTPA (Diethylene Triamine Pentacaetic Acid) renal scintigraphy  scintigraphy, the left kidney was very pale becoming increasingly better visualized later  ,6. But tOur patient had multiple renal vascular anomalies. Multiple renal arteries are not uncommon. Various reports estimate its incidence up to 32%, usually on the right side with very rare occurrence of triple arteries supplying one kidney -12. AnatSuch an extremely rare troboembolic event in patients with hemophilia B certainly do not compromise safe administration of rFVIIa. However, caution is necessary if hematuria requires administration of rFVIIa. US color doppler renal imaging before and after drug administration should be sufficient as an early warning.Written informed consent was obtained from the patient\u2019s parents for publication of this Case report and any accompanying images. A copy of the written consent is available for review by the Editor of this journal."}
+{"text": "The availability of high quality critical care is increasingly recognised as a global health problem , 2. The Evaluation of a capacity building project to enable local nurses to deliver critical care training courses in a resource limited setting (Sri Lanka).A short critical care course for nurses  was co-designed & delivered by specialist overseas nurse trainers in partnership with Sri Lankan nurse tutors. The impact of the course was assessed using: a pre & post course Multiple Choice Questionnaire (MCQ); a post course Objective Clinical Skills Assessment (OSCA) station & post course feedback questionnaires. Training was delivered in 7 blocks, from June 2013 to November 2014. A graded handover of training responsibilities occurred with lectures, skills stations & workshops increasingly delivered by local rather than overseas faculty. From March 2014 onwards the course was delivered entirely by local faculty, with coaching by overseas faculty. This process was coordinated with a Train the Trainers (TTT) programme for local faculty. The impact of the TTT for building effective training capacity was assessed by analysing the NICST course participant MCQ marks over time.In total 584 ICU nurses were trained over 16 NICST courses. Figure This training is highly rated by participants & is effective in improving clinical knowledge. The roll out of NICST has also fostered a new community of practice amongst the nurse tutor workforce in Sri Lanka, focused on delivering improved critical care skills training. The TTT approach provides sustainable training capacity within the local workforce. This approach may be of use in other resource limited settings."}
+{"text": "Takayasu arteritis (TA) is a rare chronic granulomatous vasculitis of large vessels. Initial symptoms and signs are usually non-specific, therefore a high index of suspicion is needed to make a timely and correct diagnosis.To review our experience with treatment of children with TA.We analysed patients data.In our centre we are currently treating two adolescents with TA. Patient 1 presented with arthralgia, anaemia and fatigue. Patient 2 demonstrated leg claudication. None of them had hypertension. In both of them vascular bruits and elevated inflammatory markers were present. Diagnosis was confirmed by magnetic resonance angiography (MRA). Both patients were initially treated with pulse methylprednisolone followed by a high dose oral corticosteroid in combination with methotrexate. Both patients achieved transient clinical and laboratory improvement with decreased inflammatory parameters after initial treatment. By tapering steroid therapy inflammatory parameters started to rise. Patient 2 also demonstrated less palpable leg pulses and persistent leg claudication. Follow-up MRA imaging demonstrated only partial improvement with persistent vascular changes in both patients. Because of incomplete disease control both patients were started on anti-tumor necrosis factor (TNF) alpha therapy with infliximab which resulted in good clinical and laboratory response with decreased inflammatory parameters.According to our experience anti-TNF alpha therapy appears to be a successful treatment approach in pediatric patients with refractory TA.None declared."}
+{"text": "Paravalvular aortic regurgitation (PAR) following transcatheter aortic valve implantation (TAVI) is well acknowledged. Despite improvements, echocardiographic measurement of PAR largely remains qualitative. Cardiovascular magnetic resonance (CMR) directly quantifies AR with accuracy and reproducibility. We compared CMR and transthoracic echocardiography (TTE) analysis of pre-operative and post-operative aortic regurgitation in patients undergoing both TAVI and surgical aortic valve replacement (AVR).Eighty-seven patients with severe aortic stenosis undergoing TAVI (56 patients) or AVR were recruited. CMR (1.5\u00a0T) and transthoracic echocardiography (TTE) were carried out pre-operatively and a median of 6\u00a0days post-operatively. The CMR protocol included regurgitant aortic flows using through-plane phase-contrast velocity. None/trivial, mild, moderate and severe AR by CMR was defined as \u22648%, 9-20%, 21\u201339%, >40% regurgitant fractions respectively.Pre- and post-operative left ventricular ejection fraction (LVEF) was similar. Post-procedure aortic regurgitant fraction using CMR was higher in the TAVI group . Comparing CMR to TTE, 27 of 56 (48%) TAVI patients had PAR which was at least one grade more severe on CMR than TTE . Sensitivity analysis confirmed the difference in PAR grade between TTE and CMR in the TAVI group .When compared to CMR based quantitative analysis, TTE underestimated the degree of paravalvular aortic regurgitation. This underestimation may in part explain the findings of increased mortality associated with mild or greater AR by TTE in the PARTNER trial. Paravalvular aortic regurgitation post TAVI assessed as mild by TTE may in fact be more severe. There now exists extensive registry and clinical trial data demonstrating an increased incidence of paravalvular aortic regurgitation (PAR) following transcatheter aortic valve implantation (TAVI), and consequently, increased mortality over short term follow-up -5. This By contrast to echocardiography, cardiovascular magnetic resonance (CMR) is able to directly quantify aortic regurgitation with high accuracy and reproducibility by using the technique of phase-contrast velocity mapping. CMR is not affected by the location, number or nature of regurgitant jets or thoracic structural patient factors, and therefore offers an ideal technique for assessing the severity of TAVI associated PAR. CMR has previously been well validated in the quantitative assessment of aortic valve regurgitation -10. The To date there has been several studies utilizing CMR flow imaging to assess PAR in TAVI cohorts. The majority of these trials have compared CMR assessment to that of either qualitative or semi-quantitative echocardiography -14. The In a single-center prospective control trial, we assessed the extent of PAR in patients undergoing TAVI and high-risk AVR using this highly accurate and reproducible CMR technique. We compared the CMR PAR assessment with semi-quantitative TTE assessment, still the most used technique worldwide. We hypothesized that TTE would systematically underestimate the severity of PAR in TAVI patients compared with CMR. Furthermore this underestimation would be more pronounced in the TAVI group than in the AVR group owing to the complexity of the paravalvular regurgitation.This study was approved by the Human Research Ethics Committee of Flinders Medical Centre  and conducted in accordance with the Declaration of Helsinki. All patients gave written informed consent.Ninety patients with severe aortic stenosis undergoing either TAVI or high risk  AVR were enrolled between June 2011 and July 2014. The decision to proceed with either procedural technique was made by the heart team at our institution based on clinical assessment. Three patients were excluded due to inadequate image quality , leaving 56 TAVI patients and 31 AVR patients .All transcatheter valves were Edwards Sapien XT prostheses  inserted via the femoral route. The AVR group all received bioprosthetic valves, access being via a median sternotomy using cardio-pulmonary bypass. Myocardial preservation and implantation techniques were similar in the surgical group. Four different tissue valve prostheses were used: Medtronic Mosaic\u00ae - Medtronic Inc, Minnesota USA; St Jude Medical Epic\u2122 and Trifecta\u2122, St Jude Medical Inc, Minnesota; Edwards Perimount Magna, Edwards Lifesciences, California USA.CMR  and transthoracic echocardiography  were carried out pre-operatively and post-operatively at a median of 5 and 6\u00a0days for TAVI and AVR respectively. Both CMR and echo were performed on the same day (consecutively), in random order and analysed by separate blinded operators.CMR images were analysed offline using commercially available software . The CMR protocol consisted of standard LV short and long axis views (steady state free precession images) and forward and regurgitant aortic flows using through- plane phase-contrast velocity mapping  Figure\u00a0. The imaEchocardiography was performed in the left decubitus position using commercially available Vivid E9 ultrasound machines . Data were analysed offline using EchoPAC PC Version 7  by 2 experienced echocardiography trained cardiologists. Aortic valve regurgitation was graded using a combined approach of semi-quantitative and qualitative parameters. For post-operative assessment this included visual assessment of the number of jets, jet width and the circumferential extent for paravalvular regurgitation, as per existing guidelines and the more recent VARC-2 criteria ,16. Regut-test and the chi-square statistic with Fisher\u2019s exact test as appropriate. Agreement between grade of PAR ascertained by CMR and TTE was estimated with the Wilcoxon signed-rank test and Bland-Altman analysis. These were performed separately for TAVI and AVR in sensitivity analysis. We also applied the Kappa statistics to determine the agreement on grading of AR severity consistent with Altiok et al. All statistical tests were two-tailed, an alpha value p\u2009<\u2009.05 was considered statistically significant and no adjustment was made for multiple comparisons.Data analysis was performed with SPSS\u00ae 20.0 . Descriptive comparisons between TAVI and AVR included the independent samples A total of 87 patients were recruited, 56 TAVI and 31AVR. Although TAVI patients were older, STS scores were similar between the groups . Comparing pre-procedure aortic valve regurgitation grades between imaging techniques, CMR and TTE demonstrated near identical mean values for TAVI  and AVR groups . All regurgitation was valvular in nature and less severe than the predominating stenosis. The Wilcoxon signed-rank test did not indicate a significant difference between CMR AR grade and TTE .All post-procedure regurgitation was paravalvular in nature when assessed by both TTE and intra-operative transoesophegeal echocardiography (TOE). Post-operative mean regurgitant fraction using CMR was higher in the TAVI group when compared to the AVR group (TAVI 16%\u2009\u00b1\u200913 vs. AVR 4%\u2009\u00b1\u20094 p\u2009<\u20090.001). In the AVR group only four patients had PAR, which was mild in the majority of cases Table\u00a0.Table 2In the TAVI group 52% of patients (29/56) had semi-quantitative TTE findings which graded PAR at a different value to CMR. In 93% (27/29) of these cases the PAR was graded at a lesser value by TTE . Sensitivity analysis confirmed that the difference in PAR grade was evident in the TAVI group  but not the AVR group . The CMR grade (continuous) is plotted by TTE grade in Figure\u00a0Our principle findings show that: (1) using CMR quantitative analysis there was significantly more PAR in the TAVI group than AVR group; (2) semi-quantitative transthoracic echocardiography underestimates the degree of paravalvular AR when compared to quantitative CMR; (3) there was no difference between CMR and TTE in pre-procedure native valvular aortic regurgitation. To the best of our knowledge this is the first time CMR assessment of TAVI associated PAR has been reported with a matched surgical AVR control group. Additionally this is the largest series describing PAR evaluation using CMR of a single transcatheter valve type (Edwards Sapien XT), which holds relevance when transcatheter programs are selecting their preferred devices.CMR has been specifically compared to echocardiography in the assessment of TAVI associated PAR in three prior studies. Ribeiro et al. compared CMR and TTE (VARC-2 criteria) in 42 patients who had Edwards Sapien XT transcatheter valves, finding TTE underestimated PAR in 62% of cases . ConversThe potential importance of CMR quantification of PAR is underscored by the finding that, after converting CMR regurgitant fraction to regurgitant grade, 74% of patients were classified as having mild or greater PAR. This compares to a range of 21 \u2013 61% reported in prior echocardiographic based studies . FurtherThe finding of significant corroboration between CMR and TTE in the assessment of pre-procedure  aortic regurgitation offers two key insights. The first is that it validates CMR techniques for assessing aortic valve regurgitation with those of TTE. Secondly it objectively confirms that the echocardiographic techniques which are readily applicable to native valve or intravalvular regurgitation are inherently unreliable in the transcatheter PAR setting. Our findings regarding pre-procedure regurgitation are supported by earlier work, which also found consistent agreement between TTE and CMR in pre-procedure aortic valve regurgitation . Despitemild PAR with increased mortality was a particularly unexpected finding of the PARTNER trial [Paravalvular aortic regurgitation (PAR) remains a significant and underestimated issue for transcatheter valves despite the impending arrival of third generation devices. Until TAVI can match surgical PAR rates and hence reduce associated increased mortality AVR will remain first line therapy. Furthermore, there is now a large population of patients with transcatheter valves who are affected by mild or greater PAR. It is widely accepted patients with PAR face increased morbidity and mortality and there may be an opportunity to intervene either medically or procedurally should the accurate assessment offered by CMR be broadly adopted . The assER trial . We specWe propose that PAR can be easily, reproducibly and accurately assessed using CMR. The increased incidence of PAR with TAVI compared to AVR is confirmed using quantitative CMR assessment. Furthermore we offer a hypothesis that the association of mortality with mild AR in the PARTNER trial may be due to limitations of echocardiography causing underestimation of the degree of PAR."}
+{"text": "Sinus venosus atrial septal defects (SV-ASD) have nonspecific clinical presentations and represent a diagnostic imaging challenge. Transthoracic echocardiography (TTE) remains the initial diagnostic imaging modality. However, detection rates have been as low as 12%. Transesophageal echocardiography (TEE) improves diagnostic accuracy though it may not detect commonly associated partial anomalous pulmonary venous return (PAPVR). Cardiac magnetic resonance (CMR) imaging provides a noninvasive, highly sensitive and specific imaging modality of SV-ASD. We describe a case of an adult male with exercise-induced, paroxysmal supraventricular tachycardia who presented with palpitations and dyspnea. Despite nondiagnostic imaging results on TTE, CMR proved to be instrumental in visualizing a hemodynamically significant SV-ASD with PAPVR that ultimately led to surgical correction. Sinus venosus atrial septal defects (SV-ASD) involve the insertion of the superior or inferior vena cava and account for 2\u201312% of all atrial communication abnormalities [A 59-year-old male with a past medical history of hypertension presented with a two-month history of exertional palpitations, lightheadedness, and dyspnea. His resting ECG was normal. On exercise stress testing, the patient developed supraventricular tachycardia (SVT) with a ventricular rate of 292 beats per minute with reproducible symptoms . TransthA right heart catheterization (RHC) revealed severe pulmonary hypertension with a mean pulmonary arterial pressure of 35\u2009mmHg and an elevated pulmonary arterial oxygen saturation of 81%. Left heart catheterization with selective coronary angiography demonstrated no evidence of coronary artery disease. The cardiac catheterizations were performed prior to any suspicion for intracardiac shunting, immediately following the diagnosis of supraventricular tachycardia. A full oxygen saturation evaluation on RHC was not performed for unclear reasons. Transesophageal echocardiography was also not performed at the request of the patient; CMR imaging was offered as an alternative imaging option.On CMR, a large SV-ASD was observed with severe right atrial and ventricular enlargement Figures  and 3. TThe patient subsequently underwent successful surgical correction of the SV-ASD and PAPVR with an initial resolution of symptoms. At a routine six-month follow-up, TTE demonstrated normal right atrial and ventricular size and function . There wSinus venosus atrial septal defects have nonspecific clinical presentations with a variable age of onset and should always be considered in the setting of unexplained right atrial and ventricular enlargement. Advanced imaging modalities may be required to facilitate a diagnosis given the location of the defect and their associated anomalous vascular connection(s). Transthoracic echocardiography remains first line in diagnostic evaluation though detection rates have been reported as low as 12 to 44% with the highest success rate utilizing the subcostal view , 4.Transesophageal echocardiography has been shown to increase the detection of SV-ASD and the presence of PAPVR , 6. In aCardiac magnetic resonance imaging has been shown to accurately detect SV-ASD and identify anomalous pulmonary venous connections. In a small retrospective review of patients without a conclusive diagnosis despite TEE, CMR was able to successfully identify a sinus venosus defect in 7 of 11 patients . This moA comprehensive approach must be undertaken when evaluating a patient with unexplained right heart dilation. Routine initial diagnostic imaging techniques may not prove sufficient to establish a diagnosis particularly in the case of sinus venosus defects given the location and associated anomalies. The collective data obtained by CMR provides additive diagnostic value when determining future management to include surgical correction, particularly when other methods have not established a diagnosis."}
+{"text": "Komagataeibacter europaeus CECT 8546, an acetic acid bacterium characterized by its ability to overproduce cellulose. This species is highly resistant to acetic acid and commonly found during vinegar elaboration.The present article reports the draft genome sequence of the strain  Acetobacteraceae. They are obligate aerobic microorganisms that are able to produce acetic acid from ethanol and are the main bacteria responsible for vinegar production. The species Komagataeibacter europaeus (formerly Gluconacetobacter europaeus [The acetic acid bacteria (AAB) are a group of Gram-negative bacteria that belong to the family uropaeus ) was firK.\u00a0europaeus CECT 8546 was isolated from grape vinegar produced by the traditional method in the experimental cellar Mas dels Frares . Chromosomal DNA was isolated using the MasterPure complete DNA purification kit . For whole-genome sequencing, the Genome Analyzer II  and the 454 GS-FLX TitaniumXL  pyrosequencing systems were used. Preparation of shotgun libraries was performed according to the protocols of the manufacturers and resulted in 8,419,806 paired-end Illumina reads (112 bp) and 83,045 pyrosequencing reads. Initial hybrid de novo assembly using the MIRA software (The strain K.\u00a0europaeus CECT 8546 consists of a chromosome with 4.11\u00a0Mb and an overall G+C content of 61.31%. Automatic gene prediction was performed using the software tool Prodigal (The genome of Prodigal . Genes cProdigal , respectProdigal  was usedProdigal . MoreoveProdigal .In addition, the strain CECT 8546 presents the ability to biosynthesize cellulose very quickly. This biopolymer is the main component of the biofilm that AAB develop in the liquid-air interface during traditional vinegar elaboration . This biLHUQ00000000. The version described in this paper is version LHUQ01000000.This whole-genome shotgun project has been deposited at DDBJ/EMBL/GenBank under the accession number"}
+{"text": "Idiopathic Pulmonary Fibrosis (IPF) is a progressive, incurable fibrotic interstitial lung disease with a prognosis worse than many cancers. Its pathogenesis is poorly understood. Activated platelets can release pro-fibrotic mediators that have the potential to contribute to lung fibrosis. We determine platelet reactivity in subjects with IPF compared to age-matched controls.Whole blood flow cytometry was used to measure platelet-monocyte aggregate formation, platelet P-selectin expression and platelet fibrinogen binding at basal levels and following stimulation with platelet agonists. A plasma swap approach was used to assess the effect of IPF plasma on control platelets.Subjects with IPF showed greater platelet reactivity than controls. Platelet P-selectin expression was significantly greater in IPF patients than controls following stimulation with 0.1 \u00b5M ADP (1.9% positive \u00b10.5 (mean \u00b1 SEM) versus 0.7%\u00b10.1; p\u200a=\u200a0.03), 1 \u00b5M ADP  and 10 \u00b5M ADP . Platelet fibrinogen binding was also increased, and platelet activation resulted in increased platelet-monocyte aggregate formation in IPF patients. Re-suspension of control platelets in plasma taken from subjects with IPF resulted in increased platelet activation compared to control plasma.IPF patients exhibit increased platelet reactivity compared with controls. This hyperactivity may result from the plasma environment since control platelets exhibit increased activation when exposed to IPF plasma. Idiopathic pulmonary fibrosis (IPF) is the most common fibrotic interstitial lung disease and has a prognosis worse than many cancers Epidemiological studies have demonstrated an association between IPF and vascular diseases including cardiovascular disease and venous thromboembolism Blood platelets play a central role in thrombosis through rapid activation and aggregation at sites of vascular injury. Transient activation of platelets also induces pro-inflammatory and pro-fibrotic effects In the present study we measured markers of platelet activation in IPF patients under basal conditions and following stimulation with platelet agonists and investigated the effect of plasma from IPF patients on platelet activation. Our data demonstrate that IPF is associated with platelet hyperactivity that may be caused by the plasma environment.Patients with a diagnosis of idiopathic pulmonary fibrosis according to ATS/ERS criteria Written informed consent was obtained from all participants and the study was approved by the Hull and East Riding Local Research Ethics Committee (LREC ref 08/H1304/54).Venous blood was collected using a 21G butterfly needle and vacutainer system . The first 4.5 mls of blood collected was discarded because artefactual platelet activation may occur during venepuncture. Citrated whole blood was added to tubes containing a saturating concentration of one or more of the following antibodies: fluorescein isothiocyanate (FITC)-conjugated monoclonal mouse anti-human CD42b ; phycoerythrin (PE)-conjugated monoclonal mouse anti-human CD14 ; PE-conjugated monoclonal mouse anti-human CD62P ; or FITC-conjugated polyclonal rabbit anti-human fibrinogen . To study the sensitivity of platelets to activation, some tubes were supplemented with adenosine diphosphate (ADP)  or the protease activated receptor - 1 (PAR1) agonist TFLLR . Single colour flow cytometry was used to assess platelet P-selectin expression and fibrinogen binding. Two-colour flow cytometry was used to identify the proportion of monocytes forming aggregates with one or more platelets  based on established methods In order to assess the effect of IPF plasma on control platelets a plasma swap approach was used. Blood from IPF patients and controls was used for the preparation of platelet-poor plasma. Washed platelets from control subjects were suspended in phosphate buffered saline (PBS) and divided into three aliquots. Plasma from the same donor was added to the first aliquot to form an autologous control. Plasma collected from a different control patient was added to the second aliquot to form an allogeneic control. Plasma from a patient with IPF was added to the third aliquot. The ratio of platelet suspension to plasma was 1\u22361 (v/v). Samples were incubated with PE-conjugated anti-human CD62P antibody  under basal conditions and in the presence of ADP  for 20 minutes prior to fixation and flow cytometric analysis. Additional detail on the methods for assessing the effects of IPF plasma on control platelets is provided in data supplement Flow cytometry was performed using a FACS Calibur flow cytometer  and the data were analysed using CellQuest Pro software . Statistical comparisons of platelet-monocyte aggregate formation, platelet P-selectin expression and platelet fibrinogen binding between IPF and controls were performed using unpaired t-tests. A paired t-test was used to assess the difference in P-selectin expression between the groups in the plasma swap experiment. A p value of <0.05 was considered significant.Patients with IPF and controls were matched for age and gender. When whole blood was stimulated with ADP (1\u201310 \u00b5M) or TFLLR (1\u201310 \u00b5M), subjects with IPF demonstrated significantly greater platelet-monocyte aggregate formation compared with controls . The perHaving established that platelet-monocyte aggregates were increased in IPF, we next examined other markers of platelet activation. Consistent with increased platelet-monocyte aggregates we found that platelet P-selectin expression was elevated in whole blood from IPF patients compared with controls. Stimulation with all concentrations of ADP led to greater increases in platelet P-selectin expression in IPF patients compared with controls . Similar findings were observed following stimulation with TFLLR . No diffThe percentage of platelets binding fibrinogen was significantly higher in IPF patients compared with controls following stimulation with 0.1 \u00b5M and 1 \u00b5M ADP . There was no significant difference in fibrinogen binding under basal (unstimulated) conditions . The increase in fibrinogen binding in IPF subjects following stimulation with TFLLR did not reach statistical significance .We next examined whether the platelet hyperactivity observed in IPF was caused by a primary platelet defect or the plasma environment. Re-suspension of washed control platelets in plasma from IPF subjects led to elevated P-selectin expression when compared with platelets suspended in autologous control or allogeneic control plasma. IPF plasma increased P-selectin expression under both basal conditions (p<0.05) and following stimulation with ADP at concentrations of 0.1 and 1 \u00b5M (P\u22640.01) . FurtherWe have demonstrated platelet hyperactivity in patients with IPF using two mechanistically different agonists (ADP and TFLLR) and three different markers of platelet activation, namely platelet-monocyte aggregate formation, platelet P-selectin expression, and platelet fibrinogen binding. Increased platelet-monocyte aggregate formation is a sensitive marker of platelet activation To explore whether the hyperactivity phenotype in IPF was the result of an alteration of the platelets or their environment we used the plasma swap approach, which has been used successfully in previous studies to examine the role of plasma The two patient groups in this study were well matched in terms of age and gender. At the time of undertaking the platelet assays there was no evidence-based disease modifying treatment for IPF Although not statistically significant, there was a higher prevalence of cerebrovascular disease in the IPF group. There is a recognised association between cerebrovascular disease and platelet activation It has recently been demonstrated that patients with COPD have increased levels of circulating platelet-monocyte aggregates compared to age and smoking status matched controls IIb\u03b23It is recognised that the choice of ex-vivo anticoagulant can impact platelet-monocyte association. Citrate results in lower levels of platelet-monocyte aggregates secondary to calcium chelation The present study does not establish a temporal relationship between platelet activation and development of IPF, and in isolation we cannot conclude whether the observed increased platelet reactivity is an important phenomenon at the onset of the disease or represents a secondary response to pulmonary fibrosis. Although epidemiological studies have reported that the increased incidence of cardiovascular events and venous thromboembolism in IPF patients predates the presentation of lung disease Therefore, in this small study of platelet activation in IPF we present clear evidence of increased platelet reactivity in IPF patients compared to controls and demonstrate that this effect can be reproduced in control platelets incubated in IPF plasma. This provides insight into the link between IPF and vascular diseases and we have described a mechanism by which platelet activation may perpetuate fibrosis. Activation of platelets represents an early stage in thrombosis and is unaffected by treatment with the vitamin K antagonist warfarin. The lack of benefit from anticoagulant therapies in IPF may be because the wrong component of the thrombotic process has been targeted We have demonstrated increased platelet reactivity in IPF patients that is reproducible with diverse agonists and different markers of platelet activation. The increased activation and reactivity of control platelets when incubated in IPF plasma suggests that the abnormal platelet response in IPF is due to the plasma environment. This is the first report of increased platelet reactivity in IPF patients providing insight into the relationship between IPF and vascular disease and highlighting the need for further investigation of the role of platelets in IPF pathogenesis.We thank Dr Laura Sadofsky and Chris Crow for helpful comments and technical support and Dr Jakob Dudziak for his ICT expertise.File S1Tables S1-S6.(DOCX)Click here for additional data file."}
+{"text": "At the ESC Congress 2015 in London, six different Hot Line sessions were organised. The six topics were acute myocardial infarction, atrial fibrillation/pacing, diabetes/pharmacology, hypertension, heart failure, and coronary artery disease. Hot Line sessions are usually the main attraction of the ESC Congress as novel data are being presented for the first time [Cyclosporine Improve Clinical Outcome in ST-elevation Myocardial Infarction Patients?) trial failed to show that cyclosporine improved clinical outcomes or prevented adverse left ventricular remodelling in anterior ST-segment elevation myocardial infarction (STEMI). The goal of the trial was to evaluate treatment with cyclosporine compared with placebo among subjects undergoing primary percutaneous coronary intervention for anterior STEMI.The CIRCUS  trial failed to show that aldosterone antagonists were beneficial to patients with myocardial infarction without heart failure.The ALBATROSS  trial showed that peri-infarct pacing did not prevent left ventricular remodelling or improve functional, or clinical outcomes during 18 months of follow-up in patients with a large first myocardial infarction.The PRomPT  trial aimed to evaluate dual antiplatelet therapy (DAPT) for an additional 36 months among subjects who received a drug-eluting stent and were event-free at 12 months. The trial failed to reach primary outcome; however, extended duration of DAPT non-significantly reduced ischaemic events without increasing bleeding.The OPTIDUAL  trial failed to show a reduction in NT-proBNP levels for finerenone versus eplerenone; however, secondary outcomes favoured finerenone.The ARTS-HF  trial showed that sitagliptin improves glycaemic control without increasing adverse cardiovascular events. Among diabetic subjects with documented cardiovascular disease, sitagliptin was non-inferior to placebo on the outcome of adverse cardiovascular events.The TECOS  study evaluated treatment with lixisenatide versus placebo in patients with type 2 diabetes presenting with an acute coronary syndrome. Although lixisenatide showed significant changes in biomarkers, a neutral effect upon cardiovascular death, myocardial infarction and stroke was found.The ELIXA  showed that adverse cardiovascular event rates were similar between celecoxib and nonselective nonsteroidal anti-inflammatory drugs (NSAID). The goal of the trial was to evaluate treatment with celecoxib compared with a nonselective NSAID among subjects with arthritis and no known cardiovascular disease.The SCOT  trial showed that bivalirudin did not reduce major or net adverse events versus heparin; however, bleeding/death was reduced and stent thrombosis increased. Several lines of evidence even suggest an increased risk of stent thrombosis with bivalirudin.The MATRIX  study showed that benznidazole did not reduce progression of Chagas disease cardiomyopathy among patients with Chagas disease. However, it was found that a 40\u201380 day treatment with this antiparasitic medication significantly reduced parasitic activity in the blood.The BENEFIT  trial showed that guided pulmonary vein isolation in comparison to conventional pulmonary vein isolation did not reduce late recurrence atrial fibrillation at 1 year follow-up.The PRESERVATION I showed that a novel Bioabsorbable Cardiac Matrix (BCM) is safe but does not benefit STEMI patients with large infarcts; it does not prevent left ventricular remodelling or other adverse outcomes.OptiVol Fluid Status Monitoring and CareLink Network\u2019 (OptiLink) study assessed the effect of intrathoracic impedance monitoring, through automatic wireless telemedicine notification on all-cause death and cardiovascular hospitalization. The primary composite endpoint did not differ between the two groups (telemedicine guided system or controls).The \u2018Optimization of Heart Failure Management Using Medtronic Calcium Up-Regulation by Percutaneous Administration of Gene Therapy in Cardiac Disease Phase 2b\u2019 (CUPID2) trial, investigating the efficacy and safety of intracoronary administration of adeno-associated virus type I (AAV1)/SERCA2a in patients with advanced heart failure, showed that treatment with AAV1/SERCA2a was safe but failed to improve the rate of recurrent events as well as the time to the first terminal event.The \u2018Servo-Ventilation in Patients with Chronic Heart Failure\u2019 (SERVE-HF) showed that the composite primary endpoint  did not differ between intervention and control group. In fact, all-cause death and cardiovascular death were elevated in the treatment arm.The \u2018Treatment of Sleep-Disordered Breathing with Predominant Central Apnoea with Adaptive The focus of this Comment is to briefly highlight those trials that had a negative  outcome. Over the past years, trials with a negative outcome seem to outnumber trials with a positive outcome during the annual ESC Congresses , 3. The At a first glance the \u2018negative\u2019 outcomes of these trials seem rather disappointing. One could therefore really wonder whether all Hot Line studies were truly hot. However, it should be realised that the label \u2018positive\u2019 or \u2018negative\u2019 hinges on a p-value of <\u20090.05 or >\u20090.05; this might in principle have nothing to do with the clinical implication of a study, be it positive or negative. Secondly, \u2018negative\u2019 usually only applies to the primary endpoint; in some instances the drugs studied in the above-mentioned trials showed improved safety beyond the neutral finding. Finally, the ultimate proof of the value of a large clinical study is incorporation into the guidelines \u20138.l\u2019art pour l\u2019art approach; are all the above-described studies really needed? Are the studies truly hypothesis-driven? Will the outcome of the study change the treatment policy for the individual patient? Finally, will it impact the existing guidelines [Nevertheless, there is a flipside of the coin. Sometimes one cannot escape the feeling that also in science there is a idelines , 10? The"}
+{"text": "Clinical complications of Sjoegren\u2019s syndrome include myelitis and skin manifestations. There is scarce observational data and a lack of randomised controlled studies regarding the treatment of Sjoegren\u2019s syndrome in the presence of such complications.Here we report the case of a 41-year-old Caucasian female patient with biopsy-proven Sjoegren\u2019s syndrome who initially presented with generalized exanthema and subsequently developed acute extensive transverse myelitis. In view of the rapid deterioration we opted for an intensive treatment using a combination of corticosteroid pulse therapy, plasmapheresis and cyclophosphamide, which we later changed to rituximab. Under that treatment the skin manifestations resolved entirely whereas transverse myelitis showed incomplete remission.Severe neurological and dermatological complications may occur in Sjoegren\u2019s syndrome. This suggests a close yet currently unclear pathogenetic relationship. Intensive immunosuppressant treatment resulted in significant improvement of both symptom clusters. Skin manifestations may precede other severe complications in Sjoegren\u2019s syndrome and therefore require particular attention. Sjoegren\u2019s syndrome (SS) is an autoimmune disease that primarily affects the exocrine glands and leads to keratoconjunctivitis and xerostomia . SystemiThe co-existence of SS and psoriasis has rarely been described before, the mutual immunological factors being unclear . The manHere we report the case of a 41-year-old female patient with biopsy-proven SS who rapidly developed severe exanthema and extensive transverse myelitis.A 41-year-old Caucasian woman was admitted to the department of dermatology with generalized maculopapular exanthema  imaging revealed extensive transverse myelitis reaching from the caudal medulla oblongata to level C7 Figure\u00a0A and B aConcerning the neurological differential diagnosis, there was no history of previous radiation to the spine or clinically apparent optic neuritis, aquaporin 4 antibodies were negative and there were no brain abnormalities suggestive of MS on magnetic resonance imaging (MRI). Furthermore, we could neither find evidence for an arterial occlusion, a compressive aetiology or a viral or fungal infection nor another connective tissue disease -especially leukocytoclastic vasculitis or lupus erythematosus. Subacute cutaneous lupus erythematosus (SCLE) as an important differential diagnosis of psoriasiform dermatitis was excluded since histological characteristics for SCLE  were absent. In synopsis of all clinical and serological findings we considered the extensive transverse myelitis to be SS-associated.2 every six months). Since then, the patient is regularly seen for the administration of rituximab and has had no relapse so far. The combination of plasmapheresis, corticosteroid pulse therapy and subsequent immunosuppression significantly improved the severe symptoms, but only an incomplete remission was achieved: while moderate paraparesis with decreased sensation of both legs and urinary retention remained , generalized maculo-papulosquamous exanthema, dyspnea and oculomotor impairment resolved completely. A follow-up MRI after cyclophosphamide therapy showed significant improvement and no evidence of myelitis . With this treatment regimen tetraparesis and dyspnoea gradually improved but generalized exanthema worsened. For long-term therapy we chose cyclophosphamide (8\u00a0cycles). When reaching the maximum cumulated dose of cyclophosphamide after 6\u00a0months we switched to rituximab  involvement remains unclear. In our case, high dose corticosteroids, plasmapheresis and long-term immunosuppression with cyclophosphamide followed by rituximab was obviously effective in stopping the suspected autoimmune inflammation but could not reverse the neurological damage. Therefore, in any case of unclear myelopathy, the coincidence of skin manifestations and cranial neuropathies should serve as a red-flag for an autoimmune disorder and should result in further screening for autoimmune disorders including SS.Written informed consent was obtained from the patient for publication of this Case Report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal."}
+{"text": "We report on Japanese patients who showed neurological deterioration induced by sitting after cervicothoracic posterior decompression with instrumented fusion, but showed immediate neurological recovery after bed rest.Patients showed incomplete paraparesis caused by the ossification of the posterior longitudinal ligament at uppermost thoracic spine. Cervicothoracic posterior decompression with instrumented fusion was performed. Postoperatively, the patients showed partial paraparesis when they were sitting. They showed rapid recovery from lower extremity paralysis upon lying down. After strict bed rest for one month, those patients showed no apparent development of paralysis during sitting.In patients with postoperative residual anterior spinal cord compression, micromotion might exacerbate neurological symptoms. Ossification of the longitudinal ligament (OPLL) is one of anterior spinal cord compressive lesions at the uppermost thoracic spine, and is often treated using a posterior approach to decompression because of the anatomical complexity of the upper mediastinum . OPLL paA 71-year-old Japanese woman complained of difficulty walking caused by OPLL at T2-3. C7\u2013T5 PDF surgery was performed  for case 1 and 3.5\u00a0mm cervical rod for case 2. Upper thoracic spinal cord might be vulnerable for external force because of its specific blood supply ; therefoIn conclusion, we recommend surgeons be alert to the possibility of micromotion after cervicothoracic PDF surgery for OPLL. Thicker or more rigid rods for the PDF surgery may suppress this micromotion.Written informed consent was obtained from both of the patients for publication of this Case Report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal."}
+{"text": "A 12-year-old boy with known Klippel-Feil Syndrome involving fusion of the C5-C6 vertebrae presented to the clinic complaining of a 4-year history of dyspnea on exertion. The patient was referred to our practice following multiple unsuccessful bronchodilator treatments for the presumptive diagnosis of asthma. The patient's medical history included multiple hospital admissions at a different institution for critical respiratory tract infections during infancy. Of note, fluoroscopic evaluation of the patient during those admissions did not reveal diaphragmatic paralysis.What is Klippel-Feil Syndrome and how is it classified?What are the extraspinal manifestations of this condition?How was the diagnosis of unilateral diaphragmatic paralysis confirmed in this patient?Describe how diaphragmatic paralysis was treated in this patient as well as the postoperative course.,3,1Klippel-Feil Syndrome (KFS) is a congenital skeletal disorder characterized by a defect in cervical spine segmentation leading to various degrees of pathologic vertebral fusion in affected patients.1Klippel-Feil Syndrome is a physically debilitating and psychologically devastating congenital skeletal abnormality whose extraspinal manifestations remain poorly understood. More recent studies on KFS suggest an emerging awareness of a diverse variety of extraspinal manifestations of this disease including genitourinary, cardiovascular, and neurological sequelae.Together, clinical history and examination findings supported an incomplete phrenic nerve lesion leading to right hemidiaphragmatic paralysis. Intraoperatively, the patient was found to have an atrophic phrenic nerve arising solely from the C5 nerve root, without the expected adjacent contributions from C3 or C4. Dense adhesions (consistent with those resulting from compression neuropathy) were observed around both the C5 nerve root and the atrophic right phrenic nerve. These adhesions were most prominent in the proximal region of the nerve. An atrophic phrenic nerve fed by only the C5 nerve root is a novel finding in a patient with KFS. Direct nerve stimulation of both the C5 nerve root and phrenic nerve revealed intact but diminished activity in the diaphragm, requiring supraphysiologic threshold amplitudes (>3 mA) to elicit a response.Phrenic nerve reconstruction, including nerve decompression and transfer, was used to treat this patient. Following identification of the spinal accessory nerve, a nerve transfer was performed without nerve sacrifice. The patient began to experience symptomatic relief in the early postoperative period (1-2 weeks) with signs of improvement on radiographic imaging. On examination 1 year after his surgery, the patient's functional improvement was confirmed by postoperative electrodiagnostic and spirometric testing, which suggested enhanced nerve conduction and ventilation, respectively.The pathophysiology of acquired phrenic nerve dysgenesis in KFS is unclear, but we hypothesize that this may have occurred as a result of the skeletal abnormalities associated with the KFS phenotype. Phrenic nerve reconstruction for restoration of functional activity in the diaphragm has been expanded by the senior author (M.K.), and a recently published cohort analysis to evaluate outcomes of phrenic nerve reconstruction for diaphragmatic paralysis includes an updated treatment algorithm."}
+{"text": "Cerebellar development involves a spurt of proliferation in external granule layer (EGL) in response to shh, causing granule neuron precursors (GNPs) to proliferate. These cells subsequently differentiate into granule neurons in the inner granule layer (IGL). F3, a CNTN family molecule, can interact with NrCAM to switch GNPs from proliferation to differentiation. We aim to identify the role of NrCAM in the sonic hedgehog response in GNPs.GNPs were extracted from wildtype and NrCAM mutant P5 cerebella using Percoll gradient centrifugation. Proliferation response to shh was measured using EdU in presence/absence of F3-Fc. GNPs treated with shh/SAG were stained with antibodies against Arl13b and smo to look for differences in cilia size and smo occupancy after different treatment times.-/- and wildtype GNPs both proliferated equally in response to shh. F3 was found to block the proliferation response in wildtype but not in NrCAM-/- GNPs. F3 also failed to affect proliferation in SmoA1 GNPs with a constitutively active smo suggesting that the F3-NrCAM mediated block lay upstream of Smo. NrCAM was detected in wildtype cilia and Smo localization was affected in NrCAM-/- GNPs. No differences in cilia length were observed.NrCAMOur results suggest that NrCAM affects shh-mediated proliferation by controlling smo movement into the cilium."}
+{"text": "Recent advances in our understanding of the contributions of gut microbiota to host metabolism have renewed research interest in how distortions in microbiota activities correlate with health status. While extensive microbiota surveys have already revealed the complexity of microbiota dynamics there is a need to better understand mechanisms through which microbiota can affect host metabolism. We have recently shown that the amount of energy available to the host after intake of resistant maltodextrin varies among individuals and is associated with microbiota. Here we hypothesized that microbiota i) is associated with dietary habits, ii) correlates with colorectal cancer (CRC) risk and iii) can affect the methylation status in nearby gut epithelium, which might be a mechanism contributing to colorectal carcinogenesis.In 126 human volunteers undergoing a screening colonoscopy we determined associations between dietary intake, gut microbiota composition, epithelial methylation status and polyp prevalence. We determined: i) dietary habits using 3-day food records, FFQ (Block 98), and Meat Module Questionnaire; ii) medical history , iii) microbiota composition in a fecal sample collected before and multiple biopsy samples collected during the colonoscopy, during which we determined iv) polyp status. Microbiota composition was analyzed in DNA extracted from stool and biopsy samples using a 16S rRNA based approach. Sequence reads were binned into operational taxonomic units (OTUs) using ESPRIT and analyzed using QIIIME. We then performed a discriminant analysis to identify a microbiota pattern associated with polyp prevalence. For a subset of fecal samples a shotgun metagenomic analysis was undertaken. An exploratory methylation analysis was performed in DNA extracted from 12 biopsy samples using the Infinium HumanMethylation450 beadchip.Various microbiota associations with dietary intake as well as differences in the presence of OTUs between subjects with polyps and controls (p<0.01) were observed, with the most significant of these differences detected in subjects with high risk polyps. A predictive model based on 27 OTUs was effective in identifying subjects with at least one polyp (AUC =0.81). Butyrate producing bacteria appeared decreased among polyp cases. Methylation status at multiple sites was associated with polyp status, which correlated with specific microbiota differences.Our observations confirm microbiota contributions to host metabolism. Larger studies in targeted populations will be needed to determine more details of the complex mechanisms of interactions between microbiota activities and host metabolism."}
+{"text": "Regional ventricular elasticity is altered in ischemic heart disease and LV hypertrophy, potentially contributing to and sustaining a ventricular remodeling process. Conventional methods to measure regional ventricular elasticity in preclinical animal models require high fidelity ventricular pressure measurement, sonomicrometry transducers and dynamic modulation of preload. These procedures are highly invasive and provide only limited regional information; patient studies are prohibitive. We dynamically measure global LV elastance using undersampled radial real-time MRI and seek to find regional LV elastance in these studies. This requires tracking LV motion derived from wall thickness measurements in a large number of real-time image frames at high accuracy. We assessed several motion tracking algorithms and characterize their fidelity with respect to true motion labeled by experts and sensitivity to residual radial streak artifact.A series of short axis MR slices were acquired in 9 patients using a golden-angle radial bSSFP trajectory  and reconstructed via conjugate gradient-SENSE based iterative reconstruction. Two independent researchers manually segmented the datasets and the movies were restricted to three full heartbeats to limit the number of images. Image registrations were performed between the initial end-diastolic frame and all subsequent frames. The image registrations were performed using b-spline and symmetric diffeomorphic (SyN) image registration across a range of spatial scales  improved results relative to the smaller step size (0.1). We believe the ideal spatial scale is a tradeoff between sufficient resolution to capture the cardiac motion and avoiding local minimums. In terms of metrics, smaller changes in the results were observed but the mean squares resulted in the best overall result.Symmetric diffeomorphic image registration of moderate spatial scale allows for accurate tracking of myocardial motion and estimation of wall thickness from a large number of real-time image frames.K99-HL108157, R01-HL103723, T32HL007954, T32-EB009384."}
+{"text": "Repetitive elements comprise at least 55% of the human genome with more recent estimates as high as two-thirds. Most of these elements are retrotransposons, DNA sequences that can insert copies of themselves into new genomic locations by a \u201ccopy and paste\u201d mechanism. These mobile genetic elements play important roles in shaping genomes during evolution, and have been implicated in the etiology of many human diseases. Despite their abundance and diversity, few studies investigated the regulation of endogenous retrotransposons at the genome-wide scale, primarily because of the technical difficulties of uniquely mapping high-throughput sequencing reads to repetitive DNA.RepEnrich to study genome-wide transcriptional regulation of repetitive elements. We show that many of the Long Terminal Repeat retrotransposons in humans are transcriptionally active in a cell line-specific manner. Cancer cell lines display increased RNA Polymerase II binding to retrotransposons than cell lines derived from normal tissue. Consistent with increased transcriptional activity of retrotransposons in cancer cells we found significantly higher levels of L1 retrotransposon RNA expression in prostate tumors compared to normal-matched controls.Here we develop a new computational method called Our results support increased transcription of retrotransposons in transformed cells, which may explain the somatic retrotransposition events recently reported in several types of cancers.Supplementary material is available for this article at 10.1186/1471-2164-15-583 and is accessible for authorized users. L1PA retrotransposons are the most recent family of primate specific L1 LINE retrotransposons and show a high degree of homology due to their evolutionary recent divergence from a common L1 retrotransposon.Figure S17Effect of read length on repetitive element subfamily read assignment. Analysis of simulated data by RepEnrich reveals key features and biases associated with estimating repetitive element enrichment in high-throughput sequencing data. Read length affects the ability to distinguish between highly homologous repetitive element subfamilies. A simulated ChIP-seq sample was trimmed from 100 base pairs to 50 and 30 base pairs. The identical sample sequenced with different read lengths were analyzed by RepEnrich. The reads from each sample that were categorically assigned to repetitive elements was then examined for the number of distinctive repetitive element subfamilies the reads aligned. A) Log10 proportion of reads plotted as a function of number of repetitive element subfamilies reads aligned. B) Reads analyzed by RepEnrich were binned and determined as falling into a unique repetitive element subfamily, 2- 10 repetitive element subfamilies, or >10 subfamilies.Table S1Description of publically available datasets used in this study. Set 1\u20137 refers to how the datasets were grouped into separate GLM models that were used in our analysis"}
+{"text": "Delirium is a frequently occurring complication of critical care, occurring in approximately 45% of unplanned UK ICU admissions . The preThis study prospectively investigated 41 patients. Medical and surgical general ICU patients were included after 24 hours of sedation and mechanical ventilation. The researchers calculated PRE-DELIRIC scores for each patient. PRE-DELIRIC involves recording 10 variables, submitted into an online algorithm that estimates the percentage risk of delirium. We diagnosed delirium with the CAM-ICU which was performed 12 hourly [The PRE-DELIRIC scores predicted a mean rate of delirium of 39%. PRE-DELIRIC risk scores ranged from 4 to 93% Figure . Six (15Our observation that <30% of patients experienced delirium is less than the reported prevalence in similar settings and our own audits. This study demonstrates that there is some agreement between recorded rates of delirium and predicted rates using PREDELIRIC. We suggest that PRE-DELIRIC can be used in quality/audit work on UK ICUs in order to assess attempts to improve the management of delirium. Further work is required to assess the utility of PRE-DELIRIC as a risk assessment tool in individual patients."}
+{"text": "The neurological hallmark of TTR-FAP is a length-dependent axonal neuropathy that initially involves the unmyelinated and small myelinated nerve fibers that mediate pain and temperature sensation, causing sensory disturbances that typically start in lower limbs. Subsequent degeneration of larger myelinated fibers results in large fiber sensory deficit and muscle weakness.The disease can be difficult to recognize due to extreme phenotypic heterogeneity and nonspecific clinical symptoms even within the same mutation.In TTR-FAP related to Val30Met mutation, different neuropathy phenotypes have been reported mainly in patients from non endemic areas as well in late onset cases.We described 3 TTR-FAP Val30Met early onset cases from endemic areas with a different neuropathy phenotype that can be easily misdiagnosed as a different entity. One case presented as a bilateral carpal tunnel syndrome without neuropathy; another with a demyelinating neuropathy with predominant upper limb involvement and other with a demyelinating neuropathy with conduction blocks mimicking a CIDP.TTR-FAP is frequently misdiagnosed, e.g. as idiopathic polyneuropathy or chronic inflammatory demyelinating polyneuropathy, and may be greatly under diagnosed. However, early accurate diagnosis of TTR-FAP is crucial for effective disease control."}
+{"text": "The reverse CART technique provides the potential to modify the retrograde procedure by improving the controlled movement of the retrograde wire and improve the success rates of percutaneous coronary intervention (PCI) of chronic total occlusion (CTO). Development of interventricular hematoma is a rare complication of CTO PCI. A 63-year-old man with effort angina with a right coronary artery CTO lesion underwent PCI by retrograde approach from the LAD to a septal branch. A contrast \u201cstain\u201d was demonstrated surrounding the septal collateral channel used for the retrograde approach at the end of the procedure without symptom. Echocardiography indicated an increased interventricular septum thickness with low echo signals region and decreased contractility. Cardiac magnetic resonance (CMR) imaging using gadolinium showed a diffusely thickened septum with a low signal fusiform neocavitation delimited by an enhanced-signal ring suggesting intraventricular septal dissecting hematoma. After conservative treatment, follow-up echocardiogram and CMR showed the resolution of the hematoma without clinical events. This case highlights the potentially lethal complication of septal perforator dissection and hematoma that may cause severe myocardial injury caused by retrograde approach for CTO PCI. The reverse CART technique has given the potential to modify the retrograde procedure by improving the controlled movement of the retrograde wire without advancing the balloon retrogradely, which potentially reduces the septal channel injury and improves the success rates . In thisA 63-year-old man with effort angina was found to have a chronic total occlusion (CTO) of the mid right coronary artery (RCA) by coronary CT examination. Diagnostic coronary angiography confirmed the RCA CTO to be 20\u2009mm long . RetrogrDuring the procedure, the patient remained hemodynamically stable and asymptomatic. A contrast \u201cstain\u201d was demonstrated surrounding the septal collateral channel used for the retrograde approach at the end of the procedure .Postprocedure echocardiography demonstrated an increased interventricular septum thickness with low echo signals core and abnormal motion . PostproDevelopment of interventricular hematoma is a rare complication of percutaneous coronary intervention for chronic total occlusion (CTO) . Previou"}
+{"text": "PET semi-quantitative methods such as relative uptake value can be robust but offer no biological information and do not account for intra-subject variability in tracer administration or clearance. Simultaneous multimodal measurements that combine PET and MRI not only permit crucial multiparametric measurements, it provides means of applying tracer kinetic modelling without the need for serial arterial blood sampling. In this study we adapted an image-derived input function (IDIF) method to improve characterization of glucose metabolism in an ongoing dementia study. Here we present preliminary results in a small group of frontotemporal dementia patients and controls. IDIF was obtained directly from dynamic PET data guided by regions of interest drawn on carotid vessels on high resolution T1-weighted MR Images. IDIF was corrected for contamination of non-arterial voxels. A validation of the method was performed in a porcine model in a PET-CT scanner comparing IDIF to direct arterial blood samples. Metabolic rate of glucose (CMRglc) was measured voxel-by-voxel in gray matter producing maps that were compared between groups. Net influx rate (Ki) and global mean CMRglc are reported. A good correlation (r = 0.9 p<0.0001) was found between corrected IDIF and input function measured from direct arterial blood sampling in the validation study. In 3 FTD and 3 controls, a trend towards hypometabolism was found in frontal, temporal and parietal lobes similar to significant differences previously reported by other groups. The global mean CMRglc and Ki observed in control subjects are in line with previous reports. In general, kinetic modelling of PET-FDG using an MR-IDIF can improve characterization of glucose metabolism in dementia. This method is feasible in multimodal studies that aim to combine PET molecular imaging with MRI as dynamic PET can be acquired along with multiple MRI measurements."}
+{"text": "Ipilimumab blocks the immunologic checkpoint cytotoxic T lymphocyte antigen-4 (CTLA-4) and improves overall survival in patients with metastatic melanoma. Since only a subset of patients achieves benefit from ipilimumab, biomarkers that can predict patient outcome are needed. CTLA-4 blockade has been shown to affect the peripheral T cell receptor (TCR) pool, but whether diversity of the peripheral TCR repertoire is relevant as a biomarker for ipilimumab remains unknown.In this pilot study, we analyzed the baseline (pretreatment) peripheral blood TCR repertoire in 12 patients with metastatic melanoma treated with ipilimumab at 3mg/kg . TCR diversity was evaluated using a multi-N-plex polymerase chain reaction (PCR) assay which measures TCR combinatorial diversity between V and J genes from genomic DNA. The diversity of the TCR pool was studied through richness (observed V-J rearrangements) and clonality (evenness of the repertoire based on frequencies of specific V-J rearrangements). The Wilcoxon rank sum test was used to compare results between patients with clinical benefit and those without. A receiver operating characteristic (ROC) curve was used to determine an appropriate threshold for dichotomized analysis . Association with benefit in the low vs. high groups was assessed through a Fisher's exact test. Overall survival was studied through log-rank analysis.There was a significant difference in diversity richness (p = 0.033) and in clonality (p = 0.028) between patients with and without clinical benefit. Dichotomized analysis showed that none of the patients with low diversity richness  nor low clonality  achieved clinical benefit. 4 out of the 5 patients with a high clonality had clinical benefit. There was no significant difference in overall survival between patients with low vs. high diversity richness (p = 0.218) and clonality (p = 0.26).In a small group of melanoma patients treated with ipilimumab, TCR diversity in the peripheral blood at baseline was associated with patient outcomes. Further investigation is ongoing in larger cohorts of patients treated with novel immunologic checkpoint antibodies to explore these preliminary findings and determine whether TCR diversity can be used as a predictive biomarker in cancer immunotherapy.Written informed consent was obtained from the patient for publication of this abstract and any accompanying images. A copy of the written consent is available for review by the Editor of this journal."}
+{"text": "Abnormal structural and functional plasticity in cortical and subcortical brain regions may be an important aspect of migraine pathophysiology. Resting state magnetic resonance imaging allows studying functionally interconnected brain networks. Whether there is a relation between the plasticity of resting state networks and integrity of thalamic microstructure during the migraine cycle is not known. To verify functional connectivity between brain networks at rest and its relationship with thalamic microstructure in migraine without aura (MO) patients during and between attacks.Twenty-four patients with untreated MO underwent 3T MRI scans during (n=10) or between attacks (n=14) and were compared to a group of 15 healthy volunteers. We used MRI to collect resting state data among four selected resting state networks, identified using group independent component (IC) analysis. Fractional anisotropy (FA) values of bilateral thalami were retrieved from a previous diffusion tensor imaging study on the same group of subjects and correlated with resting state ICs Z-scores.We found a significant reduced functional connectivity between the default mode network and the visuo-spatial system between attacks, and between the executive control network and the dorso-ventral attention system during attacks. When HV and migraine groups were combined, ictal and interictal selected ICs Z-scores correlated negatively with bilateral thalami FA values.The present results are the first evidence supporting the hypothesis that abnormal dynamics of the connectivity between thalamus and functional cerebral networks at rest could contribute to the recurrence of migraine attacks.Written informed consent to publication was obtained from the patient(s)."}
+{"text": "Infusions with cytokine-activated NK cells obtained from blood of MHC mismatched donors have shown some promising results especially in patients with myeloid leukaemia. There is also indirect evidence that infusions of NK cells as part of a stem cell transplant result in lower relapse rates post-transplant when donor and recipient are mismatched for KIR receptors on NK cells.Collecting NK cells form donors requires them to undergo leukapheresis with subsequent removal of CD3+ lymphocytes (to prevent GvHD) and expansion and activation of the NK cell enriched fraction with IL-2. In contrast, the continuously growing NK cell line NK-92 can be easily expanded to clinical scale in bioreactors. The broad cytotoxicity of NK-92 is due to the lack of most of the KIR receptors while expressing a range of activating receptors.We report here results from concluded and ongoing clinical phase I studies with NK-92 cells in patients with advanced cancer, that confirm its safety profile. Anti-tumour responses were seen in patients with some advanced haematological malignancies and solid tumours. NK-92 also provides a platform for further genetical engineering. A variant has been generated that expresses a high affinity FcgIIIRA receptor that can augment the treatment efficacy of mAbs that utilise ADCC to kill target cells. Various investigators are using the NK-92 cells as a platform to introduce specific tumour antigen receptors (i.e. CAR) to make them targeted to specific tumors such as melanoma, myeloma, leukaemia or brain cancer. Video-lapse studies show that those CAR engineered NK-92 cells specifically kill tumour antigen expressing cancer cells and are able to do 'serial killing'. The cell expansion process for NK-92 has been streamlined and made more economical using various bioreactor designs.The human clinical grade NK-92 cell line has many advantages over peripheral blood NK cells as a cell therapy product for cancer patients. Results from phase I clinical trials confirm its safety profile. This unique cell line is now tested in phase II studies for efficacy in various cancers and is also further developed through genetic engineering to target specific tumours through CAR. NK-92 are an off the shelf tumour targeted local and systemic cell treatment."}
+{"text": "Ventilator-associated pneumonia (VAP) is a common and serious problem in ICUs. Several studies have been conducted to determine the effectiveness of Gram stain of tracheal aspirates for diagnosing VAP. However, the effectiveness for predicting causative microorganisms and guiding appropriate initial antibiotic therapy has not been evaluated. The purpose of this study is to determine whether Gram stain of tracheal aspirates can guide appropriate initial antibiotic therapy for VAP.We retrospectively assessed two hypothetical empirical antibiotic treatment algorithms for VAP on an 18-bed ICU. Data on consecutive episodes of microbiologically confirmed VAP were collected over a period of 22 months and divided into a derivation (1 February 2013 to 30 November 2013) and validation (1 December 2013 until 15 November 2014) cohort. We constructed two algorithms in the derivation cohort. One is a local ecology-based algorithm (LEBA), according to clinical risk factors for MDR and susceptibility results in our hospital. The other is a Gram stain-based algorithm (GSBA). The selection of antibiotics on GSBA was directed against pathogens predicted from the results of bedside Gram staining of tracheal aspirates collected just before antibiotic therapy. Subsequently, LEBA and GSBA were retrospectively reviewed and compared with actually prescribed antibiotics in the validation cohort.P < 0.001). GSBA recommended carbapenems in significantly less episodes than LEBA (P < 0.001) and the same episodes as actually prescribed initial therapy (P = 1). However, there was significant increase of antibiotic coverage rates in GSBA compared with the actually prescribed initial therapy .The first 50 VAP episodes made up the derivation cohort and the subsequent 50 VAP episodes the validation cohort. Antibiotic coverage rates by applying LEBA and GSBA were identical (96% vs. 96%). GSBA proposed more narrow spectrum therapy as compared with LEBA (Antibiotic coverage rates on GSBA were comparable with LEBA. The use of GSBA would result in a significant reduction of the administration of broad-spectrum antibiotics. Bedside Gram staining may be useful to guide appropriate initial antibiotic therapy for VAP."}
+{"text": "Initial response to growth hormone (GH) varies considerably. In severe GH deficiency initial response varies across the group by almost 100%. In common non-GH deficient disorders such as idiopathic short stature (ISS) and children born small for gestational age (SGA) initial response varies by more than 100%.The explanation for the wide response to GH treatment can be clustered into three broad groups; (i) non-compliance with GH therapy, (ii) clinical characteristics associated with GH responsiveness and (iii) mutations and common gene variants in the GH-IGF-I axis.(i) Non-compliance with GH therapy: The commonest explanation for variable GH response is missed GH doses. In a national prospective study of GH compliance in New Zealand children; 34% of children missed more than one GH dose per week. Maori and Pacific children missed an additional GH dose each week than Caucasian children. Predictably, poor compliance (\u22654 doses/week missed) was associated with a far poorer growth response than good compliance (height velocity SDS +0.4 vs +2.8). Even moderate compliance (2-3 doses/week missed) was associated with a poorer growth response (height velocity SDS +1.4 versus +2.8). Interestingly, paediatricians were unaware of GH non-compliance. GH response can only be maximised when more effective GH delivery devices are developed that record the date and time GH is administered to enable paediatricians to more effectively address compliance.(ii) Clinical characteristics associated with GH responsiveness: There is a differential response to GH therapy according to the underlying disorder. GH deficient children are more responsive than those with Turner Syndrome or idiopathic short stature who are in turn more responsive than SGA children (as shown by height velocity and serum IGF-I for a given GH dose). Furthermore, across the normal birth weight range we have recently shown that progressive reduction in birth weight SDS is associated with a progressively lower IGF-I response during IGF-I generation testing. Across growth disorders; more severe GH deficiency, taller parents, shorter stature, younger age at the start of treatment and heavier children are all parameters found to be associated with greater initial and sustained response to GH treatment. Michael Ranke has pioneered individualised GH dosing through GH prediction modelling across growth disorders. GH response can be predicted by inserting common clinical characteristics into a prediction equation that includes adjusting the dose. Prediction modelling is of greatest benefit to children with adverse clinical characteristics in whom greater initial GH doses will lead to greater growth response.(iii) Mutations and common gene variants in the GH-IGF-I axis: Downstream gene mutations in this axis  are relatively rare causes of short stature, poor growth and GH response. Conversely common gene variants are being increasingly sought that influence stature, growth and GH responsiveness. Initial reports suggested a common GH receptor exon 3 deletion was associated with a better response to GH than the full length form in SGA and ISS children. Further studies have found little if any effect of the GH receptor deletion on initial or sustained growth response in SGA, Turner Syndrome or GH deficiency. Future studies are likely to focus on panels of common gene variants across the GH axis rather than examining individual genes to better characterise GH responsiveness."}
+{"text": "Plant responses to drought stress depend on highly regulated signal transduction pathways with multiple interactions. This complex crosstalk can lead to a physiological outcome of drought avoidance or tolerance/resistance. ABA is the principal mediator of these responses due to the regulation of stomatal closure that determines plant growth and survival, but also other strategies of droughtresistance such as osmotic adjustment. However, other hormones such as JA seem responsible for regulating a subset of plant responses to drought by regulating ABA biosynthesis and accumulation and ABA-dependent signalling, but also by ABA independent pathways. Here, we review recent reports of ABA\u2013JA hormonal and molecular interactions within a physiological framework of drought tolerance. Understanding the physiological significance of this complex regulation offers opportunities to find strategies of drought tolerance that avoid unwanted side effects that limit growth and yield, and may allow biotechnological crop improvement. ABA is the main driver of stomatal closure which is probably the most effective mechanism to minimise dehydration. In terms of water stress sensing, stomata and roots are the most important organs that integrate environmental conditions with plant water status, with an important distinction depending on the origin (root or leaf) of the stress sensation Kramer . Both soAt the molecular level, there are thousands of ABA dependent genes controlling growth, senescence, secondary metabolism, protein biosynthesis and osmotic adjustment to coordinate plant behaviour under stress conditions  can diminish ABA accumulation  stress conditions, and is associated with resistance to biotic stress and wounding in stress signalling. Of the JA precursors, 12-oxophytodienic acid (OPDA) is one of the most important due to its possible independent roles in signalling downstream of JA. The Isoleucine conjugate form of JA, jasmonic acid Isoleucine (JA-Ile) has been characterized as the key signalling compound in JA-dependent responses due to its interaction with the receptor Coronatine-Insensitive 1 (COI1). Several recent publications have demonstrated JA\u2019s involvement in water stress responses , NAC and MYC/MYB TFs Fig.\u00a0. UsuallyOryza sativa, the MYC-family TF OsbHLH148 interacted with OsJAZs in response to drought  and jin-1  mutants showed no biomass reduction while this treatment approximately halved biomass of WT and jar1 plants  than WT plants (9\u00a0%) when water was withheld, and detached air-dried leaves had a higher photosystem II efficiency (Fv/Fm) than non-transformed plants. This suggests greater stomatal closure to maintain leaf water status and protect the photosystems. It is uncertain whether these specific mechanisms will be relevant to maintaining yields in dryland rice production. In contrast, another publication dealing with MYC2-related signalling reported that after ceasing watering, then maintaining a moderate drought by daily irrigation (leaf relative water content (RWC) averaged 65\u00a0%), both  Tardieu .versus antagonism of ABA-JA in water stress and interaction with ET) requiring caution in assessing phenotypes.The Ethylene (ET) transcription factor family are interesting targets for both JA-ABA interactions and ET. ERF5 and ERF6 are two redundant TF that are involved in leaf growth inhibition under mild drought stress  enhanced drought and cold tolerance in Arabidopsis by inducing ABA hypersensitivity  under drought (rain was excluded from 10\u00a0days before heading to 20\u00a0days after heading) and normal conditions respectively  greatly decreased grain filling rate under both normal and drought conditions. Since improved root development is a common strategy for drought avoidance; using root specific promoters . This causes ion efflux thereby lowering cellular turgor due to water efflux out of the guard cells and hence causing stomatal closure. This signal transduction pathway, along with involvement of JA and other hormones was recently reviewed  and reactive oxygen species (ROS) Fig.\u00a0, due to nts Fig.\u00a0. To explnts Fig.\u00a0. Brieflynts Fig.\u00a0. This woaba) and plants treated with the ABA biosynthesis inhibitor fluridone  induction , suggesting that MeJA treatment is JA-Ile dependent and hence COI-1 dependent. These experiments expose the variability of the stomatal responses to exogenous hormonal treatment and the necessity of assessing apoplastic hormone concentration adjacent to the guard cells to better compare epidermal bioassays with in planta experiments. This is important to distinguish hormonal crosstalk (JA influencing ABA biosynthesis in this particular example) from molecular interactions in a signalling pathway leading to a physiological outcome .However, there are also some discrepancies in the direct effect of exogenous treatment of MeJA on stomatal closure Table\u00a0. In Arabpr) can also influence plant water status to mediate transpiration. While it is important not to underestimate the importance of root morphology and anatomy in mediating Lpr  had a lower Lpr  in nutrient solution can also increase Lversus JA and JA-Ile). We also need to assess the direct influence of jasmonates in responses to drought as distinct from the indirect influence through ABA biosynthesis and signalling. It is important to unveil these interactions because they offer an opportunity to exploit the natural complexity of drought signalling. This may allow us to enhance crop performance by inducing drought tolerance and resistance mechanisms that allow better yields in sub optimal conditions, thereby avoiding conservative strategies that sensitively close the stomata to maintain tissue water status, but limit photosynthesis thereby incurring yield penalties.While jasmonates seem involved in drought stress responses, a more comprehensive assessment of environmental and physiological responses  are necessary to understand the molecular mechanisms that can potentially improve crop yields in water-limited environments. Assessing ABA and JA interactions in drought stress responses needs to consider the three levels of interactions summarised in this short review . Accurate hormonal quantification of ABA and JA, JA-Ile and ideally OPDA in relevant tissues is necessary (Dave et al."}
+{"text": "Sound-induced flash illusions(SIFI) permit to evaluate cross-modal audio-visual perception. When one flash is accompanied by two beeps, it is perceived as two flashes('fission'illusion); a 'fusion' illusion occurs when a single beep causes the fusion of a double flash stimulus. SIFI strictly depends on cortical excitability: healthy controls perceive less illusions by increasing visual cortex excitability through anodal tDCS .to evaluate if, due to cortical hyperexcitability, differences in SIFI occur in migraine and further changes can be found across migraine cycle, migraine chronification an drug overuse.we enrolled 64 patients with episodic migraine, 32 with-(MWA) and 32 without-aura(MWO) , 44 patients with chronic migraine with medication overuse headache , and 20 healthy controls . All underwent a paradigm for SIFI induction where had to report the number of flashes seen. 13 of MWO and 12 out of MWA were examined in both ictal and interictal phaseall migraine groups showed significantly less SIFI than controls(p<.0001); illusions are more reduced in in chronic migraine and particularly in those overusing triptans(p<.05).results point to a condition of visual cortical hyperresponsivity in patients with chronic migraine in analogy to what observed in episodic patients expecially during ictal phase. This is in agreement with the view of chronic migraine as a 'never ending attack'. The greater effect showed in triptan overuser can follow to down-regulation of 5HT1 receptors.No conflict of interest."}
+{"text": "To communicate imaging findings and interpretation precisely and comprehensively within a multidisciplinary treatment team written radiology reports are essential. Structured reporting systems increasingly take advantage of conventional free-form reports. Therefore we developed a visual imaging report chart and evaluated its acceptance by radiologists and oncologists in comprehensive cancer centers.Six imaging report charts of representative CT follow-up examination of patients with metastatic melanoma were recorded. Each chart includes a short and focused written text as well as a visual reporting diagram, which is composed of two sections: (1) patient characteristics; and (2) schematic documentation and graphical and pictorial visualization of the radiologic findings including documentation of imaging findings, treatment response according to qualitative or standardised criteria, clinical recommendation and the course of tumour burden. In total 36 reviewers  compared the report charts with the corresponding conventional free-text report by a questionnaire grading their degree of satisfaction by a 10 point Likert-scale. Statistical significance was evaluated by one-way analysis of variance (ANOVA) and Student\u2019s t-test.Referring oncologists rated improvement of therapy decision making for oncologic patients significantly higher than radiologists (p<0.01). A significant difference (p<0.005) was observed between radiologists and clinicians regarding their opinion on time-saving in working routine due to our reporting chart (5.1 vs. 8.7 respectively).Structured reporting and documentation of CT examinations in metastatic disease is well appreciated by referring oncologists. The proposed standardised imaging report chart has the potential to improve therapy decision making in the multidisciplinary context."}
+{"text": "Current commercial wall linings are produced using labour intensive fabric weaving methods. This study explored the effectiveness of inexpensive monofilament mesh linings produced by extruding insecticide impregnated polyethylene and poly(ethylene-co-vinyl acetate) (EVA) directly into a net format.Dichlorodiphenyltrichloroethane (DDT), pyrethroids, organophosphates and carbamates are insecticides recommended by the World Health Organisation (WHO) for malaria vector control . Long LiPolyethylene and EVA were extruded with pyrethroids  and organophosphates (ca. 0.5 wt.% insecticide) respectively through a dye to form monofilament meshes. Scanning Electron Microscopy (SEM) and Confocal Fluorescence Microscopy (CFM) was used to characterize the presence of insecticide on the surface of the monofilaments. Efficacy testing was done using standard WHO bioassay tube tests.\u00ae to be effective, the insecticides have to be available on the monofilament surface since they are contact poisons. SEM and CFM micrographs show that pyrethroids are present and evenly distributed on the surface of the monofilament mesh. The WHO effectiveness criterion is a mortality exceeding 80% after 24 hours following a 30 minute exposure of An. arabiensis mosquitoes to test samples. The pyrethroid impregnated mesh samples achieved 100% mortality in this test even after 24 months of storage. Samples impregnated with organophosphates failed to achieve the WHO criterion. Poor performance of the organophosphate insecticides in the EVA matrix was probably due to the high solubility of these insecticides in this polymer.For NetlonMonofilament polyethylene mesh impregnated with pyrethroid insecticides was successfully produced by a simple direct extrusion technique. It is an inexpensive method for the production of slow-release polymer-based wall linings. Laboratory efficacy tests suggest that this ITWL technology may be a potential substitute for IRS and it may also complement LLIN."}
+{"text": "Durable complete response rates of 20% have been observed in clinical trials of patients with metastatic melanoma employing adoptive cell transfer (ACT) of patient derived tumor infiltrating lymphocytes (TIL). Here we provide a detailed analysis of the response of TIL administered to a patient with metastatic melanoma who exhibited a complete response ongoing greater than 3 years. Using whole exome and RNA sequencing and bioinformatic analysis of the patient's matched tumor and normal gDNA we identified over 4,000 non-synonymous somatic mutation variants. We screened 745 somatically mutated genes using tandem minigene constructs expressing transcripts expressed in autologous tumor cells whose expression levels were greater than 0.1% of the levels of \u03b2- actin. These tandem minigenes were then transfected into autologous B cells and then analyzed for their ability to stimulate the administered T cells. Our results indicated that the autologous TIL distinctly recognized 10 somatically mutated gene products, each of which was recognized in the context of three different HLA class I restriction elements expressed by the patient's tumor. Detailed T cell clonal analysis revealed that 9 of the top 20 most prevalent clones present in the infused TIL, comprised over \u00bc of total infused cells and recognized mutated antigens. These results further supported our efforts to identify and enrich mutation-reactive T cells for the treatment of patients with metastatic cancer."}
+{"text": "Telepathology practice across international borders has become increasingly popular. Two years after the University of Pittsburgh Medical Center (UPMC) launched a telepathology consultation service with KingMed Diagnostics Laboratory in Guangzhou, China, latency issues occurred when viewing whole slide images (WSI). Our aim was to explore various image file management solutions to improve the viewing experience of digital consult cases.WSI files generated by KingMed when scanning glass slides for consultation initially resided on a Hamamatsu server, using the NDP.serve database management system. These remote files were securely accessed using a custom portal via the Internet. To try solving ongoing latency issues, WSI files were instead transferred from China to the UPMC data center using an open source product . This was a command line utility placed into a batch process. A faster high speed file transfer software solution (Aspera) was subsequently employed. This commercial software allowed immediate file transfers to occur without a user initiating the transfer.Viewing digital consult cases from Pittsburgh in the USA with WSI files residing on a server in China negatively impacted viewing of images. Image display deteriorated to about 2 minutes/case. Transferring files with the open source product provided transfer speeds of 2-3\u2009MB/second but suffered from intermittent dropped connections. Employing the commercial software permitted more reliable transmission of digital files with 75\u2013100\u2009MB/second transfer speeds.Successful global telepathology requires dedicated image management. Transfer of files to local servers delayed the process by up to 24 hours but greatly improved the overall turn-around time of digital consultations. This was partly negated by employing high speed file transfer software. Transfer of digital files helped overcome network latency issues experienced with China and enhanced the viewing experience for end-user digital consultants."}
+{"text": "This study investigated the safety profile and potential \"therapeutic\" effect of intravenous ultrasmall superparamagnetic iron-oxide (USPIO)-based iron administration regarding infarct healing in patients with ST-elevation myocardial infarction (STEMI).Seventeen study patients  and 22 matched controls  both with primary reperfused STEMI underwent multi-parametric CMR studies in the first week and three months after acute MI. Only IRON patients received a single intravenous bolus of 510 mg elemental iron as ferumoxytol (FerahemeTM) within four days following acute MI.Three months after study inclusion, all patients were alive and there were no adverse cardiac events. Significant improvement in left ventricular (LV) ejection fraction  as well as shrinkage of infarct size were seen in both groups at follow-up. There was a more pronounced decrease in infarct size in the IRON group  in addition to a significant decrease in both endocardial extent and prevalence of transmural infarctions in IRON but not in CONTROL patients. A significant decrease in LV end systolic volume was only seen in the IRON group .Intravenous iron administration in acute STEMI patients is associated with both improved infarct healing and beneficial global left ventricular remodelling (compared to matched controls). These findings together with the good safety profile make USPIO-based iron administration a promising future candidate as a \"diagnostic\" and \"therapeutic\" adjunctive solution in acute MI management.This work was financially supported by a grant from the German Federal Ministry of Education and Research ."}
+{"text": "Vascular cerebral dysfunction restricted to the posterior circulation in migraineurs has been reported. In this preliminary study we compared mean flow diastolic velocity in the posterior cerebral artery during visual stimulation in interictal state headache-free subjects and migraineurs with aura.Trancranial color-coded duplexsonography was used to assess mean flow diastolic and systolic velocity changes in the posterior cerebral artery, in particular P2, during visual stimulation.An increase in vascular reactivity of mean flow diastolic velocity was observed during visual stimulation in headache-free subjects  and in the patients affected by migraine with aura , without any differences between right and left sides. Reactivity of mean flow diastolic velocity to visual stimulation was found significantly higher in Group 2  vs Group 2  (p < 0.001). In contrast, no differences in flow systolic velocity between the two groups were observed.These results indicate that occipital cortex is involved in migraineur patients with aura. Moreover, these patients exhibit a larger cerebrovascular response during visual stimulation compared to headache-free subjects.Written informed consent to publish was obtained from the patient(s)."}
+{"text": "Managing spinal deformities in young children is challenging, particularly early onset scoliosis (EOS). Surgical intervention is often required if EOS has been unresponsive to conservative treatment particularly with rapidly progressive curves. An emerging treatment option for EOS is fusionless scoliosis surgery. Similar to bracing, this surgical option potentially harnesses growth, motion and function of the spine along with correcting spinal deformity. Dual growing rods are one such fusionless treatment, which aims to modulate growth of the vertebrae. The aim of this study was to ascertain the extent to which semi-constrained growing rods (Medtronic) with a telescopic sleeve component, reduce rotational constraint on the spine compared with standard rigid rods and hence potentially provide a more physiological mechanical environment for the growing spine.Six 40-60kg English Large White porcine spines served as a model for the paediatric human spine. Each spine was dissected into a 7 level thoracolumbar multi-segment unit (MSU), removing all non-ligamentous soft tissues and leaving 3cm of ribs either side. Pure nondestructive axial rotation moments of +/-4Nm at a constant rotation rate of 8deg/s were applied to the mounted MSU spines using a biaxial Instron testing machine. Displacement of each vertebral level was captured using a 3D motion tracking system (Optotrak). Each spine was tested in an un-instrumented state first and then with appropriately sized semi-constrained growing rods and rigid rods in alternating sequence. The rods were secured by multi-axial pedicle screws (Medtronic) at levels 2 and 6 of the construct. The range of motion (ROM), neutral zone (NZ) size and stiffness (Nm/deg) were calculated from the Instron load-displacement data and intervertebral ROM was calculated through a MATLAB algorithm from Optotrak data.Irrespective of the order of testing, rigid rods significantly reduced the total ROM compared with semi-constrained rods (p<0.05) which resulted in a significantly stiffer spine for both left and right axial rotation (p<0.05). Analysing the intervertebral motion within the instrumented levels 2-6, rigid rods showed reduced ROM compared with semi-constrained growing rods and compared with un-instrumented motion segments.Semi-constrained growing rods maintain similar stiffness in axial rotation to un-instrumented spines, while dual rigid rods significantly reduce axial rotation. Clinically the effect of semi-constrained growing rods as observed in this study is that they would be expected to allow growth via the telescopic rod components while maintaining the axial flexibility of the spine and improved capacity for final correction."}
+{"text": "A 53-year-old man, previously healthy, presented with a slow-progressive enlarging mass in the midfrontal area which had developed 14 years previously without headache. On physical examination, this nodular reddish mass (11 x 7 x 5 cm) was fluctuant to pressure and tethered to the underlying frontal bone (A). There was no neurological deficit and no superficial lymph nodes. Cranial computed tomography scan showed an irregular median calvarial defect with poorly bony defined margins and left frontal sinus invasion (B-C). Magnetic resonance imaging revealed intracranial extension of the tumour which invaded the dura and the superior longitudinal sinus (D-E). Local biopsy was performed and histological study consisted with a dermatofibrosarcoma. In this specific case, radiotherapy was planned before surgical excision and craniofacial reconstruction. Dermatofibrosarcoma is a slow-growing mesenchymatous tumour of the skin with high local malignancy and great opportunity of recurrence. It usually occurs in the trunk or extremities. In the majority of cases the tumour remains asymptomatic for a long time. Head  and maxillofacial involvement is rare particularly with skull vault and intracranial extension. To improve local control after surgery, wide excision is recommended but difficult in significant anatomic region as in our case."}
+{"text": "It is unclear if children after heart transplantation (HTX) are at risk for developing increased myocardial fibrosis. Diffuse myocardial fibrosis can be estimated by myocardial longitudinal relaxation (T1) times.Twenty cardiovascular magnetic resonance (CMR) studies in 17 patients after HTX  were analysed retrospectively and compared to CMR studies in nine healthy controls . Patients with clinically significant rejection were excluded. T1 measurements were performed at a single mid-ventricular short axis slice orientation before and > 10 minutes after the application of 0.2 mmol/kg gadopentetate dimeglumine (Gd) in the interventricular septum (IVS), LV lateral wall and the complete LV myocardium (Image). The tissue-blood partition coefficient was calculated as a function of the ratio of T1 change of myocardium as compared to blood.Pre-contrast T1 times before the application of Gd were significantly higher in HTX patients compared to controls , whereas the reduced post-contrast T1 times in the HTX patients showed a trend towards being shorter than in controls but failed to reach statistical significance. Tissue-blood partition coefficients were elevated in patients after HTX in the LV lateral wall  and the complete LV myocardium . The difference in the IVS failed to reach statistical significance .Diffuse fibrosis is present in children after HTX as evidenced by pre- and post-contrast myocardial T1 mapping. The technique may be suitable for the detection of early signs of adverse remodeling after HTX.This study was partly funded by the Labatt Family Heart Centre, Witchell Fellowship, and by Siemens."}
+{"text": "Negr1 gene locus retrieved from the UCSC genome browser. This approach could be adopted to identify putative regulatory non-coding RNAs in other tissues and diseases.Long non-coding RNAs and microRNAs control gene expression to determine central nervous system development and function. Neuronal growth regulator 1 (NEGR1) is a cell adhesion molecule that plays an important role in neurite outgrowth during neuronal development and its precise expression is crucial for correct brain development. The data described here is related to the research article titled \u201cA long non-coding RNA, BC048612 and a microRNA, miR-203 coordinate the gene expression of Neuronal growth regulator 1 (NEGR1) adhesion protein\u201d  Specifications TableValue of the data\u2022in silico analysis of the genetic signatures and expression pattern of long non-coding RNAs associated with the Negr1 gene.This data provides a comprehensive \u2022Negr1 gene expression.This data is useful in understanding the regulatory relationship between non-coding RNA gene expression and \u2022The methodology provided can be used to postulate regulatory relationships between long non-coding RNAs and proximal genes.\u2022This approach could be adopted to identify putative regulatory non-coding RNAs in other tissues and diseases which could be evaluated with further functional studies.in silico analysis carried out on the Negr1 gene locus for genetic signatures and expression patterns of long non-coding RNAs in proximity to the Negr1 gene The data in this article describes the initial Negr1 gene promoter region was analyzed using the UCSC Genome Browser Negr1 gene promoter  The promoter . PresencNegr1 gene transcription start sites as well as putative regulatory transcription factors was carried out (Further interrogation of the BC048612 lncRNA and ried out . RegRNA ried out .To determine if there is any interaction between the BC048612 lncRNA and miR-203, the BC048612 sequence was analyzed for putative binding sites for miR-203. RegRNA analysis did not predict any miR-203 binding sites on the BC048612 lncRNA The authors declare that they have no competing interests."}
+{"text": "Insects and their six-legged relatives (Hexapoda) comprise more than half of all described species and dominate terrestrial and freshwater ecosystems. Understanding the macroevolutionary processes generating this richness requires a historical perspective, but the fossil record of hexapods is patchy and incomplete. Dated molecular phylogenies provide an alternative perspective on divergence times and have been combined with birth-death models to infer patterns of diversification across a range of taxonomic groups. Here we generate a dated phylogeny of hexapod families, based on previously published sequence data and literature derived constraints, in order to identify the broad pattern of macroevolutionary changes responsible for the composition of the extant hexapod fauna. The most prominent increase in diversification identified is associated with the origin of complete metamorphosis, confirming this as a key innovation in promoting insect diversity. Subsequent reductions are recovered for several groups previously identified as having a higher fossil diversity during the Mesozoic. In addition, a number of recently derived taxa are found to have radiated following the development of flowering plant (angiosperm) floras during the mid-Cretaceous. These results reveal that the composition of the modern hexapod fauna is a product of a key developmental innovation, combined with multiple and varied evolutionary responses to environmental changes from the mid Cretaceous floral transition onward. Hexapoda, including insects and their six-legged relatives, are the most species-rich animal clade in terrestrial ecosystems and collectively comprise over half of all described extant species Attempts to explicitly test these ideas within a phylogenetic framework have either been restricted to particular orders The dated phylogeny used in this study contains 874 higher taxa of Hexapoda . Taxa weRhyniognatha hirsti from the early Devonian Using our dated tree we estimated the crown divergence of Hexapoda, i.e. the divergence of true insects from Entognatha  as occurring in the Ordovician , which is consistent with other recent molecular clock estimates At higher taxonomic levels, lineage through time plots  indicateDespite this apparent stability in the origination of higher taxa, the application of birth-death models In addition to these broad patterns, diversification shift models identified a further forty-three clades on the tree potentially associated with shifts in diversification rates . These sIn contrast with these relict groups, most of the shifts leading to a net increase in taxonomic richness are comparatively recent  and are Unsurprisingly, several upshifts in diversification within Holometabola also involve groups directly associated with the angiosperm radiation, with notable examples including leaf and longhorn beetles (Chrysomeloidea) Ultimate explanations of insect diversification can be classified into morphological key innovations and ecological interactions The phylogeny of 874 terminal taxa, representing familial groups within Hexapoda was inferred based on eight widely sampled molecular markers including nuclear  and mitochondrial  protein coding sequences and 16S, 18S and 28S rRNA sequences. All included taxa are chimeric, i.e. the sequences used are assembled from multiple individuals and species, such as to reduce the problem of non-overlapping sampling within the source datasets and to maximize gene coverage for each of the sampled terminals. All gene partitions were aligned using MAFFT The fully resolved maximum likelihood topology estimated above was used as the basis for a relaxed independent gamma rates clock implemented in Mr. Bayes 3.2 Estimates of extant richness for terminal taxa were compiled from recent encyclopedic sources . Models of clade diversification were implemented in R v 2.15.1 Figure S1Nodal support on the phylogeny. Nodes marked with circles are either constrained (red) or have high bootstrap support .(TIF)Click here for additional data file.Figure S2Topology showing 95% confidence intervals on node ages (transparent blue bars). Black rings denote 100 Ma intervals from the present. Nodes denoted with red circles are involved in calibration (see (TIF)Click here for additional data file.Figure S3The fifty shifts with the highest rates of recovery in samples from the MCMC chain  plotted  Shifts are denoted as (TIF)Click here for additional data file.Table S1Estimates of extant species richness for terminal groups and GenBank accession numbers for sequences used in phylogenetic reconstruction.(XLSX)Click here for additional data file.Table S2Fossil calibrations implemented in dating the tree topology. Calibrated nodes are plotted on (XLSX)Click here for additional data file.Table S3Parameter values and shifts in species richness associated with MEDUSA model shifts inferred across the mean topology. Shifts listed here are plotted on (XLSX)Click here for additional data file.Table S4The fifty most robustly recovered shifts inferred from 500 samples from the post-burnin Markov Chain Monte Carlo (MCMC). Shifts are plotted on (XLSX)Click here for additional data file.Datafile S1Tree topology in Nexus format. Contains two tree files with a) an undated cladogram including bootstrap support for nodes and b) a dated topology including confidence intervals for the node ages and denotation of inferred shift events matching (TXT)Click here for additional data file.Datafile S2Alignment and MrBayes instructions in Nexus format. Contains the implemented alignment after processing with the commands and priors used in setting the MrBayes dating run.(TXT)Click here for additional data file.Text S1Supplementary Experimental Procedures and Discussion. Contains further details of experimental procedures, discussion of topology and reliability of diversification shift estimates, and cited references for fossil calibrations and species richness estimates Click here for additional data file."}
+{"text": "Idiopathic inflammatory myopathies are heterogeneous systemic autoimmune diseases that are characterized by progressive muscle weakness and typical inflammatory infiltration in skeletal muscle. It is known that a cardiac involvement may occur; the frequency varies between 9% and 72%, mainly depending on patient selection and diagnostic procedures applied. Most common finding is a progressive (systolic) heart failure. Diagnosis may be difficult in patients that exhibit exercise limitation due to peripheral muscle weakness.It has been shown that cardiac magnetic resonance imaging (CMR) is reliably able to provide important information concerning cardiac function and inflammatory processes in a single exam. Therefore, objective of our prospective study was to assess and characterize myocardial involvement in patients with histological defined idiopathic inflammatory myopathies by a comprehensive CMR protocol.Fifty-three consecutive patients with histologically proven idiopathic inflammatory myopathy were enrolled into the study.All patients underwent CMR examination in a 1.5-T whole body scanner using a 32-channel phased-array cardiac surface coil. Volumetric and functional assessment was performed using 3D short-axis steady-state free precession sequences covering the entire left and right ventricle. Early myocardial enhancement was assessed before and shortly after the admission of gadolinium based contrast agent by T1-weighted fast spin-echo sequences. Inversion-recovery gradient-echo sequences were acquired for the evaluation of late gadolinium enhancement (LGE) 10-15 minutes after administration of 0.2 mmol/kg gadolinium based contrast agent .CMR images were analyzed by two experienced and blinded readers in consensus.Reduced left ventricular function (ejection fraction < 60%) was present in 9 (17%) patients. These patients exhibited significantly higher blood levels of CK-MB  than patients with preserved LVEF. Early myocardial enhancement  was more often present  as well as LGE patterns consistent with myocardial inflammation . LGE was most often observed in the inferior and lateral segments.The results of this study show that CMR is able to detect cardiac involvement in idiopathic inflammatory myopathies. Early diagnosis using CMR could result in early therapy of heart failure, leading to beneficial ventricular remodeling and thus improving quality of life and survival in these patients."}
+{"text": "Invasive glioblastoma multiforme (GBM) is the most common malignant primary tumor of the central nervous system with an estimated annual incidence of 3.15 cases per 100,000 in the USA. Current therapies have been unsuccessful in curing malignant gliomas that are highly proliferative and infiltrating, containing regions of necrosis and hypervascularization. Novel therapeutic approaches are critically needed. A glioma specific immune response offers a potential anti-tumor benefit by immune targeted elimination of tumor cells and memory capability that may prevent future recurrence, a feature of aggressive GBM. A number of GBM tumor associated antigens (TAAs) have been studied in preclinical and clinical studies. However, most of these TAAs are HLA motif predicted T cell epitopes derived from over-expressed proteins. A systematic analysis of the naturally processed and therefore most clinically relevant MHC class I associated T cell epitopes presented by glioma cells has never been reported. A number of tumor associated over expressed glycoproteins have been identified as biomarkers and have been proposed as a potential immunotherapeutic target for various cancers including GBM. Tumorigenesis involves dysregulation such as over production or high turnover of proteins that are involved in tumor initiation, progression, unlimited growth, invasion, immune evasion, therapy resistance and survival. One of the key features of dysregulation is aberrant glycosylation of glycoproteins that are involved in these cancer pathways. In this study, we attempt to identify and characterize T cell epitopes presented on the U87 human glioblastoma cells and select epitopes that are derived from glycosylated proteins to develop a multi-epitope based therapeutic vaccine product that induce specific T cell responses against lethal GBM. Towards this goal, we enriched GlcNAc expressing glycoproteins using L-PHA lectin and identified total of 66 glycopeptides derived from 59 different glycoproteins with aberrant GlcNAc glycosylation from U87 cells via glycoproteomic analysis. We also used an immunoproteomic approach to investigate MHC class I presented peptides in tumor cells. Those selected MHC class I epitiopes were derived from glycosylated proteins that had been identified previously. In addition, these peptides were able to activate CD8+ T cell responses against glioma cells. Thus the selection of T cell epitopes derived from aberrantly glycosylated proteins forms the foundation for the development of a multi-epitope based therapeutic vaccine that induces specific T cell responses against lethal GBM."}
+{"text": "Molecular chaperone Hsp70 is well known for its ability to stimulate innate and adaptive anti-cancer immune response. In in vivo studies we proved the efficacy of the intratumoral delivery of Hsp70 in the model of intracranial glioma C6 in animals. Based on our preclinical 12 patients with diagnosis of malignant brain tumour were enrolled in clinical trial. Following tumour resection protein was infused into tumor cavity. Specific immune response was evaluated in delayed hypersensitivity test (DTH). Peripheral blood was monitored for possible changes in lymphocyte subpopulations cytokine levels and cytolityc activity of NK-cells. Additionally cytokine production was analyzed in dynamics in liquor after injection of Hsp70. All patients were monitored for adverse effects.2-helpers towards cytokines from Th1-mediated response . This data corresponded to changes in lymphocyte subpopulations. NK-cell activity was not altered.Intratumoral injections of Hsp70 were well tolerated in patients. One patient had complete clinical response and one partial response documented by radiological findings. In three patients we observed positive DTH-test. In peripheral blood we observed a shift from cytokines of those provided by ThThis pilot study demonstrated for the first time feasibility and safety of intratumoral delivery of recombinant Hsp70 in cancer patients. Based on our preclinical and clinical findings we proposed the novel hypothesis of immunomodulatory mechanism of Hsp70. Our results suggest that purified Hsp70 can induce specific effective anti-tumor immune response and warrants further investigation in randomised clinical trials."}
+{"text": "EditorialAcquired Immune Deficiency Syndrome (AIDS) is a social-health problem. Injection drug use, sharing needles and sexual contacts are considered as the main ways of Human Immunodeficiency Virus (HIV) transmission from person to person in Central Asian countries as well as Iran . In rece"}
+{"text": "Cardiac stress MRI has grown to a well established method to detect hypokinesia or perfusion deficits due to ischemia. Commonly, myocardial load is generated by the administration of adenosine or dobutamine, which is associated by a higher complication rate compared to exercise stress testing. Our purpose was to evaluate the use of an MR conditional pedal ergometer for cardiac stress MRI.We included 15 patients with coronary heart disease until now. All patients underwent exercise stress MRI at a whole-body 3 Tesla MR system and received real-time TRUFI CINE imaging and first-pass perfusion imaging before and after stress testing as well as late enhancement (LE) PSIR sequences after stress. All images were visually rated by three experienced radiologists.As shown on LE images, two patients suffered from silent myocardial infarction and showed stress-induced hypokinesia and slight perfusion deficits nearby the infarction scar. In additional 5 patients, we detected segmental hypokinesia and endocardial perfusion deficits due to exercise. 3 patients exhibited endocardial perfusion deficits without hypokinesia. 5 patient did not show any abnormalities due to stress.Exercise stress of the myocardium is a helpful method to detect ischemic area in cardiac MRI.Nothing to declare."}
+{"text": "A 21 year-old male patient was admitted with symptoms of exertional dyspnea andpalpitation. The physical examination revealed a grade 3/6 systolic murmur, best heardover the left 3-4th intercostal space. Transthoracic echocardiography disclosed aseparate chamber (asterisk) in the interventricular septum. The apical portion of thechamber consisted of muscle tissue and the basal portion consisted of membranous andaneurysmatic tissue (Panel A). There was a muscular \"tunnel-like\" structure connectingthe left ventricle and chamber at mid ventricular level. The color and continuous waveDoppler imaging revealed a bidirectional flow across the passage .The patient underwent three dimensional transthoracic echocardiographic examinations,which revealed two separate septa. Between these septa there was a third chamber(asterisk). It was connected to both left (via the tunnel at the muscular septum) andright ventricles . The membranousseptal aneurysm was separated from the left ventricle by a thin membrane, without anypassage across it (Panel D). MRI findings were consistent with echocardiographic images(Panel E). Ventriculography and coronary angiography were performed. The coronaryarteries were normal; the left ventriculography showed the muscular andmembranous/aneurysmatic portions of the malformation (Panel F). The patient was advisedto undergo a surgical procedure, but he refused and was discharged with recommendationsabout control visits."}
+{"text": "Right ventricular (RV) dilatation is a key imaging criterion of the 2010 modified task force criteria for the diagnosis of arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D), which makes accurate and reproducible volumetric anaylsis essential. We wanted to evaluate the effect of using new thresholding software in volume analysis compared to standard manual contouring on reproducibility and accuracy.Retrospective RV volume analysis was performed on 20 anonymised cases of suspected ARVC. 8mm contiguous short-axis cine steady-state free precession (SSFP) data was acquired from the base of the ventricles to the apex on a 1.5 Tesla MRI scanner. Volumetric analysis was then analysed using two different commercially available softwares: (1) Semi-automated blood pool thresholding with CVI42  and (2) Manual contouring with Argus Syngo . Independent analysis was performed by four different experienced observers, two for each software. RV papilla and trabeculations were excluded from the blood volume. Indexed RV end diastolic volume (IEDV), end systolic volume (IESV) and ejection fraction (EF) were recorded. Statistical analysis included Bland-Altman plots and intraclass correlation coefficients (ICC) to assess for accuracy and interobserver variability.There was excellent interobserver agreement in RV volumes for both blood pool thresholding  and manual contouring , with no statistically significant difference between each set of two observers (p>0.05).2=0.93, IESV r2=0.95), Bland-Altman analysis demonstrated significant mean bias . The thresholding values were consistently lower than the manual contouring.Whilst there was good correlation between indexed volumes between the two methods (IEDV rThe average contouring time with thresholding was slightly shorter at 190 seconds compared to 262 seconds for manual contouring.The significant mean bias between thresholding and manual contouring raises important questions about the reliability between different tools we use to perform volume analysis. The bias may due to enhanced detection of more subtle trabeculations in the RV wall which would normally be excluded manually by the observer. Partial voluming occurs at the interface of the endocardium and blood pool, which may cause thresholding software to underestimate volumes. In addition, it is unclear if the software used itself may contribute to this bias. This is of particular importance in ARVC where there are currently clearly defined thresholds for abnormal RV volumes, however these factors should be considered whenever instutions upgrade software, or when comparisons are made to reference values performed with specific software.This research was supported by NIHR Bristol Cardiovascular Biomedical Research Unit."}
+{"text": "Evidence of abnormal color vision processing in migraine comes from observation of positive symptoms during visual aura, effects of strong color contrast triggering attacks and of colored-spectacles reducing migraine frequency. Although the central or peripheral basis of such color misperception remains unclear, several authors reported a selective deficit of shortwavelength cones (S-cones). Sound-iTwenty-two MoA patients  and 12 unimpaired healthy volunteers with no family history of migraine  were enrolled. Migraine patients were tested interictally. None of the patients enrolled had taken any prophylactic drug during the 3 months prior to the experiment.Every participant took part in two randomized experimental sessions. Experiment 1 consisted of the Farnsworth-Munsell 100-hue test: the disks in 4 different trays had to be arranged to form a smooth color sequence between two reference disks. Experiment 2 consisted in reporting the number of flashes seen on a black screen in isolation or in different combinations with beeps.Cone deficits were more prevalent in the migraine (72%) than in the control group (0.08%). S-cone deficit (56.2%) was still the most frequent alteration detected in our sample. Accordingly with previous results MoA patients as a whole showed no significant difference in SIFI perception as compared to controls even if a trend towards reduced illusory percept was found. However, when performing subgroup analyses, the MoA group with S-Cone defect showed significantly less fission illusions as compared to the group of healthy subjects (p < .0001).S-Cone dysfunction is highly prevalent in migraine; patients with such functional retinal impairment show higher levels of visual cortical excitability. The results of the study seem to establish a strong  relationship between retinal and visual cortical dysfunctions found in migraine. Further evidence  is needed to define the role and interplay of such abnormalities in migraine pathophysiology.Written informed consent to publication was obtained from the patient(s)."}
+{"text": "Hybrid surgical approaches are gaining popularity. Minimally invasive aortic valve replacement and percutaneous coronary intervention [PCI] is well documented. We wanted to explore the feasibility of trans-catheter aortic valve implantation [TAVI] and off pump coronary artery bypass grafts [OPCAB].We proposed that in TAVI patients where PCI is not possible or has failed, trans-aortic TAVI with concomitant OPCAB would be a suitable alternative.A 77 year old man admitted following an out of hospital cardiac arrest was found to have an occluded left anterior descending (LAD) artery, a patent stent in a dominant circumflex and a small diseased right coronary. Past medical history included myocardial infarctions on four occasions, PCI, and severe left ventricular failure. Echocardiography demonstrated severe, calcific aortic stenosis and poor left ventricular function. The multi-disciplinary team recommended TAVI. Work up identified abdominal aortic aneurysm which precluded trans-femoral TAVI approach. A perfusion scan confirmed viable myocardium in the LAD territory. He was put forward for trans-aortic TAVI with OPCAB surgery .The procedure was performed as planned without any complications. Post-operative echocardiogram confirmed a well-placed valve. The patient was treated for a chest infection and discharged home on 8th post-operative day. He was seen at the outpatient clinic at 8 weeks and was asymptomatic and with good exercise toleranceTrans-aortic TAVI and OPCAB is a potential alternative to conventional aortic valve replacement and coronary artery bypass surgery as well as the hybrid approach of minimally invasive aortic valve replacement and PCI.Written informed consent was obtained from the patient's next of kin for publication of this abstract and any accompanying images. A copy of the written consent is available for review by the Editor of this journal."}
+{"text": "Weaning from mechanical ventilation is an important concern in ICU clinical practice. Surface electromyography (sEMG)  is a nonTwenty-one adult and clinically stable patients undergoing assisted mechanical ventilation for more than 48 hours were investigated during pressure support (baseline) and during a 2-hour CPAP trial. sEMG of diaphragm (costmar), intercostal and sternocleidal (accessory muscles) was recorded with a dedicated device  simultaneously with airway waveforms and expressed as the ratio of the signal during baseline. Diaphragmatic electrical activity from a nasogastric tube (EAdi) of 14 of those patients was also measured.P = 0.7). On the other hand, the activation of accessory muscles increased significantly during the same period (P = 0.01) and was strongly correlated with respiratory rate  and inversely with tidal volume . In patients with EAdi we confirmed a tight correlation between costmar and EAdi . See Figure The rapid shallow breathing index was lower than 105 in all patients and only one patient failed the trial. We observed that the mean inspiratory value of costmar increased immediately after switch to CPAP but did not significantly vary during the CPAP trial (ANOVA, sEMG indicated that while diaphragm activation remains constant during the CPAP period, accessory muscles were progressively recruited and particularly in the conditions of increased respiratory rate and lower tidal volumes."}
+{"text": "The promyelocytic leukemia zinc finger (PLZF) transcription factor is directly implicated in tumor suppression although the relevant target genes remain poorly defined. Shi et al. now implicate smooth muscle \u03b1-actin and changes in cytoskeletal architecture as key downstream targets of PLZF in opposing cellular transformation.PLZF is a transcriptional repressor belonging to the POZ-Kr\u00fcppel (POK) family of transcription factors with critical roles in oncogenesis, development and stem cell maintenance -7. The aSubsequent to its original characterization in the context of leukemia development, tumor suppressive functions have been attributed to PLZF in other cell types and tissues -19. UsinOncogenic stimuli that drive cellular transformation often trigger an accompanying remodeling of the cytoskeleton that results in altered cell morphology and growth properties . Further"}
+{"text": "Monitoring guidance for clinical trials recommends the use of central and on-site monitoring practices. Comparing the efficiency of on-site monitoring visits targeted as a result of central statistical monitoring (CSM) procedures, versus those that were not, could help to improve trial conduct.The monitoring plan in a large long-term multicentre international trial required that sites received routine monitoring visits every nine months. Oversight of this trial was augmented by central statistical monitoring that identified high scoring sites as priority for further investigation. To validate this approach high scoring sites, and some low scoring sites (in the same countries) identified by the country teams as potentially problematic were visited.Over a twelve month period 21 sites  received a comprehensive monitoring visit from the senior monitor. Only 1 site identified by CSM had no findings, versus 7 of the comparator sites. Minor findings indicative of \u2018sloppy practice\u2019 were identified at 12 sites (10 CSM versus 2 comparator). At 1 site identified by CSM there were serious findings indicative of an under-performing site.On-site visits triggered by CSM are more efficient than undirected routine visits. Furthermore, information from CSM can help focus the nature of on-site visits and any interventions required to improve site quality, e.g. additional training on data collection or event reporting. Study costs will be reduced if resources are directed to improving the performance of sites of concern, leaving lower risk sites to receive less frequent on-site monitoring."}
+{"text": "High Flow Nasal Cannulae (HNFC) is commonly used to improve oxygenation in critically ill patients. But it effects on diaphragm motion and end expiratory lung volumes (EELV) are not well described.To assess and compare effects of different flows of HFNC and conventional facemask on the diaphragm excursion. Secondary outcomes were to assess effects on patient discomfort, PaO2/FiO2 ratio, EELI and TDI variation measured by electrical impedance tomography (EIT).Cross-over single prospective study on patients undergoing a major abdominal surgery and high respiratory risk assessed by ARISCAT score > 26 admitted in a surgical intensive care unit.Twenty consecutive patients were included. The mean ARISCAT score was 41. The mean right diaphragmatic excursion was significantly increased with increasing inspiratory flow . Linear regression analysis showed a dependent speed increase without ceiling effect. Lung volumes were also significantly increased compared to baseline, with increasing total flow  and equally PaO2 . A significant decrease in respiratory rate was observed . No difference were noted in the modified score Borg and the right or left side.Application of progressive flow through HFNC improves diaphragmatic excursion, lung volumes and oxygenation while decreasing respiratory rate, speed-dependent manner. Its clinical impact remains to be seen in the population of high respiratory risk patients undergoing major abdominal surgery."}
+{"text": "Stress- induced cardiomyopathy is acute, reversible left ventricle mainly apical dysfunction in patients with normal coronary angiography. Rarely it regards basal segments, therefore defined as \u201cinverted stress- induced cardiomyopathy\u201d. While classic form mostly affects postmenopausal women, inverted variant occurs essentially in younger females, always triggered by stress. It can also develop after medical procedures and surgery. Herein we report such unique case of 36- year old woman after cesarean delivery.A 36- year- old white woman at 40\u00a0week of gestation was admitted to hospital for elective repeated cesarean delivery. During caesarean delivery under spinal anaesthesia a previously healthy woman became hypotensive, requiring ephedrine to maintain her blood pressure. Three hours after delivery the patient presented acute heart failure and pulmonary oedema. Due to low blood pressure she demanded the administration of inotropic agents. Owing to respiratory failure and gradual deterioration of consciousness, mechanical ventilation was applied. Results of additional tests finally excluded pulmonary thromboembolism and acute coronary syndrome. The transthoracic echocardiography revealed severe left ventricular systolic dysfunction, ejection fraction 30\u00a0% with hypokinesis of the mid and basal segments of posterior, anterior and lateral wall with preserved contractility of the apical segments. The diagnosis of inverted stress- induced cardiomyopathy was set upon the overall clinical data. Both echocardiography and magnetic resonance imaging performed on the fifth day showed complete recovery of myocardial function. The patient was discharged after 15\u00a0days in good overall condition. At 12- month follow- up she remained asymptomatic with no echocardiographic abnormalities.Inverted stress- induced cardiomyopathy may occur in postpartum period, especially in combination with spinal anesthesia and adrenergic stimulants administration. The clinical awareness and multimodality imaging of possible diagnosis and further management of this unexpected variant of acute heart failure after caesarean delivery is required. Stress- induced cardiomyopathy (SIC) also known as \u201ctakotsubo cardiomyopathy\u201d is characterized by reversible left ventricular dysfunction with chest symptoms (pain or dyspnea), electrocardiogram changes that mimic those of acute coronary syndrome (ACS) and minor elevation in serum levels of cardiac enzymes in patients with normal coronary angiography . While eWe report an extremely rare case of inverted SIC which occurred in young women after cesarean delivery.A 36- year- old white woman at 40\u00a0week of gestation was admitted to a local obstetric clinic for elective repeated cesarean delivery due to slanting position of the fetus. Both her previous and current pregnancy were uncomplicated. Her past medical history was unremarkable and no family history of cardiac disease was reported. The caesarean delivery was performed following the administration of standard spinal anesthesia. During surgery the patient became hypotensive and ephedrine was injected to maintain her blood pressure in the normal range. Three hours after delivery of healthy male infant, the patient complained of nausea, increasing dyspnoea and palpitations. On physical examination tachycardia with ventricular extra systoles and pulmonary rales were detected. Her blood pressure was 80/40\u00a0mmHg and demanded the administration of inotropic agents . Owing to worsening of oxygen saturation up to 70\u00a0% and gradual deterioration of consciousness, mechanical ventilation was applied and the patient was transferred to intensive care unit. Chest X ray indicated pulmonary congestion. Emergency computer tomography excluded pulmonary thromboembolism (PE) and confirmed severe pulmonary oedema Fig.\u00a0. The patIt has been shown that SIC predominantly affects postmenopausal woman . AlthougThe pathophysiological mechanism of SIC is still not completely understood. Several possibilities have been discussed but increased levels of catecholamine and vasoconstrictive substances appear to play crucial role in triggering SIC . It can Minatoguchi et al. identified a total of 18 (8 from Western countries) confirmed cases of symptomatic P- SIC . Most woIn conclusion, this case shows that inverted SIC may occur in young women, particularly in postpartum period, especially in combination with spinal anaesthesia and adrenergic stimulants administration.On the basis of our experience we recommend the clinical awareness of possible diagnosis and further management of this unexpected variant of acute heart failure after caesarean delivery. Although initially the inverted stress- induced cardiomyopathy may seem dramatic, proper and accurate diagnosis usually leads to patients positive and successful outcome.I confirm that the study has been approved by Medical University of Lodz Ethics Committee.I confirm that formal written consent to publish all participant\u2019s data was obtained from individuals involved in the study."}
+{"text": "Comprehensive genomic and proteomic analyses demonstrate that there is nearly universal activation of the PI3K pathway in glioblastoma (GBM) patients . PersistOncogenic signaling pathways directly promote metabolic reprogramming to upregulate the biosynthesis of proteins, nucleotides, amino acids and lipids, required for the enhanced growth of cancer cells. These alterations include aerobic glycolysis known as the Warburg effect, which provides cancer cells selective advantages through enhanced catabolism of glutamine . GlutamiWe recently examined the role of glutamine metabolism in response to mTOR-targeted treatments for GBM . SurprisThese results demonstrate that the inhibition of mTOR signaling is sufficient to change the metabolic characteristics of GBM cells. Increasing GLS expression to elevate glutamate levels could be a method of compensating for the loss of TCA intermediates that occurs when mTOR inhibition reduces glycolysis. It is possible that mTOR inhibition may also induce the use of glutamine carbon sources to sustain the TCA cycle. Glutamate-derived \u03b1KG can be metabolized through the oxidative TCA cycle and/or reductively catabolized into isocitrate and citrate . It willAnother open question concerns the functional link between mTORC1 and glutamine metabolism. A recent study demonstrated that mTORC1 inhibition decreases glutamine metabolism by upregulating SIRT4 expression to suppress GDH activity . We founGLS has two isozymes in humans: kidney-type glutaminase (KGA) and liver-type glutaminase (LGA), which are encoded by GLS and GLS2 genes, respectively . GLS hasGBM is the most common adult malignant primary brain tumor and is one of the most lethal cancers. The median survival for GBM patients is 12-18 months from the time of initial diagnosis despite surgery, radiation and chemotherapy. Therefore, new therapeutic approaches are desperately needed. Recent genomic and proteomic analyses have developed biomarker-driven strategies and potential \u201cGBM-specific molecular targets\u201d have been applied over the last several decades. However, drug resistance to this category of therapeutics has led to minimal clinical efficacy to date. Our study provides new insight into GBM resistance mechanisms to targeted therapies and offers a compelling rationale for the simultaneous inhibition of mTOR and GLS as a promising combination therapy for this challenging brain cancer."}
+{"text": "Medical flow cytometry (FACS) provides diagnostic answers by detecting the presence and concentration of cell populations, and/or by measuring concentrations of cell surface markers expressed on cells. Currently, FACS is limited to high complexity laboratories with time consuming pre-analytical steps, requiring trained technologists available only during business hours. The Accellix table top flow cytometer automates the process with results available within 20 minutes. Sample preparation and reading are performed in a dedicated disposable cartridge. Analytical data processing utilizing proprietary algorithms provides answers directly to the user.The Accellix disposable cartridge-based platform implements sample preparations using three reagent blisters. The three Accellix CD64 cartridge blisters contain staining cocktail of conjugated monoclonal antibodies, lysis buffer and reference beads respectively. Once sample processing is complete, the sample flows through a dedicated reading channel where data is acquired. The present study compared the results of neutrophil CD64 levels performed by standard laboratory FACS and the Accellix system in ICU infected and control patients and normal volunteers.In a demonstration of cell surface marker quantitation a comparison study of 118 blood samples showed a correlation coefficient of 0.94 for Accellix determined neutrophil CD64 compared to those determined using a FACS. The comparison of the CD64 levels performed by the FACS and the Accellix system are shown in figure"}
+{"text": "Such an open forum will help focus on novel annotations and on optimally benefiting from the energy of many experts. As proof-of-concept, we annotated protein subcellular localization in 100 abstracts cited by UniProtKB. The detailed comparison between our new corpus and the original UniProtKB annotations revealed sustained novel annotations for 42% of the entries (proteins). In a unified linked annotation resource these could immediately extend the utility of text corpora beyond the text-mining community. Our example motivates the central idea that linked annotations from text corpora can complement database annotations.Annotators of text corpora and biomedical databases carry out the same labor-intensive task to manually extract structured data from unstructured text. Tasks are needlessly repeated because text corpora are widely scattered. We envision that a The natural language processing (NLP) and biomedical research communities have in common that they invest great effort into making high-quality manual annotation of biomedical literature. The focus and the annotation strategies of the two communities have, however, differed so much that collaborations remained stunningly limited. Most text corpora contain detailed markup of only a few types of entities and relationships in a limited number of abstracts or articles   .model organisms: Homo sapiens (50 entries), Saccharomyces cerevisiae (baker's yeast with 25 entries), and Arabidopsis thaliana as a plant (25 entries). We used 46 of the 100 abstracts to develop our annotation guidelines that are available at https://www.tagtog.net/-corpora/loctext.We assembled a corpus of 100 PubMed abstracts referenced by UniProtKB. We focused on three tagtog system  [http://reflect.ws) [https://www.tagtog.net/-corpora/loctext under the Creative Commons Attribution 4.0 (CC-BY 4.0) license.Two of us (TG & SV) then annotated the remaining 54 abstracts. The two annotations agreed at F1 = 94% for entities and at F1 = 80% for relationships. We normalized protein names to UniProtKB and localizations to GO identifiers. The resulting corpus contains 306 annotated relationships in 201 different UniProtKB proteins with 48 GO distinct localization terms. All annotations were made within the framework of the Linked annotations from text corpora can complement database annotations only if manual corpus annotations identify relationships not captured by existing databases. Therefore, all our annotations were done from scratch without using database annotations. Comparing our \"from scratch\" annotations with those from UniProtKB revealed important novelty added by our text corpus.Arabidopsis RabF2a (UniProtKB entry RAF2A_ARATH) is localized to endosomes  proteins in 34 abstracts  compliant.We envision a linked annotation resource to continuously grow, supported by annotation tools making it easy for corpus developers to link future annotations; for example, through a standard JSON format. Not all linked annotations need to be made manually, though. Including also results from automatic text mining pipelines would help address the challenge of the prohibitively high costs of large-scale manual annotation . Associa"}
+{"text": "Focused ultrasound (FUS) can penetrate soft tissue noninvasively and induce physiological effects deep within target tissues. MR-image guidance, lesioning precision, sparing of healthy tissue and absence of ionizing radiation make FUS an ideal modality for brain interventions. Based on the encouraging results in treating patients with chronic pain or movement disorders through thermal ablation of thalamic and subthalamic targets, noninvasive transcranial MR guided focused ultrasound (tcMRgFUS) recently received CE marking for functional neurosurgery. Here, we report the world\u2019s first successful application of noninvasive tcMRgFUS for tumor ablation in a patient suffering from a centrally located malignant glioma.Case Report: A 63 year old patient presented in our clinic with tumor recurrence in the left thalamic and subthalamic region five years after first surgery for a glioblastoma.\u00ae system  integrated into a clinical 3T MR system . The patient received local anesthesia for positioning a stereotactic frame , and prophylactic administration of paracetamol and ondansetron for preventing pain or nausea. Post-interventional assessment included follow-up MRI immediately after and on days 1, 5 and 21 after the procedure. The patient was awake and responsive during the whole intervention with stable neurological assessment and without additional medication needed. In the 3 hours lasting procedure, a total of 25 sonications were applied with up to 19\u2019550 Joules of acoustic energy. 17 sonications reached ablative temperatures of over 55\u00b0C with a maximum of 65\u00b0C, as recorded by intraoperative realtime MR thermometry. MRI scans acquired immediately after the intervention revealed significant lesions to the sonicated tumor tissue that were particularly well visible in DWI and ADC maps. Later on, contrast-enhanced MRI showed well-circumscribed volumes of non-perfused tissue, indicative for ablated tumor tissue. As expected from earlier experience, perifocal edema developed around the thermal lesions, but gradually disappeared during the follow-up period. Neurological examination on day 5 revealed improvement of the preexisting right arm paresis while no additional neurological deficits were observed.After giving informed written consent he was included in our ongoing clinical phase-1 study on the feasibility and safety of tcMRgFUS for the treatment of brain tumors. Due to the location of the tumor within eloquent brain areas and considering previous radiotherapy and various cycles of different chemotherapeutics, surgical resection was excluded as a treatment option. The tcMRgFUS procedure was performed using the ExAblate NeuroThe successful ablation of a brain tumor demonstrates the feasibility of noninvasive tcMRgFUS tumor surgery. Further clinical interventions in the context of our ongoing clinical phase I study will be needed to assess the safety and efficacy of tcMRgFUS for brain tumor treatment and its relevance for future treatment strategies against brain tumors."}
+{"text": "Compulsive sexual behaviour (CSB) is relatively common and has been associated with significant distress and psychosocial impairments. CSB has been conceptualized as either an impulse control disorder or a non-substance \u2018behavioural\u2019 addiction. Substance use disorders are commonly associated with attentional biases to drug cues which are believed to reflect processes of incentive salience. Here we assess male CSB subjects compared to age-matched male healthy controls using a dot probe task to assess attentional bias to sexually explicit cues. We show that compared to healthy volunteers, CSB subjects have enhanced attentional bias to explicit cues but not neutral cues particularly for early stimuli latency. Our findings suggest enhanced attentional bias to explicit cues possibly related to an early orienting attentional response. This finding dovetails with our recent observation that sexually explicit videos were associated with greater activity in a neural network similar to that observed in drug-cue-reactivity studies. Greater desire or wanting rather than liking was further associated with activity in this neural network. These studies together provide support for an incentive motivation theory of addiction underlying the aberrant response towards sexual cues in CSB. Compulsive sexual behaviour (CSB), also termed hypersexual disorder or sexual addiction, is relatively common and associated with significant distress and psychosocial impairments Disorders of addiction are characterized by biases in selective attention towards drug cues We compared CSB subjects and matched healthy volunteers using a dot probe task to assess attentional biases to sexually explicit cues versus control stimuli and neutral cues versus control stimuli. As the latency of the stimulus has been shown to play a role in whether subjects engage in an early orienting facilitation response or a later inhibitory response CSB subjects were recruited via Internet-based advertisements and therapist referrals. Healthy volunteers were recruited from community-based advertisements in East Anglia. Screening of the CSB participants was conducted using the Internet Sex Screening Test (ISST) All CSB subjects and age-matched healthy volunteers were male and heterosexual given the nature of the cues. Healthy volunteers were matched in a 2\u22361 ratio with CSB subjects. Exclusionary criteria included being under 18 years of age, history of substance use disorders, current regular user of illicit substances (including cannabis), and having a serious psychiatric disorder, including current moderate-severe major depression (Beck Depression Inventory >20) or obsessive-compulsive disorder, or history of bipolar disorder or schizophrenia  Subjects completed the UPPS-P Impulsive Behaviour Scale Subjects viewed a computer screen while placing their left and right index fingers of the letter \u2018s\u2019 and \u2018l\u2019 of the keyboard. Subjects were told that they would see two images (including explicit images) followed by a green dot . The goaThe primary outcomes were the difference in reaction time (RTdiff) between the cues  and paired neutral furniture cues /) for the three conditions. As the latency of the stimulus prior to the target  has been shown to play a role in whether subjects engage in an early orienting response or a later inhibitory response a priori hypothesis that attentional bias to early SOA would be higher to Explicit versus neutral cues but not to a Neutral person versus neutral Control cue in CSB subjects compared to healthy volunteers. P<0.05 was considered significant. Other analyses such as Erotic versus neutral Control cues for early SOA and analyses for late SOA were conducted on an exploratory basis. To assess the influence of SOA, we also compared early versus late SOA for Explicit person cues using related-samples Kruskal-Wallis tests for each group on an exploratory basis.Subject characteristics and questionnaire scores were compared using independent t-tests or Chi-square tests. The RTdiff data were inspected for outliers (scores>3 SD above group mean) and tests for normality were conducted using Shapiro-Wilkes . As the RTdiff scores for Explicit materials were not normally distributed , non-parametric analyses were conducted. We compared RTdiff between groups using Kruskal-Wallis test focusing on the early SOA. We focused on the a priori hypothesis, CSB subjects had greater attentional bias to Explicit stimuli (P\u200a=\u200a0.022) but not to Neutral person cues (p\u200a=\u200a0.495) for the early SOA  years) and 44 age-matched (mean age 24.16 (SD 5.14) years) heterosexual male healthy volunteers without CSB were assessed. Two of 22 CSB subjects were taking antidepressants or had comorbid generalized anxiety disorder and social phobia (N\u200a=\u200a2) or social phobia (N\u200a=\u200a1) or a childhood history of ADHD (N\u200a=\u200a1). The characteristics of the CSB subjects are reported in arly SOA . In explarly SOA .In exploratory analyses, healthy volunteers had greater attentional bias to Explicit stimuli in the late compared to early SOA (p\u200a=\u200a0.013) but there were no differences between latencies in CSB subjects (p\u200a=\u200a0.601). Similarly there were no differences between SOAs for the Neutral cue comparing early versus late SOAs for either the healthy volunteers (p\u200a=\u200a0.404) or CSB subjects (p\u200a=\u200a0.550). There were also no significant differences between groups for all raw RTs to the cues or neutral Control stimuli for all conditions and stimuli SOAs  .CSB subjects  had similar ratings of attractiveness of the Neutral person cues relative to healthy volunteers . All subjects reported that they had not previously viewed the Explicit or Erotic stimuli.Using the dot probe task, one commonly used to assess attentional bias in disorders of addiction, we show that CSB subjects have enhanced attentional bias towards sexually explicit stimuli but not to neutral cues.in early SOAs. These findings suggest a role for an early attentional orienting response underlying the relationship between CSB and sexually explicit cues.The mechanisms underlying cue reactivity and attentional bias may reflect classical conditioning in which neutral stimuli (conditioned stimulus) are repeatedly paired with rewarding stimuli , such that the conditioned stimulus eventually elicits a conditioned response such as physiological arousal or craving. Following conditioning, these conditioned stimuli or drug cues acquire incentive-motivational properties thus acquiring salience, biasing attention and becoming \u2018wanted\u2019 This predictive conditioned stimulus is believed to elicit an early orienting attentional response. Our task makes some attempt to address this initial fast automatic shifting of attention. Visual cues presented for less than 200 msec are more likely to reflect an initial attentional bias. Subjects require at least 50 msec to shift attention to a cue Alternatively, the results may represent the effects of familiarity with the category of Explicit stimuli in CSB subjects. A possible role for use-independent exposure has been suggested based on the lack of difference between attentional bias using a Stroop task in patients and a control group of employees in a substance use facility That the early orienting response to erotic stimuli was similar between CSB subjects and healthy volunteers was not unexpected, highlighting the salience of sexually relevant stimuli. Healthy male volunteers have shown enhanced initial orientation and maintenance of attention as measured by the number of first fixations and relative fixation time during eye-tracking to sexually preferred stimuli compared to non-preferred stimuli Our current findings dovetail with our recent observation that CSB subjects have enhanced activity to sexually explicit cues in the ventral striatum, amygdala and dorsal anterior cingulate activity, the same network activated in drug cue reactivity in disorders of addiction The study has multiple limitations. Only heterosexual male subjects were studied, and future studies should examine individuals of various sexual orientations and females That attentional bias is a feature across drug and natural rewards suggests a potential role for attentional bias as an important construct in the dimensional approach towards disorders"}
+{"text": "Direct measurement of [Ca2+] distributions in dendritic spines is experimentally difficult but we can investigate this hypothesis using mathematical models of Ca2+ diffusion.Capocampus . However2+ diffusion in three dimensions. We then study our model using finite element methods. The model allows predictions of intracellular [Ca2+]-field responses to combinations of pre- and post-synaptic spikes with nanometre and millisecond spatio-temporal resolution. Our results so far indicate that Ca2+ signalling is highly spatially non-uniform and that Ca2+ signal differences between induction protocols is dependent on location within the spine. This has implications for the ultimate biological role of the Ca2+ signal given that the relevant receptors in the spine are organised inhomogeneously [We have developed a spatio-temporal model of Caeneously ."}
+{"text": "Sleep is known to be important for memory consolidation , and memDuring sleep, replay events are associated with specific patterns of neuronal activity. Replay is seen in cortex during sleep oscillation \u2013 a rhythmic (< 1Hz) state in which periods of activity (active or Up states) alternate with quiet periods (silent or Down states), while replay in the hippocampus is associated with sharp-wave ripple events \u2013 irregularly brief bouts of high frequency (>150 Hz) firing . It is bIn the present study, build on our previous research , we deveIn this study we designed a computational model of ripple generation that emphasizes the role of axo-axonic cells in selecting which pyramidal cells are participating in ripple activity, hence what sequence is replayed during a given ripple. In our model, high-frequency firing of the perisomatic interneurons mediate high-frequency LFP oscillations in pyramidal neurons while axo-axonic interneurons define specific sequence of pyramidal cell firing. Using such model, we investigate the timing relationship between cortical slow-wave oscillations and hippocampal ripples. Our study proposes a novel mechanism of hippocampal ripple generation and predicts how interactions between different electrographic events during sleep may contribute to coordinated replay in cortical and hippocampal networks."}
+{"text": "Spontaneous mesenteric haematoma is a rare condition that occurs due to localized bleeding in the mesenteric vascular tree of a bowel segment in the absence of an identifiable cause. Here we report a case of spontaneous mesenteric haematoma during an inflammatory exacerbation of Crohn\u2019s disease. The patient underwent surgical management for small bowel obstruction secondary to Crohn\u2019s disease, however the concurrent presence of a spontaneous mesenteric haematoma in the mid-jejunal mesentery was successfully managed conservatively. This case identifies the first association of spontaneous mesenteric haematoma with an exacerbation of Crohn\u2019s disease and highlights the need to consider rare differential diagnoses such as SMH when performing radiological assessment of unexplained symptoms in inflammatory bowel disease patients. Spontaneous mesenteric haematoma (SMH) is a rare condition of unknown aetiology. It can be managed conservatively in the event that there is no associated mesenteric haemorrhage. It must be clinically distinguished from spontaneous mesenteric intraperitoneal haemorrhage  where there is rupture or bleeding from a specific mesenteric vessel due to an unknown cause that typically requires urgent surgical management due to its high mortality. This report presents the first case in the literature associating SMH with an inflammatory exacerbation of Crohn\u2019s disease.9/L and a C-reactive protein (CRP) of 7\u00a0mg/L. Her symptoms initially resolved with intravenous hydrocortisone but promptly recurred with worsening malnutrition despite intensifying steroid therapy. She had not received any formal anticoagulation other than prophylactic subcutaneous low-molecular weight heparin (20\u00a0mg once daily) during the period of her hospitalization. Repeat CT scan  and purine analogue (azathioprine) therapy. She was a non-smoker and aside from well-controlled essential hypertension had no other significant co-morbidities. Her inflammatory bowel disease had already required two previous hospitalizations, and she had suffered from symptoms of intermittent pain and bloating with constipation throughout the 12\u00a0months since her diagnosis. In the preceding month a computed tomography (CT) scan revealed 3 segments of Crohn\u2019s disease strictures with prestenotic dilatation and an inflammatory appearance  is a rare condition that occurs due to localized bleeding in the mesenteric vascular tree of a bowel segment with unknown aetiology -8. It caPatients with isolated SMH typically present with non-specific symptoms of generalised abdominal pain and as a result the haematoma is usually identified on imaging modalities such as CT. Although the cause is unknown, the disease process may be associated with unidentified anticoagulation mismanagement or even undiagnosed connective tissue disease -8.Our case demonstrates the presence of localised mid-jejunal mesenteric fat haematoma. Localised visceral inflammation is a recognised contributor to confined microvascular bleeding  so that Mesenteric fat has been recently recognised an essential location for the generation of Crohn\u2019s gastrointestinal inflammation ,12. HereOur intraoperative findings of mesojejunal haematoma reflect the current underestimation of Crohn\u2019s ileitis, demonstrating explicit involvement of the mesenteric fat with an associated mesenteric haematoma. This case also highlights how mesenteric abnormalities such as SMH may explain refractoriness or recurrence of symptoms despite intensifying steroid therapy. Indeed, it is possible that ileal compression caused by a mesenteric mass such as this may explain many of the symptoms accredited to Crohn\u2019s strictures. As a result, we believe that an increased awareness of the role of the bowel mesentery may give new insights into Crohn\u2019s disease pathogenesis. Furthermore, assessment for mesenteric abnormalities may guide future clinical and radiological assessment of unexplained symptoms in patients suffering form this multi-systemic inflammatory process, and identify rare differential diagnoses such as SMH.We describe a case of spontaneous mesenteric haematoma in a female patient suffering from an exacerbation of Crohn\u2019s disease and intestinal stenosis. The mesenteric haematoma was identifiable both on pre-operative computerised tomography and intra-operatively. This case identifies the first association of spontaneous mesenteric haematoma with an exacerbation of Crohn\u2019s disease and highlights the need to consider rare differential diagnoses such as SMH when performing radiological assessment of unexplained symptoms in inflammatory bowel disease patients.Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.CRP: C-reactive protein; TLR: Toll-like receptor; NOD: Nucleotide-binding oligomerization domain; SMH: Spontaneous mesenteric haematoma; CT: Computerized tomography.The author(s) declare that they have no competing interests.PM carried out the procedure, assisted by HA and DB. HA, JM and AM drafted the manuscript. HA finalized the manuscript in agreement with the senior author PM. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2482/14/35/prepub"}
+{"text": "Dendritic cells (DCs) are central players of the immune response because they regulate both innate and adaptive immune cells. As part of the leukocyte infiltrate of various tumours they can initiate antitumour immune responses through the activation of tumour-specific T cells.However, tumours employ strategies to evade the immune response by manipulating the differentiation and activation of DCs.+CD209+ expressing myeloid cell type that displays characteristics of both DCs and macrophages. As one example, ercDCs showed good antigen cross presentation which is a prototypic DC function and a prerequisite for the activation of T effector cells in local tumour tissue. To better understand the relationship of ercDCs to other myeloid cell types and to get insight in functional pathways operative in ercDCs we performed transcriptome analysis using Affymetrix\u00ae gene arrays comparing ercDCs, cDCs, proinflammatory M1 and GM-CSF macrophages and alternatively activated M2 macrophages. Cell types were generated in parallel from monocytes of 15 healthy donors. RNA was extracted using the Qiagen\u00ae RNeasy Micro kit. To reduce population variability, RNA from each cell type- from 5 donors- was pooled and 3 biological replicates generated. Clustering of normalised values showed that ercDCs differ from the other myeloid cell types. Further analysis included heat mapping and creation of signaling pathways using pathvisio software. Focusing on the cross presentation pathway, a gene list was assembled through literature mining and each gene was assigned an expression value using microarray data. A comparison using the heat map representation revealed that the expression pattern of ercDCs was most similar to GM-CSF macrophages and least to M1 macrophages. Comparison based on fold changes generated by normalisation to cDCs revealed highest similarity between ercDCs and M2 macrophages. Particularly, transcription of genes involved in receptor-mediated endocytosis and the vacuolar pathway were upregulated in ercDCs indicative that cross presentation could be active in ercDCs.Previously we described 'enriched-in-renal-carcinoma DCs' (ercDCs) as an unusual CD14"}
+{"text": "The concealed phase of arrhythmogenic right ventricular cardiomyopathy (ARVC) may initially manifest electrophysiologically. No studies have examined dynamic conduction/repolarization kinetics to distinguish benign right ventricular outflow tract ectopy (RVOT ectopy) from ARVC's early phase. We investigated dynamic endocardial electrophysiological changes that differentiate early ARVC disease expression from RVOT ectopy.1-S2 restitution protocol.22 ARVC  patients without right ventricular structural anomalies underwent high-density non-contact mapping of the right ventricle. These were compared to data from 14 RVOT ectopy and 12 patients with supraventricular tachycardias and normal hearts. Endocardial & surface ECG conduction and repolarization parameters were assessed during a standard SDefinite ARVC without RV structural disease could not be clearly distinguished from RVOT ectopy during sinus rhythm or during steady state pacing. Delay in Activation Times at coupling intervals just above the ventricular effective refractory period (VERP) increased in definite ARVC (43\u00b120 ms) more than RVOT ectopy patients  or Normals  and a progressive separation of the repolarisation time curves between groups existed. Repolarization time increases in the RVOT were also greatest in ARVC . Surface ECG correlates of these intracardiac measurements demonstrated an increase of greater than 48 ms in stimulus to surface ECG J-point pre-ERP versus steady state, with an 88% specificity and 68% sensitivity in distinguishing definite ARVC from the other groups. This technique could not distinguish patients with genetic predisposition to ARVC only (probable ARVC) from controls.Significant changes in dynamic conduction and repolarization are apparent in early ARVC before detectable RV structural abnormalities, and were present to a lesser degree in probable ARVC patients. Investigation of dynamic electrophysiological parameters may be useful to identify concealed ARVC in patients without disease pedigrees by using endocardial electrogram or paced ECG parameters. Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) is a disease of cardiomyocyte adhesion; initial myocyte slippage and loss of gap junction integrity is followed by more overt structural changes, with characteristic fibrofatty replacement of cardiomyocytesPre-clinical work has highlighted putative mechanisms by which arrhythmias in ARVC may occur. Genetically modified mice deficient in plakophilin-2 exhibit slow conduction in the absence of significant histological anomalies and heterozygous desmoplakin knock out mice have impaired conduction reserve To date, clinical studies on the electrophysiology of patients with ARVC have overwhelmingly concentrated on patients with established ventricular macroscopic structural markers as a principle feature of their disease. These studies have demonstrated that patients with ARVC exhibit slow conduction within the right ventricle and low endocardial bipolar voltages, indicative of endocardial fibrosisonly because of a definite family history/mutation carrier status without evidence of significant structural disease such that they have earlier/milder disease than customarily reported in ARVC. Patients with benign RV outflow tract ectopy (RVOT ectopy) can be viewed as an important control population as they may be expected to exhibit secondary features & adaptations associated with frequent ectopy. Differentiation between ARVC and RVOT ectopy groups will highlight salient disease features rather than merely adaptations to ectopy.We have demonstrated significant dynamic conduction and repolarization differences between desmoplakin mutation carriers and controls, but there has been no direct comparison of the dynamic electrophysiological changes in early ARVC versus patients with outflow tract ectopy (RVOT ectopy)We hypothesized that patients with early ARVC would exhibit slowing of conduction & repolarization changes compared to RVOT ectopy patients under conditions of electrical stress, even prior to detectable structural disease. Furthermore, we hypothesized these myocardial electrophysiological changes would manifest on the surface ECG which ultimately may be of value in the development of a diagnostic test.The research was approved by University College London Hospitals Ethics Committee A (08/H0714/97), prior written informed consent to participate in this study was obtained from all participants.did not have major imaging criteria for ARVC Patients aged 18\u201365 years with definite or probable ARVC by modified task force criteria  were prospectively recruited to participate in the study and informed consent was obtained. All patients underwent detailed imaging assessment including echocardiography/MRI and were only included in this study if they 10 ml whole blood samples were obtained from ARVC patients and family members. Genomic DNA was extracted using a commercially available DNA extraction kit . Index cases were part of a larger patient cohort comprehensively screened for mutations in desmoplakin, plakoglobin, plakophilin-2, desmoglein-2 and desmocollin-2. Primer pairs for DSP exons were designed in flanking intronic sequences and are available on request. Polymerase chain reaction (PCR) amplification and direct sequencing on an ABI 3130 Genetic Analyzer were performed using standard protocols as previously described 1S2 restitution protocol. This protocol consisted of performing 8 beat trains of pulses (S1) at 400 ms coupling intervals followed by a single, premature stimulus (S2). The S1S2 coupling interval was reduced sequentially from 400 ms by 20 ms until 300 ms, then by 5 ms intervals until failure to elicit a ventricular response (refractoriness) was reached. The S1S2 interval was increased by 8 ms and then further reduced by 2 ms steps to establish the Ventricular Effective Refractory Period (VERP) and proximal end of the restitution curve. Two-second intervals were left between trains. 12 lead electrocardiograms were recorded throughout the procedure.The procedure for non-contact mapping has been previously described in detail elsewhere 24 \u201cvirtual\u201d unipolar electrograms were placed in 4 columns of 6 across the RV chamber on the Ensite console. Global data was thus acquired from the entire geometry  and goodmin) was used as the local activation time  to the steepest negative deflection  method and the alternative method. Both have come under intense theoretical and experimental scrutiny, and here we present results using the classical method Fractionation of activation was determined by counting the number of deflections in the differential of the unipolar electrogram 2 .Mean Increase of Delay is a convenient surrogate measure of conduction velocity restitution. In brief, the activation time is plotted against coupling interval during a restitution curve pacing sequence. Mean Increase in Delay refers to the mean increase in activation time as the coupling interval is reduced to ERP, and is expressed as millisecond increase in delay per millisecond reduction in coupling interval (ms/ms). This was calculated as previously described 1-S2 protocol. Signals were filtered with bandpass settings of 0.1 \u2013 50Hz. Measurements were performed manually using on-screen calipers at 200 mm/sec (MF & AS) blinded to the patient diagnosis. Timings were measured from the pacing stimulus to a) the earliest sharp component of the QRS complex, b) the peak of the QRS complex c) the end of the QRS complex (i.e. the J-point), d) the peak of the T-wave and e) the end of the T-wave (12-lead ECGs were recorded simultaneously during the Se T-wave . These m2) and mean increase in delay) were made using student's t-test with correction for multiple comparisons. Continuous parametric data derived from electrogram data were modeled using mixed-effects linear regression and statistical significance was inferred from the modelAll statistical computing was performed in R software  was applied to surface ECG data to determine optimum cut-offs attempting to distinguish ARVC from a mixed group of patients. This is a decision-learning technique that enables optimal splits in a group formed on different observations to occurRecursive partitioning (a.k.a. 22 patients with definite (12 pts) or probable (10 pts) ARVC were studied (mean age 46\u00b111 years)25 consecutive patients with monomophic ventricular ectopy (9652\u00b18444 beats/24 h), structural normal hearts and normal resting ECGs underwent non-contact mapping and EP studies. 14 of these patients had >18 m follow-up with no recurrence of ventricular ectopy off antiarrhythmic medication, and no features suggestive of ARVC. These patients were analyzed as the RVOT ectopy group (age 45\u00b114 years). Twelve further patients undergoing electrophysiological studies \u00b1 ablation for supraventricular tachycardia with structurally normal hearts acted as Normal controls (age 43\u00b118 years).No significant differences in RV activation times, ARI or repolarization time were observed between groups .2, a measure of uniformity of conduction, was higher in both ARVC groups and in normal controls than in the RVOT ectopy patients . There were no differences between either of the ARVC or normal control groups.Differences in slowest measured activation gradient  between groups did not reach statistical significance, although activation gradients in ARVC and RVOT ectopy groups were 20% lower than controls . rIn steady state pacing, RV activation took significantly longer in probable ARVC patients than in RVOT ectopy subjects , but this did not reach statistical significance in the definite ARVC group (91\u00b121 ms) or normal controls (94\u00b128 ms). There was a trend to longer repolarization times in the ARVC groups when compared to the RVOT ectopy group , but no group was significantly different from normal (303\u00b142 ms).1S2 coupling intervals just longer than VERP (pre-VERP) than in other groups  than in RVOT ectopy patients  or Normal controls .The activation delay curves were plotted for each electrode in every patient. Mean increase in delay, a measure of cumulative delay in activation times over all coupling intervals, were greater in the ARVC patients .The maximum slopes of ARI restitution curves were marginally steeper in the probable ARVC and RVOT groups compared to normal, but there was no statistically significant difference between the definite ARVC group and any other group . There were no significant differences in the odds ratio of having a maximum ARI restitution slope of >1 in any segment between patient groups.In sinus rhythm, more fractionation was observed in RVOT ectopy patients than in definite or probable ARVC or normal controls. However, during pacing at steady state, RVOT ectopy and both ARVC groups had more fractionation than normal controls  & 7. At Single intracardiac electrophysiological predictors were generally poor at differentiating definite ARVC from RVOT ectopy, but an increase in the local activation time of >47 ms at ERP compared to in steady state pacing gave a sensitivity of 70% and a specificity of 74% in predicting definite ARVC over RVOT ectopy. A mixed-effects logistic regression model was created to explore the predictive potential of combining intracardiac variables. The resultant model has an area under the curve of 0.85 , Table 3increase in activation time at ERP by 36\u00b113%compared to steady-state was observed in the definite ARVC group than in the other groups  gave a sensitivity of 67% and specificity of 88% in the diagnosis of definite ARVC . A reducThis is the first study to compare differences in conduction and repolarization kinetics in an ARVC population with earlier disease than customarily reported with benign RVOT ectopy cases. The key findings include: 1) Marked conduction delay in patients with early ARVC when pacing at short coupling intervals, which was not evident in sinus rhythm. This exists on a spectrum, with definite ARVC exhibiting more conduction delay than probable ARVC patients compared to normals. 2), Progressively longer local repolarization times as coupling intervals decrease towards VERP in definite ARVC patients versus normal controls & RVOT ectopy subjects. 3) Marked differences in fractionation at short coupling intervals pre-VERP throughout the right ventricle between patient groups, with more fractionation in both ARVC and RVOT ectopy patients. 4) Surface ECG biomarkers of conduction/repolarization dynamics provide diagnostic information - an increase in the time from pacing stimulus to full ventricular activation (defined as the end of the QRS complex i.e. the \u201cJ-point\u201d) of greater than 48 ms gave an 88% specificity and 68% sensitivity of distinguishing definite ARVC from other groups.Previous clinical studies have demonstrated electrophysiological abnormalities in established ARVC with significant structural disease, including prolonged RV activation times in sinus rhythm and low endocardial bipolar electrogram voltages 1-S2 restitution protocol, particularly in the outflow tract compared to SVT controlsAn earlier study of desmoplakin mutation carriers demonstrated that these patients have significantly greater mean increases in delay during an SOur observation of an increase in induced conduction slowing with premature extrastimuli can be regarded as evidence of a lack of conduction reserve. This is consistent with data implying a sodium current deficit in murine models of ARVC Importantly, it was primarily the family history of ARVC or mutation carrier status that allocated these patients to the \u201cDefinite ARVC\u201d group in our study. In the absence of gene testing, 4/12 of the definite ARVC cases would be regarded as borderline. This implies that in a population of combined probable and definite cases the predictive accuracy of this partitioning method may be increased. Indeed, when both groups are combined, the classification tree was able to distinguish any ARVC patient from a combined group of RVOT/Normals with a sensitivity of 67% and specificity of 84%.We can speculate why a disparity may exist in the degree of induced activation delays between these two groups. Six patients in the definite ARVC group exhibited a surface 12-lead ECG feature of disease at rest, versus none in the probable ARVC group . Lack ofEven the patients with more advanced disease did not demonstrate global RV activation delays in sinus rhythm, but it was more marked at short coupling intervals during RV pacing. The dynamics of repolarization were also significantly affected, amplifying effects of conduction delay in ARVC and creating significantly more prolonged repolarization times pre-VERP than steady state versus controls and RVOT ectopy patients. Digital examination of the signal averaged ECG may yet reveal previously hidden features of conduction delay in these patients, but this fell outside of the scope of this study.The partitioning tests identified stimulus to T-wave peak interval as a potential distinguishing feature between normal and probable ARVC patients. This measure reflects a composite of activation and repolarisation phenomena, and could be seen as a surface ECG marker of the intracardiac repolarisation time changes observed .2 values indicating uniformity of conduction were observed compared to RVOT ectopy cases. Similarly, we have reported more uniform conduction in Brugada Syndrome versus controls Two phenomena were observed in the RVOT ectopy patients: consistently shorter repolarisation times versus supraventricular tachycardia patients and ARVC, cases and increased fractionation compared to control cases. The shorter repolarisation times may reflect a memory phenomenon induced by the high ventricular ectopic burden. A shortening in ARI occurs and with it a reduction in refractory period, thus allowing local myocytes to be more susceptible to activation. The high degree of fractionation in benign RVOT ectopy patients similar to that seen in ARVC also deserves comment. Conduction delay and fractionation occurs in ARVC due to fibrofatty replacement and/or dissociation of preferentially conducting myocardial pathways through reduced gap junction coupling and Na channel downregulation Taken together, features of conduction delay, increased repolarization times and mild fractionation at short coupling intervals pre-VERP would support a diagnosis of early ARVC over that of a benign RVOT ectopy, with a logistic model demonstrating a positive predictive value of 80% from the presented data. These differences can also be identified simply using paced-QRS-T-wave parameters.dynamic surface ECG conduction-repolarization parameters may be of diagnostic value in early disease.This study confirms that reduced conduction reserve develops early in ARVC before detectable structural RV changes on conventional imaging ensue. This has important implications since sudden cardiac death can occur in patients with minimal histological changes in the sub-clinical phase of ARVC and thus a more sophisticated clinical evaluation using dynamic conduction-repolarization changes is required de novo population will be required for an impartial assessment of the diagnostic utility of paced J-point hysteresis. Logistical regression models can highlight the differences between groups in this study, but cannot be taken as a diagnostic test based on the data presented.The human mapping technique evaluates endocardial electrophysiology and thus mid-myocardial and epicardial effects of ARVC could not be assessed. This is important since structural changes manifest epicardially prior to progressing endocardially The probable ARVC group still represents a diagnostic dilemma as a gold standard test is lacking, yet our data has important pathophysiological implications for the understanding of the development of arrhythmias in this population. Disease progression in increasingly understood as initially an epicardial phenomenon, we were not able to examine epicardial effects with our mapping or pacing strategy. Non-contact mapping may be insensitive at identifying low-voltage fractionation in small areas.Early ARVC exhibits greater conduction delay and dispersion of repolarization, particularly at short coupling intervals, than either normal hearts or benign RVOT ectopy. Fractionation is mildly increased in early ARVC, but also significantly in benign RVOT ectopy. The dynamic differences in conduction, repolarization and fractionation are manifest on the surface paced ECG & could help refine the early identification of early concealed ARVC patients from those with benign outflow tract ectopy.Figure S1Examples of restitution curves from a patient with ARVC and from a normal control. Repolarisation time, ARI and activation time are plotted against coupling interval. Points represent means of four repeated measurements. Early activated sites are shown in red, late in blue.(TIFF)Click here for additional data file."}
+{"text": "Unilateral renal agenesis with vesicoureteral reflux in the ipsilateral full length ureter is a rare phenomenon. Herein we report a case of 10-year old boy who presented with recurrent urinary tract infections. No renal tissue was identified on left side in various imaging studies. Micturating cystourethrogram (MCUG) showed left sided refluxing and blind ending ureter. Left ureterectomy was done because of recurrent UTI in the refluxing system. A 10-year-old male child presented with several episodes of hematuria associated with mild dysuria for the last two years. He was a proven case of urinary tract infections (UTI) and was on chemoprophylaxis with nitrofurantoin (50 mg/day) since last 6 months. General physical and systemic examinations were normal. Urine examination revealed pus cells but culture grew no organisms. Hemogram, blood urea and serum creatinine levels were in normal range. Ultrasonography (USG) did not show left kidney in lumbar and other ectopic locations. Right kidney was normal in shape, size and location with normal echotexture. No evidence of dilated ureter on either side was reported. CECT with CT urogram confirmed the USG findings . MCUG showed refluxing full length blind ending ureter on left side. Left ureter was minimally dilated without any tortuosity. Urinary bladder was normal . DMSA scan showed no functional left renal tissue. Right kidney was normal on radioisotope scan. The diagnosis of left renal agenesis with blind ending left ureter and ipsilateral vesicoureteric reflux (VUR) was made. Antibiotics were given empirically for two weeks. MCUG, repeated after resolution of clinical symptoms and normalization of urine report, showed left sided VUR. Cystoscopy showed normal lower tract including a normal trigone. Retrograde pyelography (RGP) showed full length left ureter with proximal blind end. Due to recurrent UTI with VUR in spite of chemoprophylaxis, exploration with excision of the whole ureter was undertaken. On exploration no evidence of left renal tissue was found. Postoperative period was smooth and the child is symptom free at follow-up.Unilateral renal agenesis (URA) is an uncommon condition. Most cases of URA are associated with absent ipsilateral ureter or if ureter is present it is small near bladder end. Normally ureter develops from a bud which arises from mesonephric duct. Kidney develops when there is interaction between ureteric bud and metanephric blastema. In renal agenesis either ureteric bud is absent or interaction of ureteric bud with metanephric blastema does not occur.[1] When ureteric bud fails to fuse with renal plate, it results in blind ending ureter.[2] URA may be due to in-utero regression of multidysplastic kidney.[3]Isolated URA is usually asymptomatic. A blind-ending ureteric bud has a higher than normal incidence of vesicoureteric reflux and therefore may get acutely inflamed. It may result in hematuria, calculus formation or recurrent UTI.[1] Systemic examination and routine urine examination may be normal as found in the index case.MCUG is the gold standard to demonstrate the presence of VUR. Length of blind ending ureter and grade of reflux can also be determined. In our case, MCUG showed full length refluxing left sided blind ending ureter. Management of these cases depends upon symptoms. Surgical excision of blind ending ureter is advised in case of non-resolving VUR or breakthrough UTI. Both open and laparoscopic retroperitoneal approach may be used.. [6] Unilateral renal agenesis may be associated with ipsilateral refluxing blind ending full length ureter which can lead to recurrent urinary tract infection and its removal is thus indicated.Source of Support: NilConflict of Interest: None declared"}
+{"text": "Pulmonary nodules are commonly observed in patients with cancer as well as in patients with no known malignancy particularly in heavy smokers. Most of these nodules are small (less than 8 mm). Even in cancer patients a large proportion of these small nodules are benign . The likNon-solid nodules (ground glass opacities) are more likely to represent lung cancer (adenocarcinoma) than solid nodules ,5. HowevConsolidation or diffuse ground glass usually represents benign disease such as pneumonia. However, in adenocarcinoma with predominantly lepidic growth consolidation or diffuse ground glass may be due to cancer spread in the lung.Pleural effusion may be due to malignant spread  or to several benign conditions . Malignancy is usually confirmed by cytologic analysis of pleura fluid. However, imaging may suggest malignancy if solid pleural lesions are demonstrated within the effusion particularly at the lung base. Unilateral effusion, particularly in the left hemithorax or on the side of the underlying malignancy  also suggests malignant effusion.Solid pleural lesions may be clearly benign such as pleural lipoma or calcified pleural plaques in patients with asbestos exposure. Non-calcified focal solid lesions may be benign  or malignant. Although pleural carcinomatosis is usually associated with effusion solid metastases without effusion can occur. Diagnosis usually requires histology ."}
+{"text": "We report the good outcome of combined intravitreal aflibercept injection and photodynamic treatment in a case with fundus flavimaculatus (FFM) and unilateral subretinal neovascular membrane (SRNM). A 57-year-old man with FFM and unilateral SRNM who was treated with two consecutive ranibizumab injections with no improvement at another institution was referred to us. He was treated successfully with three aflibercept injections three months apart and a single photodynamic treatment performed a week after the initial aflibercept injection. Six weeks after the last aflibercept injection visual acuity was improved and submacular exudation exhibited dramatic resolution with a moderate degree of residual scarring. SRNM formation is rarely observed in eyes with FFM and a satisfactory outcome can be achieved with a proper treatment. Fundus flavimaculatus (FFM) is characterised by the fishtail-like or round, white-yellowish flecks confined to the retinal pigment epithelium that are scattered diffusely throughout the posterior pole and extend out to the midperiphery and the related visual symptoms commence between the third and fourth decade of life and progress slowly \u20133.During the course of the disease progressive macular atrophy is a much more common finding than the rarely diagnosed subretinal neovascular membrane \u201314. HereA 57-year-old man had a nine-month history of visual decline in the right eye and had received two intravitreal ranibizumab injections for presumed exudative macular degeneration elsewhere. He was referred to us for further evaluation. His family and medical history were unremarkable. On our examination, his best-corrected visual acuity was counting fingers at 2 meters in OD and 20/25 in OS. Slit-lamp examination was normal OU. Fundus examination showed multiple widespread pisciform flecks throughout the posterior pole and midperipheral retina in OU with severe subfoveal exudation and intraretinal fluid in OD Figures . AutofluERG demonstrated subnormal dark adapted responses of rods while photopic cone responses were mildly reduced with prolonged implicit times. Both scotopic 30\u2009Hz flicker and maximum responses were also decreased in amplitude . Our dia2 verteporfin injected intravenously over a period of 10 minutes followed by the occlusion of lesion area five minutes later with a 689\u2009nm diode laser for 83 seconds with 50\u2009J/cm2 at an intensity of 600\u2009mw/cm2. A spot size of 3500\u2009\u03bcm was used. Two additional 2\u2009mg intravitreal aflibercept injections were given three months apart. Six weeks after the third injection, his best-corrected visual acuity was 20/200 and subretinal exudation showed dramatic resolution with a residual scar in the OD (Figures Due to unsatisfactory anatomic and visual outcome with two previous ranibizumab injections and the presence of large feeder vessel-like changes noted in the fluorescein and indocyanine green angiographies, we elected proceeding with a combination of photodynamic therapy and aflibercept injection. We preferred aflibercept over ranibizumab as the patient might not be followed up monthly due to his profession. Seven days after the administration of initial 2\u2009mg aflibercept injection standard photodynamic treatment was performed in OD, namely, 6\u2009mg/m Figures .There were anecdotal case reports discussing the place of several treatment modalities and describing the outcome of patients with SRNM in association with FFM. In earlier reports, either observation \u20136, 9 or Tejerina and friends  injectedIntravitreal aflibercept treatment has been proven to be efficacious in exudative age-related macular degeneration . Moreove"}
+{"text": "Cardiac magnetic resonance imaging (CMR) is routinely performed to monitor progression and response to interventions in congenital and acquired heart diseases. Cross-sectional CMR studies report normalized reference ranges for cardiac parameters according to age decile together with assessments of short-term inter-study variability; however, most clinical imaging is repeated at much greater intervals of time. There are no prospective CMR data defining long-term changes in cardiac structure and function among healthy subjects. Without such data, it is difficult to determine whether serial changes in cardiac parameters observed in patients reflect disease progression or are merely the consequence of normal ageing. We examined the \"within patient\" changes in left ventricular (LV) volumes, mass and function over 12 months in a well-characterized cohort of healthy adults.We identified 21 healthy controls  who did not proceed to uni-nephrectomy after recruitment into an observational study assessing the cardiovascular effects of live kidney donation (NCT01028703). All subjects were asymptomatic and had a 10-year risk of a cardiovascular event of <20% (QRISK-2), a normal stress echocardiogram and normal haematology and biochemistry profiles. Exclusion criteria included: any history of cardiovascular disease, including hypertension; diabetes; glucose intolerance; chronic kidney disease; first degree relative with a proven or potentially inheritable cardiac condition. Subjects underwent CMR imaging  at baseline and 12 months. Analysis of SSFP images was performed offline  by a single blinded observer (W.E.M.) for assessment of LV volumes, systolic function and mass. Baseline studies were repeat analyzed by the same trained observer to assess intra-observer variability. A subset of participants underwent repeat imaging within 1 hour to determine inter-study variability.There were no significant changes in any LV parameter indexed to body surface area at 12 months (Table These data have particular importance for both clinical practice and observational research: for patients undergoing annual CMR, changes in LV structure and function can be largely attributed to disease progression rather than ageing.WEM is supported by a British Heart Foundation Clinical Research Training Fellowship."}
+{"text": "Phytophthora ramorum genetic lineage EU2. We sequenced genomes of seven isolates collected in Northern Ireland between 2010 and 2012. Multiple genome sequences from P. ramorum EU2 will be valuable for identifying genetic variation within the clonal lineage that can be useful for tracking its spread.Here we present draft-quality genome sequence assemblies for the oomycete  Finally, we generated scaffolds and performed gap-filling with SSPACE 3.0 We used the Illumina HiSeq to generate 100-bp paired sequence reads from genomic DNA prepared from seven isolates of EU2 collected from multiple sites in Northern Ireland between 2010 and 2012 . We filtP. ramorum Pr102 genome sequence We estimated the completeness of our assemblies with the CEGMA pipeline Phytophthora plant pathogens P. ramorumP. ramorum EU2 will be valuable for identifying genetic variation within the clonal lineage that can be useful for tracking its spread Genome sequences have been invaluable in the study of"}
+{"text": "Purpose. Pathophysiology of macular hole (MH) is not yet well defined but the advances of spectral domain optical coherence tomography (SD-OCT) give us access to further detailed imaging. We report a case with macular inner segment ellipsoid (ISe) band loss and cone outer segment tips (COST) line changes seen in SD-OCT preceding MH appearance in a young patient. Methods. 21-year-old woman presented with a partial central scotoma, metamorphopsia, and a 20/25 vision in her right eye. Past medical history was positive for laser assisted in situ keratomileusis (LASIK) surgery 7 months ago with no complications. Macular SD-OCT showed ISe band loss and COST line elevation. She was followed a month later with visual acuity deteriorating to 20/200 and a full thickness MH. Results. The patient underwent a pars plana vitrectomy with internal limiting membrane peeling. Her visual acuity 2 months later was 20/20. Conclusion. SD-OCT can identify preliminary changes, yet to be described, preceding MH formation. Our patient demonstrated ISe band loss and COST abnormalities on SD-OCT a month prior to MH development. SD-OCT should be considered in young patients with subtle visual symptoms and mild changes in visual acuity that are not readily explained by ophthalmological exam. Macular hole (MH) is an idiopathic condition that in most cases is related to posterior vitreous detachment (PVD) and is mainly seen in the elderly. The minority of cases are observed in younger patients with a history of blunt ocular trauma as well as in myopic patients after laser assisted in situ keratomileusis (LASIK) surgery , 2.Spectral domain optical coherence tomography (SD-OCT) provides further detailed imaging that allows the detection of early anatomical changes, enabling us to alter and/or refine current theories.Different pathophysiological mechanisms might be involved in MH formation depending on vitreous syneresis and posterior hyaloid status. Several theories have emerged involving tangential traction  and anteWe report a case of a young patient who at first presented with subtle visual symptoms on the right eye. Her SD-OCT showed changes in the inner segment (ISe) band and cone outer segment tips (COST) line preceding MH formation in the absence of any vitreomacular interface abnormality in the ophthalmological examination.A 21-year-old female patient presented to the retina clinic with a new onset of partial central scotoma and metamorphopsia in her right eye (RE). Best corrected visual acuity (BCVA) of the RE was 20/25. Left eye (LE) was asymptomatic with BCVA of 20/20. She had no history of trauma and reported having a successful LASIK surgery in both eyes seven months earlier with BCVA of 20/20 in both eyes after surgery. She had a positive ocular family history, with her father being operated for a unilateral idiopathic MH. Dilated fundus examination did not reveal any retinal findings in both eyes. Therefore, a SD-OCT  was performed and showed an ISe band loss and COST line changes at the subfoveal area with no other findings in the RE . She wasA 23-gauge pars plana vitrectomy was performed in the RE. The posterior hyaloid was found to be very adherent and the surgeon faced difficulties trying to induce a PVD using high aspiration with the vitrector probe. A brilliant blue stain was injected to facilitate the visualization of the internal limiting membrane (ILM) on the margins of the macula . The ILMGass studied the pathophysiology of MH and suggested that the majority of macular holes begin as a central dehiscence with little loss of retinal tissue following tangential traction . BiomicrStudies by SD-OCT showed minor changes in the outer foveolar structure, especially in the COST line, in either eyes with a foveolar yellow spot or eyes with vitreomacular traction , 10. We We speculate that the strong vitreomacular adherence observed during vitrectomy might have induced vitreoretinal interface changes that caused changes in the outer retina with no apparent signs of traction on ophthalmoscopy. In patients with a strong vitreomacular adhesion, ISe band loss and COST line changes on SD-OCT may be a harbinger for MH formation; these patients should be followed closely. We are unaware of any publications on OCT changes preceding MH formation in young patient as we described with normal fundus examination.There is a higher incidence of MH in patients with a positive familial history of MH, suggesting the involvement of genetic factors . Our patAlthough there are reports of MH cases after LASIK surgery , we beliIn conclusion, SD-OCT can identify preliminary changes at the level of the foveal ISe band and COST line preceding MH formation. Therefore, it should be considered in young patients with subtle visual symptoms and mild changes in visual acuity that are not readily explained by ophthalmological examination."}
+{"text": "Acute respiratory distress syndrome (ARDS) is characterized by damage to the alveolar epithelial-endothelial barrier resulting in neutrophil influx and pulmonary oedema. The activation of platelet and secondary capture of neutrophils may play an important role in propagation of inflammation in ARDS . Variousin vivo human model of acute respiratory distress syndrome, induced by inhaled lipopolysaccharide (LPS).To test the hypothesis that aspirin reduces pulmonary inflammation in an Healthy subjects were enrolled in a double-blind, placebo-controlled study and were randomised to receive aspirin 75mg or aspirin 1200mg or placebo (1:1:1) for seven days prior to LPS inhalation. Measurements were performed in bronchoalveolar lavage (BAL) fluid obtained at 6 hours after inhaling 50 micrograms of LPS.33healthy subjects were enrolled. There was no significant difference between aspirin 75mg and aspirin 1200mg. Data for both aspirin groups were combined. Aspirin pre-treatment reduced LPS induced BAL neutrophilia (figure This study shows for the first time that aspirin can reduce neutrophilic inflammation in the lung in humans. Further clinical studies are warranted to assess its ability to reduce neutrophil mediated inflammation in ARDS."}
+{"text": "Activity of GFR/PI3K/AKT pathway inhibitors in glioblastoma clinical trials has not been robust. We hypothesized variations in the pathway between tumors contribute to poor response. We clustered GBM based on AKT pathway genes and discovered new subtypes then characterized their clinical and molecular features. There are at least 5 GBM AKT subtypes having distinct DNA copy number alterations, enrichment in oncogenes and tumor suppressor genes and patterns of expression for PI3K/AKT/mTOR signaling components. Gene Ontology terms indicate a different cell of origin or dominant phenotype for each subgroup. Evidence suggests one subtype is very sensitive to BCNU or CCNU . AKT subtyping advances previous approaches by revealing additional subgroups with unique clinical and molecular features. Evidence indicates it is a predictive marker for response to BCNU or CCNU and PI3K/AKT/mTOR pathway inhibitors. We anticipate Akt subtyping may help stratify patients for clinical trials and augment discovery of class-specific therapeutic targets. WHO grade IV astrocytoma or glioblastoma (GBM) are the most common primary brain tumors and, unfortunately, the most aggressive. Median survival of patients harboring these tumors is approximately 14 months. Despite a committed effort to investigate new chemotherapies, molecularly targeted therapies, immunotherapies, surgical and radiological approaches, there has been little improvement over the last 30 years. Inadequate classification of GBM may have contributed to the difficulty of developing new therapies by decreasing power of clinical trials and underestimating benefit of class-specific drugs. It may also have confounded discovery of class-specific pathways and drug targets.We know GBM diagnosed by histopathology is a collection of molecular and clinical subtypes. For example, there are two classes of GBM based on clinical presentation However, molecular classification of GBM is still in its infancy. There is no consensus on the number of subtypes and which classifiers best identify them. In addition, there is considerable reassignment of tumors to different classes depending on classifier used. We also have little information on which oncogenic pathways are active in subtypes and how subtypes respond to standard and experimental therapeutics. These questions need to be addressed before molecular classification can be reliably incorporated into clinical trials and patient treatment.Alterations in the growth factor receptor/phosphatidylinositol 3-kinase/AKT (GFR/PI3K/AKT) pathway occur in most human cancers including at least 85% of GBM The GFR/PI3K/AKT pathway is complex and nonlinear having many inputs from other pathways The discovery dataset (GBM195) consisted of 181 GBM  from 3 datasets http://kinasource.co.uk/Database/substrateList.php) (3) evidence from Pubmed of phosphorylation by AKT , (4) evidence from Pubmed that a gene regulates or is regulated by AKT either directly or indirectly . Eliminating the genes with low variability across tumors within the discovery dataset left the 69 most variable genes used to classify AKT subgroups in the discovery dataset  enrichment analysis was dominated by generic GBM biological processes; therefore we used a single-sample approach analogous to the method used by Verhaak and Barbie http://www.sanger.ac.uk/research/areas/humangenetics/cnv/]. For experiments that compare broad CNA in the discovery and validation dataset we identified broad copy number alterations in the validation dataset as follows. Briefly, we found the average q value  for 15 genes spaced evenly across the region of interest. If > 50% of genes had a q value less than expected by chance after correcting for multiple testing (q < 0.25), that region was called as a copy number alteration.The GISTIC algorithm http://www.cbioportal.org/public-portal/). One hundred and eighty six of the 215 tumors with RPPA data could be assigned to an AKT class and were used for analysis. Correlation coefficients between two antibodies against the same protein were high indicating adequate antibody specificity and pre-processing of data .Level 3  reverse phase protein array (RPPA) data was downloaded from the cBio Cancer Genomics Portal  in AKT subgroups from discovery  and valiPhillips, TCGA and G-CIMP subgroups distributed non-randomly in AKT subgroups  and S4. AKT subgroups have different clinical characteristics  and S4. Consistent with the less aggressive character of SL tumors, there was a trend toward decreased endothelial proliferation , and palisading necrosis  in the validation dataset . There wSurvival differences between subgroups suggest AKT subtypes are either prognostic or predictive . Since AKT influences response to chemotherapy We used TCGA data to investigate how molecular alterations partition in subgroups. All subgroups had unique broad  and/or fAn integrated analysis of mutations, CNA and mRNA expression in glioma-associated genes shows some AKT subgroups had similar features as TCGA subgroups . The AKTWe find subgroups have distinct patterns of expression of mRNA , proteinWe used Gene Ontology (GO) to investigate the biological role of genes expressed in tumors and how terms partition in subgroups. Each subgroup, except CLAS, had a high percentage of tumors with functionally related terms that suggested a different dominate biological process . The CLAThe major finding is that AKT pathway genes classify GBM into at least five patient subgroups with unique clinical and molecular characteristics. The results were validated in an independent dataset of non-overlapping samples, suggesting AKT classes reflect underlying structure in the data and do not arise from chance or technical artifacts such as batch effects and patient sampling. Taken together these data add to previous results suggesting histopathologically diagnosed GBM is a collection of molecular subgroups with fundamental differences in biology and clinical behavior. This approach advances classification of GBM by splitting out groups not previously identified by other approaches and expands our understanding of molecular aberrations underlying subgroups.We interpret with caution the finding that SL patients treated with BCNU or CCNU have appreciably longer survival than SL patients receiving other treatments . Inhomogeneity between the cohorts (including treatment protocols and institution providing tumor) could impact survival. However, age and IDH1 mutation status clearly do not contribute since patients in the longer surviving cohort were older and had less IDH1 mutations. If validated these results suggest AKT classification is a predictive marker that identifies a subset of GBM patients with sensitivity to BCNU/CCNU. Interestingly, there is a subset of anaplastic oligodendroglial tumors characterized by 1p19q loss of heterozygosity (LOH) and IDH1 mutations that significantly benefits from procarbazine, CCNU, and vincristine (PCV) chemotherapy Mutations in IDH1 are a common and early event in low grade glioma, they are present in secondary GBM We found distinct patterns of expression for PI3K/AKT/mTOR components in subgroups. Our results suggest gene products that inhibit AKT and mTOR are important regulators of PI3K/AKT/mTOR/S6 axis output. In our model the loss of AKT and mTOR inhibitors  increases output of the AKT/mTOR/S6 axis in the MES subgroup. Conversely, increased expression of these inhibitors decreases output in the SL subgroup. In an apparent paradox, p-AKT expression is low in the MES subgroup. We suggest AKT phosphorylation is held in check in the MES subgroup by (1) heightened activity of an mTOR/S6K/IRS1 negative feedback loop How do these results compare with other approaches that use mRNA to classify GBM? AKT classification is complementary to previous classification methods but divides GBM into more subgroups. It gives patient subgroups with statistically significant differences in survival while Phillips Survival differences found in the discovery dataset were diminished in the validation dataset. Inhomogeneity's between datasets that could confound comparisons including (1) age , (2) patient populations , (3) treatment . In addition, performance of the validation dataset is typically not as robust as the discovery dataset One AKT subgroup was not found in the validation dataset (C1). We know morphological heterogeneity can result in inconsistent intra- and inter-observer diagnosis of grade and histological type  GO term analysis suggests different cells of origin/dominant biological processes for each subgroup . Red indicates total consensus (consensus index of 1) while white indicates no consensus (consensus index of 0).(TIF)Click here for additional data file.Figure S2Average expression of AKT pathway genes in subgroups. Hierarchical clustering using AKT pathway genes was used to group GBM patients and genes in the discovery (GBM 195) dataset. Tumors in the validation dataset were grouped by AKT class keeping the same order of genes. The expression of AKT pathway genes in each class was averaged and is shown as a heatmap; red and green is high and low expression respectively.(TIF)Click here for additional data file.Figure S3Log2  DNA copy number in subgroups. Amplifications (red) and deletions (blue) in subgroups (y axis) were determined by segmentation analysis of normalized signal intensities from TCGA SNP arrays using GISTIC and viewed with IGV by chromosomal location (x axis).(TIF)Click here for additional data file.Table S1Clinical information for tumors in GBM195.(XLSX)Click here for additional data file.Table S2AKT pathway gene classifiers used for the discovery and validation datasets.(XLSX)Click here for additional data file.Table S3Distribution of clinical and molecular information by subgroup in the discovery dataset (GBM195). The table lists the number of tumors with the specified feature in each subgroup in the discovery dataset. Features with statistically significant enrichment in a subgroup after Bonferroni correction (p < 0.05) are highlighted.(XLSX)Click here for additional data file.Table S4Distribution of clinical and molecular information by subgroup in the validation dataset (TCGA). The table lists the number of tumors with the specified feature in each subgroup in the validation dataset. Features with statistically significant enrichment in a subgroup after Bonferroni correction (p < 0.05) are highlighted in dark grey. Features with statistically significant enrichment in a subgroup before Bonferroni correction are highlighted in light grey.(XLSX)Click here for additional data file.Table S5GO term analysis of genes differentially expressed in subgroups. The % of individual tumors within a subgroup that are enriched for a specific GO term is shown, ordered by decreasing representation. GO terms enriched in \u2265 40% of tumors are highlighted light grey. Neurodevelopmental terms are highlighted with dark grey.(XLSX)Click here for additional data file.Table S6Focal DNA amplifications in subgroups. Copy number alterations in subgroups were evaluated using GISTIC and the q score for statistically significant focal DNA copy number gains (q score < 0.25) listed. Focal copy number changes common to all subgroups  are not reported.(XLSX)Click here for additional data file.Table S7Focal DNA deletions in subgroups. Copy number alterations in subgroups were evaluated using GISTIC and the q score for statistically significant focal DNA copy number losses (q score < 0.25) are listed. Focal copy number changes common to all subgroups  are not reported.(XLSX)Click here for additional data file."}
+{"text": "Epigenetic factors, principally CpG methylation, are widely held to play a dominant regulatory role in controlling the locus' activity. The purpose of this study was to examine its behavior in ES cells and determine if this locus could be exploited for use in screen-based investigations. We have derived multiple vyA ES cell lines from the C57BL/6 strain and generated a cell line carrying a GFP-reporter gene (vyA/GFPA). Use of the DNA demethylating drug 5-azacitidine on various ES cell lines does not induce either agouti or GFP expression. Methylation analysis reveals that although most lines display normal methylation at IAP elements in general, the vyA IAP element is essentially unmethylated. In addition, we find that different repeat compartments are epigenetically unstable in a number of derived cell lines.The  Retrotransposons constitute a large proportion of the mammalian genome and pose a significant threat to its integrity vyA) mouse strain is one of the best-studied examples of how a retroelement can interfere with neighbouring gene expression resulting in a phenotypic consequence. Over 50 years ago, the allele arose spontaneously as a result of an I\u03941-class intracisternal A particle (IAP) retrotransposon inserting into an upstream non-coding exon (pseudoexon 1A) of the agouti gene, located about 100 kb from the first coding exon agouti expression agouti expression and such animals are termed pseudoagouti. The IAP is subject to epigenetic regulation and the activity state of the vyA allele is inversely correlated with DNA methylation at the IAP element The agouti viable yellow  cells derived from vyA animals and their utility.To date, all studies on the role of DNA methylation at the vyA animals . To increase the number of embryos, female animals received injections to stimulate superovulation (gonadotrophin from pregnant mare serum) followed by human chorionic gonadotrophin. 3 days after detection of a copulation plug, females were sacrificed and uterine horns dissected out. Embryos were flushed out and collected before being individually seeded onto mitomycin-C treated mouse embryonic fibroblasts in standard FBS-containing ES cell media supplemented with 2i (PD03259010 and CHIR99021) in 96-well plate format. 2i was only included during the initial derivation phase. Six days after initial seeding, wells were tryplated onto MMCT-MEFs and passaged every third day. Established ES cell clones were checked by morphology and expanded up for further experiments. All animals used for this study were covered by a Home Office Project License under The Animals (Scientific Procedures) Act 1986 to S.K.T.O. In addition, this research study was approved by the UCL Research Ethics Committee. Mice were humanely sacrificed at a designated establishment by cervical dislocation.Timed matings were set up between male and female vy-GFPA replacement construct was generated using a bacterial artificial chromosome (BAC) (RP23-466H11) containing approximately 180 kb of mouse chromosome 2 encompassing the agouti locus (CHORI). A 17.4 kb fragment of this was retrieved into the vector pL253 by BAC recombineering in the recombineering strain SW102 agouti locus. For the eGFP cassette, pEGFP-C1 (Clontech) was used as the template and PCR-amplified using primers spanning the Start ATG and SV40 early mRNA Polyadenylation Signal. The replacement construct was sequence verified before being used to target one of the vyA ES cell lines derived (clone B5). Targeting was performed as previously described vy-neoA), this was further expanded and the neo selection cassette was removed by transient transfection using the Cre expression plasmid pCAGGS-Cre neo cassette (vy/AGFPA) were expanded and used in the experiments described. Primer sequences (5\u2032 to 3\u2032) used to generate the amplicons shown in TTG GAG GCA GCC TAG ACA CT (Primer A); TTG GAG GCA GCC TAG ACA CT (Primer C); GAA TTC CTC TAA GAT ACA TTG ATG AGT (Primer D). Primer sequences used to sex derived ES cell lines: AGA GAT CAG CAA GCA GCT GG (sry_F); TCT TGC CTG TAT GTG ATG GC (sry_R).The agouti genotyping, the probe used is as described in Duhl et al. Kit extracted DNA  was digested using the appropriate enzyme. 10 \u00b5g and 1 \u00b5g of DNA was digested for genotyping and methylation analysis Southern blots, respectively, for 6 hours. Digested DNAs were resolved on 0.8% TAE gels by electrophoresis before image capture. Gels were then depurinated , denatured  and neutralized  before blotting onto a 0.45 mm Nylon membrane  overnight. The next day, transferred DNA was fixed by UV cross-linking then incubated in Prehybridization Solution  for at least two hours before overnight incubation with radiolabelled probes. For methylation analysis, probes used were described previously TGA CAG GAG TCT GCG GAG TA (qAgouti_F); TCT TGG ATT TCT TGT TCA GTG C (qAgouti_R); TTG GCA GAT AAG GCC ACC TA (qIAP_F); AAT TTC TTG GGC AGC CTC TAC (qIAP_R); TCG TGA CCA CCC TGA CCT AC (qGFP_F); AAG TCG TGC TGC TTC ATG TG (qGFP_R). UPL probes and reference genes used: Agouti , IAP , GFP .Total RNA was extracted using TRIZOL reagent according to the manufacturer's protocol (Life Technologies). Prior to use for PCR, RNAs were DNase I treated  to remove any residual contaminating DNA. Expression of the different sequences indicated was determined using the Roche Universal Probe Library System (Roche Diagnostics). To detect IAP, a suitable hydrolysis probe was generated using a full-length consensus IAP sequence (GenBank accession number M17551). Primer sequences (5\u2032 to 3\u2032) used: RIPA lysates were prepared from pelleted cells. Following lysis on ice, and centrifugation to clarify, samples were quantified and diluted into 1\u00d7 Laemmli Buffer. Approximately 50 \u00b5g of lysate was loaded in each lane of a 10% Mini-Protean TGX Gel (Bio-rad). Following separation by electrophoresis, proteins were transferred onto PVDF membrane. Membranes were then blocked in 1\u00d7 PBS+0.1% Tween-20 (PBST)+5% milk for one hour before incubating with anti-GFP antibody  overnight. The next day, membranes were washed in PBST , before incubation with secondary antibody  for one hour at room temperature. Membranes were then washed in PBST , before HRP signal was developed using Luminata Forte Western HRP Substrate (Millipore). Signals were detected by exposure onto Hyperfilm ECL (Amersham). Post-signal acquisition, membranes were washed in PSBT and re-probed using anti-tubulin antibody  using the same methods as described.GTA GAG GTT TAA GGA TTT AGA TTG GTG (Avy bis fwd); AAC CCA CAA AAC CAA AAT CTT CTA C (Avy bis rev).Kit-purified DNA was bisulphite converted using the EZ DNA Methylation Lightning Kit (Zymo Research) according to the manufacturer's protocol. Cloning and analysis were performed as previously described Prior to the start of drug treatment, ES cells were seeded and grown in culture for 42 hours. Drug-containing media was then added to cells and the cells left for a further 30 hours before harvesting for analysis.vyA locus as a \u2018controlling element\u2019 is that the associated IAP element aberrantly controls agouti expression. From the existing data in animals/differentiated cells, the vyA IAP is predicted to be regulated by DNA methylation at the 5\u2032 LTR sequence. We therefore reasoned that this would be an ideal system from which to generate a GFP-based reporter cell line for use in screen-based approaches to identify novel regulators necessary for retrotransposon silencing. To that end, we derived ES cells from animals where the vyA IAP element has been inbred onto the C57BL/6 background. Images of representative derived lines are shown in vyA allele , we detected robust and ectopic agouti expression by qRT-PCR (vyA ES cells did not induce agouti expression (Oct4-GiP), we were unable to induce GFP expression in our targeted reporter cell line using either 5-aza or the histone deacetylase inhibitor Trichostatin A (TSA) , suggest it plays a major role in silencing multiple classes of retroelements including IAPs Under the prevailing model and combined with our observations we predicted that loss of DNA methylation at IAP elements, including the  qRT-PCR . Howeverpression . This wa A (TSA) . Therefoagouti and GFP expression. To that end, we examined the methylation status within the repeat compartment of eleven different vyA ES cell lines that were derived. Primers designed to detect the presence of the Sry locus by PCR confirmed that all the cell lines analysed were Sry+ and therefore XY , we asked whether the thylated .agouti/GFP expression. Furthermore, although we were unable to directly assess the expression status of the vyA IAP element, these data suggest that at least in pluripotent stem cells, regulation of the downstream agouti locus is uncoupled from the methylation state of this IAP element's LTR.This provides an obvious explanation as to why 5-aza-treatment failed to induce vyA IAP LTR in ES cells. Our initial intention was to generate a cell line that could be used in screen-based approaches to uncover novel epigenetic regulators of retrotransposon silencing. Our observation that the vyA IAP is apparently unmethylated offers insight into the unusual behaviour of the IAP at this particular locus. ES cells are derived from the inner cell mass of blastocyst embryos vyA locus from blastocysts derived from both pseudoagouti and yellow animals vyA IAP we observe in our various cell lines reflects a failure to correctly establish methylation following this erasure, or if methylation is correctly established but is rapidly lost upon ES cell derivation. Given that our bisulphite data indicate that methylation can (rarely) be detected at the locus, we favor the latter interpretation that the vyA IAP is inherently epigenetically unstable during the pluripotent state.To the best of our knowledge, this is the first study to examine the methylation state of the Genetic data have long supported the importance of DNA methylation in silencing IAP elements but the mechanism remains unclear vyA locus requires refinement. That is, control of the vyA IAP LTR cryptic promoter by DNA methylation and regulation of downstream agouti expression does not operate in pluripotent stem cells. Prior studies show that in pseudoagouti animals, where the vyA IAP is presumably silent, the IAP is significantly less methylated than other closely related IAPs vyA locus does not control promoter activity of the vyA IAP. A broader implication of our study is that although IAP activity is constrained by DNA methylation it is likely that not all IAP elements are dependent on this mode of regulation. It has been estimated that there are between 1,000 to 2,500 IAP elements present per haploid genome Our results also indicate that the prevailing model of the vyA locus demonstrate that DNA methylation-independent mechanisms ensure repression of the locus in pluripotent stem cells. A candidate pathway involves sequence specific KRAB-ZF proteins and KAP1, the latter being important in repression of endogenous retroviruses in murine ES cells Through interference with transcription of nearby genes, retrotransposon-derived controlling elements have the potential to affect gene expression. The mechanisms by which they are silenced are not fully understood. Our results on the well-studied vyA IAP in differentiated cells is a consequence of other signals that control the activity of the locus between generations. This has implications for the nascent field of environmental epigenetics and studies that attribute perturbations in DNA methylation, particularly in the early embryo, as the mechanism responsible for diet/environmentally induced alterations in gene expression.Finally, our data also suggests that the presence of DNA methylation at the"}
+{"text": "MRI-guided Electrophysiology (EP) procedures integrate real-time MRI images with catheter position during Radiofrequency Ablation (RFA) of arrhythmias . Using sCatheter position and cardiovascular structure were updated from MR images Figure  in the fTen volunteers without training in EP procedures were recruited to participate in a simulated RFA procedure to evaluate the performance with and without the proposed endoscopic view and haptic interface. RFA targets were pre-defined at the left pulmonary veins inside a left atrium model reconstructed from the preoperative image data from a cardiac patient Figure . The subThe proposed image-based catheter haptic guidance and endoscopic view improved RFA procedural time and accuracy, and reduced the risk of perforation."}
+{"text": "The following information is missing from the Acknowledgements section: The research leading to these results has partly received funding from the EU-FP7-SOCIOEC project under grant agreement No. 289192."}
+{"text": "A small number of recent reports have suggested that altered placental DNA methylation may be associated with early onset preeclampsia. It is important that further studies be undertaken to confirm and develop these findings. We therefore undertook a systematic analysis of DNA methylation patterns in placental tissue from 24 women with preeclampsia and 24 with uncomplicated pregnancy outcome.We analyzed the DNA methylation status of approximately 27,000 CpG sites in placental tissues in a massively parallel fashion using an oligonucleotide microarray. Follow up analysis of DNA methylation at specific CpG loci was performed using the Epityper MassArray approach and high-throughput bisulfite sequencing.Preeclampsia-specific DNA methylation changes were identified in placental tissue samples irrespective of gestational age of delivery. In addition, we identified a group of CpG sites within specific gene sequences that were only altered in early onset-preeclampsia (EOPET) although these DNA methylation changes did not correlate with altered mRNA transcription. We found evidence that fetal gender influences DNA methylation at autosomal loci but could find no clear association between DNA methylation and gestational age.Preeclampsia is associated with altered placental DNA methylation. Fetal gender should be carefully considered during the design of future studies in which placental DNA is analyzed at the level of DNA methylation. Further large-scale analyses of preeclampsia-associated DNA methylation are necessary. Preeclampsia is a hypertensive disorder that affects 5\u20137% of all pregnancies and is one of the major obstetrical complications resulting in fetal morbidity and mortality Numerous studies have identified altered gene expression in the placentas of mothers affected by preeclampsia Although the relationship between DNA methylation and gene expression at the level of transcription is complex, there is strong evidence that altered DNA methylation, particularly within the regulatory regions of expressed genes, has a significant influence on transcription Given our relatively limited understanding of epigenetic alterations in preeclampsia, it is important that further studies are undertaken so that reported associations between DNA methylation and preeclampsia may be verified and expanded upon. Therefore we have undertaken an analysis of DNA methylation in the context of preeclampsia using a commercially available microarray that is able to simultaneously assess DNA methylation levels at 27,000 CpG dinucleotides.All patients provided written informed consent for use of their samples and de-identified clinical data under the umbrella of the Preeclampsia Program Project (PEPP study) and related ancillary studies. These women delivered at Magee-Womens Hospital within the years 1997\u20132007, and were recruited from clinics and private practices. This protocol was approved by the University of Pittsburgh Institutional Review Board (Protocol # IRB 0404159). Clinical and demographic characteristics of the individuals recruited to take part in this study are shown in A panel of clinicians met monthly to adjudicate the pregnancy outcome diagnosis of all the women. Preeclampsia was defined as gestational hypertension with proteinuria in accordance with the National High Blood Pressure Education Program Working Group Report on High Blood Pressure in Pregnancy 2]). Maternal race was by self-report at enrollment.All participants had no prior history of renal or vascular disease, and were non-smokers (<100 cigarettes in lifetime). Status of tobacco smoking was determined by self-report; these data were obtained during the pregnancy or immediately postpartum to minimize the potential problems caused by changing smoking habits during pregnancy. In a previous study of our patient population, there was no significant discordance between self-report of smoking status and maternal plasma cotinine concentration using a cutoff value of \u22652.0 ng/ml (P\u200a=\u200a0.49), with 82% agreement and \u03ba coefficient of 0.64 Placental biopsies were obtained immediately after delivery from the maternal side of the placenta, in regions free of infarcts between the placental margin and cord insertion. Decidua was removed by blunt dissection. The tissue was immediately transported in saline to the laboratory, flash frozen in liquid nitrogen and stored at \u221280\u00b0C for later use.To isolate DNA, 180-\u00b5L buffer ATL  and a 5-mm steel bead were added to each placenta sample. The samples were then homogenized in a TissueLyser (Qiagen) for 20 s at 30 Hz. The DNA was then purified using the DNeasy Blood and Tissue kit as per the manufacturer's protocol.DNA samples were prepared for microarray analysis and methylation status determined as previously described . P values were adjusted using Benjamini and Hochberg's method to control the false discovery rate (FDR) at 10%. DNA methylation data has been deposited at the Gene Expression Omnibus repository (GE59274).www.urogene.org/methprimer) or BiSearch (http://bisearch.enzim.hu). PCR products were amplified as separate reactions using Pfu Turbo Cx , Platinum Taq  or ZymoTaq (Zymo Research). Primer sequences, melting temperatures (Tm) and cycling conditions are shown in Tables S1A and S1B in DNA was bisulfite converted using Zymo's EZ DNA Methylation Gold kit as per manufacturer's protocol . Bisulfite specific primers were designed using Methprimer  on the methylation data to visualize the similarity of the methylation profiles across the samples. For hierarchical clustering, we used the Ward's minimum variance method, and chose respectively the Euclidean distance between the methylation rate of all probes, as well as 1\u2013 Pearson's correlation between the log ratio of the signal B to signal A of all probes, as the distance between two samples. The same two types of distance metric were also used in the multi-dimensional scaling analysis of the methylation data. Both types of unsupervised learning analyses were performed using the statistical computing program R.The clinical and demographic data for the 48 subjects who provided placental samples are presented in We first compared DNA methylation patterns in placental tissue samples from preeclampsia cases with normal controls by Infinium microarray. This identified a small number of differentially methylated CpG sites  when compared to normal controls who delivered at term. These previous studies, which controlled for gender bias by removing all X chromosome data points prior to analysis, reported no differences when comparing late onset preeclampsia samples (>34 weeks gestation) with normal pregnancy controls. To be consistent with these previous study designs we therefore reanalyzed our data, after excluding X chromosome-specific probe results, to compare EOPET (n\u200a=\u200a9) samples with all normal controls (n\u200a=\u200a24). As shown in Given previously published evidence that gestational age at time of delivery is a major contributor towards altered DNA methylation http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?targ=self&form=html&view=quick&acc=GSE44711). We hypothesized that reduced CpG methylation in a given sample cohort (preeclampsia or control) identified in our own data would correlate with an increase in transcription. We could find no overlap between genes containing differentially methylated CpG sites  samples.Furthermore, we identified a significant lack of correlation between multiple independent data sets from three separate studies.It is notable that we identified minimal overlap between our data and two previously published studies describing differences between normal controls and EOPET A number of notable differences in DNA methylation of specific genes were observed in our data. For example, the expression of Purinergic Receptor P2X, Ligand-Gated Ion Channel, 4 (P2RX4) has been shown to be elevated in both pre-term and term placental samples from preeclampsia cases compared to normal controls. CpG methylation within the P2RX4 promoter was reduced in preeclampsia samples relative to controls in our data, suggesting elevated transcription It is somewhat surprising that our gender-specific analysis of preeclampsia-related changes in DNA methylation  and 3 idIt is not surprising that the inclusion of X chromosome-specific data resulted in clear gender-dependent hierarchical clustering patterns. Notably, when X chromosome data were removed, samples were still broadly separated into gender-associated clusters and statistically significant gender-dependent autosomal alterations in DNA methylation were observed. These observations are worthy of further study at higher resolution with a larger sample size. The identification of autosomal origins of gender-specific differences is significant because previous studies of DNA methylation in preeclampsia have controlled for fetal gender by simply removing X chromosome specific probes from the analyses In summary, we have undertaken a systematic analysis of preeclampsia-associated DNA methylation changes in the placenta. We identified a number of differentially methylated CpG sites in tissues from preeclampsia patients including a number that were altered only in EOPET cases compared to controls.Figure S1Hierarchical clustering, with respect to gestational age at delivery, of DNA patterns in placental tissues from preeclampsia patients.(TIF)Click here for additional data file.Figure S2A. Hierarchical clustering, with respect to fetal gender, of DNA patterns in placental tissues from preeclampsia patients. B. MDS Analysis, with respect to fetal gender of DNA patterns, in placental tissues from preeclampsia patients. C. Hierarchical clustering with respect to fetal gender of DNA patterns in placental tissues from normal controls. D. MDS Analysis with respect to fetal gender of DNA patterns in placental tissues from normal controls.(TIFF)Click here for additional data file.File S1Tables S1\u2013S8. Table S1A - Bisulfite Sequencing Primers and Tm's. Table S1B- PCR reaction conditions used. Table S1C. Epityper MassARRAY Primer Sequences. Table S2A-Preeclampsia-Associated Changes in Placental DNA Methylation Without Control for Fetal Gender: CpG sites at which samples from preeclampsia samples are more highly methylated than those from normal controls are shown. Table S2B- Preeclampsia-Associated Changes in Placental DNA Methylation Without Control for Fetal Gender: CpG sites at which samples from normal controls are more highly methylated than those from affected individuals are shown. Table S3A- Fetal Gender-Dependent Preeclampsia-Associated Changes in Placental DNA Methylation: CpG sites at which samples from normal controls are more highly methylated (<10%) than those from affected individuals are shown. Table S3B- Fetal Gender-Dependent Preeclampsia-Associated Changes in Placental DNA Methylation: CpG sites at which samples from preeclampsia samples are more highly methylated (<10%) than those from normal controls are shown. Table S4A- DNA Methylation Changes in Early Onset Preeclampsia (EOPET) Versus Normal Controls.% methylation levels for all significant differentially methylated CpG sites in EOPET  and normal controls . Adjusted p values are shown with FDR controlled at 10%. Table S4B- DNA Methylation Changes in Early Onset Preeclampsia (EOPET) Adjusted p values are shown with FDR controlled at 10%. Table S5A- Genes previously identified as containing differentially methylated CpG sites (reference 17) that were confirmed using our statistical/infomratic piepline. Table S5B- Genes identified from published data (reference 17) using our statistical/informatic pipeline containing differentially methylated CpG sites that were not previously identifed. Table S6A- Genomic Coordinates of Targeted DNA Methylation Analsysis Loci. Table S6B- Genomic Coordinates of Targeted DNA Methylation Analsysis Loci. Table S7- Gene expression differences between EOPET and normal placental tissue samples. Table S8A- Gender specific differences in DNA methylation at autosomal loci in normal samples.(XLSX)Click here for additional data file."}
+{"text": "Grating-coupled propagating surface plasmons associated with silver-nanoparticle 2D crystalline sheets exhibit sensitive plasmonic resonance tuning. Multilayered silver-nanoparticle 2D crystalline sheets are fabricated on gold or silver grating surfaces by the Langmuir\u2013 Blodgett method. We show that the deposition of Ag crystalline nanosheets on Au or Ag grating surfaces causes a drastic change in propagating surface plasmon resonance (SPR) both in angle measurements at fixed wavelengths and in fixed incident-angle mode by irradiation of white light. The dielectric constant of the multilayered silver nanosheet is estimated by a rigorous coupled-wave analysis. We find that the dielectric constant drastically increases as the number of silver-nanosheet layers increases. The experimentally obtained SP dispersions of Ag crystalline nanosheets on Au and Ag gratings are compared with the calculated SP dispersion curves. The drastic change in the surface plasmon resonance caused by the deposition of Ag-nanoparticle 2D crystalline sheets on metal grating surfaces suggests the potential for applications in highly sensitive sensors or for plasmonic devices requiring greatly enhanced electric fields.The online version of this article (doi:10.1186/2193-1801-3-284) contains supplementary material, which is available to authorized users. In recent years, surface plasmon resonance (SPR) phenomena have attracted considerable attention because of the extremely strong enhancement and confinement of electric fields near metal surfaces Knoll . Two kinRecently, tuning of propagating SPR properties has attracted considerable interest from those seeking to develop applications for plasmonic devices . The grating samples were mounted on a \u03b8-2\u03b8 goniometer. A halogen lamp as the white light source or a HeNe laser was used for the excitation of SPs. P-polarized light was collimated by objective lens and irradiated on the grating samples. The reflected zero-order light was detected by a spectrometer. SPR excitation experiments were carried out at a fixed incident angle as a function of wavelength or at a fixed wavelength as a function of incident angle. Grating-coupled SPR modeling was performed on G-Solver  using rigorous coupled-wave analysis.Silver nanoparticles were synthesized by thermal reduction of a silver acetate precursor in a melt of myristic acid, as described earlier  is the wavelength-dependent dielectric constant of silver given by the classical Drude\u2019s free-electron model. As shown in Figure\u00a0Here, We studied the SP excitation properties of Ag crystalline nanosheets on Au and Ag grating surfaces, and found a drastic change in SP excitation from angular measurements at fixed wavelength and from measurements at fixed incident angle under irradiation with white light. The SPR dips were drastically shifted when Ag crystalline nanosheets were deposited on the grating surfaces. The experimentally obtained SP dispersion data of the Ag crystalline nanosheets on Au and Ag gratings were compared to calculated SP dispersion curves. A large shift in the wavelength or dip angle by the deposition of Ag nanoparticle 2D crystalline sheets on a metal grating surface based on the drastic change in the surface plasmon resonance suggests the potential for applications in highly sensitive sensors or for plasmonic devices requiring greatly enhanced electric fields.Supporting Information. (PDF 384 KB)Additional file 1:"}
+{"text": "Cardiovascular Magnetic Resonance (CMR) with respiratory commands is the gold standard technique to measure cardiac volumes. Although cardiac volumes can be measured during free breathing in patients with congenital heart disease (CHD), its accuracy is unknown. Therefore, the aim of this study was to compare cardiac volumes acquired during free breathing with volumes acquired during breath hold commands.Cardiac volumes were measured in every patient using both free breathing and breath hold techniques, by a routine standard steady state free precession (SSFP) cine sequence in axial slice orientation. The sequence parameters were always identical besides the number of averages being three during free breathing and one during breath holds. Volumes were determined in a blinded fashion by endocardial contouring and then correlated using the coefficient of determination and compared by Bland Altman analysis. Eleven younger patients with CHD aged median 4 yrs, range 3 months-14 yrs, were examined under general anesthesia and intubation (intubated younger patient group). Twelve older patients with CHD aged median 20 yrs, range 11-61 yrs were examined consciously (conscious older patient group).The agreement of the end systolic volume (ESV) and end diastolic volumes (EDV) between scanning with and without respiratory commands in both ventricles was excellent in the intubated younger patients  and less acceptable in the consciously examined older patients  (see Figure Cardiac volumes can be quantified very accurately during free-breathing in young patients with congenital heart disease by CMR using standard routine imaging techniques. If needed, even in older patients cardiac volumes can be quantified reasonably accurate during free-breathing. Therefore, free-breathing is an alternative technique for patients not able to hold their breath and thus obliterating the need of anesthesia for many patients undergoing CMR. In addition it will provide a chance for the CMR to assess the hemodynamics in a resting physiologic condition.All authors have no conflict of interest."}
+{"text": "Contrast echocardiography has an established role for enhancement of the right heart Doppler signals, the detection of intra-cardiac shunts, and most recently for left ventricular cavity opacification (LVO). The use of intravenously administered micro-bubbles to traverse the myocardial microcirculation in order to outline myocardial viability and perfusion has been the source of research studies for a number of years. Despite the enthusiasm of investigators, myocardial contrast echocardiography (MCE) has not attained routine clinical use and LV opacification during stress has been less widely adopted than the data would support. The purpose of this review is to facilitate an understanding of the involved imaging technologies that have made this technique more feasible for clinical practice, and to guide its introduction into the practice of the non-expert user. Two aspects of micro-bubbles are important \u2013 their gas content and the nature of their shell. Recently-approved micro-bubbles almost universally involve encapsulation of a high molecular weight gas, which improves the persistence of the bubble, optimising the number available in the left heart chambers. Air has a greater propensity to dissolve into solution and although currently unattractive because of loss of gas before arrival on the right side of the heart, better encapsulation may allow its resurgence \u2013 the benefit would be more rapid disappearance when the bubble bursts. The nature of the shell or surface modifying agent, which improves stability and prevents dissolution, may become important for new targeted imaging approaches.Even when optimal microbubble delivery to the myocardium is achieved with invasive coronary  or aortiMicro-bubbles oscillate (expand and contract) in the ultrasound field. The pattern and nature of their oscillation, and thus the nature of the backscatter signal, differs, depending on the acoustic power of the transmitted ultrasound field, which is expressed on modern ultrasound machines as the mechanical index (MI). In general echocardiography, the amplitude of returning backscatter depends on the nature of the insonated structure, and is represented by brightness on the formed image. Most backscatter returns at the same frequency as the transmitted ultrasound .very low mechanical index imaging (MI < 0.1), micro bubbles demonstrate linear oscillation, where the contraction and expansion of the micro bubble are equal. All returning micro bubble backscatter remains within the range of the frequency transmitted by the transducer  \u2013 as for surrounding structures , generates nonlinear oscillation of the micro bubble whereby expansion is greater than contraction. In addition to the usual backscatter of a particular amplitude within the range of the fundamental frequency, the bubbles also produce backscatter of (lesser) amplitude at harmonic frequencies . In. In42]. Like stress echo and nuclear perfusion imaging, MCE is also limited by the qualitative nature of the interpretation. Subtle differences in video intensity between vascular beds may not be visually evident, potentially reducing the sensitivity for the detection of stenosis. Quantitative methods may help to alleviate this limitation and possibly reduce intra-observer and inter-observer variability in assessment.The process of quantitative myocardial contrast echo was validated in open chest dogs using intermittent imaging, and the same destruction-replenishment approach is used for contemporary qualitative assessment . At a stplateau myocardial video intensity (A) represents the myocardial blood volume. The rate of rise of the slope (\u03b2) represents the mean myocardial red blood cell velocity and their product (A*\u03b2) represents myocardial blood flow. Wei demonstrated an excellent linear relationship between absolute myocardial blood flow measured with radiolabelled microspheres and myocardial contrast echo derived myocardial blood flow. While ECG gated intermittent triggered harmonic imaging was used to validate these measurements, both power Doppler and real time techniques have subsequently demonstrated similar results in animal experiments  where y is the video intensity at the pulsing interval or time t, A is the plateau video intensity and \u03b2 represents the rate of rise of the slope. In this model the riments -46)..plateau More recently, Wei evaluated the ability of MCE to calculate flow reserves from these measurements in humans , using It is now well recognised that regional or global ventricular dysfunction does not necessarily imply irreversible necrosis. Hypokinetic, akinetic or dyskinetic, yet viable myocardium may be stunned or hibernating. Myocardial stunning occurs after a period of acute ischaemia, despite restoration of completely normal blood flow. The natural history of stunning is of spontaneous improvement in the viable myocardium over time. Hibernating myocardium is the term used to describe the presence of significant ventricular dysfunction in patients with chronic CAD, which recovers after revascularisation. Improvement in function of sufficient numbers of viable but hibernating segments is associated with symptomatic benefit and improved survival. Sadly, Radionuclide scanning, dobutamine echocardiography, MRI and PET scanning are currently available modalities, each with various advantages and disadvantages but similar efficacy for prediction of myocardial functional recovery after revascularization. MCE may also have an important role in this clinical setting. Viable myocardium is associated with preservation of the micro-vasculature, and as micro-bubbles act as pure intra-vascular tracers, the presence of myocardial perfusion by any MCE technique at rest implies viability  has been very low. There have been particular theoretical concerns raised about histologic abnormalities and cardiac marker elevation in animals with high MI imaging, and whiIn recent months the agent SonoVue (a phospho-lipid shell encapsulating sulphur hexafluoride gas), approved in Europe, was withdrawn from clinical use because of adverse events including fatalities related to idiosyncratic hypersensitivity reactions. At this stage, specific details about the dose of agent and imaging modality used in these cases is not available.Advances in micro-bubble development, combined with the development of contrast specific imaging modalities have enabled not only excellent LVO, but reliable qualitative and quantitative assessment of myocardial perfusion by ultrasound, following intravenous injections of micro-bubbles. Use of this technology during stress echo increases sensitivity and improves the non-invasive evaluation of CAD.Power Doppler 4CV at rest in normal subject.Click here for fileA4CV standard harmonic imagingClick here for fileContrast LVO with standard harmonic imagingClick here for fileReal time MCE with LVO and myocardial perfusion.Click here for fileContrast LVO with ideal machine settings to optimize image quality and frame rateClick here for file3-D non contrast imagingClick here for file3-D imaging with contrastClick here for fileReal time 3-D without contrastClick here for fileReal time 3-D with contrast.Click here for fileMr CC PLAX view restClick here for fileMr CC PLAX view stressClick here for fileMr CC PSSAX view restClick here for fileMr CC PSSAX view stressClick here for fileMr CC A4CV restClick here for fileMr CC A4CV stressClick here for fileMr CC A2CV restClick here for fileMr CC A2CV stressClick here for fileMr CC ALAX view restClick here for fileMr CC ALAX view stressClick here for fileMr CC contrast 4CV restClick here for fileMr CC contrast 4CV stressClick here for fileMr CC contrast 2CV restClick here for fileMr CC contrast 2CV stressClick here for fileApical HCM standard 4CVClick here for fileApical HCM contrast restClick here for fileMr JD Rest PSAXClick here for fileMr JD Rest A4CVClick here for fileMr JD Rest PLAXClick here for fileMr JD Rest A2CVClick here for fileMr JD Rest ALAX viewClick here for fileMr JD Rest contrast 4CVClick here for fileMr JD Rest contrast A2CVClick here for fileMr JD Stress PLAXClick here for fileMr JD Stress PSSAXClick here for fileMr JD Stress A4CVClick here for fileMr JD Stress A2CVClick here for fileMr JD Stress ALAX viewClick here for fileMr JD Stress contrast 4CVClick here for fileMr JD Stress contrast 2CVClick here for fileMr JD angiogram.Click here for fileMr T 4CV restClick here for fileMr T 4CV stressClick here for fileMr T 2CV restClick here for fileMr T 2CV stressClick here for fileMr T 2CV contrast restClick here for fileMr T 2CV contrast stressClick here for fileMr T cath LCAClick here for fileMr T cath RCAClick here for fileMr JD curve fits A4CVClick here for file"}
+{"text": "Faecal samples are frequently used to characterise the gut microbiota in health and disease, yet there is considerable debate about how representative faecal bacterial profiles are of the overall gut community. A particular concern is whether bacterial populations associated with the gut mucosa are properly represented in faecal samples, since these communities are considered critical in the aetiology of gastrointestinal diseases. In this study we compared the profiles of the faecal and mucosal microbiota from ten healthy volunteers using bacterial culturing (culturomics) and next-generation sequencing targeting the 16S ribosomal nucleic acid (rRNA) gene. Paired fresh rectal biopsies and faecal samples were processed under stringent anaerobic conditions to maintain the viability of the bacteria. Four different sample types were analysed: faecal (F), faecal homogenised (FHg), biopsy tissue (B) and biopsy wash (BW) samples.\u00a0p\u2009=\u20090.972) but showed strong clustering of samples from individual donors. However, the rectal biopsy tissue (B) samples had a significantly altered bacterial signature with greater abundance of Proteobacteria and Acidobacteria compared to faecal (F) and faecal homogenised (FHg) samples. A total of 528 bacteria encompassing 92 distinct bacterial species were isolated and cultured from a subset of six volunteer samples (biopsy washes and faeces). This included isolation of 22 novel bacterial species. There was significant similarity between the bacterial species grown in anaerobic culture and those identified by 16S rRNA gene sequencing .There were no significant statistical differences in either bacterial richness or diversity between biopsy washes (BW) and faecal (F) or faecal homogenised (FHg) samples. Principal coordinates analysis of a Bray\u2013Curtis distance matrix generated from sequence variant tables did not show distinct clustering between these samples (PERMANOVA; This study showed that the bacterial profiles of paired faecal and rectal biopsy wash samples were very similar, validating the use of faecal samples as a convenient surrogate for rectal biopsy-associated microbiota. Anaerobic bacterial culture results showed similar taxonomic patterns to the amplicon sequence analysis disproving the dogma that culture-based methods do not reflect findings of molecular assessments of gut bacterial composition.Video abstractThe online version contains supplementary material available at 10.1186/s40168-022-01354-4. The gut microbiota is a complex entity comprising of myriad species of bacteria, archaea, fungi and viruses that are critical in homeostasis and disease . There iFaecal samples have been commonly used as surrogate representatives of bacterial communities residing in the colon but there is debate on whether faecal samples accurately represent the mucosa-associated bacteria \u201312. MostThere has been a recent resurgence of culturing techniques with a specific focus on anaerobic conditions for collection and assessment of the gut bacterial species which has narrowed the gap with the more modern assessment of the enteric microbiome by next generation sequencing , 21. TheMost of the colonic bacterial species are strict anaerobes and there is a paucity of data that combines 16S rRNA gene assessment of faecal and mucosal samples collected and assessed under anaerobic conditions. Multiple studies have shown that the colonic microbiota is significantly altered after bowel preparation prior to colonoscopy, \u201326 whileThis current study on healthy volunteers is based on paired faecal and biopsy samples obtained from the rectum during flexible sigmoidoscopy (without prior bowel preparation) that were collected on the same day and transported and cultured in an anaerobic environment. This assessment removes the potential confounders affecting previous studies and provides accurate profiling of the anaerobic bacterial species residing loosely adherent to the mucosa and in the intestinal lumen of \u2018healthy\u2019 individuals. The study also underscores the importance of stringent anaerobic culture techniques in the assessment of the gut microbiota in addition to the 16S rRNA gene sequencing in this healthy cohort.Ten healthy subjects aged 27\u201343\u00a0years with normal BMI (defined as 18\u201325), and no history of any chronic diseases were recruited to the study. Details of exclusion criteria and individual biometric information can be found in Table\u00a02 during the procedure) and placed immediately into anaerobic tissue transport medium  to preserve the viability of anaerobic bacteria. Samples were transported to the laboratory immediately in cool bags and were processed within 1\u20132\u00a0h of collection under stringent anaerobic conditions. A schematic of sample collection and processing is presented in Fig.\u00a0Enrolled volunteers were invited to the Albyn Hospital, Aberdeen, Scotland where they underwent flexible sigmoidoscopy for collection of rectal biopsy samples. The volunteers did not receive any bowel preparation. Six mucosal pinch biopsy samples were collected from the rectum  of each volunteer anaerobically  .Additional file 5:Figure S1. Rarefaction plots for every sample for the alpha diversity metrics a) Observed Species, b) Chao, c) Shannon Index, d) Simpson Index and e) Good\u2019s Coverage.Additional file 6:Figure S2. PCoA plots based upon Bray Curtis Diversity metrics for different volunteers showing inter-individual differences in the bacterial profile of both biopsy and faecal samples. Each volunteer is represented by a different colour, revealing the four linked samples.Additional file 7:Figure S3. PCoA plots based upon Bray Curtis Diversity metrics for different sample types.Additional file 8:Figure S4. Log relative abundance of taxa with significantly different abundance at the phylum level between biopsy tissue (red) and biopsy wash (blue) samples.Additional file 9:Figure S5. Log relative abundance of taxa with significantly different abundance at the genus level between biopsy tissue (red) and biopsy wash (blue) samples.Additional file 10:Figure S6. qPCR estimation of bacterial loads in the different sample types.Additional file 11:Table S5. Total viable counts of anaerobic bacteria enumerated on growth plates from biopsy wash (BW) and faecal (F) samples.Additional file 12:Table S6. Bacterial identification.Additional file 13:Figure S7. Detection of fermentation acids in media following growth of individual isolates in pure culture. Acid production split for biopsy wash (BW) and faecal (F) bacterial isolates. The upward arrow indicates fermentation acid production whilst the downward arrow represents consumption during bacterial growth in pure culture. Bacterial isolate numbers shown on the x-axis correspond to bacterial identities detailed in Additional file"}
+{"text": "Tuberculosis (TB) is a chronic granulomatous inflammation usually involving the lung parenchyma and hilar lymph nodes. Extra-pulmonary involvement is seen in \u223c20% of all TB cases. Developing tuberculosis following treatment for another primary medical condition is a rare occurrence. Iatrogenic literally means illness caused by medical examination or treatment.Mycobacteria have been used to treat a few medical conditions and the therapeutic use has been validated extensively in literature. The mycobacteria used for therapeutic purposes are supposed to be either attenuated or non pathogenic strains. Growth and dissemination of this mycobacterium is a rare but serious possibility. Reactivation of latent mycobacterial infection following therapy is also a part of iatrogenic mycobacterial infection.We report a retrospective study investigating adverse events manifesting with development of iatrogenic tuberculosis. The data was obtained from a tertiary care centre over a period of 2 years. Diagnosis of tuberculosis was established based on clinical, radiological(chest X-Ray and High resolution CT scan), sputum smear microscopy and skin/tissue biopsy and Xpert MTB/RIF. Tuberculin skin test(TST) and Interferon gamma release assay (IGRA) were used as additional diagnostic tests.The search yielded 26 cases of iatrogenic tuberculosis, with a median age of 56.5 years. Most common cause was reactivation of latent tuberculosis due to use of anti-TNF alpha biologic agents(53.8%). Development of Tuberculosis verrucosa cutis following BCG inoculation for verruca vulgaris was noted in about 19.2% of cases and Tubercular abscess due to Mycobacterium w or BCG inoculation for Covid-19 was noted in 11.5% cases. Bacillus Calmette Gu\u00e9rin(BCG) induced balanitis secondary to therapy for Carcinoma urinary bladder was noted in 7.69%of cases.Bacillus Calmette-Guerin or BCG induced balanitis following use of intravesical immunotherapy for treating early-stage urinary bladder cancer and successful clearance of lesions post therapyTuberculosis Verrucosa Cutis following Immunotherapy for plantar wartsAll patients were managed successfully with anti tubercular therapy. These observations indicate that tuberculosis infection can develop in previously healthy individuals in endemic zones following biologic therapy of use of mycobacterial agents for other therapeutic indications.All Authors: No reported disclosures."}
+{"text": "Plant Physiology initiated the Assistant Features Editor (AFE) program five years ago to help disseminate discoveries published in the journal and to train the next generation of editors and reviewers. Our AFEs are promising early-career scientists and they bring their passion for science to our journal, communicating to our readers each month some of the most exciting advances in research.News and Views articles, blog posts, and related material highlighting content of special interest in Plant Physiology. They have grown professionally and will build on their experience with the journal. Many of our previous AFEs have moved onto independent academic positions after completing their terms at Plant Physiology. We hope to call the AFEs to serve as regular members of the editorial board when they have become more established in their careers.The AFEs have added substantially to the plant science community and to the journal. Their contributions have expanded our content through https://plantae.org/2023-plant-physiology-assistant-features-editors/) who started last month and will work alongside our seasoned crew.The program is designed to rotate off a number of AFEs each year and to add new members at the beginning of each year. Sixteen of our AFEs stepped down from the editorial board this past month, and we would like to take this opportunity to thank them all for their contributions. We would also like to welcome the 19 new AFEs Jiawen Chen Joke De Jaeger-Braet Manuel Gonzalez-Fuente Henning Kirst Yee-Shan Ku Aida Maric Hannah McMillan Sebastian Moreno Dyoni Oliveira Lara Pereira Moona Rahikainen Janlo Robil Alaeddine Safi Maria-Angelica Sanclemente Henryk Straube Jiaqi Sun Kyle Swentowsky Ryo Yokoyama The new AFEs are joining those who started in January of 2022, listed below, who will stay on for one more year to continue writing News and Views, help with the transition, and mentor the new AFEs.Alexandra Burgess Amanda Cardoso Jian Chen Gustaf E. Degen Marieke Dubois Guadalupe Luc\u00eda Fern\u00e1ndez-Milmanda Yana Kazachova Amy Lanctot Divya Mishra M\u00edriam Os\u00e9s-Ruiz .Yadukrishnan Premachandran Jos\u00e9 Manuel Ugalde Yajin Ye"}
+{"text": "Meta-analyses suggest that patients with schizophrenia show deficit in working memory \u2013 both verbal and visual \u2013 and are more distractible. Working memory disturbances are even regarded as the central deficit in schizophrenia by some researchers. Theta synchronization  is related to cognitive control and executive functioning during working memory encoding and retention.The main goal of the study was to gain more understanding of the nature of working memory deficit and attentional distractibility in schizophrenia.35 patients with schizophrenia and 39 matched controls were enrolled in our study. Participants performed a modified Sternberg working memory task that contained salient and non-salient distractor items in the retention period. A high-density 128 channel EEG was recorded during the task. Event-related theta (4-7 Hz) synchronization was analyzed during working memory encoding (learning) and retention (distractor filtering) in a later time window (350-550 ms).Patients with schizophrenia showed weaker working memory performance and increased attentional distractibility compared to the control group: patients had significantly lower hit rates (p < 0.0001) and higher distractor-related commission error rates (p < 0.0001). Theta synchronization was modulated by condition (learning < distractor) in both groups but it was modulated by salience only in controls .Our results suggest that patients with schizophrenia show diminished cognitive control compared to controls in response to salient distractors. Difficulties in cognitive control allocation may contribute to the behavioral results observed in this study.No significant relationships."}
+{"text": "RSC Advances.The following article \u2018Novel fatty chain-modified GLP-1R G-protein biased agonist exerts prolonged anti-diabetic effects through targeting receptor binding sites\u2019 has been published in The Royal Society of Chemistry was contacted by a reader who raised concerns about scientific errors in this article, and that some of the content may have been reproduced without appropriate acknowledgement.The authors were contacted for comment but have not responded to these concerns.RSC Advances is publishing this Expression of Concern to alert readers to the concerns raised. An Expression of Concern will continue to be associated with the article until we receive conclusive evidence regarding the reliability of the reported data.Laura Fisher15/11/2022RSC AdvancesExecutive Editor,"}
+{"text": "Traumatic aortic regurgitation (AR) is a rare complication of blunt chest trauma. We described the case of a 35-year-old male who presented to our hospital with shortness of breath 7 years after sustaining blunt chest trauma associated with a motorcycle accident. Transthoracic and transesophageal echocardiogram detected severe AR with two separate jets. The patient was diagnosed with congestive heart failure due to severe AR, and surgical aortic valve replacement was performed. A large perforation of the right coronary cusp likely sustained during the initial blunt chest trauma injury was confirmed surgically. As AR caused by blunt chest trauma can gradually worsen, it is necessary to confirm if there is a history of trauma in patients with severe AR of unknown origin."}
+{"text": "To determine the association between childhood involvement with social services and adult mental ill-health, using uptake of psychotropic medication as a proxy indicator.This longitudinal population-wide study linked primary care data on all children born 1985-1991 in Northern Ireland  to social services data (1985-2015) and psychotropic medication prescribing data (2010-2015). Multilevel logistic regression models explored psychotropic medication uptake  at ages 18-30 years given exposure to social services in childhood, clustered by GP practice. Additional analysis explored the sociodemographic characteristics and social care experiences  associated with medication uptake within social care subgroups.Over 1 in 10 adults (10.3%) were known to social services in childhood . During follow-up 58.5% of care experienced adults were in receipt of psychotropic medication compared to 26.9% of peers never known to social services. Care experienced adults were three to six times more likely to be in receipt of medication  than adults never known to social services. Adults deemed Not In Need in childhood (received no services) were at equivalent risk of psychotropic medication to those deemed In Need (received at-home care/support packages). Experiences before and during involvement with social services showed variable association with receipt of psychotropic medication in adulthood.Adults known to social services in childhood are more likely to receive psychotropic medication than peers never known, with number of referrals and placement type key predictors. Adults known as a Child in Need are equally as likely as those assessed as Not in Need, suggesting possible missed intervention opportunities."}
+{"text": "A 63-year-old man known for mitral valve replacement (MVR) with a bi-leaflet mechanical valve (Open Pivot Medtronic 31) one year previously, presented with chest discomfort, a new murmur, and modestly increased inflammatory markers. He had been treated with warfarin with satisfactory home- and laboratory-monitored INR levels since the operation. In particular, he had several INR measurements in the preceding 3 months which had all been within the therapeutic range.Panels A and B; Videos 1 and 2). Blood cultures were negative including for fastidious microorganisms. Treatment with unfractionated heparin and antibiotics was given empirically for 2 weeks, and although inflammatory markers normalized, repeat TOE showed a progression to severe MVR obstruction with increased mass size now partially restricting also the anterolateral occluder . Persistent obstruction on transthoracic imaging was subsequently demonstrated and re-sternotomy surgery was therefore advised. Surgical inspection revealed a laminated thrombus on the posteromedial occluder of the MV prosthesis (Panels E and F).A transoesophageal echocardiogram (TOE) revealed a non-mobile mass adjacent to the posteromedial occluder causing restricted opening and partial obstruction of the MVR (Panel G). Unveiling pro-thrombotic mechanisms is paramount for secondary prevention: surgical reconstruction of the papillary muscle head was performed alongside redo MVR surgery.We report partial thrombosis and obstruction of a mechanical MVR with inherently low thrombogenicity profile despite demonstrably adequate anticoagulation. We hypothesize that the unusual anatomical interaction between a high posterior papillary muscle head, thickened chords, and the MVR led to locally turbulent flow and thrombus formation in the posteromedial region of the prosthesis  on the atrial side of the mechanical mitral valve with the partial opening of the posteromedial leaflet due to an obstructive mass. Panel B: Continuous wave Doppler across the MV showing increased gradients. Panel C: Three-dimensional zoom showing completely obstructed posteromedial occluder and partially restricted anterolateral occluder due to enlarging mass (*) on the atrial side of the MVR. Panel D: Continuous wave Doppler showing worsening mitral stenosis across the partially occluded mechanical mitral valve. Panels E and F: Surgical inspection of the excised MV prosthesis revealed a laminated thrombus on the atrial surface  and ventricular one (F). Panel G: Three-dimensional zoom and 2D transthoracic echocardiography (three-chamber) image showing complex interaction between high posterior papillary muscle head (PPM), thickened chords, and a very close MVR (distance = double arrow) which likely led to turbulent flow locally and thrombus formation in the posteromedial region of the prosthesis."}
+{"text": "Endoscopic ultrasound-guided hepaticogastrostomy (EUS-HG) is increasingly being used as an alternative to percutaneous transhepatic biliary drainage (PTBD) after unsuccessful endoscopic retrograde pancreatography (ERCP). This technique has also been utilized for diagnosis of malignant biliary obstruction by providing biliary access for antegrade cholangioscopy with biopsies and brushings for cytology and fluorescent in situ hybridization (FISH). However, the potential impact of EUS-HG on surgical candidacy in cases with resectable disease remains unknown. We present three patients who underwent pancreaticoduodenectomy (Whipple procedure) for suspected distal malignant biliary obstruction following EUS-HG. Biliary drainage was achieved in all three patients preoperatively and a diagnosis of malignancy could be established in two of the three cases using this technique. There were no procedure-related complications. The HG metal stent was removed eight weeks post-operatively with cholangiogram showing a patent hepaticojejunostomy in all three patients. Mean length of follow-up after EUS-HG was 298 +/- 96 days. Our case series demonstrates that EUS-HG is an effective method to achieve biliary decompression in patients with an inaccessible papilla. The mature HG tract can subsequently be used to obtain a tissue diagnosis. Lastly, EUS-HG does not preclude patients from undergoing a curative Whipple procedure. In patients with malignant biliary obstruction, endoscopic retrograde pancreatography (ERCP) is the current standard of care for biliary decompression. However, ERCP is unsuccessful in 5-10% of cases due to surgically altered anatomy or tumor invasion causing ampullary distortion or gastric outlet obstruction ,3.\u00a0Endoscopic ultrasound-guided hepaticogastrostomy (EUS-HG) is emerging as a suitable alternative to PTBD in patients after failed attempt at ERCP. EUS-HG has been associated with\u00a0similarly high technical and clinical success rates with fewer reinterventions when compared to PTBD . In addiIn this case series, we describe EUS-HG in three patients with suspected malignant biliary obstruction after unsuccessful ERCP. EUS-HG achieved biliary decompression and assisted with tissue diagnosis but did not preclude future surgical intervention.Procedure detailAll EUS procedures were performed by a single endosonographer using a linear echoendoscope . A dilated segment 3 biliary radicle was identified from the lesser curvature of the stomach and punctured with a 19-gauge fine needle aspiration (FNA) needle . Contrast was injected resulting in opacification of the biliary tree. A 0.025 inch in diameter and 450 cm in length straight tip VisiGlide 2 wire (Olympus) was advanced past the left hepatic duct into the distal bile duct and the small bowel. The HG tract was dilated using a 6 mm x 4 cm Hurricane biliary dilating balloon  followed by placement of an 8 mm x 80 mm fully covered, self-expandable, and non-foreshortening Gore Viabil biliary stent . The metal stent was anchored using a 7 Fr x 18 cm double pigtail plastic biliary stent with the proximal end in the stomach and the distal end past the ampulla and in the small bowel  scan demonstrated slightly increased intra- and extrahepatic biliary ductal dilation compared to imaging one year prior. On ERCP, narrowing of the duodenal sweep was visualized with abnormal appearing duodenal mucosa Figure . The duoEUS-HG was then performed according to the above description. Cholangiogram on follow-up ERCP two weeks after EUS-HG showed a 10 mm long stricture in the distal common bile duct (CBD). Cholangioscopy  was performed antegrade through the HG tract and a high-grade stricture was visualized in the distal CBD with evidence of neovascularization.\u00a0SpyBite forceps (Boston Scientific) were unable to be advanced to the level of the stricture due to the acute angulation of the cholangioscope in the intrahepatic duct. Brushings were performed for cytology and FISH Figure .Cytology showed rare groups of highly atypical glandular cells, suspicious for adenocarcinoma. FISH was positive for malignancy of the pancreatobiliary tract. Patient then underwent successful pancreaticoduodenectomy (Whipple procedure) with simultaneous removal of plastic HG stent 55 days after EUS-HG. Surgical pathology confirmed extrahepatic cholangiocarcinoma  Figure .Follow-up ERCP was performed at eight weeks after the Whipple procedure. Cholangiogram through the HG tract showed a patent hepaticojejunostomy Figure .\u00a0The HG metal stent was removed and was not replaced. He subsequently was treated with adjuvant chemotherapy and radiation. Patient has had follow-up for 405 days after EUS-HG and is doing well clinically.\u00a0Case 2A 48-year-old female with history of obesity, chronic obstructive pulmonary disease (COPD), and prior cholecystectomy presented to hepatology clinic for evaluation of abnormal liver enzymes. Pertinent labs are noted in Table Two weeks post EUS-HG, patient returned for cholangiography and cholangioscopy through the HG tract. Cholangiography showed a high-grade stricture in the distal CBD with upstream ductal dilation Figure .Cholangioscopy with intraductal biopsies and brushings for cytology and FISH were performed and were suggestive of malignancy Figure .\u00a0Patient eventually underwent successful Whipple procedure with surgical pathology examination confirming locally advanced pancreatic adenocarcinoma (T1cN2). The HG metal stent was removed eight weeks post-Whipple without need for replacement. She was started on adjuvant chemotherapy post-surgery and is clinically doing well after 269 days of follow-up.\u00a0Case 3An 81-year-old female with history of COPD presented for evaluation of incidentally found abnormal liver enzymes. Labs are shown in Table Cold forceps biopsies of the mass later revealed an adenoma with no evidence of malignancy. On EUS, the common bile duct was dilated with extension of mass lesion\u00a0into the distal CBD and pancreatic duct (PD) for more than 1 cm Figure .The patient underwent successful EUS-HG in the same session without complication. Cholangiogram showed a dilated CBD measuring 17 mm with a high-grade stricture in the distal CBD Figure .\u00a0Given the size of the ampullary adenoma with extension into the distal CBD and PD, a decision was made to proceed with surgical management without the need for further diagnostic evaluation. She had a successful pylorus-preserving Whipple procedure 37 days after EUS-HG. Surgical pathology confirmed an ampullary tubulovillous adenoma with complete excision. After surgery, the HG metal stent was removed without necessitating replacement. Patient remains in good clinical condition after 219 days of follow-up.\u00a0ERCP can be technically unfeasible in patients with surgically altered gastrointestinal anatomy or tumor invasion causing distortion of the ampulla or gastric outlet obstruction. Traditionally, these patients have been managed primarily with percutaneous drainage. While PTBD has proven efficacious at achieving biliary decompression, it is burdened by substantial risk for adverse events and negative impact on patient quality of life ,3,5.\u00a0EUS-guided biliary drainage (EUS-BD) was first described in 2001 by Giovannini et al. as an endoscopic option for these patients . This teEUS-HG was first utilized for management of malignant biliary obstruction in 2003 . With thWhile the initial indication for EUS-HG was palliation of malignant biliary obstruction, its applications have since broadened to include treatment of benign biliary diseases. The HG tract can serve as a conduit for performing antegrade treatment of biliary lithiasis, benign strictures, and bile leaks . Stone rIn addition to assisting with antegrade therapies for benign biliary disease, the HG tract can also be used to aid in the diagnosis of suspected malignant biliary strictures. First, brushings can be performed with tissue sent for cytology and FISH. As reportedly previously, antegrade cholangioscopy can be also performed through the HG tract ,13-15. TWhile EUS-HG is now more widely used for biliary decompression in malignant obstruction, little is known about its potential impacts on surgery. A case series looking at EUS-CD for decompression as a bridge to surgery reported five cases of successful pylorus sparing Whipple procedure after EUS-CD . HoweverOur case series highlights the role of EUS-HG in suspected malignant biliary obstruction after unsuccessful ERCP. In each patient, successful biliary decompression was accomplished without adverse events. In two cases, cholangioscopy with biopsies and brushings for cytology and FISH helped in establishing a diagnosis of malignancy. In the third case, cold forceps biopsies demonstrated an ampullary adenoma with intraductal extension and hence diagnostic evaluation was not pursued. Lastly, EUS-HG did not impact surgical candidacy in any of the cases.EUS-HG is a safe and effective alternative to PTBD for biliary decompression when ERCP is not feasible. In cases of suspected malignant biliary obstruction, it also enables further diagnostic evaluation to be performed and does not preclude future surgical options."}
+{"text": "Clinicians in mental healthcare have few objective tools to identify and analyse their patient\u2019s care needs. Clinical decision aids are tools that can support this process.This study examines whether 1) clinicians working with a clinical decision aid (TREAT) discuss more of their patient\u2019s care needs compared to usual treatment, and 2) agree on more evidence-based treatment decisions.Clinicians participated in consultations (n=166) with patients diagnosed with psychotic disorders from four Dutch mental healthcare institutions. Primary outcomes were measured with the modified Clinical Decision-making in Routine Care questionnaire and combined with psychiatric, physical and social wellbeing related care needs. A multilevel analysis compared discussed care needs and evidence-based treatment decisions between treatment as usual (TAU) before, TAU after and the TREAT-condition.First, a significant increase in discussed care needs for TREAT compared to both TAU conditions  was found. Next, a significant increase in evidence-based treatments decisions for care needs was observed for TREAT compared to both TAU conditions .TREAT improved the discussion about physical health issues and social wellbeing related topics. It also increased evidence-based treatment decisions for care needs which are sometimes overlooked and difficult to treat. Our findings suggest that TREAT makes sense of ROM data and improves guideline-informedcare.No significant relationships."}
+{"text": "Community health workers (CHWs) play essential roles in implementing community-based behavioral lifestyle interventions. This qualitative analysis aimed to explore what program factors and CHW characteristics would help improve CHW performance in the Mobility and Vitality Lifestyle Program (MOVE UP), a community-based behavioral weight-management intervention for improving mobility among overweight or obese older adults. The MOVE UP program was implemented from January 2015 to June 2019 at 23 community-based sites in Pittsburgh, Pennsylvania. Trained and supported CHWs delivered 32 group sessions over 13 months. We collected data from semi-structured interviews with 21 CHWs and 14 community key informants (community site directors or coordinators); seven focus group discussions with participants from 9 sites, and 124 pieces of graduation advice provided by MOVE UP graduates for future participants; onsite CHW performance observation at 18 sites, and 124 meeting memos of support phone calls with CHWs. Interviews and focus groups were audio-recorded and transcribed verbatim. All data were thematically analyzed in a deductive approach, using the CHW generic logic model. Emerging themes were: Trained CHWs still require onsite support by experienced CHWs or training staff to deliver the first session; Participants need a Q&A session by specialists to address their questions beyond CHWs\u2019 knowledge; Desirable CHW characteristics could increase CHWs\u2019 relation and accessibility to participants, such as the same age group, similar weight loss experience, and living or working in the same community. These findings provide important insight as to recruiting and supporting CHWs in a community-based behavioral lifestyle intervention for older adults."}
+{"text": "Food insecurity has been indicated to associate with more depressive symptoms. Supplemental Nutrition Assistance Program (SNAP) is an established anti-poverty government program that targets food insecurity. The goal of this study was to assess whether SNAP generosity, defined at the state level, impacts the relationship of food insecurity and depressive symptoms among older Americans. We linked state-level SNAP policy data to the individual-level data of older adults (aged 60+) from the longitudinal Health and Retirement Study . Our study baseline was survey year 2000. A state is considered SNAP generous when it eliminates income/assets limit from its SNAP eligibility criteria. All HRS participants reported their food insecurity status and depressive symptoms biennially. Participants were followed until 2018. We conducted state fixed-effect models adjusted for demographic and health measures. Results indicate household food insecurity was associated with higher risk of elevated depressive symptoms  from a fixed effect logistic model, and this effect was stronger when living in non-generous states compared with generous states though confidence intervals were too wide to be conclusive . The relative excess risk due to interaction (RERI) was 0.17 . Our study finding suggested that there is no to weak evidence that state-level SNAP generosity may alleviate or offset the risk of depressive symptoms associated with food-insecurity."}
+{"text": "Inclusion of nanoparticles boosts thermal performance and is essential for thermal transport. The current investigation has been made to conduct research on heat mass transport in synovial material with the mixing of hybrid and tri-hybrid comprising variable viscosity past over a heated surface having constant density and a steady environment. The conservation laws have been considered in the presence of Lorentz force, heat generation/absorption, modified heat and mass fluxes together with chemical reaction. The mathematical model is developed in Cartesian coordinate in the form of coupled partial differential equation (PDEs). The derived PDEs are simplified by a boundary layer approach (BLA) and reduced PDEs have been converted into ordinary differential equation (ODEs) using scaling group Similarity transformation. The converted ODEs are highly nonlinear and have been solved numerically by finite elements scheme (FES). The used scheme is effective for nonlinear problem and can be frequently utilized to tackle nonlinear problems arising in mathematical physics. They have used FEM to know numerical results of model related to non-Fourier\u2019s along with variable viscosity. Sohail et al.2 performed model of Sutterby fluid inserting suspension of nanomaterial along with thermal radiation past stretching surface in the presence of variable fluidic properties. They have used a numerical approach to conduct consequences. Nazir et al.3 conducted numerical impacts of Carreau\u2013Yasuda martial in mass species and thermal energy inserting hybrid nanomaterial under the occurrence of thermal properties numerical implemented by finite element approach. Sohail et al.4 computed boundary layer flow regarding Carreau martial in heat energy in a disk considering bio-convection phenomena. They have implemented numerical method to investigate numerical results. Nazir et al.5 performed the thermal enhancement of ternary hybrid nanoparticles in Sisko martial involving heat generation over stretchable cylinder. They implemented FEM and include the tri-hybrid nanomaterial was significant the best performer to enhance heat energy. Imran et al.6 investigated the performance of shapes impacts into hybrid nanoparticles past flat frame considering solar collector. Imran et al.7 studied the impacts of thermal radiation and magnetic field including variable fluidic properties and slip conditions past a vertical heated frame. Danish et al.8 conducted numerical consequences of Williamson liquid inserting nanoparticles in the presence of thermal radiation and activation energy. Chen et al.9 discussed enhancement regarding heat energy in Maxwell liquid in the presence of titanium oxide and alumina oxide in rotating disks. Sohail et al.10 studied features of non-Newtonian liquid in heat energy using Joule heating and heat flux approach. Mebarek-Oudina et al.11 studied two heat energy sources in mixed convection phenomena in a trapezoidal cavity using moving walls. Chabani et al.12 investigate heat energy enhancement in triangular enclosure considering suspension regarding hybrid nanoparticles involving elliptic obstacle. Fares et al.13 investigated the performance of entropy generation in magnetized flow in the presence of Darcy\u2013Forchheimer model using base liquid (silver and water) in a square enclosure. Abo-Dahab et al.14 securitized MHD features in Casson liquid considering nanoparticles involving dual behaviors of surface (suction and injection) past stretchable surface. Mebarek-Oudina et al.15 discussed applications of nanoparticles in heat energy mechanism using various enclosures. Dhif et al.16 investigated the performance of hybrid nanofluids in solar collectors in this study. Zamzari et al.17 studied mixed convection in a vertically heated channel to determine various aspects of entropy production. Using this method, multiple aspects of entropy production were examined to determine how they were affected. Li et al.18 determined the flow and thermal properties of a Darcy\u2013Forchheimer fluid using a non-Fourier method and a Prandtl method. To achieve this objective, nanoparticles were incorporated into a Darcy\u2013Forchheimer motion. Klazly et al.19 studied comparative consequences among non-Newtonian for single-phase and Newtonian for single-phase containing nanoparticles in the presence of two-phase models in backward-facing step. Klazly et al.20 developed empirical equation to visualize viscosity of nanofluid involving empirical and theoretical results. Bogn\u00e1r et al.21 investigated comparative consequences among fluid dynamics and similarity in Blasius flow considering nanoparticles. Thriveni and Mahanthesh22 discussed features based on convective heat transfer in hybrid nanofluid considering in two cylinders. Mackolil and Mahanthesh23 estimated thermal energy associated with Marangoni approach in hybrid nanofluid including sensitivity analysis. Mahanthesh24 discussed features regarding quadratic radiative flux containing nanoparticles in the presence of enhancement of kinematics regarding nanoparticles. Mahanthesh et al.25 performed new investigation based on quadratic Boussinesq approximation and quadratic radiation involving nanofluid. Shruthy and Mahanthesh26 computed Rayleigh-B\u00e9nard in rheology of Casson liquid inserting suspension of hybrid nanoparticles. Shalini and Mahanthesh27 discussed performance of dusty nanoparticles in Newtonian martial considering suspension of nanoparticles in the presence of coriolis force.Researchers got much attention on studying nanoparticles to boost thermal performance. Nanoparticles are immersed in different materials (base fluid) to improve thermal performance. Nanomaterial plays a vital role in the treatment of cancer therapy and is frequently used in industries in different physical processes. Several studies have been conducted on nanomaterial for thermal and mass transportation. For instance, Nazir et al.Comprehensive review on literature demonstrates that study on mass species and heat energy in the presence of Cattaneo-Christov heat flux model (CCHM) along with chemical reaction and heat absorption in synovial fluid is not investigated yet. Such complex model involving suspension of three types of nanoparticles considering two viscosity models is not studied yet. Additionally, hybrid nanomaterial and tri-hybrid nanomaterial are inserted in ethylene glycol. Present model is numerically solved by finite element method (FEM). Analysis is divided into five sections. Section one, section two, section three, section four and section five are based on literature review, mathematical procedure, numerical method and conclusions, etc.Model regarding mass and heat energy transport in synovial fluid is developed for constant density and steady flow past a stretching surface. Viscosity is considered as function temperature and concentration. Suspension of tri-hybrid nanoparticles into fluidic motion is made composite of silicon dioxide, titanium oxide and aluminum oxide in the presence of base liquid named ethylene glycol. Fluidic motion regarding various nanoparticles is produced with the help of wall velocity. Heat and energy solute particles are carried out using concept of non-Fourier\u2019s law including heat generation/absorption and chemical reaction. Figure\u00a0The concept of BLA (boundary layer approximations) are used to achieve system of PDEs areMomentum equation for Model-I which isMomentum equation for Model-II which isThe required BCs of current analysis areSimilarity variables are delivered asThe Correlations of hybrid nanoparticles and nanoparticles are used and Table A system in term of ODEs is derived asEquation\u00a0 is reducSkin friction coefficients for two models in term of viscosity areConcentration rate and heat energy rate are Desired residuals are known as weighted and residuals are integrated over each elements regarding computational domain;The integration process is implemented for development of week form regarding residual equations and mesh free survey is shown through Table Stiffness elements are obtained via residual procedure called Galerkin approximations;Measure tolerance and error procedure. Table Numerical solution of dimensionless ODEs is achieved using finite element method (FEM) which is presented with the help of Fig.\u00a0Comparative features in term of two viscosity models are studied over a 2D stretchable sheet. A non-Fourier\u2019s approach is considered in energy as well as concentration equation. Heat source and chemical species are addressed. Additionally, suspension of various nanoparticles  is inserted in base fluid) termed as ethylene glycol. The productive complex biological model is numerically handled using a finite element approach. Detail reports and discussion are mentioned below.In the current subsection, acceleration into fluidic particles is measured in Figs.\u00a0The comparative thermal features are estimated versus time relaxation, heat source parameters for model-I and model-II considering in Figs.\u00a0Figures\u00a0mentclasspt{minimamentclasspt{minimaImpacts of Sherwood number, heat transfer rate and skin friction coefficient are predicted versus variation in Weissenberg, heat source, magnetic and Schmidt numbers. These visualizations are recorded in Table Velocity profile is declined using higher numerical values of magnetic field intensity based on Lorentz force.Velocity profiles for model-I have less magnitudes rather than magnitudes for velocity profiles for model-II.External heat source brings enhancement into thermal energy and flow behavior.Cooling process thermal process can be achieved significantly by using mechanism of ternary hybrid nanofluid rather than mechanism of hybrid nanofluid.Production of mass species and thermal energy for case of model-II as compared for model-I.Mass diffusion decreases versus impacts of chemical reaction number and Schmidt number.Current development is applicable in biological field which is used in condyloid joints, hinge joints, pivot joints.Such complex analysis is applicable in biological field which is used in condyloid joints, hinge joints, pivot joints and shoulder joints.Comparison thermal aspects and solute aspects among model-I and model-II including tri-hybrid nanomaterial are observed past stretching frame. Heat energy and diffusion into mass species are carried out by non-Fourier\u2019s approach. Additionally, heat source and chemical species are implemented. Such complex problem is developed and numerical tackled by finite element approach. Main finding of such complex problem are mentioned below."}
+{"text": "The COVID-19 pandemic introduced many societal changes, including the need to use technology to communicate with healthcare providers. For many this was a new form of communication. This study examines (1) who older adults identified as healthcare providers and (2) reflected on how communications with formal healthcare providers changed during the pandemic. This data is a subset of a cross-sectional descriptive survey that was distributed electronically to a sample of community-dwelling older adults aged 65 years and older (N=323). Qualitative data was analyzed using thematic analysis. Quantitative data was analyzed using descriptive statistics. Participants averaged 72.7 years of age and 74.5% were retired. Just over \u00bc of the sample identified nurses as part of their formal healthcare team; however, participants who identified nurses as formal healthcare providers had fewer negative themes regarding telehealth communication with healthcare providers compared to those who did not. They were also more likely to support in-person and technology driven communication models in the future. Telehealth remains an evolving form of primary healthcare that was utilized throughout the COVID-19 pandemic. Many older adults in our study considered it a resource that requires further optimization while others were staunch opponents to its continued employment in healthcare settings. Nurses are a vital part of our healthcare system and frequently interact with patients and families to coordinate care. Further research should examine how different scopes of nursing practice can support the implementation of telehealth to improve care delivery among community-dwelling older adults."}
+{"text": "Mental health disorders have become one of the leading diagnoses causing sickness absence. Previous studies have examined the impact of single employment characteristics or working conditions on sickness absence. However, few studies have investigated the effect of a multidimensional construct of precarious employment on sickness absence. Therefore, this study aims to describe sickness absence due to common mental disorders (CMD) as a proxy for access to social security benefits among precarious and non-precarious workers with mental health problems.Cohort register-based study of the total Swedish population aged 27 to 61 years residing in Sweden in 2016 and having mental health problems defined as being prescribed Selective Serotonin Reuptake Inhibitors (SSRI) in 2017 . Individuals were classified as precariously employed or not based on a precarious employment score measured multidimensionally in 2016 . The outcome was the incidence of the first sickness absence episode due to CMD co-occurring with SSRI treatment in 2017. Logistic regression models will be performed.The following results are preliminary. Precariously employed treated with SSRI were 8,68% in 2017. The distribution of a first sickness absence episode due to common mental disorders was similar in precarious and non-precarious workers . Individuals directly employed (12.20%), with multiple jobs holding (14.62%), and low-medium income levels (14%) had higher sickness absence incidence due to common mental disorders. There were slight differences by gender.In these preliminary results, no differences were found between precarious and non-precarious workers with mental health problems in the distribution of sickness absence due to CMD. Further analysis will be conducted to investigate whether precarious employment is associated with sickness absences.Sickness absence due to common mental disorders is similarly distributed among precarious and non-precarious workers.Individuals with multiple jobs, low-income levels, and directly employed show higher sickness absence incidence due to common mental disorders."}
+{"text": "Proactive coping helps to reduce stress \u201cin advance\u201d \u2013 by possible stressors\u2019 anticipating . Does it helps to reduce distress in hazardous work environment with extremely high uncertainty level \u2013 like in healthcare professionals\u2019 work at the beginning COVID-19 pandemic? Data showed the lover level of proactive coping in healthcare professionals in comparison with non-medical group . The acute issue is to investigate proactive coping among medical professionals with different stress level.Specialists of Moscow public dispensaries  were checked during pandemic breakout (April 2020) - in order to compare proactive coping and job stressors\u2019 subjective evaluation in groups with high and low chronic states.The diagnostic set included: the job stress survey ; the proactive coping inventory ; the chronic stress and fatigues inventories .Cluster analysis by combination of stress-fatigue scores extracted equal 22% of professionals in risk subgroups. Surprisingly no proactive coping differences were found in nurses; among doctors preventive coping is significantly lower in risk subgroup . Revealed job stressors in risk groups for nurses are quite typical; but for doctors they are unusual: extreme workload , low coworkers support , lack of positive feedback .Despite the undeniable workload increase, well-to-do professionals perceived no high job stressors. In risk subgroup with lack of preventive coping, perceived stressors are likely connected with inability to predict strain increase and to minimize the impact of its negative effects ."}
+{"text": "A low-income country, Moldova is facing a rapidly growing burden of non-communicable diseases with a cardiovascular disease mortality rate of 202.2 per 100'000. Scarce resources require urgent preventative actions and involvement of communities and patients in the definition and design of locally relevant health promoting activities. Our intervention is a holistic, whole-of-community approach to foster local leadership in health promotion for the prevention of cardiovascular risks. The Healthy Life project to reduce the burden of non communicable diseases, funded by the Swiss Agency for Development and Cooperation (SDC), operates since 2016 in rural communities of Moldova. We present a 5-step model towards initiating Healthy Communities in Moldova based on 5 complementary steps:1. Raising awareness on cardiovascular risk factors through community education seminars tailored to audience needs2. Building multisectoral community coalitions for health between local elected leaders and community representatives around local health data and locally defined health priorities3. Fostering community leadership in defining local health solutions through health asset mapping exercises4. Community-led small projects based on identified needs and assets to improve local cardiovascular health5. Empowering chronic patients for healthy behavior change through community-based self-management workshopsThe Healthy Communities intervention was rolled out to 40 communities in 20 districts, reaching 1332 direct beneficiaries. Important learning emerged from social accountability mechanisms embedded in community coalitions which ensure regular, health-focused dialogue on community health. Using local assets to health problem solving is changing the perspective on the resourcefulness of community actors in health. Progress towards sustainability is achieved by local public authorities and community making a matching contribution to start-up funding to small projects.\u2022\u2002Our Healthy Communities model proposes a strength-based vision of health promotion which empowers community coalitions to self-organize for the prevention of cardiovascular risk factors.\u2022\u2002We promote bottom-up approaches that strengthen local health governance and community leadership into defining and addressing local health priorities."}
+{"text": "Adolescents with major depressive disorder (MDD) often show reduced prefrontal functional connectivity with the subcortical regions than healthy controls (HC) . However, relatively little is known about longitudinal effects of antidepressant (AD) treatment on resting state functional connectivity (RSFC) in the prefrontal cortex (PFC).This study aimed to investigate abnormal PFC RSFC in MDD adolescents compared to HC and longitudinal effects of AD on PFC RSFC.This study included 59 adolescents with MDD and 43 HC. MDD adolescents were treated with escitalopram in an 8 week, open-label trial. The treatment outcome was assessed by Children\u2019s Depression Rating Scale (CDRS-R) and patients showing at least a 40% improvement in CDRS-R scores from baseline to week 8 were defined as \u201cresponders\u201d. Functional and T1 images collected before and after treatment were processed using AFNI and Freesurfer. Our seed was the lateral PFC . T-tests and repeated measures ANCOVAs, controlling for age and IQ, were conducted to examine abnormal PFC RSFC and longitudinal effects of AD on LPFC RSFC.Relative to HC, MDD showed increased LPFC RSFC with the posterior middle temporal gyrus (pMTG) and superior frontal cortex (SFG) involved in attentional networks. Responders showed greater changes in LPFC RSFC with the MTG and SFG after AD treatment compared to non-responders and HC .Our finding suggests that reduced LPFC RSFC with the pMTG and SFG reflecting decreased attentional network connectivity may serve as a biomarker to predict AD treatment outcome in adolescents with MDD.No significant relationships."}
+{"text": "What do patients talk during a clinic evaluation? What do they report besides referring physical complaints? It is crucial to value \u2019hidden\u2019 symbolic issues under a conversation between patient and his/her doctors and nurses. Elderly people are at increased risk of developing Chronic Obstructive Pulmonary Disease (COPD) that requires the management of associated emotions. In advanced stages, they need to use Long-term Home Oxygen Therapy (LTOT) as part of treatment. Patients perceive difficulties with its use, generating anguish.To explore meanings of emotional experiences as reported by patients regarding LTOT, seen in a public university outpatient service.Qualitative design. Semi-directed interviews with open-ended questions were carried out with seven elderly patients at Pulmonology Outpatient Clinic at General Hospital at University of Campinas, diagnosed with COPD and using LTOT in period 2019 to 2020. Data were analyzed using Content Analysis with the support of Webqda software. COREQ checklist was used.Three categories emerged from interviews: (1) Changes of self-image perception with great dissatisfaction in not recognizing their selves physically. (2) Sadness with social isolation and feelings of awkwardness regarding themselves. (3) Affective aspects bringing the need to re-mean old family supports.Simply listening to reports of emotional complaints implies only a description of a clinical condition of the psychic sphere. Elderly patients with COPD bring psychological representations of their clinical condition that call for a symbolic interpretation. If such patients become aware of hidden meanings, they can better manage their fears and other uncomfortable feelings.No significant relationships."}
+{"text": "There have been numerous efforts to increase workforce participation among Medicaid beneficiaries in an effort to reduce program costs. We know little, however, about whether Medicaid beneficiaries with low workforce participation live in communities that support employment. The purpose of the current study was to determine if community disadvantage was associated with workforce participation among late middle-aged Medicaid beneficiaries, an age group that commonly faces difficulty entering the workforce. Participants were 1418 Medicaid beneficiaries ages 51-64 who participated in the 2016 wave of the Health and Retirement Study, a population-based study of community-dwelling adults aged >50. Community disadvantage was measured using the Social Vulnerability Index (SVI). We evaluated the association between community social vulnerability and reduced workforce participation (defined as working < 20 hours per week). We performed additional analyses to determine if the association between community disadvantage and reduced workforce participation was driven by any one of four subthemes of the SVI:(1) community socioeconomic status, (2) household composition/disability, (3) minority status & language and (4) housing type & transportation. Community disadvantages was associated with reduced workforce participation . Analyses by SVI theme showed that the association between community disadvantage and reduced workforce participation was largely driven by community socioeconomic status (SES). Those living in low SES communities were more likely to report reduced workforce participation than those living in high SES communities: . Policy interventions that focus on disadvantaged communities are likely needed to improve employment rates among late middle-aged Medicaid beneficiaries."}
+{"text": "Homebound persons living with dementia (PWD) require healthcare services that proliferate with physical and cognitive changes over time. PWD often experience fragmented care that results in poor health outcomes and delayed healthcare access. The objective of the Virginia at Home Program (VaH), a recently initiated home-based primary care (HBPC) program, is to promote long-term sustainability and proliferation of HBPC. The study purpose was to examine the impact of VaH on the overall care and outcomes of homebound PWD and their families. We used quantitative and qualitative methods to describe the impact of VaH on patient care and outcomes over six months. We compared clinical outcomes  at baseline and six months using paired t-tests. We also conducted semi-structured phone interviews at baseline and six months with PWD-caregiver dyads. Thirty PWD-caregiver dyads enrolled. Of the 17 dyads that completed both visits, PWD\u2019s physical function and caregiver\u2019s burden decreased significantly over time (ps < .05). There was a significant improvement in PWD\u2019s behavioral symptoms over the six-month period (p=.03). Three preliminary themes emerged from qualitative data: 1) participants established trusting relationships with the VaH team, 2) VaH supported caregivers in their caregiving responsibilities, and 3) participants met their pre-program goals through increased healthcare access. Findings suggest that the HBPC intervention improved care satisfaction and healthcare access and alleviated caregiver burden. Future studies should consider introducing HBPC programs in this hard-to-reach population to decrease acute care utilization and health care costs while improving care satisfaction and quality."}
+{"text": "There are no current established guidelines for the role of antimicrobial suppression therapy in management of prosthetic joint infection (PJI). In 2013, the IDSA provided initial treatment guidelines for PJI but did not address suppressive therapy. The guidelines do not address suppressive therapy beyond the initial 4-6 weeks for non-staphylococcal infections nor do they address suppressive therapy after 3-6 months of treatment for Staphylococcal infections. Practitioners must delicately balance the risk of PJI recurrence and the negative effects of continued antibiotic therapy including toxicity and resistance. In this study, we surveyed Infectious Disease providers to better understand their antimicrobial suppression practice patterns in different clinical scenarios.We surveyed Infectious Disease providers across the United States from April 2022 to May 2022. We received 78 unique response from 31 different states. Basic demographic data was obtained. Providers presented six multiple choice clinical scenarios and were asked if they would start suppressive therapy and the duration of suppressive therapy.The preliminary data revealed that practice patterns vary greatly amongst providers in the management of antibiotic suppressive therapy in PJI. Of the 6 scenarios, only half had greater than 50% consensus . Scenario 1 involved a patient who underwent a single stage revision. It was of particular interest as 51.3% of providers indicated they would stop antimicrobial therapy and 48.7% indicated they would extend antimicrobial therapy with 25.6% electing for lifelong suppressive therapy.Practice patterns for antimicrobial suppression therapy in knee PJI varies significantly among providers. Even with IDSA guidelines addressing Staphylococcal PJI, the practice patterns among infectious diseases providers still varied greatly especially with regards to single stage revisions. Additional randomized controlled trials examining the best way to manage antimicrobial suppression in PJI would be helpful, and would allow for development of evidence-based guidelines. We also plan to survey orthopedic surgeons using the same clinical scenarios to see if there is a difference in management styles.All Authors: No reported disclosures."}
+{"text": "Many people suffering from psychotic disorders report persistent auditory verbal hallucinations (\u2018voices\u2019) despite pharmacological and psychological therapy. Interest is growing in approaches that emphasise the personal relationship between the patient and their voice(s). AVATAR therapy is one such approach that uses a digital representation (avatar) of a selected voice to facilitate a three-way discussion between patient, therapist and voice, the therapist speaking either as him/herself or in the digitally transformed voice of the avatar. Objectives: To describe AVATAR therapy and an ongoing multi-centre clinical trial. Methods: Encouraging findings from an earlier controlled trial (AVATAR1) comparing AVATAR therapy and supportive counselling informed our current multi-site cost-effectiveness trial of brief and extended versions of the therapy compared to treatment as usual (AVATAR2). Results: AVATAR1 delivered in 7 weekly sessions resulted in a reduction in the frequency, distress and power of voices that was significantly superior to supportive counselling. Clinical experience suggested that some participants improved in response to the early focus on anxiety while others seemed more responsive to later more formulation-driven approach. These findings led us to the current ongoing three arm clinical trial comprising a brief (6 session) focus on anxiety/assertiveness, an extended (12 session) formulation-driven approach both approaches compared to treatment as usual. Conclusion: Previous AVATAR studies suggest this is a therapy with considerable promise. It can be delivered through widely available laptop computers, usually in clinic but also remotely via existing commercial platforms. The current trial will address questions about dissemination, training and cost-effectiveness in NHS settings.The digital technology employed in AVATAR therapy is provided by licence for the trial from Avatar Therapy Ltd"}
+{"text": "As the pandemic continues to spread worldwide, many of healthcare facilities are exploring new methods to keep their patients safe from potential hospital-acquired infections (HAIs) during the pandemic. This study explored the attitudes about artificial intelligence (AI) among providers who utilized AI-based hand hygiene monitoring system (HHMS) at a rural medical center during the pandemic.A self-administered questionnaire was mailed to 48 healthcare providers at a rural medical center in north Texas, with a 75% percent response rate (n = 36). The survey collected information on providers attitudes about AI-based HHMS use. In addition, the study also examined the relationship between provider\u2019s well-being and the level of satisfaction with the AI-based HHMS use. The lessons learned from this study will be used to determine important factors to consider when attempting to advance and expand AI technologies in rural healthcare settings.Results revealed that the integration of AI technology within the existing electronic health record (EHR) system remains a challenge for many providers. Plus, the lack of user-centered design approaches to incorporate the AI tool into existing workflows has reduced providers satisfaction about the new technology.The findings suggested that although AI technology has great promise to reduce the number of hospital-acquired infections (HAIs), successfully implement of an AI-based tool that meets the expectations of users requires significant levels of consolidation to ensure that it fits within the existing workflows and is accepted by users.\u2022\u2002AI application indirectly affects the well-being of providers, particularly in rural healthcare settings.\u2022\u2002A better AI application interface design that meets the expectations of providers is needed."}
+{"text": "A fifteen-year-old male patient sustained a posteriorly dislocated right capital femoral Delbet type Ib epiphyseal fracture-separation and a right acetabular posterior column fracture after a low-energy trip and fall. The capital femoral epiphysis was closed reduced and fixed with cannulated screws on an urgent basis. He underwent acetabular osteosynthesis via a Kocher-Langenbeck approach two days thereafter. Twenty-two months after injury, he was weight-bearing on the right lower extremity without radiologic evidence of avascular necrosis or clinical evidence of pain or functional deficit.  Fracture-separation of the capital femoral epiphysis comprises only 8% of skeletally immature femoral neck fractures in the Delbet and Colonna classification. Prognosis is worse with ipsilateral hip dislocation due to the risk of avascular necrosis from disruption of the medial femoral circumflex artery. Urgent referral to a trauma center and treatment by appropriate specialists enables good long-term results after this uncommon traumatic injury pattern. Acetabular fractures in skeletally immature patients are relatively rare. In a review of over 7,000 patients in the German Pelvic Trauma Registry, only 153 patients were less than fourteen years old , of which only fifteen (9.8%) sustained acetabular fractures .Traumatic hip dislocations are more common than acetabular fractures in the pediatric population and often associated with sports activities or high-energy trauma; a case series of six patients from Turkey in 2014 included five posterior hip dislocations, one of which involved a transepiphyseal fracture . In a 19Delbet and Colonna classified fracture-separation of the capital femoral epiphysis as a rare lesion accounting for just eight percent of femoral neck fractures in skeletally immature patients  of the pelvis and right femur  showed aThe patient was taken urgently to the operating room on the day of presentation by a pediatric orthopaedist (R.C.) for closed manipulation and reduction using axial traction. Given the low energy mechanism and resultant posteroinferiorly displaced capital femoral epiphyseal fracture-separation, and the absence of any epiphyseal fragments remaining attached to the distal femoral neck fracture fragment, the displaced physeal fracture-separation was closed reduced with minimal manipulation. The reduced capital epiphysis was percutaneously stabilized with two 6.5\u2009mm cannulated screws . The femThe patient then returned to the operating room on hospital day two for open reduction and internal fixation of the right acetabulum  via a KoAt the two-month follow-up, he was no longer following weight-bearing restrictions and he and his mother reported no pain or functional deficit. Radiographs  revealedOur report demonstrates that urgent reduction and pinning of an acute Delbet Ib displaced capital femoral epiphysis with concurrent reduction of the displaced hip joint, closely followed by osteosynthesis of the acetabulum, is a feasible treatment option for this uncommon traumatic injury pattern if referred in a timely fashion to a trauma center with an available specialist or specialists adept at caring for those injuries.Van Nortwick et al. performed a Ganz osteotomy to repair a posterior transphyseal SH III hip fracture-dislocation in a thirteen-year-old male; he had no osteonecrosis or functional limitations at two-year follow-up . MehlmanShaath et al. reported a case of a thirteen-year-old female who sustained a transphyseal SH I femoral neck fracture and posterior hip dislocation with ipsilateral transverse-posterior wall acetabular fracture; intraoperatively, several incarcerated articular fragments were removed from the hip joint and she underwent open reduction and internal fixation of the acetabulum and femoral neck . After tThese previous similar cases and our case demonstrate that timely surgical intervention with appropriate subspecialist consultation can provide excellent outcomes in complex pelvic and acetabular traumatic injuries. In particular, this case demonstrates that staged surgical intervention can lead to excellent long-term outcomes after a traumatic acetabular injury.Limitations of this case report include the inability to obtain close follow-up due to pandemic-related outpatient visit restrictions. However, this patient's case shows that pediatric patients can achieve good long-term results with return to all activities."}
+{"text": "Frailty is a key hallmark of aging and exercise has been shown to delay aging effects. This study was initiated based on the hypothesis that voluntary wheel running (VWR) starting at 12 mo until 18 or 22 mo of age would benefit the female murine musculoskeletal system. Based on the final body weight, the mice were separated into high (HBW) and low body weight (LBW) subgroups. Beneficial effects of VWR were observed on soleus muscle mass and contractile force at both ages, although HBW led to greater increases at 22 mo. VWR increased fiber cross-sectional area by 20%, leading to more type I and fewer IIA fibers in soleus. HBW mice were resistant to age-related decline in Extensor digitorum longus (EDL) mass and contractile force. EDL in 18 mo HBW also showed 15% higher contractile force following VWR while muscle from 18 & 22 mo LBW responded to VWR with greater osteocyte protective factor secretion. Skeletal adaptation to VWR was also dependent on body weight, with HBW showing higher femoral cortical thickness and area under sedentary conditions. VWR maintained osteocyte dendrite number in HBW. VWR increased periosteal and endosteal circumferences in HBW, suggesting compensation for loss of material strength. Consistent with this, VWR maintained higher bone mechanical properties in 18mo LBW. In summary, VWR alters musculoskeletal parameters depending on body weight with HBW contributing to more muscle mass and strength to prevent sarcopenia while bone retains better mechanical properties in LBW but HBW contributes structural modification to prevent osteopenia."}
+{"text": "Codetta is a Python program for predicting the genetic code table of an organism from nucleotide sequences. Codetta can analyze an arbitrary nucleotide sequence and needs no sequence annotation or taxonomic placement. The most likely amino acid decoding for each of the 64 codons is inferred from alignments of profile hidden Markov models of conserved proteins to the input sequence.http://eddylab.org/software/codetta/codetta2.tar.gz and at http://github.com/kshulgina/codetta.Codetta 2.0 is implemented as a Python 3 program for MacOS and Linux and is available from Bioinformatics online. Almost all of life uses the same decoding scheme; however, dozens of clades have evolved alternative genetic codes where the meaning of one or more codons is changed  and predicts the genetic code from coding regions with recognizable homology. For each codon, the best amino acid meaning is selected; thus, Codetta can detect canonical stop and sense codons with new amino acid meanings (i.e. stop-to-sense and sense-to-sense reassignments). Codetta does not predict termination codons and cannot detect sense-to-stop reassignments.Codetta performs three main steps, in order:Alignment. A preliminary six-frame standard genetic code translation of the input sequence is aligned to profile HMMs of conserved proteins using the HMMER hmmscan program  and 82 mitochondrial genomes with 18 alternative genetic codes affecting 14 different codons (27 Kb average genome size). For the mitochondrial comparison, we used a custom-built profile HMM database of mitochondrial proteins to demonstrate usage of the custom profiles feature; we also repeated the Codetta analysis with Pfam. Complete results and a breakdown of per-codon prediction accuracy are provided in -r option).Genetic code prediction requires high sensitivity to find rare codon reassignments but also a high positive predictive value (PPV) to avoid overwhelming predictions with errors. To assess how well Codetta and FACIL predict codon reassignments, we identified codon predictions that differed from the standard genetic code (predicted codon reassignments) and compared to the annotated genetic code to determine if they are correct . For theIn the mitochondrial test set, Codetta predicted three sense codon reassignments that we counted as errors in In btac802_Supplementary_DataClick here for additional data file."}
+{"text": "Older Chinese Americans face many socioeconomic barriers including limited English proficiency, low educational levels, and limited access to care. These socioeconomic disadvantages not only contribute to an increased risk of developing dementia but also worsen inequitable access to effective strategies to promote cognitive health. Cognitive training is shown to be beneficial to maintain or enhance cognitive function. However, most prior interventions were tested exclusively in non-Hispanic Whites. To address this gap, we aim to adapt empirically supported cognitive training activities into a culturally and linguistically relevant mHealth cognitive training intervention. The adaptation process of the cognitive training includes focus groups (n=6/group) with older Chinese Americans (3 groups) and adult children (2 groups) to adapt cognitive training components to our target population. We will then organize an experience-based co-design workshop to further refine the intervention. Engaging end-users early will optimize the development of a culturally and linguistically relevant cognitive training intervention."}
+{"text": "Although largely preventable, tooth decay  is among the most common health conditions worldwide and contributes to substantial dental treatment expenditures. While Fluoride Toothpaste (FT) is considered an essential strategy for oral health prevention, its market price has been shown to vary substantially across various settings. Against this background, the present study aimed to develop a decision analytical model to evaluate the cost-effectiveness of FT in various settings.Leaning on WHO CHOICE methodology, evidence scoping and an expert consensus were facilitated to extract model input parameters which were then fed into cost-effectiveness-analyses (CEA) for FT. The cost-effectiveness of the interventions was expressed as cost per Disability-Adjusted Life Year (DALY) averted.The CEA identified a high likelihood for FT to be a cost-efficient treatment strategy in settings with comparably low market prices for FT. FT was less likely to be a cost-efficient treatment strategy in settings with comparably high market prices for FT.The developed decision analytical model is suitable to inform policymakers about the extent to which FT represents good value-for-money under different market prices.\u2022\u2002Fluoride toothpaste can provide high value for money as an oral health preventive strategy.\u2022\u2002Policymakers need to ensure the affordability of fluoride toothpaste in order to harvest relevant efficiency gains."}
+{"text": "In pairwise comparisons, postgraduate education was associated with more positive attitudes towards relapse risk (p\u2009=\u20090.004) when compared to diploma-educated respondents. No significant associations were observed between years of clinical experience and participant responses. Our findings highlight important aspects of clinician attitudes that could improve harm reduction education and integration into clinical practice.Stigma and other barriers limit harm reduction practice integration by clinicians within acute psychiatric settings. The objective of our study was to explore mental health clinician attitudes towards substance use and associations with clinical experience and education level. The Brief Substance Abuse Attitudes Survey was completed among a convenience sample of mental health clinicians in Vancouver, British Columbia. Five predefined attitude subgroups were evaluated. Respondents\u2019 attitudes towards substance use were associated with level of education on questions from two (non-stereotyping [ North America is currently in the midst of an unprecedented opioid epidemic. The number of opioid-related deaths is rising steadily across Canada, with the highest mortality rate occurring in British Columbia . Many inIndividuals with both psychiatric and substance use issues are at increased risk for drug-related death , especiaGiven the disconnect between the scientific evidence for and the resistance to harm reduction among health care providers, it is critical to examine how clinician attitudes towards substance use influence the harm reduction best practices in psychiatric settings. The objective of our study was to explore mental health clinician attitudes towards substance use and associations with clinical experience and education level.n\u2009=\u200971) of mental health clinicians  between May and June 2022 at a tertiary care hospital in Vancouver, British Columbia. Participants were recruited via email based on internal distribution lists and informed consent was obtained electronically. Eligible participants were employed fulltime, parttime or casual within the hospital and had at least one year of experience in an acute psychiatric setting. The survey included socio-demographic questions  and the 25-item Brief Substance Abuse Attitudes Survey (BSAAS). The BSAAS [p values for multiple comparisons. Statistical analyses were performed using SAS version 9.4. Ethics approval was obtained from the Providence Health Care/University of British Columbia Review Board.We conducted an online cross-sectional survey among a convenience sample , were employed as nurses (48%), with bachelor\u2019s (44%) or master\u2019s (23%) level education and fewer than ten years of experience in their primary clinical role (71%) (Table p\u2009=\u20090.012) and treatment optimism (p\u2009=\u20090.008) (Table p\u2009=\u20090.004) when compared to diploma-educated respondents. In contrast, no pairwise effect was observed between education type with respect to propensity for hard drug use (p\u2009=\u20090.310) within the non-stereotyping subgroup. No significant associations were demonstrated between years of clinical experience and attitudes towards substance use  that could improve harm reduction education and integration into clinical practice.Prior research has identified that negative attitudes are consistently viewed as barriers to evidence-based harm reduction practices . Even thWe observed no associations between years of experience and clinician attitudes in our sample. This nonsignificant finding was in contrast to our hypothesis and existing literature which suggests that more experience and therefore increased contact with individuals who use substances fosters more positive attitudes ; howeverFurther research is required to understand elements of education\u00a0and training that are associated with more positive attitudes towards and improved care for individuals who use substances. The limitations of this study include a low proportion of non-nursing providers, generalizability to other regions or settings and the cross-sectional survey design with assessments of attitudes at a single time-point."}
+{"text": "To determine whether convolutional neural networks can detect morphological differences between images of microbiologically positive and negative corneal ulcers.A cross-sectional comparison of prospectively collected data consisting of bacterial and fungal cultures and smears from eyes with acute infectious keratitis at Aravind Eye Hospital. Two convolutional neural network architectures (DenseNet and MobileNet) were trained using images obtained from handheld cameras collected from culture-positive and negative images and smear-positive and -negative images. Each architecture was trained on two image sets: (1) one with labels assigned using only culture results and (2) one using culture and smear results. The outcome measure was area under the receiver operating characteristic curve for predicting whether an ulcer would be microbiologically positive or negative.There were 1970 images from 886 patients were included. None of the models were better than random chance at predicting positive microbiologic results .These two state-of-the-art deep convolutional neural network architectures could not reliably predict whether a corneal ulcer would be microbiologically positive or negative based on clinical photographs. This absence of detectable morphological differences informs the future development of computer vision models trained to predict the causative agent in infectious keratitis using corneal photography.These deep learning models were not able to identify morphological differences between microbiologically positive and negative corneal ulcers. This finding suggests that similar artificial intelligence models trained to identify the causative pathogen using only microbiologically positive cases may have potential to generalize well, including to cases with falsely negative microbiologic testing. After obtaining consent, eligible subjects underwent standard evaluation for corneal ulcer patients, including a detailed clinical history and slit lamp examination. All subjects then underwent external photography using a handheld Nikon D7100 camera with a 105-mm macro lens according to a standardized photography protocol, which has been successfully employed in several previous clinical trials.Subjects then underwent corneal scraping with heat sterilized Kimura spatulas according to the standard of care. Specimens were prepared for gram stain, KOH smear, bacterial culture on blood agar, and fungal culture on potato dextrose agar. Smear and culture results were determined by experienced microbiology technicians.This study adhered to the tenets of the Declaration of Helsinki and was approved by the internal review board at Oregon Health & Science University and Aravind Eye Hospital (project code RES2020050BAS). Informed consent was obtained from all participants. All cases of clinically diagnosed infectious keratitis were considered eligible for inclusion, as long as the external photographs and microbiologic specimens were obtained.,,Images were labeled according to their microbiologic results. Overall, both smears (Gram stain and KOH)https://github.com/tkredd2/MobileNet_to_predict_corneal_ulcer_culture_positivity), and all hyperparameters used to train the models are available in Subjects were allocated randomly into the training set (80%), validation set (10%), or test set (10%). Care was taken to ensure that all images associated with a particular subject were allocated to the same image set, to prevent label leakage. During training, image augmentation was performed to minimize overfitting using random flipping along the vertical axis and random rotation up to 20\u00b0 in either direction. Images were then resized according to the standard input size for these deep CNNs (224 \u00d7 224 pixels) using the bilinear interpolation algorithm. Two model architectures were evaluated: MobileNetV2 and DenseNet201. These two architectures were previously found to have the highest performance among deep CNNs for distinguishing bacterial and fungal keratitis using this same imaging modality.There were 934 subjects with clinically diagnosed infectious keratitis recruited for this study. Forty-eight subjects were excluded from the analysis because of missing results on one or more microbiologic tests, resulting in 1970 images from 886 subjects in the final dataset. This included 444 ulcers of the right eye (50.2%) and 442 of the left eye (49.8%). There were 521 cases that were culture positive (59%) and 365 that were culture negative (41%). Among those that were culture positive, 164 demonstrated bacterial growth (32%), 374 demonstrated fungal growth (72%), and 17 (3%) grew both bacteria and fungi .\u00a0Using the less restrictive definition of microbiologic positivity incorporating both culture and smear results, we found that 690 cases were culture and/or smear positive (78%) and 197 were culture and smear negative (22%). Among those that had positive results on either culture, gram stain, or KOH smear, 216 cases demonstrated the presence of bacteria (31%), 519 demonstrated fungi (75%), and 46 were polymicrobial (7%). The test set defined according to both culture and smear results consisted of 211 images; 28 (13%) culture and smear negative and 183 (87%) culture or smear positive. The validation set consisted of 200 images; 24 (12%) culture and smear negative and 176 (88%) culture or smear positive. The training set consisted of 1590 images; 176 (11%) culture and smear negative and 1414 (89%) culture or smear positive.Pseudomonas aeruginosa (34%), followed by Streptococcus pneumoniae (15%) and Nocardia species (11%). There were 374 cases (42%) that demonstrated fungal growth in culture. Fusarium was the most commonly identified fungal pathogen (28%), followed by Aspergillus (18%) and dematiaceous molds (18%).Gram stains demonstrated bacteria in 166 cases (19%), with the majority demonstrating gram-positive cocci or gram-negative bacilli . There wThe area under the receiving operating characteristic curve (AUC) for differentiating microbiologically positive and negative corneal ulcers was determined for each of the four CNNs. The AUC for the DenseNet trained using only culture results was 0.48  . The AUCThese results demonstrate that two different CNN model architectures did not identify morphological differences between clinical photographs of microbiologically positive and negative corneal ulcers, regardless of how microbiologic positivity is defined. This work has implications for the future development of diagnostic artificial intelligence models for infectious keratitis.\u2013Prior studies have demonstrated that these computer vision model architectures are capable of recognizing meaningful morphological differences between bacterial and fungal keratitis in corneal photographs.Streptococcus pneumoniae, Pseudomonas aeruginosa, and Nocardia) and fungal species (Fusarium and Aspergillus) were the same between our study and this prior work.,The epidemiology of the etiologies for infectious keratitis included in this study is comparable to prior studies in South India. Lalitha et al.Acanthamoeba or viral keratitis) or sterile keratitis . However, all subjects with a suspected acanthamoeba-related ulcer undergo confocal microscopy at Aravind, which would exclude a large majority of potential cases. In addition, viral necrotizing keratitis is very rare and would be less likely to masquerade as a culture-negative case, and the clinical volume of infectious keratitis in South India is such that the diagnostic expertise of these cornea specialists is very high.Several potential limitations should be considered. First, the term culture-negative referred to images that did not have positive bacterial or fungal results, but it is possible that a few of these culture-negative cases included other infectious etiologies (e.g., Our results demonstrate that these state-of-the-art computer vision models were not able to differentiate between microbiologically positive and negative corneal ulcers based on external photographs, regardless of whether cultures or smears were used to determine the microbiologic status. These findings suggest that the CNNs used to distinguish the underlying etiology of infection in subjects with corneal ulcers may generalize well to microbiologically negative cases, even if they are trained using supervised learning with only microbiologically positive cases. Additional model evaluation studies in population-based samples are a necessary next step in the determination of whether these deep learning models may provide clinical benefit to patients with this potentially blinding condition."}
+{"text": "Cholinergic regulation of hippocampal theta rhythm has been proposed as one of the central mechanisms underlying hippocampal functions including spatial memory encoding. However, cholinergic transmission has been traditionally associated with atropine-sensitive type II hippocampal theta oscillations that occur during alert immobility or in urethane-anesthetized animals. The role of cholinergic regulation of type I theta oscillations in behaving animals is much less clear. Recent studies strongly suggest that both cholinergic muscarinic and nicotinic receptors do actively regulate type I hippocampal theta oscillations and thus provide the cholinergic mechanism for theta-associated hippocampal learning. Septal cholinergic activation can regulate hippocampal circuit and theta expression either through direct septohippocampal cholinergic projections, or through septal glutamatergic and GABAergic neurons, that can precisely entrain hippocampal theta rhythmicity. The hippocampus has been widely accepted as the brain region for memory encoding and short-term memory storage. The hippocampus receives major excitatory inputs from entorhinal cortex and sends the major output back to the entorhinal cortex ,2. The hSeptal cholinergic and GABAergic inputs to the hippocampus have been traditionally deemed as the pacemakers of theta oscillations, providing rhythmic excitatory and inhibitory hippocampal inputs, respectively . HoweverThere is strong evidence supporting cholinergic involvement in not only type II theta but also type I theta. Several studies have observed elevated septal cholinergic firing rate or hippocampal acetylcholine (ACh) release during both type I and type II theta dominant behavioral states ,21,22,23Both hippocampal muscarinic and nicotinic receptors may contribute to theta regulation ,26,27,28Calcium imaging studies showed that calcium activities in dorsal CA1 pyramidal neurons are high during theta states including active exploration and REM sleep, and low during non-theta states including quiet wakefulness and slow wave sleep. Systemic or local hippocampal administrated mAChR antagonist scopolamine significantly reduced calcium activities in pyramidal neurons . Higher MSDB is indispensable for both type I and type II theta generation and has been proposed as the host of theta pacemakers ,47,48. TOther than septal GABAergic neurons, septal glutamatergic neurons can also regulate theta frequency. Rhythmic optogenetic activation of local septal glutamatergic neurons lineally entrained hippocampal type I theta frequency in behaving mice in the 6\u201310 Hz range but had little effect on peak theta power . Septal Although direct optogenetic activation of septal cholinergic neurons only had mild effect on type I theta , septal cholinergic activation can still regulate theta through septal GABAergic and glutamatergic neurons, or through direct septohippocampal cholinergic pathway. Systemic or intraseptal administration of atropine mildly decreased type I theta frequency in freely moving rats ,51. The In addition to theta oscillations, there are gamma oscillations in the hippocampus with a frequency ranging from 25 to 100 Hz . Gamma oRecordings from the CA1 area of freely moving mice show that gamma activity is amplitude-modulated at \u03b8 frequencies. This theta-gamma coupling is stronger during active exploration than during awake immobility. Intraperitoneally administrated atropine increased theta irregularity, reduced gamma power and theta-gamma coupling during explorative behavior . Stronge+ current [The mechanism underlying this cholinergic modulation of theta-gamma coupling is not clear. Studies suggest that hippocampal interneurons are critical for gamma generation. Slow gamma is driven by interneurons that are activated by CA3 inputs, while fast gamma is driven by interneurons activated by medial entorhinal cortical inputs ,74,76,87 current . Gamma a current , suggestSeptal cholinergic neurons are activated during both type II and type I theta states. Cholinergic activation can regulate hippocampal theta through both direct septohippocampal cholinergic pathway and indirect local septal circuit . ElevateLocal septal cholinergic action is essential for type II theta generation but is less important for type I theta and usually only has a moderate effect on type I theta frequency regulation. The relationship between type II theta centered on septal hippocampal loop and type I theta centered on the entorhinal hippocampal loop is currently unclear. Some researchers consider that type II theta coexists with type I theta in behaving animals and is only unmasked by anesthesia administration. It is also possible that each type of theta only occurs during its preferential states. Even if type II and type I theta coexist in behaving animals, it is still not clear if and how they are integrated to modify various aspects of behavior outcomes. Current studies seem to suggest that type II theta is more related to internal drive arising from past experiences, and type I theta is more related to external drive arising from ongoing activities.Cholinergic transmission can target both glutamatergic and GABAergic neurons in MSDB and the hippocampus through both mAChRs and nAChRs. It is currently unclear if septal cholinergic activation directly regulates septal GABAergic neurons or indirectly through local glutamatergic neurons, or both, and what cholinergic receptor subtypes underlie such mechanisms, respectively. An Intersectional Recombinases-mediated Area-and-cell-Specific gene Excision (IRASE) method has recently been developed to achieve receptor knockout with spatial and cell-type specificity . In this"}
+{"text": "Urothelial cancer is a difficult type of tumour entity. It may be harmless and easily treated, it can be bothersome with constantly recurrent disease affecting quality of life and it is lethal once progressed to metastatic disease. The course of this disease may be assumed but often is not anticipated. Treatment algorithms vary from office-based tumour fulguration over cystectomy and or nephroureterectomy to complex systemic therapy. During the past years new treatment options have been developed such immunotherapy or drug conjugates hereby increasing life expectancy in a still deadly disease.Although guidelines have been blown up with information, still there is lack of knowledge in many cases. Examples? We used to treat urothelial cancer with predominant neuroendocrine component with primary chemotherapy but most patients only survived months after cystectomy. Changing to early cystectomy in low volume disease has provided better results. A young woman with pulmonary metastases has not responded to chemotherapy or immunotherapy. After several surgical treatments she achieved long term recurrence free disease. A patient had massive urothelial tumours in both upper tracts and in his bladder but never developed metastases. Every Urologist and Uro-Oncologist has similar stories to tell. These are patients we learn from each other but you will never find answers within guidelines as they rely on randomized controlled trials or at least on big cohort studies.The reader of this issue may find some answers that have not been told. Therefore, I encourage everyone to read through the following articles:Sharma et\u00a0al. present the rare case of a 19-year-old male with advanced urothelial carcinoma of the bladder. They performed whole-exome sequencing to identify potential treatment targets hereby presenting potential driver mutations and raising the question whether mutations in genes involved in ion channels may be engraving tumours.Xu et\u00a0al. A patient with neuroendocrine carcinoma of the ureter colliding with squamous cell carcinoma is discussed respecting current literature of only 16 previous cases worldwide. In this case the combination of surgery and systemic therapy (cisplatin/etoposide) has provided prolonged survival. Another small cell neuroendocrine carcinoma case is presented by Qing et\u00a0al. They describe the rapid disease progression despite surgery and adjuvant systematic therapy including PD-L1 immuno-checkpoint inhibition (ICI) combined with radiotherapy.Another highly interesting case is reported by Li et\u00a0al. administered the PD-1 inhibitor Tislelizumab that showed remission in an isolated renal calyceal urothelial carcinoma. Zan et\u00a0al. used the PD-1 inhibitor Toripalimab combined with the multi-targeting tyrosine kinase inhibitor Anlotinib in last line sequence which resulted in long-term clinical response for over 25 months in a patient with metastatic disease.Systemic treatment of urothelial cancer consists of platinum-based chemotherapy and ICI therapy. Up to date, the antibody-drug conjugate Enfortumab vedotin has been approved by FDA and EMA for treatment after failure of the two previously mentioned therapies. Especially the use of immuno-checkpoint inhibitors may lead to long-term survival in metastatic urothelial carcinoma which has rarely been described before. New checkpoint inhibitors have been developed and are now increasingly used. Therefore, we present two case reports in which treatment success by using new PD-1 inhibitors are reported. Cai et\u00a0al. present a case of a 56-year old male patient who developed recurrent disease in the ureteral cutaneous stoma after radical cystectomy. Interestingly they performed a completely intracorporal resection of the tumour and ileal conduit surgery. They describe their procedure step by step.Robot assisted surgery is increasingly used in complex situations. I hope you find this selection of case reports worth reading.The author confirms being the sole contributor of this work and has approved it for publication."}
+{"text": "Previous studies have established a connection between higher mindfulness and cognitive abilities; however, few studies have considered the mechanism underlying this relationship. The cognitive benefit of mindfulness may be through reduced fatigue and daytime sleepiness. This study examined if higher, naturally occurring mindfulness is associated with higher subjective cognition and whether lower fatigue or sleepiness mediate this relationship. Two independent samples of nurses (N1=60 inpatient (IP); N2=84 outpatient (OP)) completed 14 days of ecological momentary assessment (EMA). Fatigue/sleepiness, mindfulness, and subjective cognition  were assessed using EMA. The 5-item Mindful Attention Awareness Scale assessed state mindfulness. Multilevel mediations were conducted in Mplus to account for the nested data. At the within-person level, daily subjective cognition was higher than average on days when mindfulness was higher in both OP and IP samples. This association was mediated by lower levels of fatigue  and lower sleepiness . The daily indirect pathways were found after controlling for between-person differences; those with higher mindfulness reported higher subjective cognition through lower fatigue, and this effect was only significant in OP nurses . Results highlight the importance of monitoring momentary mindfulness and intervening on daily fatigue and sleepiness as these may influence one\u2019s subjective cognition and ultimately their objective performance. These findings may help identify modifiable factors to promote quality of care in nurses and their own well-being."}
+{"text": "Pulmonary arterial hypertension (PAH) is a rare, progressive disorder. PAH is caused by a wide spectrum of pathologies but the cause remains undetermined on many occasions and patients are classified in the idiopathic group.Here we report a young woman with rare congenital visceral abnormalities presenting with severe pulmonary hypertension.Pulmonary hypertension is a complex disorder. Search for uncommon conditions that lead to pulmonary hypertension is necessary to determine the best management options.The online version contains supplementary material available at 10.1186/s43044-022-00273-x. Pulmonary hypertension (PH) is defined as an increase in mean pulmonary arterial pressure of 20\u00a0mm Hg or greater at rest with the stipulation that pulmonary vascular resistance (PVR) is\u2009\u2265\u20093 Woods units, as evaluated by right heart catheterization. In PH there is pathologic medial hypertrophy, intimal proliferation and fibrotic changes mainly in the distal pulmonary arteries. Remodeling in the pulmonary vasculature leads to right heart failure and progressive decline in functional capacity. The early symptoms of PH are non-specific, and the diagnosis is often made in advanced stages of the disease with worse long-term outcomes . PH assoAn 18-year-old asymptomatic female who was candidate for vaginal reconstruction surgery due to Mayer\u2013Rokitansky\u2013K\u00fcster\u2013Hauser (MRKH) syndrome was referred to our tertiary care center following incidental finding of right sided cardiac chamber enlargement and severe pulmonary arterial hypertension in a transthoracic echocardiography performed prior to the gynecologic surgery. The patient had uterine agenesis and primary amenorrhea with normal external genitalia. She showed normal developmental and pubertal milestones. On genetic study she had normal female karyotype of 46, XX. In physical examination there was scoliosis of the spinal bones.Chest X-ray depicted dilated pulmonary artery, right ventricular enlargement and scoliosis Fig.\u00a0. In twelLaboratory data were negative for autoimmune and rheumatic causes of pulmonary hypertension. We found a relatively low platelet count of 118,000 per microliter of blood plus mild increases in liver enzymes and total bilirubin levels. Although the patient had previously undergone abdomino-pelvic sonography for her gynecologic problems that only reported uterine agenesis, we decided to perform a repeat sonography in search for possible liver abnormalities or portal hypertension with regards to unexplained thrombocytopenia. Interestingly abdominal sonography showed that the portal vein was totally absent and right liver lobe was atrophic.Further evaluation by abdominal CT-angiography revealed congenital absence of intra-hepatic portal branches with direct drainage of abdominal veins to inferior vena cava resulting in extra hepatic porto-systemic shunt in favor of Abernathy type 1 visceral malformation. There was also gut malrotation and evidence of MRKH syndrome with underdeveloped uterus and normal ovaries. Computed tomographic angiography of the heart and pulmonary arteries showed no evidence of pulmonary parenchymal involvement and no chronic pulmonary thromboembolic disease or vascular shunts Fig.\u00a0.Fig. 3CoRight heart catheterization data confirmed severe pre-capillary pulmonary hypertension with pulmonary arterial pressure of 100/40\u00a0mmHg, normal cardiac output, normal capillary wedge pressure and no left to right shunts. Abdominal vascular angiography showed the complete absence of portal vein with splenic and superior mesenteric veins confluence draining directly to inferior vena cava forming a mesentero-systemic shunt  imaging helps delineate cardiac morphology and function and non-invasively assess the hemodynamics. CMR also provides valuable prognostic information. Right heart catheterization is necessary to confirm the diagnosis, ascertain PH severity and carry out vasoreactivity testing when clinically indicated \u20135.Pulmonary hypertension occurs in about 1\u20135% of patients with portal hypertension. Abernethy malformation or congenital extra hepatic portosystemic shunt is a rare abnormality of the portal venous system with shunting of portal blood into the systemic venous system. Abernethy malformation has two subtypes. In type I that is more frequent in females, the portal vein and intrahepatic portal circulation are entirely absent. In type II the portal vein is hypoplastic. In the absence of portal venous system the intestinal and splenic veins drain directly to the inferior vena cava, left renal vein or the left hepatic vein creating a porto-systemic shunt and varying degrees of portal hypertension. As the normal enterohepatic circulation is diminished, the toxins and vasoactive material from the intestine are bypassed to the systemic circulation without being metabolized in the liver leading to liver damage, hepatopulmonary syndrome, pulmonary hypertension and arterio-venous fistulas. Pulmonary arterial hypertension develops as a result of chronic vasoconstrictive effect of toxic vasoactive substances on the pulmonary vascular bed. There is also an increased risk of hepatic neoplasms. Type II could be treated by surgery or interventional methods of shunt elimination \u20138. Our pSkeletal and visceral anomalies including hepatobilliary, splenic and genitourinary anomalies have been reported in Abernethy malformation . Our patPulmonary hypertension is a complicated and multifactorial disorder requiring multidisciplinary assessment. Search for unusual and rare conditions that may cause pulmonary hypertension including congenital visceral abnormalities is important in determining the prognosis and treatment.Additional file 1: Abdominal vascular angiography showing\u00a0 absence of portal vein with splenic and superior mesenteric veins confluence draining directly to inferior vena cava."}
+{"text": "Intensive professional training is widely used in modern organizations, as it helps employees adapt to dynamic work and technology changes . Relaxation techniques may reduce the negative effects of intense learning processes . They can also enhance the productivity of the training itself by helping to achieve optimal states for the completion of learning goals.Our study concerns differences in mastering relaxation techniques by employees of younger and middle-age groups during intensive professional training.Sample - 62 employees, participants of communication training. The 15-min session of progressive relaxation combined with autogenic formulae was conducted after 5 hours of intensive training. Measures: standard psychological and physiological functional state tests ; an information perception task.The efficiency of the relaxation techniques varied between different age groups: younger participants (aged 20-30) were more successful in managing both tasks \u2013 learning new relaxation skills and achieving deeper rest . They were also more prepared for completing the information perception task (they made less mistakes). Older participants (aged 30-50) experienced more difficulties with the new relaxation skills and used relaxation primarily to restore their psychophysiological resources, rather than to prepare for the upcoming training task.The results showed that relaxation techniques provide a system optimization effect on the participants of intensive training programs, though participants\u2019 individual differences  should be taken into account when planning the outcomes of such interventions.No significant relationships."}
+{"text": "A 74-year-old female with previous permanent pacemaker insertion for complete heart block and no history of connective tissue disease presented to our regional cardiothoracic center with progressive exertional shortness of breath. Nine years later, when the patient was 83 years old, a computed tomography scan of the thoracic aorta revealed an isolated aneurysm of the aortic root measuring 7.6 \u00d7 5.1 cm at the sinus of Valsalva. A 74-year-old female with previous permanent pacemaker insertion for complete heart block and no history of connective tissue disease presented to our regional cardiothoracic center with progressive exertional shortness of breath. Transthoracic echocardiogram (TTE) confirmed severe calcific aortic stenosis associated with a pseudo-bicuspid aortic valve, and coronary angiography  showed aNine years later, when the patient was 83 years old, a surveillance transthoracic echocardiogram suggested aortic dilatation. A computed tomography (CT) scan  of the tThe case was discussed at our departmental aortic multidisciplinary team meeting. Owing to the patient\u2019s generalized frailty and the perceived perioperative risks associated with repeat surgery, conservative management was advised with ongoing medical follow-up.Judicious clinical assessment combined with periodic echocardiographic surveillance following surgical valve intervention is essential to monitor residual or concurrent non-intervened valve disease. As demonstrated in this case, such an approach can also identify novel pathologies affecting the heart and great vessels, permitting their operative management where appropriate. Although the delayed aortic root expansion following aortic valve replacement is well documented, the prophylactic replacement of the aortic root when not significantly dilated (< 45 mm) is not justified by current guidelines in non-aortopathy populations."}
+{"text": "True Luminal A breast cancer represents an endocrine sensitive, surgically curable disease that does not mandate systemic chemotherapy as part of the management paradigm. This disease is reliably identified by a Recurrence Score (RS)\u2009<\u200925 using the OncotypeDX\u00a9 21-gene expression assay . RegrettAdditionally, this conclusion from the RxPONDER trial lags considerably behind the de-escalation of surgery in early-stage breast cancer: There is a habitual tendency to prescribe untargeted chemotherapy in Luminal A breast cancer to improve survival, perhaps lessons could be learned from trials conducted in the advanced setting. In the recent MONALEESA-7 and PALOMA-3 trials, the addition of cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors to conventional endocrine agents enhanced survival for premenopausal women with metastatic Luminal A disease. Moreover, evidence from the SOFT and TEXT trials illustrate that adjuvant tamoxifen alone is appropriate for most premenopausal patients with early-stage disease, while absolute improvements of 10\u201315% observed in \u2018high recurrence risk\u2019 patients using ovarian suppression and exemestane versus tamoxifen alone. While it is unsurprising that CET prescription improves outcomes in premenopausal women, the oncological outcome observed from these targeted therapies far supersede the reported absolute benefit from CET described in the RxPONDER trial , 3. WhilThe molecular insights from Paik et al. revealed the etiology of the small benefit in NSABP B-20 and prevented the perpetuation of the ongoing inappropriate therapeutic strategy . TranslaOverall, the conclusion from this piece is quite simple: A treatment strategy that involves chemotherapy for patients with a RS\u2009<\u200925 risks the prolongation of a fallacy that opposes the scientific reasoning supporting personalized appropriate treatment strategies for breast cancer. A translational approach may help to minimize recurrence, maximize quality of life, and build on the novel insights gleaned from the molecular era. The next phase of neoadjuvant translational research trials must focus on deciphering the relatively small proportion of premenopausal patients with RS\u2009<\u200925 who are a recurrence risk and optimize the therapeutic strategy appropriately. Surely, we cannot prolong the suboptimal care of this generation or expose our prospective patients to untargeted toxic therapy which is neither justified nor effective for the majority."}
+{"text": "Adaptive thinking demands a balance between manifestations of intrapsychic activity and reliance on requirements of the outer reality. Features of responses to Rorschach\u2019s III card could provide information about subject\u2019s ability to preserve the dialectical tension between the two poles of external and internal realities during solving tasks related to interpersonal relationships.To compare reality-fantasy relations during Rorschach\u2019s III card responding in patients with schizophrenia, neurocognitive impairment and normal subjects.Participants were 12 young adult inpatients with schizophrenia, 14 students without mental disorders and 12 inpatients with neurodegenerative diseases of old age. Reality-Fantasy Scale (RFS) was applied to assess responses to Rorschach\u2019s III card. RFS scale ranges from \u20135  to 5  .Patients with schizophrenia  demonstrated tendency to fantasy domination  if compared with the students . Patients with neurodegenerative diseases , conversely, had difficulties to apply fantasy during solving Rorschach task .Express Rorschach testing using III card could be useful to provide screening data of thinking tendencies related to situations of social interaction. Also it provides a mental pabulum regarding role of cognitive impairment in schizophrenia in relation to significance of affective dependence of their thinking process.The reported study was funded by RFBR, project number 20-013-00772"}
+{"text": "A 52-year-old man presented with temporal haemoptysis and chest pain 6 months after radiofrequency catheter ablation for atrial fibrillation. Computed tomography revealed severe stenosis in the left upper pulmonary vein (PV) and complete occlusion of the left lower PV. A modified sutureless repair of the left PV obstruction was successfully performed. This modified procedure provides a feasible, safe and effective means of treating PV obstruction, even in cases with distal extension of stenosis. The incidence of pulmonary vein (PV) stenosis following radiofrequency catheter ablation of atrial fibrillation is \u223c1% [1]. The incidence of pulmonary vein (PV) stenosis following radiofrequency catheter ablation of atrial fibrillation is \u223c1% , 3. SeveA 52-year-old man diagnosed with temporal haemoptysis, chest pain and low-grade fever was admitted to our hospital. He had undergone radiofrequency catheter ablation for atrial fibrillation 6 months earlier. Computed tomography revealed multiple patches of consolidation in the left lower lobe with minimal pleural effusion Fig.\u00a0A. Three-Cardiopulmonary bypass was established under general anaesthesia via median sternotomy. Cardiac arrest was observed by antegrade cardioplegic perfusion. Moderate hypothermia at a nasopharyngeal temperature of 28\u00b0C was applied to obtain a bloodless operative field, in combination with a blower using carbon dioxide. Left upper and lower PV lesions were identified after the heart was retracted to the right. The left lower PV and its branches were peripherally dissected beyond the pericardial cavity because of a lesion that was widely obstructive due to fibrous thickening. The left atrial appendage was longitudinally incised from the apex and then separately extended towards the upper and lower PVs beyond the lesion Fig.\u00a0C. The paA high rate of restenosis is associated with interventional therapy with or without stent placement for iatrogenic PV stenosis post-catheter ablation procedures (3). Surgical repair represents an alternative option stemming from congenital PV malformation surgery experience, where the sutureless technique is a well-established treatment . This teIn this case, the left lower PV required distal dissection beyond the pericardial cavity because of a widely obstructive lesion. In the sutureless technique, the extra-pericardial cavity was closed using a bovine pericardial patch. This procedure did not apply stress to the PV incision line. Moreover, the peripheral PV orifice was protected via the overlying flap. We anticipate a low risk of pseudoaneurysm formation with this technique in view of normal intracardiac pressures. Direct oral anticoagulation is planned for at least 6\u2009months after surgery. Long-term follow-up is warranted as restenosis is a well-recognized complication. This modified procedure provides a feasible, safe and effective means of treating PV obstruction, even if the lesion extends distally to the peripheral branches.Conflict of interest: none declared.Interactive CardioVascular and Thoracic Surgery thanks Steven Hunter and the other anonymous reviewer(s) for their contribution to the peer review process of this article."}
+{"text": "Hearing loss is highly prevalent but disparities exist in hearing care. Delivering care in partnership with community health workers (CHWs) is an established approach to addressing disparities but has not been robustly studied in hearing care. We recruited older adults with hearing loss from community sites in Baltimore, MD. The 2-hour intervention consists of fitting a low-cost amplification device and counseling.151 participants were randomized. The primary outcome was change in communication function . Communication function significantly improved in the intervention group, with an intention to treat estimated average treatment effect of a -12.98 point change . In the first randomized control trial of a CHW-delivered hearing care intervention for older adults using low-cost amplification devices, participants receiving the intervention demonstrated a treatment effect comparable to prior studies of conventional hearing aids fit by audiologists."}
+{"text": "J Transl Med [HPV Selfy assay  fulfils international validation criteria for hrHPV testing on clinician-collected cervical samples (Meijer guidelines) [In primary cervical cancer screening, it is crucial to use only hrHPV tests that are clinically validated according to international guidelines in order to reduce the risks of missing relevant disease and of over-treatment. In the recent ansl Med  paper, Adelines)  as well delines) . Our perHPV Selfy (index test) [Validation requires an appropriately composed study population comprising a sufficient number of diseased subjects, derived from a continuous screening population or from a clearly described selection of CIN2+\u2009cases and <\u2009CIN2 controls . Avian eex test) , but it ex test) . This maex test)  and confHPV Selfy on self-samples was non-inferior to clinician-collected samples was flawed by critical statistical errors. The number of subjects with discordant self+\u2009/clinician\u2212 and self\u2212/clinician+\u2009results  in the HPV Selfy assessment [Collaborations between science and industry are instrumental to advance clinical research, however contractual independency of researchers and autonomy of publication enhance scientific credibility. We observe that sixteen of thirty six authors (including the first and last) of the JTM paper are affiliated\u00a0with the manufacturer of the assay. In the 2020 list of validated HPV assays , assays sessment . We reco"}
+{"text": "Optic nerve infiltration as the first sign of isolated central nervous system relapse of acute lymphoblastic leukemia (ALL) is rare. A seven-year-old girl with standard-risk B-cell ALL who was in remission presented with sudden onset of left eye pain and loss of vision. Examination revealed no perception to light in the left eye with positive relative afferent pupillary defect. The optic disc was hyperemic and swollen with total obscuration of the disc margin associated with central retinal artery and vein occlusion. Magnetic resonance imaging of the brain and optic nerve showed left intraorbital optic nerve thickening associated with perineural enhancement and intraconal fat involvement.Lumbar puncture revealed leukemic infiltration with blast cells after a week of eye symptoms, while bone marrow aspiration was negative for malignant cells. A diagnosis of left leukemic optic nerve infiltration with central retinal artery and vein occlusion was made. A high index of suspicion with repeat cerebrospinal fluid sampling is crucial to confirm the diagnosis as vitreous biopsy may fail to reveal infiltrative cells. Optic nerve involvement is reported to occur in one-sixth to 34% of leukemic cases ,2. HowevThis article was previously presented as a meeting poster at the 33rd\u00a0Asia-Pacific Association of Cataract & Refractive Surgeons (APACRS)-Singapore National Eye Centre (SNEC) 30th Anniversary Virtual Meeting on July\u00a030-31, 2021.A seven-year-old girl with standard-risk B-cell ALL diagnosed two years ago who had completed her systemic and prophylactic intrathecal chemotherapy and was in complete remission for two months presented with sudden onset of left eye pain and loss of vision. It occurred upon awakening from sleep and was associated with throbbing headaches. She did not have any complaint over the right eye. She had no history of hyperleucocytosis, extramedullary disease, or CNS involvement during her first diagnosis of ALL. Systematically, there was no preceding fever or signs of systemic infection.Her left visual acuity was non-perception to light with positive relative afferent pupillary defect. Right visual acuity was 3/3 on the Sheridan Gardiner test. Anterior segment was unremarkable in both eyes. Left eye fundus examination revealed a markedly swollen, hyperemic optic disc bulging into the vitreous with total obscuration of the disc margin. Retinal veins appeared very dilated and tortuous with presence of pale, edematous macula and retina. There were flame-shaped intraretinal hemorrhages in all four quadrants with vitreous hemorrhage inferiorly. There were no cotton wool spots Figure , Panel BAn urgent magnetic resonance imaging (MRI) of the brain and optic nerve showed left intraorbital optic nerve thickening associated with perineural enhancement and intraconal fat involvement Figure . The rigFundus fluorescein angiography revealed a complete absence of choroidal, retinal artery, and venous filling of the left eye for up to seven minutes while the right eye showed leakage from the optic disc  and initial lumbar puncture (LP) were negative for malignancy. Second LP was done a week later together with anterior chamber tapping and vitreous biopsy. Cerebrospinal fluid cytology showed presence of blast cells, suggestive of leukemic infiltration of the CNS Figures , 3B. AntIn view of relapse of leukemia with isolated CNS involvement, she was started on reinduction chemotherapy UK ALL R3 including intrathecal methotrexate. Neither local ocular chemotherapy nor radiotherapy was initiated. To date, her left eye remains without perception to light with right eye vision maintained\u00a0without\u00a0deterioration to date.ALL is an aggressive malignant proliferation of lymphoblasts with peak prevalence between the ages of one and four . It can Optic nerve is known to be a\u00a0sanctuary for leukemic cells which is relatively unaffected by systemic chemotherapy and even intrathecal chemotherapy . Cases oIn our case, despite intrathecal chemotherapy, which was given for CNS prophylaxis at the first diagnosis of ALL, and achieving complete remission after completion of chemotherapy, she developed isolated CNS relapse.The majority of patients with CNS relapse present with symptoms such as altered mental status, headache, and cranial nerve palsy while only a minority (6.5%) report blurred vision as the initial complaint . This waRosenthal\u00a0classified\u00a0optic nerve infiltration in leukemia into prelaminar and retrolaminar . In prelThere are limited cases reported on central retinal vascular occlusion in ALL in contrast to other lymphoproliferative disorders such as lymphoma -12. A caA review by Myers et al. found that malignant cells are identified in the cerebrospinal fluid in a majority of leukemic infiltration cases . In our Vitreous biopsy has value in diagnosing a leukemic relapse when there is presence of dense vitreous cellular infiltration . Shenoy Optic nerve infiltration may be the only initial presentation indicating relapse of ALL following attainment of disease remission. A high index of suspicion and prompt diagnosis may not only avoid irreversible loss of vision but more importantly can be life-saving for the patient. Repeated cerebrospinal fluid analysis may be necessary in the event of initial negative results for malignancy."}
+{"text": "We present a case of a 68-year-old man who presents with worsening cough and dyspnoea 12\u00a0months after undergoing radiofrequency ablation therapy for atrial fibrillation. Investigation revealed complete occlusion of the left lower pulmonary vein and partial stenosis of the left upper pulmonary vein. He underwent a stage surgical resection with the first stage being a left lower lobectomy for the non-viable lobe followed by a repair of the left upper pulmonary vein via anastomosis with the left atrial appendage. This staged procedure yielded excellent results and avoided the need for a left-sided pneumonectomy. The formation of pulmonary vein stenosis following radiofrequency ablation (RFA) therapy for patients with atrial fibrillation (AF) is a recognized complication. The mechanism of stenosis formation can occur in either the early or late post procedural phase. It is driven by myocardial necrosis and this acute inflammatory process can promote thrombus formation in the early stage. Late-stage stenosis results from the fibrotic changes associated with myocardial fibrosis that can also involve the pulmonary veins which leads to venous contraction and stenosis.We present a case of staged repair of a left upper and lower pulmonary vein stenosis which formed secondary to percutaneous RFA which preserved the functional left upper lobe and avoided the need for a left pneumonectomy.A 68-year-old man with a history of refractory paroxysmal AF and severe left ventricular dysfunction underwent catheter-guided percutaneous RFA. After initial improvement in symptoms and left ventricular (LV) function, over a period of 12\u00a0months the patient developed persistent cough and worsening exertional dyspnoea presenting with NYHA III symptoms.Repeat transthoracic echocardiogram demonstrated no deterioration in left ventricular function to coincide with symptom progression. A computed tomography (CT) chest demonstrated patchy infiltrates in the left lower lobe and a small pleural effusion. After multi-disciplinary team (MDT) presentation, a dedicated CT pulmonary vein study was obtained demonstrating pulmonary vein stenosis of the upper left pulmonary vein and complete occlusion of the lower left vein. A ventilation perfusion (V/Q) scan confirmed the lower lobe to be non-functional but the upper lobe still viable. A staged procedure was planned to avoid the need for a pneumonectomy.The patient underwent a staged left lower lobectomy and pulmonary vein repair as a staged procedure. The left lower lobe was resected as a video-assisted thoracoscopic procedure. Intraoperatively, the left lower lobe was oedematous with dense inflammatory adhesions to the chest wall. During the lobectomy, the left upper pulmonary vein was dissected in preparation for the planned upper pulmonary vein repair. Histopathology confirmed the left lower lobe to be necrotic .The patient was returned to the operating room 3\u00a0days later to undertake repair of the left upper pulmonary vein stenosis via sternotomy. The patient was placed onto cardiopulmonary bypass using antegrade Del Nido cardioplegia. Opening of the left atria revealed a circumferential stenosis of the left upper pulmonary vein. The vein was stapled at the left atrial junction and then trimmed off. The left atrial appendage was opened, several minor trabeculations were resected and the left upper pulmonary vein anastomosed to the appendage . When weCatheter RFA is an effective treatment modality for both permanent and paroxysmal AF in patients who have been unsuccessfully treated with antiarrhythmic drug therapy . RandomiPV stenosis can be managed with balloon dilation or venous stenting. Both procedures carry a risk of restenosis with rates of >50% balloon dilation and\u2009>\u200925% reported . Early i"}
+{"text": "Credentialing in GI endoscopy is not a universally standardized process. National guidelines may provide a framework for local training, however in certain settings, training committees set minimal competency requirements that must be met before a clinician can be accredited to practice independently. There is a paucity of literature assessing the inter-societal and geographic variability in guidelines and training requirements in endoscopy.To systematically review the available credentialing guidelines proposed by different GI endoscopy societies and affiliated training committees internationally.We conducted a systematic review according to the PRISMA guidelines. A comprehensive literature search was performed for credentialing guidelines for GI endoscopy from inception until January 2022. Two reviewers screened and one reviewer abstracted data using a pre-defined data collection form.From the 653 records obtained from our search, 20 credentialing guidelines from 12 different GI societies were ultimately included in the review. These guidelines encompassed the following procedures and outlined the following key-performance indicators; a) Colonoscopy: the recommended minimum number of procedures performed ranged from 150-275 with a minimum cecal intubation and adenoma detection rate of 85-90% and 20-30% respectively; b) EGD: the minimum number of procedures prior to credentialing ranged from 130-1000, the minimum duodenal intubation rate ranged from 95-100%, and the range for minimum number of upper GI bleeds managed was 20-45 ; c) ERCP: the recommended minimum number of procedures prior to credentialing ranged from 100-300 cases with a minimum selective duct cannulation rate of 80-90%. Guidelines for flexible sigmoidoscopy, EUS and capsule endoscopy were also obtained.There is a general concordance amongst the various international GI societies with regards to minimum procedural volume and performance in key procedural tasks prior to credentialing, however the use of validated education assessment tools was lacking in the majority of guidelines. Additional KPI\u2019s need to be explored for less routinely performed procedures such as EUS and capsule endoscopy.NoneNone Declared"}
+{"text": "Prior work suggests that more frequent or higher exposure to stressors relates to less positive affect and more negative affect in daily life. Limited knowledge exists about whether subjective appraisals of such stressors  also have negative links to daily well-being. This study examines this link using data from an 8-day daily dairy study (n=675 days) in an online sample of older adults . We also explored potential psychological moderators particularly relevant to the experience of aging . Results from multilevel models indicate that people reported more negative affect and less positive affect on days with more negative appraisals, especially on those days when they also had more negative self-views of aging. These findings highlight S-VOA as psychological resources that help people cope with stressful events in everyday life."}
+{"text": "She is currently receiving the ICE  regimen for persistent Langerhans cell sarcoma (LCS). This case highlights the phenomenon of transdifferentiation, in which neoplastic B cells are thought to convert to a histiocytic or Langerhans cell phenotype via unknown mechanisms. The case also highlights the value of histopathologic examination of multiple biopsy specimens for accurate diagnosis and design of a treatment plan in patients in whom PET/CT shows dichotomous SUV values.A 31\u2010year\u2010old woman presented with abdominal pain and a recent history of chest pain and B symptoms. Physical examination showed lymphadenopathy on left side of face/upper neck and mild splenomegaly. Laboratory workup showed microcytic hypochromic anemia , and elevated serum lactate dehydrogenase of 366 U/L. Positron emission tomography/computed tomography (PET/CT) imaging showed dichotomous"}
+{"text": "Iatrogenic aortic dissection is a rare but potentially fatal complication of percutaneous coronary intervention (PCI). Iatrogenic aortic dissection following PCI is rare with most cases reporting dissection originating within the coronary vessels with propagation into the ascending aorta. In this specific case, dissection was without coronary involvement, with dissection extending from the ascending aorta into the descending aorta and iliac vessels. Although PCI via radial approach is associated with fewer vascular complications than with femoral approach, significant adverse outcomes may still occur and require prompt intervention. This case highlights the highly atypical presentation of iatrogenic aortic dissection following cardiac catheterization presenting as acute limb ischemia. In such patients as with ours, immediate surgical intervention is necessary with overall poor prognosis. Iatrogenic aortic dissection (IAD) secondary to PCI may present variably and without prompt diagnosis and intervention, while outcomes may be unfavorable. Percutaneous coronary intervention via radial approach has been associated with reduced complications and bleeding rates when compared with femoral approach; however, features associated with radial approach may predispose patients to aortic dissection with coronary involvement. We present the rare case of extensive type A aortic dissection extending into the descending aorta causing limb ischemia following right radial heart catheterization.We present a 56-year-old male with past medical history of coronary artery disease status post-PCI \u00d72 presenting with chest pain and dyspnea. Labs were remarkable for elevated troponin (1.24\u2009ng/mL), and EKG findings were consistent with NSTE-ACS with ST depression more so within inferior leads. He was medically optimized with ACS directed therapy while troponins continued to uptrend (3.04\u2009ng/mL) overnight. Transthoracic echocardiogram demonstrated normal systolic function (EF: 50-54%) with normal aortic root diameter (3.4\u2009cm) and aortic valve function. Right radial arterial area was prepared, and a 5-French Tiger catheter was used to perform the right coronary angiography. Catheter was unsuccessful in engaging the left coronary artery despite multiple attempts and therefore was replaced with a 6-French JL4 diagnostic catheter, and left coronary angiography was performed. Left heart catheterization was remarkable for significant 80% stenosis of the mid left anterior descending artery (LAD). For the PCI part of the procedure, the EBU 4, 6-French guide catheter was used to support and engage the left coronary artery, and the 0.014 runthrough wire was used to cross the lesion and parked distally. The target lesion at the mid LAD was predilated using the 3.0 \u00d7 20\u2009mm Emerge compliant balloon with sequential inflation followed by the placement of a Boston Scientific Synergy 3.5 \u00d7 48\u2009mm drug-eluting stent from proximal to mid LAD. Post-PCI results were satisfactory with TIMI grade 3 flow and without dissection of left main and other coronary arteries . Within Radial approach has gained significant interest and usage within interventional cardiology. One of the more significant aims of this approach includes decreasing bleeding and postoperative complications. Comparisons between percutaneous angioplasty using radial and femoral approach showed similar clinical outcomes with decreased access site complications using radial approach . DespiteWhat makes our patient's case incredibly unique is the extent of dissection from the ascending aorta into the abdominal aorta and run-off vessels affecting the relative organ systems. In this case, the patient's symptoms of severe flank pain and lower extremity paresthesia soon after PCI were the only emergent signs of the underlying complication. Imaging confirmed extensive dissection of the abdominal aorta with dissection extending into the left renal, inferior mesenteric, and left iliac arteries causing the relative symptoms in this case. Such cases involving the ascending and descending aorta have high mortality rates and require extensive surgery known as the \u201celephant trunk\u201d procedure. Our patient was sent to a tertiary medical center where replacement of the supracoronary ascending aorta with arch repair was followed by treatment of the distal aortic aneurysm. Unfortunately, due to this patient's critical condition and extensive dissection, he expired soon after the initial procedure. To the best of our knowledge, this is the first case reporting ascending aortic dissection involving the abdominal aorta and vessels causing limb ischemia using right radial approach. In conclusion, although radial access may hold certain advantages, rare but fatal complications exist which may be more frequent using radial approach. Such complications may be secondary to complex anatomy of the upper extremity vasculature predisposing these patients to catheter-induced trauma and subsequent dissection with supracoronary entry . In suchIn conclusion, although radial access may have certain advantages, rare however significant complications may exist likely secondary to the complex anatomy of the upper extremity vasculature predisposing such patients to catheter-induced trauma. In such cases, immediate recognition and medical management is crucial in avoiding extensive dissection, thereby reducing mortality. To the best of our knowledge, this is the first case reporting extensive aortic dissection involving the abdominal aorta and run-off vessels causing limb ischemia using right radial approach."}
+{"text": "Stereolithography based 3D printing of microfluidics for prototyping has gained a lot of attention due to several advantages such as fast production, cost-effectiveness, and versatility over traditional photolithography-based microfabrication techniques. However, existing consumer focused SLA 3D printers struggle to fabricate functional microfluidic devices due to several challenges associated with micron-scale 3D printing. Here, we explore the origins and mechanism of the associated failure modes followed by presenting guidelines to overcome these challenges. The prescribed method works completely with existing consumer class inexpensive SLA printers without any modifications to reliably print PDMS cast microfluidic channels with channel sizes as low as ~75 \u03bcm and embedded channels with channel sizes as low ~200 \u03bcm. We developed a custom multi-resin formulation by incorporating Polyethylene glycol diacrylate (PEGDA) and Ethylene glycol polyether acrylate (EGPEA) as the monomer units to achieve micron sized printed features with tunable mechanical and optical properties. By incorporating multiple resins with different mechanical properties, we were able to achieve spatial control over the stiffness of the cured resin enabling us to incorporate both flexible and rigid components within a single 3D printed microfluidic chip. We demonstrate the utility of this technique by 3D printing an integrated pressure-actuated pneumatic valve (with flexible cured resin) in an otherwise rigid and clear microfluidic device that can be fabricated in a one-step process from a single CAD file. We also demonstrate the utility of this technique by integrating a fully functional finger-actuated microfluidic pump. The versatility and accessibility of the demonstrated fabrication method have the potential to reduce our reliance on expensive and time-consuming photolithographic techniques for microfluidic chip fabrication and thus drastically lowering our barrier to entry in microfluidics research. Microfluidics is the study and manipulation of fluids at microscopic scales , where micro-scale physics dominate. In recent years, microfluidics has quickly emerged as a crucial tool in several biological and chemical systems, including industrial, clinical, and fundamental research. It has enabled researchers, scientists, and engineers to perform numerous parallel experiments rapidly while consuming minimal reagents as opposed to simultaneously  working with multiple conventional benchtop analytical instruments in a laboratory ,2. MicroConventional microfluidic devices are largely fabricated through microfabrication techniques derived from the Micro-Electromechanical Systems (MEMS) and the semiconductor industry  involvinAlternate microfabrication techniques such as injection molding that enable rapid prototyping also exist ,13 but aIndustrial-grade and research stage 3D printing technologies such as selective laser sintering (SLS)  and Two-Most consumer-grade desktop printers work by splitting a 3D object model into several 2D layers (slicing) and materializing the object out of liquid polymer (melted thermoplastic or liquid resins) layer by layer. The two most common types of printing technology in this space rely either on fused deposition modeling  approach or stereolithography  approach . FDM appOne of the main components of SLA printing is the use of a photopolymerization resin . The priHere we provide application specific strategies that work with ready-made masked stereolithography (MSLA) 3D printing approach to fabricate functional microfluidic chips and microfluidic components. To bring additional functionality into fabricated microfluidic chips, we develop our custom UV curable resins incorporating the combination of high molecular weight Polyethylene glycol diacrylate (PEGDA) and Ethylene glycol polyether acrylate (EGPEA) as the monomer unit to print microfluidic components with tunable mechanical and optical properties. We analyze the range of achievable optical and mechanical characteristics as a function of varying monomer composition in our custom resins. Guidelines are provided to (i) create PDMS casted microfluidic chips generated from MSLA molds (requires plasma bonding), (ii) directly print microfluidic chips with embedded channels using commercial resins (no chip bonding steps required) and (iii) directly print microfluidic chips with embedded channels at a finer resolution and additional functionality using our custom resin formulation (no chip bonding steps). The user can choose either strategy based on their need and resource availability. Finally, we demonstrate further the utility of our custom resin by 3D printing an integrated pressure-actuated pneumatic valve (with flexible cured resin) in an otherwise rigid and clear microfluidic device that can be fabricated in a one-step process from a single CAD file. We also demonstrate the integration of a 3D printed finger actuated microfluidic pumps that can be easily interfaced with the inlet ports of microfluidic devices to move precise amounts of liquids within microfluidic devices without external syringe pumps.We printed MSLA molds with positive extrusion (for PDMS casting) and embedded microfluidic channels using several consumer class desktop MSLA printers including Prusa SL1 , Elegoo Mars 2 Mono and Elegoo Mars 3 Ultra 4k Mono . The feature sets and cost of the printers are specified in The cured 3D parts were carefully taken off the build plate and were immediately submerged and washed with IPA to wash off any residual resin followed by re-rinsing with water to ensure a glossy finish. We found that this extra rinsing step helps in easy pealing of the PDMS from the SLA molds. The parts were then air dried and further cured under Prusa curing station (CW1S) for one minute. For PDMS casting, the PDMS  was poured over the SLA mold with positive features. The PDMS was cured in an oven (50 \u00b0C) for four hours. Post curing, inlet and outlet ports were cut into the PDMS followed by bonding it on a clean glass slide in a plasma cleaner  for 30 s. The entire fabrication process-from concept to microfluidic chip-takes ~6 h A.For droplet generation, we used mineral oil  as the continuous phase, and water with blue food dye pigment as the dispersed phase. We used Span 80  as surfactant. Syringe pumps  were used to drive the dispersed and continuous phases at 10 and 100 \u03bcL/min respectively. The droplet generator chip and droplets were visualized using an optical microscope . \u00ae high vacuum grease) as a sealant and lubricant. Additionally, a rubber o-ring was added to the tip of the screw to provide an airtight contact between the screw and the microfluidic chip inlet port. The o-ring has an outer diameter corresponding to the diameter of the screw. We found that a syringe plunger gasket can also be used as an alternative to the o-ring for sealing the reservoir. The 3D printed finger actuated screw pump consists of two components-a screw and an inlet port (acting like a liquid reservoir)-that can be tuned to fit virtually any microfluidic device. The inlet port was designed to embed the negative threads to accommodate the screw. We used a standard size (M4\u2013M6) screw thread since they provide several advantages over a custom thread design. The CAD model of the threaded screw can be found online and can be added to the chip design without any major modifications. To prevent liquid leakage due to the tolerances of the printed screws, we used silicone based vacuum grease (Dow Corningn: 700)  as the monomers. We chose Phenylbis  phosphine oxide (Cas: 162881-26-7) (Also known as Irgacure 819) as the photoinitiator and 2-nitrophenyl phenyl sulfide (NPS) (Cas: 4171-83-9) as the UV absorber  = [1:1] + IRG 819 (1% mensions A. While on depth B. Even ton depth A. This d\u22121). EGPEA monomer shows characteristic peaks at the 750\u2013690 cm\u22121 and 1490 cm\u22121 regions corresponding C=C bending and C=C stretching frequencies respectively. PEGDA-700 monomer shows a characteristic broad peak at 1111 cm\u22121 region corresponding to ester linkage. First, the mixture with equal amounts of the two monomers  retains the characteristic peaks of both EGPEA and PEGDA monomeric resins  for all variations. The resins were printed to form tensile specimens resembling a dog-bone shape to ensure that most of the tensile stress is concentrated in the middle of test specimen  forcing the specimen to break at that region. The setup enabled us to obtain standardized stress-strain profiles for printed parts for a range of resin compositions B. From tcP = lP \u2212 aP) which is the pressure differential arising from the difference in pressure of the flowing liquid (lP) in the microfluidic channel and applied pneumatic pressure (aP). The closing pressure then becomes the minimum pressure required to completely close the pneumatic valve and halt the liquid flow in the microfluidic channel  without any modifications to accurately print (i) PDMS casted microfluidic channels with channel sizes as low as ~75 \u03bcm and (ii) embedded channels with channel size as low ~300 \u03bcm (~200 \u03bcm with custom resin formulation). We anticipate these resolutions will only improve in the coming years as the pixel density (ppi) of the new LCD displays continues to increase following Moore\u2019s law trend. Additionally, such printers can also be used to fabricate integrated microfluidic components such as finger-actuated microfluidic pumps and flexible pneumatic microfluidic flow valves. The convenience and swiftness of our proposed technique enable one to go from an \u201cidea stage\u201d to a \u201cfunctional microfluidic chip\u201d within ~hours as opposed to traditional clean room-based microfabrication (~days), which could drastically lower the barrier to entry in microfabrication and greatly accelerate lab-on-a-chip research."}
+{"text": "This study aimed to examine whether neighborhood cohesion would mitigate the adverse effect of living alone on all-cause mortality in community-dwelling older Chinese Americans. Data were drawn from the Population Study of Chinese Elderly , a longitudinal study started in 2011. Mortality was tracked through December 2021 (N = 642 deceased). Cox regression indicated that neighborhood cohesion moderated the association between living alone and all-cause mortality , showing that among participants living alone (N = 678), those with high neighborhood cohesion had a 41% lower mortality risk than their counterparts with low neighorhood cohesion. In contrast, among participants living with others, those with high and low neighborhood cohesion had a similar mortality risk. These findings highlight that strong neighborhood cohesion may protect against the increased risk of premature mortality associated with living alone in older Chinese Americans."}
+{"text": "This study aimed to examine potential risk and protective factors for binge drinking among a cohort of 15-16-year-old adolescents in the West of Ireland. This study was a cross-sectional secondary analysis of 4,473 15-16-year-olds who participated in the 2020 Planet Youth survey. Binge drinking was defined as ever consumption of five or more drinks in a two-hour period or less. Data were analysed using SPSS version 27. Multivariable logistic regression was used to examine independent associations between potential risk and protective factors and binge drinking. A p-value of < 0.05 was deemed statistically significant. The prevalence of binge drinking among participants was 34.1%. Female gender  and non-White ethnicity  were associated with reduced odds of ever binge drinking. Self-rated \u2018bad/very bad\u2019 mental health , current cigarette use  and current cannabis use  were associated with increased odds of ever binge drinking. Parental supervision  and negative parental reaction to adolescent drunkenness  reduced the odds of ever binge drinking among participants. Getting alcohol from parents was associated with increased odds of ever binge drinking . Adolescents with friends who drink alcohol had almost 5 times higher odds of ever binge drinking . Participating in team sports was also associated with increased odds of ever binge drinking . This study highlights key influences of adolescents\u2019 social environment on their binge drinking, and a need for renewed public health efforts to protect adolescents from alcohol-related harm.\u2022\u2002This study identified a high prevalence of ever binge drinking among adolescents in the West of Ireland - this is highly concerning as adolescents are vulnerable to alcohol-related harm.\u2022\u2002This study identified factors in the social environment of adolescents associated with binge drinking. This can inform public health action to protect adolescents from alcohol-related harm."}
+{"text": "Solo agers are an at-risk population of almost 14 million older U.S. adults currently living alone . Having been independent for most of their lives they often enter older age unprepared for declining health. Even though the numbers of solo agers are rapidly increasing with the aging of the Baby Boomer generation, research remains scant on this population . A mounting concern facing solo agers is finding themselves \u201cunbefriended\u201d . The risk of unbefriended status emphasizes the critical importance of advance care planning; however, many solo agers have no advance directives and factors influencing advance care planning in this group are unclear. In this mixed-methods study, we examined factors influencing advance care planning among solo agers. Survey data were collected from 467 members of a Facebook group for self-identified \u201celder orphans,\u201d six of whom subsequently participated in qualitative interviews. Among these solo agers, 55% indicated they had advance directives. Hierarchical logistic regression results indicated financial and overall wellbeing predicted having advance directives; however, perceived health risk did not. An interpretive phenomenological analysis of data from six in-depth interviews revealed emergent themes of fears of the future and reluctance to plan for end of life despite acknowledging health risks. Findings can inform policies to meet the growing needs of solo agers who may be at elevated risk of becoming unbefriended."}
+{"text": "DOI: 10.1039/C9RA08223A.Correction for \u2018Nanoporous hybrid CuO/ZnO/carbon papers used as ultrasensitive non-enzymatic electrochemical sensors\u2019 by Minwei Zhang  The author regrets that the funding information was incorrectly shown in the acknowledgements section of the original manuscript. The corrected funding acknowledgement is as shown below.The author gratefully acknowledges the research facilities provided by the Natural Science Foundation of Xinjiang (No. 2018D01C040).The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."}
+{"text": "Cognitive Reserve (CR) protects against cognitive decline and dementia but its relation to mobility disability has not been established. To address this important gap in the literature, we conducted a longitudinal investigation to test the hypothesis that higher baseline CR was associated with a lower risk of developing mobility disability in older adults.Participants were dementia-free older adults who received a brain magnetic resonance imaging and had gait speed assessments during follow-up. Using the residuals approach, CR was derived from the modified-Mini-Mental Status Examination (3MS) total score by removing variance accounted for by measures of structural brain integrity, education and race. Mobility disability was defined using a validated cutoff score in gait speed of 0.8 m/s. Logistic regression models using General Estimating Equations (GEE) were utilized to examine longitudinal associations between baseline CR and the risk of developing of mobility disability across repeated assessments.Of the participants  who were free of mobility disability at baseline, 103 developed mobility disability during follow-up (mean=3.1ys). Higher CR at baseline was associated with lower risk of developing incident mobility/disability .We provided first evidence that higher CR was associated with lower risk of developing mobilitydisability in older adults."}
+{"text": "Scarce research has examined racial differences in cardiovascular health in the context of social interactions. This study investigated whether (a) friend interactions were associated with better cardiovascular functioning, and (b) such associations vary among Black and White adults. This study employed dual assessment techniques\u2014ecological momentary assessments (EMA) and ambulatory physiological assessments\u2014to examine the co-occurrence of social interactions and cardiovascular functioning. Multilevel models revealed no racial differences in ambulatory HRV and frequency of friend interactions throughout the day. Findings revealed a between-person link of friend interactions and better HRV in the overall sample. Race-stratified models found a within-person link between friendship interaction and worse HRV and a between-person link between friendship interaction and better HRV for Blacks but not for Whites. Findings suggest friend interactions are more salient for Blacks\u2019 cardiovascular health and may serve as a modifiable factor for preventing cardiovascular diseases."}
+{"text": "Background: Pharyngitis is 1 of the most common conditions leading to inappropriate antibiotic prescriptions. When personal protective equipment (PPE) was at first constrained during the COVID-19 pandemic, Intermountain Healthcare recommended limiting rapid group A streptococcal pharyngitis (GAS) testing in urgent-care clinics to preserve PPE. Notably, the percentage of pharyngitis encounters prescribed an antibiotic and that underwent GAS testing is a key Healthcare Effectiveness Data and Information Set (HEDIS) measure. We have described our experience with urgent-care pharyngitis encounters and the impact of temporarily reducing GAS testing on antibiotic prescribing before and during the COVID19 pandemic. Method: We identified all urgent care encounters between July 2018 and August 2021 associated with a primary diagnosis of pharyngitis using ICD-10 CM codes and a validated methodology. Pharyngitis encounters were assessed for antibiotic prescriptions ordered through the electronic health record (EHR) and the use of point-of-care rapid GAS tests. Pharyngitis encounters were analyzed monthly. We assessed the percentage of encounters associated with an antibiotic prescription regardless of testing and the percentage of encounters associated with an antibiotic prescription when a GAS test was or was not performed. We examined 3 periods relating to COVID-19 and GAS testing recommendations: the prepandemic period (July 2018\u2013March 2020), the pandemic onset period (April 2020\u2013June 2020), and the pandemic period (July 2020\u2013August 2021). Results: Prior to the pandemic, the monthly percentage of pharyngitis encounters for which rapid GAS testing was performed was nearly 90% (Fig. Conclusions: Limited PPE in our urgent care centers during the initial months of the COVID-19 pandemic was associated with a mandated substantial decline in rapid GAS testing. As testing volume decreased, we noted a simultaneous relative increase of >30% in antibiotic prescribing for pharyngitis. These findings suggest that rapid streptococcal testing promotes appropriate antibiotic prescribing.Funding: NoneDisclosures: None"}
+{"text": "Elimination of ventricular tachycardia with epicardial substrate may be limited due to close proximity of the phrenic nerve. In this case report we illustrate the use of a decapolar catheter in a Foley catheter for deviating the prenic nerve to safely perform epicardial ventricular tachycardia ablation. Patients are at high risk for sudden death and ventricular tachyarrhythmias (VT) occur frequently1. Epicardial scar formation is predominantly found at the basal inferolateral left ventricle. Ablation of VTs originating from this area require an epicardial approach, but ablation can be hampered by close proximity of the phrenic nerve (PN)2. Several methods have been described for PN displacement, techniques including fluid overload or vascular or oesophageal balloon inflation3. However, it remains difficult to manoeuvre the balloon pericardially. We present our approach for PN displacement by using a Foley catheter.Pathogenic mutations of the phospholamban (PLN) gene are common in the Netherlands and may give rise to highly arrhythmogenic cardiomyopathiesA 63-year-old male patient with PLN cardiomyopathy (R14del) presented with electrical storm (multiple ICD therapies) despite using amiodarone A. ThrougWe used a Foley catheter to deviate the PN from the ablation site D\u2013E. A deTo our knowledge, this is the first report of the combined use of a decapolar catheter in a Foley catheter for deviating PN to safely perform epicardial VT ablation."}
+{"text": "Cerebral infarction due to aneurysm thrombosis in giant intracranial aneurysms is rare (1). Patients with ischemic stroke distal to an unruptured intracranial aneurysm often experience SAH after the stroke and have extremely poor prognosis (2).A 68-year-old man presented with a sudden onset of right hemiparesis and aphasia. Computed tomography (CT) revealed a high-density, round mass in the left middle cerebral artery (MCA) suspected to be an unruptured giant cerebral aneurysm . CT angiNoneTT wrote the first draft and managed all of the submission processes.We have obtained informed consent for this case report."}
+{"text": "Teaching Point: Chronic pulmonary schistosomiasis should be suspected in symptomatic patients with an endemic background presenting with migrating pulmonary lesions on high resolution computed tomography scan. A 38-year-old woman with a Sierra Leonean background presented to our institution complaining of pleural pain, fever, and cough. She had a history of human immunodeficiency virus successfully treated with triple therapy and a recent subclinical COVID-19 infection. The patient had not been to Sierra-Leone for 10 years and there was no history of recent travelling or contact with sick patients or Tuberculosis patients.Physical examination was unremarkable. Laboratory tests showed leukocytosis with eosinophilia (0.8 10.E9/l) and high CRP (33.7). Further investigation done with a urinary sample, broncho-alveolar lavage, and serological tests  concluded negative.Figure 1A). No TBC-associated lesions or calcified nodes were observed. The first follow-up HRCT was scanned after seven days  of watchful waiting without any medical therapy. These follow-up images demonstrated a spontaneous regression of some lesions where other nodular lesions demonstrated expansion compared to one week prior. Subsequently the previously described finding of migrating nodular lesions were confirmed on one-month follow-up computed tomography (CT) scan.High resolution CT (HRCT) a few days after admission demonstrated multiple nodular zones of consolidation with surrounding ground glass in the left lower lobe  and treatment was started (Praziquantel) with an interval of two weeks in between doses. On this therapy the patient improved with significant clinical response and a regression of CRP and eosinophilia.Schistosomiasis is a parasitic infection caused by parasitic blood flukes acquired during contact with infested water and is known to be an important cause of disease in sub-Saharan Afrika. It is rarely seen in Europe except for occasional tourism associated exposures.Pulmonary manifestations are most often seen after chronic hepatosplenic involvement with portal hypertension and development of collateral circulation. The eggs of the larvae are subsequently migrating to the alveolar spaces causing an eosinophilic inflammatory response. In this case the predominant HRCT finding of pulmonary involvement was the observation of diffuse nodular opacities which have already been described by Nguyen et al. in 2006 . Our casAn interesting finding in this case is that the patient was recently tested positive for SARS-CoV-2 after having a high-risk contact . It is not clear if COVID-19 infection could trigger a host\u2019s immune response to chronic indolent schistosoma infections or increase the morbidity and mortality of patients who are chronically exposed to the schistosoma parasite."}
+{"text": "A 64-year-old male patient with chronic obstructive pulmonary disease presented to our hospital with back pain. Posteroanterior chest radiography findings indicated a calcified, solid nodule having smooth borders and located on the right side, under the diaphragm . Based oEchinococcus granulosus. It is a notable health problem in regions where livestock is still widely dealt withA hydatid cyst is a parasitic disease caused by"}
+{"text": "Singapore was one of the first countries affected by COVID-19. Measures to contain the spread of COVID-19 include raising the Disease Outbreak Response System Condition (DORSCON) risk assessment to Orange and instituting a movement control order, termed as the Circuit Breaker. These measures have caused significant disruption in primary care and chronic disease management. As the first point of contact in testing suspected cases, primary care providers shifted their focus from non-COVID-19 services. Using an interrupted time series analysis, we examine the associations of DORSON Orange and Circuit Breaker on acute and chronic primary care visits among older adults aged above 50. We found significant reductions in both acute and chronic primary care visits immediately following DORSCON Orange and Circuit Breaker. DORSCON Orange was associated with a drop of 231 mean acute and chronic daily visits (95% CI -356 to -106). Circuit Breaker was associated with a further drop of 268 mean daily visits (95% CI -426 to -111). These reductions were also observed for acute and chronic visits separately. Routine chronic care appointments were deferred or cancelled to reduce the risk of transmission as patients with underlying medical conditions were at higher risk of developing severe complications. Delayed access to primary care can have profound health implications, especially for older adults. Ensuring accessibility to primary care is a key priority in maintaining population health. Understanding the impact of COVID-19 tightening measures on older adults\u2019 primary care utilisation will be useful for future public health planning."}
+{"text": "Rational design of therapeutic antibodies can be improved by harnessing the natural sequence diversity of these molecules. Our understanding of the diversity of antibodies has recently been greatly facilitated through the deposition of hundreds of millions of human antibody sequences in next-generation sequencing (NGS) repositories. Contrasting a query therapeutic antibody sequence to naturally observed diversity in similar antibody sequences from NGS can provide a mutational roadmap for antibody engineers designing biotherapeutics. Because of the sheer scale of the antibody NGS datasets, performing queries across them is computationally challenging.http://naturalantibody.com/abdiver), a free portal allowing users to compare their query sequences to those observed in the natural repertoires. AbDiver offers three antibody-specific use-cases: (i) compare a query antibody to positional variability statistics precomputed from multiple independent studies, (ii) retrieve close full variable sequence matches to a query antibody and (iii) retrieve CDR3 or clonotype matches to a query antibody. We applied our system to a set of 742 therapeutic antibodies, demonstrating that for each use-case our system can retrieve relevant results for most sequences. AbDiver facilitates the navigation of vast antibody mutation space for the purpose of rational therapeutic antibody design.To facilitate harnessing antibody NGS data, we developed AbDiver (http://naturalantibody.com/abdiver.AbDiver is freely accessible at Bioinformatics online. Monoclonal antibodies are the largest class of biotherapeutics. Development of successful antibody therapeutics requires selection and engineering of candidate sequences with favorable functional and developability properties. Knowledge of biologically possible mutations at specific positions can be employed to engineer biophysical properties of these molecules . Exploration of natural antibody diversity from NGS datasets relative to a candidate therapeutic would therefore facilitate rapid and effective antibody engineering.The richness of NGS data has implications for rational selection and design; models trained on these data have already shown promise for humanization  or the AIRR Data Commons  (ce (OAS) . We enviV-region profiling service: The AbDiver V-region natural profiling service annotates a query variable-region antibody sequence with the naturally observed amino acid frequency statistics for each position  based indexes for CDRs in full variable-region sequences and CDR3s separately. Variable sequence matches are identified based on the same length CDR1, CDR2 with one residue discrepancy allowed for CDR3. Clonotypes are identified on the basis of the same V-gene and CDR3 sequence identity. The matches are presented using IMGT-based Multiple Sequence Alignment (lignment . Search We created an online portal that facilitates the navigation of natural antibody diversity. We envisage particular application of the service to enable drawing parallels between natural and therapeutic antibodies (Financial Support: none declared.Conflict of Interest: none declared.btac151_Supplementary_DataClick here for additional data file."}
+{"text": "Social support networks provide a context within which older adults maintain their safety and well-being. Preparing for disasters and emergency situations can help older adults stay safe independent after a disaster. Self-efficacy to prepare for and handle disaster situations can influence how older adults proactively prepare and protect themselves. Fifty-four older adults 61 to 92 years of age in Eastern Iowa were interviewed before and after participating in an intervention program that helped them develop personalized disaster management plans. Participants reported seven support network members on average, ranging from one to 23. About one-third of the network members were participants\u2019 children and grandchildren, 11% were their siblings and parents, and 58% were non-family members such as friends and neighbors. Out of 549 network members identified, 245 were selected as someone participants can depend on during emergency situations; 47% were family whereas 43% were non-family members. Participants who reported higher numbers of network members whom they can depend on in emergency situations at baseline showed more increase in self-efficacy to manage disasters one-month after receiving the intervention (p=0.02). Having social support network members whom older adults feel they can turn to during emergency situations may help boost their confidence in handling and preparing for disasters through participating in a disaster preparedness program. Participants indeed identified additional members whom they could depend on in disaster situations after the intervention. Future studies may test strategies to enhance social support networks to increase confidence among older adults to prepare for and handle disasters."}
+{"text": "Neurofibromatosis type 1 (NF1) is an autosomal-dominant hereditary multi-system disorder that is associated with the development of nervous system tumours. Its incidence is estimated at 1 in 2500 newbornsAccording to the diagnostic criteria for NF1 developed by the National Institutes of HealthPlexiform neurofibromas develop in up to 50% of individuals suffering from NF1. Melanotic neurofibromas are rare tumours representing less than 1% of all neurofibromas.A 27-year-old gravida 2 para 1 Ugandan woman was admitted to the labour ward at 40 weeks of gestation in labour pains. Her first pregnancy reportedly proceeded without increase in size of the cutaneous masses -which were present before the first pregnancy- and ended in successful caesarean delivery of a healthy term baby three years before. She reported progressive increase in cutaneous trunk masses starting from the third trimester of her second pregnancy. Whereas she reportedly lost both parents during her early childhood, she reported no history of neurofibromatosis in her family. On physical examination she was normotensive and presented with caf\u00e9-au-lait macules, axillary freckling, kyphosis and large soft diffuse hyperpigmented plexiform neurofibromas involving the trunk. A clinical diagnosis of NF1 was made. Due to contracted pelvis her child was delivered by caesarean section. Accessing the abdominal cavity required incision of a large suprapubic plexiform neurofibroma, which offered less resistance to incision compared to normal adjacent tissues. The cut surfaces of the neurofibroma exuded with a mixture of blood and clear fluid. A healthy baby was delivered with neither intraoperative nor postoperative maternal complications. One week later, mother and child were discharged. At discharge both the newborn and the then 3-year-old sibling had no dermatological features of NF1. While at home the patient reported rapidly progressing size of cutaneous masses causing difficulty in breathing and inability to walk or lie down .During a home visit 11 weeks after delivery, skin biopsies were obtained from the cutaneous masses. Histopathologic examination revealed neurofibromatous tissue with diffuse infiltrative growth pattern and monomorphic spindle cells with scarce cytoplasm showing positivity for protein S100, confirming the diagnosis of pigmented diffuse type cutaneous neurofibroma without evidence for malignant transformation . ThirteeWe here report on a 27-year-old female who died shortly after her second pregnancy due to the massive progress of giant plexiform neurofibromas. Our case shows similarities to several previous reports of neurofibromatosis-associated maternal complications of pregnancy. Isikoglu et alIn accordance with Lepp\u00e4virta et alThe simultaneous occurrence of NF1 and pregnancy should warrant close interdisciplinary monitoring of the mother for possible complications. Even when previous pregnancies were not fatally complicated by NF1, subsequent pregnancies can still develop fatal NF1-related complications. In the absence of evidence of malignant transformation, maternal rapid and fatal progression of melanotic NF1 in pregnancy is still a possibility. Pregnancy hormones may influence growth dynamics of neurofibromas. The presence of large plexiform neurofibromas on the abdominal wall should not be an anatomical/surgical limitation of incision for accessing the abdominal cavity."}
+{"text": "Several studies have previously documented the development of complications stemming from injection with one of the various COVID-19 vaccines. No study, however, has discussed the spontaneous development of a soft tissue mass shortly after a COVID-19 vaccine injection. We report on 66-year-old female with concerns of a growing shoulder mass, 2 weeks after receiving a COVID-19 vaccine booster. Initial work-up with X-ray and MRI was concerning for a soft tissue neoplasm, specifically a soft tissue sarcoma. Subsequent ultrasound guided biopsy demonstrated a benign granulomatous lesion. No further management was required as the lesion spontaneously resolved during a 3-month follow-up period. It has been previously documented that vaccine components can produce granulomatous inflammation. One study reported postvaccination granulomas in children following the pertussis immunization A 66-year-old female presents to our orthopedic clinic with concerns of a right shoulder rapidly expanding palpable mass. This female with a medical history of rheumatoid arthritis (RA) and rotator cuff surgery presents to our outpatient orthopedic sports medicine clinic concerned about a mildly tender and rapidly enlarging right shoulder soft tissue mass of three weeks duration. She denies systemic symptoms of fever, appetite changes, or weight loss, as well as any antecedent major trauma or other injury. The patient had received the COVID-19 Moderna vaccine booster (3rd dose) in the same deltoid region 4 weeks prior. She notated the injection had been associated with more pain than the prior doses.On physical exam, a nonmobile firm mass was palpable along the superolateral margin of the right deltoid muscle, without overlying skin changes. Neurovascular and motor testing were negative for weakness and sensory deficits. Shoulder radiographs revealed a soft tissue mass in the region of the lateral deltoid, without calcification or underlying osseous involvement . SubsequWe present a case of a 66-year-old woman who developed a localized granulomatous reaction that presented as a mass following a COVID-19 Moderna Booster vaccine Several case reports have documented the development of granulomatous inflammation following vaccine administration. One study reported postvaccination granulomas in children following the pertussis immunization. This same group identified that the ingredient responsible was an aluminum salt adjuvant as 77% of children who developed granulomatous inflammation also developed a contact allergy to aluminum We hereby confirm consent was granted for the publication of this case by the patient, as so long as all records are de-identified."}
+{"text": "This observational study compared\u00a0the outcomes of consumers receiving community-based residential mental health rehabilitation support in Australia under a clinical staffing model and an integrated staffing model where Peer Support Workers are the majority component of the staffing profile. Reliable and clinically significant (RCS) change between admission and discharge in functional and clinical assessment measures were compared\u00a0for consumers receiving care under the clinical (n\u2009=\u200952) and integrated (n\u2009=\u200993) staffing models. Covariate analyses examined the impact of known confounders on the outcomes of the staffing model groups.\u00a0No statistically significant differences in RCS improvement were identified between the staffing models. However, logistic regression modelling showed that consumers admitted under the integrated staffing model were more likely to experience reliable improvement in general psychiatric symptoms and social functioning.\u00a0The findings support the clinical and integrated\u00a0staffing models achieving at least equivalent outcomes for community-based residential rehabilitation services consumers.The online version contains supplementary material available at 10.1007/s10597-022-01023-8. Contemporary community-based mental health residential rehabilitation services combine medium-to-long term accommodation with intensive rehabilitation and psychosocial support   over 6-to-24-months. Staff support is available 24-h a day.This study considered data from consumers admitted across three CCUs in Queensland over 3-years (12/2014-to-12/2017). One site operated the clinical staffing model, and two operated the integrated staffing model. Under the clinical staffing model, nursing staff reflect most staff roles; there are also senior allied health practitioners and medical staff. Under the integrated staffing model, PSWs reflect the majority team component (>\u200950%), with a reduction in the number of nursing roles. PSW staff have their own leadership structure and draw on their lived recovery experience to support consumers and guide clinical staff toward recovery-oriented practices. There is no specified interventional framework for PSWs at the CCUs. However, a qualitative study provides a rich description of what PSWs perceived their roles to be, emphasizing self-disclosure and connection through \u2018shared engagement in everyday activities\u2026 providing authentic opportunities to support residents deal with their experiences and fears\u2026 [building] relationships and trust\u2026 [and] reducing shame and isolation' (p5) . Ninety-one percent and 89% of eligible clinical and integrated staffing model site consumers consented. Recruitment exceeded the target to achieve\u2009>\u200980% power to detect a 15% difference in the Health of the Nation Outcome Scales (HoNOS)  and subsequent analyses were conducted on measures with\u2009>\u200950% of paired data. Where relevant, scores were transformed so that positive differences reflected improvement on all measures.SDs from the dysfunctional population mean ; [Cut-off 2] Within 2 SDs of the functional population mean ; and [Cut-off 3] Closer to the functional population mean than the dysfunctional population mean.The reliable change index (RCI) was calculated using the Christensen and Mendoza formula  .Reliable and clinically significant (RCS) change was assumed where the change between admission and discharge score exceeded the RCI Analyses were completed in IBM SPSS Statistics Version 27 . Comparability of the three sites was supported by examining measures at admission using the Kruskal\u2013Wallis test . Data from integrated staffing model sites were merged for subsequent analyses.Individual difference scores were categorized as 'reliable improvement \u2018or\u2019 no reliable improvement'  based on the RCI. The RCS improvement cut-off producing the largest proportion of improved consumers . Modelling was not undertaken for RCS improvement due to the low event rates. Independent variables (IVs) additional to the \u2018Integrated staffing model\u2019 entered in the final models were rationalized based on a threshold of p\u2009<\u20090.200 , MHI Index (64.0%), SFS (55.6%), LSP-16 (51.1%), and HoNOS . No group differences were statistically significant when the stricter RCS improvement criteria were applied.Covariate analyses are detailed in Table This study considered whether consumers receiving TRR support under integrated and clinical staffing models achieve equivalent functional and clinical outcomes at discharge. Regardless of staffing model, most consumers (50.4%-72.5%) showed reliable improvements in negative psychotic symptoms (SANS), psychological wellbeing and distress (MHI-38), social functioning (SFS), disability (LSP-16), and mental health and social functioning (HoNOS). The unadjusted odds of reliable improvement were equivalent between the staffing model groups on all measures, except in general psychiatric symptoms . No significant differences emerged in the likelihood of RCS improvement between the staffing model groups. Covariate analyses suggested that consumers admitted under the integrated staffing model were more likely to experience reliable improvement than in the clinical staffing model on two outcomes (BPRS-18 and SFS). Additional predictors of reliable improvement on the BPRS-18 were having a primary diagnosis of schizophrenia, higher HoNOS total score on admission, and lower levels of education. Additional predictors of reliable improvement in SFS emerging through the covariate analyses were the presence of comorbid substance use, involuntary mental health act status, and lower LSP-16 total scores on admission.The gains in clinical and functional outcomes are consistent with the literature supporting the positive impact of mental health rehabilitation , an outcome highly relevant to the service focus.Reliable improvements in symptoms and functioning generally occurred between admission to and discharge from community-based residential rehabilitation. Furthermore, most consumers demonstrated clinically significant improvements in negative psychotic symptoms and disability. Under the integrated and clinical staffing models, consumers had at least equivalent clinical and functional outcomes. In the context of other emerging research, our findings further emphasise the promising nature of the integrated approach as an alternative to traditional clinical staffing models. More research in other contexts will enhance the ability for future decisions about mental health rehabilitation services staffing to be evidence-informed.Supplementary file1 (PDF 907 KB)Supplementary file2 (PDF 250 KB)Below is the link to the electronic supplementary material."}
+{"text": "Correction to: European Radiology10.1007/s00330-022-08895-0The original version of this article, published on 09 June 2022, unfortunately contained a mistake. The sentence \"Two different observers performed the measurements; the plain radiographs were analyzed by an orthopedic-trained surgeon with a focus on hip preservation surgery (first author), whereas the computed tomography analysis was performed by a fellowship-trained musculoskeletal radiologist\" was corrected to read \"Two different observers performed the measurements; the plain radiographs were analyzed by an orthopedic surgery\u2013trained observer with a focus on hip preservation surgery (first author), whereas the computed tomography analysis was performed by a fellowship-trained musculoskeletal radiologist\". The original article has been corrected."}
+{"text": "Advances in cardiac surgical operative techniques and myocardial protection have dramatically improved outcomes in the past two decades. An unfortunate and unintended consequence is that 80% of the preventable morbidity and mortality following cardiac surgery now originates outside of the operating room. Our hope is that a renewed emphasis on evidence-based best practice and standardized perioperative care will reduce overall morbidity and mortality and improve patient-centric care. The Perioperative Quality Initiative (POQI) and Enhanced Recovery After Surgery\u2013Cardiac Society (ERAS\u00ae Cardiac) have identified significant evidence gaps in perioperative medicine related to cardiac surgery, defined as areas in which there is significant controversy about how best to manage patients. These five areas of focus include patient blood management, goal-directed therapy, acute kidney injury, opioid analgesic reduction, and delirium.The online version contains supplementary material available at 10.1186/s13741-022-00250-7. Enhanced Recovery After Surgery (ERAS) programs have become ubiquitous in the field of perioperative medicine and have played a key role in defining the essence of this relatively young discipline. These protocols have typically been applied to non-cardiac surgical populations  and Enhanced Recovery After Surgery\u2013Cardiac Society (ERAS\u2192-Cardiac) organizations are both committed to excellence in perioperative medicine, and in particular for patients undergoing high-risk surgery  to reduce unnecessary transfusions for patients undergoing cardiac surgery  relates to matching therapy with patient demands and avoiding the outstripping of the patient\u2019s reserve throughout their hospital course. Clinical best practice includes quantitative risk assessment  and intensive care unit (ICU)  in the past decade  criteria is neither sensitive nor specific for early identification of AKI. The limitations of serum creatinine and urine output have warranted the development of novel urinary biomarkers that have shown predictive value. Biomarkers allow the diagnosis of kidney injury to be made earlier, even in the absence of concurrent or subsequent kidney dysfunction  in perioperative cardiac medicine. There are implications for resource utilization as well as clinical outcome improvements in the five clinical topics and research questions (see Additional\u00a0file\u00a0Additional file 1. Research Questions."}
+{"text": "A 49-year-old woman developed thunderclap headaches triggered by straining during defecation. Magnetic resonance imaging (MRI) on day 3 after the onset revealed somewhat poor delineation of the bilateral distal posterior cerebral arteries without cerebral parenchymal lesions, which suggested possible vasoconstriction  and 1B. (1). Vasoconstriction has been reported to start at distal vessels and migrate more proximally to larger vessels (2). Therefore, serial MRI examinations are important for diagnosing RCVS.In RCVS, vasoconstriction can be difficult to detect in very distal branches, which can make its diagnosis challenging NoneAll authors contributed to patient care. Tetsuya Hashimoto wrote the manuscript and the other authors revised it.This study did not require IRB approval.Written informed consent was obtained from the patient to publish."}
+{"text": "Prior literature has indicated low socioeconomic status (SES) and regional differences as epidemiological risk factors for disability pension (DP) due to mental disorders.Our studies aimed to examine these associations and differences in greater detail, with separate consideration of the risk factors for mood disorders (F30\u201339) and non-affective psychotic disorder (F20\u201329) DP.Subjects (N = 36 879) were all those granted DP due to a mental disorder for the first time between 2010 and 2015 in Finland. All the subjects were matched with three controls. Education, income and occupational status were used as measures of SES. Conditional logistic regression models were used to study SES differences. Negative binomial regression analysis was used to study the levels of DP risk in the Finnish hospital districts.DP recipients had low educational and income levels and often lived alone. The risk of DP was greater in white-collar occupational groups compared with blue-collar workers. Students had the greatest risk of DP for all mental and mood disorders. Significant differences in the regional mental disorder DP risks did not appear to follow the traditional Finnish health differences.We found evidence of SES factors and regional variation associating with mental disorder-related severe loss of working and studying ability in a disorder-specific way. The increased risk of white-collar worker DP could be related to the psychosocially demanding contemporary working life. Regional variation in DP may at least partly relate to differences in regional mental health service systems.No significant relationships."}
+{"text": "Fluctuating course of delirium and complexities of ICU care mean delirium symptoms are hard to identify or commonly confused with other disorders. Delirium is difficult to diagnose, and clinicians and researchers may combine assessments from multiple tools. We evaluated diagnostic accuracy of different combinations of delirium assessments performed in each enrolled patient.Data were obtained from a previously conducted cross-sectional study. Eligible adult patients who remained admitted to ICU for >24 hours with at least one family member present were consecutively enrolled as patient-family dyads. Clinical delirium assessments (Intensive Care Delirium Screening Checklist [ICSDC] and Confusion Assessment Method-ICU [CAM-ICU]) were completed twice daily by bedside nurse or trained research assistant, respectively. Family delirium assessments (Family Confusion Assessment Method and Sour Seven) were completed once daily by family members. We pooled all delirium assessment tools in a single two-class latent model and pairwise  Bayesian analyses.Seventy-three patient-family dyads were included. Among clinical delirium assessments, the ICDSC had lower sensitivity  and higher specificity  using Bayesian analyses compared to pooled latent class analysis and CAM-ICU had higher sensitivity  and higher specificity . Among family delirium assessments, the Family Confusion Assessment Method had higher sensitivity  and higher specificity  using Bayesian analyses compared to pooled latent class analysis and the Sour Seven had higher specificity  but lower sensitivity .Results from delirium assessment tools are often combined owing to imperfect reference standards for delirium measurement. Pairwise Bayesian analyses that explicitly accounted for each tool\u2019s (performed within same patient) prior sensitivity and specificity indicate that two combined clinical or two combined family delirium assessment tools have fair diagnostic accuracy. One third of patients admitted to the intensive care unit (ICU) will develop delirium , 2 that A systematic review and psychometric analysis on five clinical delirium assessment tools  from 36 patient cohorts reported the Intensive Care Delirium Screening Checklist (ICDSC) and Confusion Assessment Method-ICU (CAM-ICU) had the highest validity and reliability among critically ill adults . Family The diagnostic accuracy of a delirium assessment tool is determined by comparing the results from a delirium assessment to a gold standard test [with 100% accuracy] . There iLatent class models are employed widely to estimate diagnostic accuracy without a gold standard  as this This diagnostic evaluation study used data from a previously published cross-sectional study  and is rRecruitment of participants was performed at a large, tertiary care academic hospital  within a single-payer health system. A multidisciplinary care team staffs the 28 closed beds of the FMC medical-surgical ICU. Eligibility criteria for study participation are listed in The study collected data in ICU up to a maximum of five days. Patient and family demographics  were collected at first delirium assessment. Patient clinical characteristics  were obtained from eCritical, a beside clinical information system validated for research purposes .Two clinical delirium assessments were completed by assessors  blind to the results of the family administered delirium assessments. The ICDSC was conducted twice daily  and is valid and reliable to screen for delirium on eight independent domains  . ICDSC dTwo family administered delirium assessments were performed once daily by family members of critically ill patients blind to results from clinical assessments. Family members assessed patient delirium using the Family Confusion Assessment Method (FAM-CAM) and the Sour Seven. Using the FAM-CAM, family members answered 11-items regarding sudden changes to patient attention, orientation, perception or concentration . The FAMboth pairwise assessments within 6-hour time windows, chosen to account for the fluctuation in delirium presentation  is not available for delirium detection and the development of such a test is likely not feasible or practical , 33. In Thomas et al.  referredLatent class analysis is frequently used to estimate diagnostic accuracy from imperfect diagnostic tests , 28. ThiOur results are in line with our earlier report  such thaWe have previously shown feasibility and acceptability of employing family administered delirium assessment tools in adult ICU , and repThe results of our study must be interpreted cautiously and there are several limitations worth noting. First, this study was conducted as a secondary analysis of data collected in an earlier observational study. Second, our data was collected from patients admitted to a single medical center. Although this center serves a large catchment area of approximately 1.8 million people and should be reasonably representative of multisystem ICU patients in academic hospitals, these finding may not be generalizable to all ICU patients. Third, nearly 20% of our sample were patients with a neurological admission status in whom delirium diagnosis is especially challenging as neurologic patients fall more under the term acute encephalopathy rather than delirium . Our abiCaring for critically ill patients includes multiple tools to identify ICU delirium. Results from delirium assessment tools employed at different times during patient care are often combined owing to no gold standard and imperfect reference standards for delirium but using several tools at a single time is impractical and infeasible. Using pairwise Bayesian analyses to explicitly account for each tool\u2019s prior sensitivity and specificity all in the same patient within 6-hours, we report that two combined clinical or two combined family delirium assessment tools have fair diagnostic accuracy.S1 Table(DOCX)Click here for additional data file.S2 Table(DOCX)Click here for additional data file.S3 Table(DOCX)Click here for additional data file."}
+{"text": "Pregnancy is known to be a risk factor for venous thromboembolism (VTE). We report the case of a pregnant patient with difficult to diagnose iliac vein thrombosis, establishing a definite diagnosis by clues of great saphenous vein reflux.A 37-year-old G1P0 woman at 35 weeks of assisted twin gestation presented with a complaint of persistent left lower limb edema and tenderness. A vascular ultrasound was used to examine the bilateral lower limb. Doppler of left lower extremity revealed continuous great saphenous vein reflux. Right saphenofemoral veins demonstrated venous stasis and no reflux. Unilateral continuous great saphenous vein reflux suggested left iliac veins obstruction or extrinsic compression. Anterograde venography showed a completely occlusive filling defect of the left external iliac vein, which is the definitive diagnosis of acute deep venous thrombosis. The patient underwent a cesarean delivery following inferior vena cava filter (IVCF) placement, and no signs of deep venous thrombosis (DVT) or pulmonary embolism (PE) were reported after delivery.In pregnant women with suspected deep vein thrombosis, it is imperative to assess the presence of unilateral continuous great saphenous vein reflux. Pregnancy is one of the major risk factors in the development of venous thromboembolism (VTE), with pregnant women having a fourfold increased risk of VTE compared with non-pregnant women . PregnanA 37-year-old pregnant woman G1P0 at 35 weeks of twin gestation complained of left leg swelling and pain for approximately 1 week. In an external imaging facility, she underwent a lower extremity ultrasound, which revealed varicosis of the left great saphenous vein.History of past illness\u00a0.Colour venous doppler ultrasound of the bilateral lower extremity revealed that the deep femoral vein, popliteal vein, proximal segments of crural veins were normal. Imaging revealed unilateral continuous saphenofemoral reflux in the left lower extremity Fig.\u00a0. The sapPregnancy is a pro-coagulant state . CombineD-dimer is physiologically elevated during pregnancy, so its utility during pregnancy is limited to ruling out DVT. According to an analysis of a prospective study  evaluatiThe recommended treatment for thromboembolism in pregnant patients consists of weight-based unfractionated heparin or low-molecular weight heparin throughout pregnancy until at least 6 weeks postpartum . The redIVCF was widely used in the daily clinical practice to prevent PE. An inferior vena cava (IVC) filter can act as a mechanical barrier in the prevention of a lower extremity or pelvic venous thrombosis from embolising to become a potentially lethal pulmonary embolus. The intended dwell time of a temporary IVCF is 7 to 35 days. Complications of IVC filters include trauma at insertion, fracture and/or migration, occlusion by thrombus or endothelialisation, penetration of the IVC and failed retrieval .Because of the morbidity and mortality associated with pregnancy-related thrombosis, a more accurate DVT diagnosis remains an important focus of future research. We present the case of a patient with suspected DVT in whom to establish a definite diagnosis by great saphenous vein reflux. Anatomical communications between superficial and deep veins should be remembered. In the lower limb, the most important superficial veins are the greater and lesser saphenous veins. Continuous great saphenous vein reflux may be a signal of iliac vein thrombosis.During my pregnancy, I had symptoms of my left leg swelling and tenderness. The doctors told me that it might be a thrombosis in my leg, I got several tests; however, the doctors were still unsure about the thrombosis. Vascular ultrasound suggested left iliac veins obstruction or extrinsic compression. Anterograde venography confirmed the diagnosis. Although I was disappointed about the diagnosis, I was glad to hear the doctors had finally a definite diagnosis."}
+{"text": "Staging of disease allows for the estimation of disease severity based on the identification of important points in the natural history of a disease. Crucially, grouping together patients at similar stages of disease severity permits for the enrichment of clinical trials . In Alzhin vivo. Several recent clinical trials screened potential participants prior to enrolment in order to only include individuals who could benefit from a specific therapy. Moreover, the recent phase II donanemab clinical trial also restricted enrolment criteria to intermediate levels of tau pathology as determined by tau-PET. A potential strategy could be to assign amyloid-\u03b2 positive participants to different clinical trials depending on their severity of tau pathology, evaluated using PET-based Braak staging. Having groups of participants with greater similarity in rates of short-term cognitive decline could increase statistical power for future trials by reducing standard error of the mean for cognitive decline within a group. Using PET for disease staging has two important advantages over fluid biomarkers. The topographical information for PET imaging allows for inferences regarding AD severity in an individual subject. Furthermore, because phosphorylated tau (p-tau) biomarkers in both CSF and plasma are more closely associated with amyloid-\u03b2 plaques than tau neurofibrillary tangles [Individuals without cognitive impairment are highly heterogenous in terms of their risk of future cognitive decline . Even re tangles , especiaTau-PET may also be useful for monitoring disease modification as a secondary outcome in pivotal randomized controlled trials. While it is not fully understood whether tau tangles themselves are causative of cognitive decline or merely upstream of it, a therapy that is associated with lower rates of tau accumulation in the experimental group could be interpreted to indicate successful disease modification. For example, if amyloid-positive individuals receiving an anti-amyloid monoclonal antibody do not accumulate tau outside of Braak I\u2013II regions while the placebo arm does, this finding could be used to support primary outcome data (presumably differences in cognitive trajectories) as evidence of disease modification. Such a finding would also provide evidence in humans to support numerous animal models of amyloid-\u03b2 pathology potentiating tau aggregation and spreading.In conclusion, disease staging systems using PET imaging have the potential to inform the design, enrichment and monitoring of randomized clinical trials in the field of AD. Given the recent success of lecanemab and the renewed interest in investments into the AD field, PET-based disease staging may increase the success of future anti-amyloid monoclonal antibody therapies, or therapies based on other mechanisms. Despite some evidence suggesting that atypical clinical variants of AD largely have tau distributions compatible with the Braak staging system , future"}
+{"text": "This study investigates mortality differences by income among first- and second-generation immigrants and the native ancestral population in Sweden. Despite immigrants\u2019 various vulnerabilities and the exhaustive evidence for a persistent inverse relationship between income and mortality in general Western populations, previous studies from outside Sweden demonstrated surprisingly weak income gradients in mortality among first-generation immigrants. Examining these associations among second-generation immigrants may help to understand this paradox.Swedish register data from 2002 to 2016 were used to study the association between individual income rank positions and all-cause mortality. The study population was restricted to ages 25-64 years. Based on \u2018relative indices of inequality\u2019 (RII) derived from Poisson regressions, we measured mortality differentials between the least and most deprived income rank positions stratified by nativity group and sex. Correspondingly, we assessed absolute differences in mortality between the most and least deprived by using \u2018slope indices of inequality\u2019 (SII).Largest inequalities in mortality by relative income rank positions (based on RII) were found for the Swedish native ancestral population that showed on average a nearly doubled mortality risk for least compared to most deprived rank position. Immigrants disclosed weak or even nullified associations between relative income rank and all-cause mortality. Mortality inequalities by income among second-generation immigrants were substantially higher relative to first-generation immigrants but somewhat lower compared to the native ancestral population. These patterns were consistent between males and females, and confirmed by the use of SII.Distinct exposures to inequality structures but also first-generation immigrants\u2019 \u2018mortality advantage\u2019 likely contribute to the considerable mortality differences by income between the studied nativity groups.\u2022\u2002Despite their social and economic vulnerabilities, first-generation immigrants in Sweden disclose weak associations between relative income rank and all-cause mortality.\u2022\u2002Second-generation immigrants in Sweden show notably higher magnitudes in income-related mortality compared with first-generation immigrants."}
+{"text": "Liver transplantation is currently the only curative treatment for patients with end-stage liver disease. However, liver transplantation can be associated with catastrophic complications in the early postoperative setting, including hepatic artery thrombosis (HAT) and portal vein thrombosis (PVT). Postoperative complications are associated with hepatic artery resistive index (RI) < 6, systolic acceleration time (SAT) > 0.08 seconds and peak systolic velocity (PSV) > 200 cm/s on doppler ultrasound (DUS). DUS is also used in an intraoperative setting to assess patency and early complications prior to the end of the operative period, allowing for early correction. This literature review evaluates the prevalence of DUS use in intraoperative settings to identify transplant complications. A lack of consistency and minimal knowledge of intraoperative DUS warrants additional research into its usage and standardization. A liver transplant (LT) is the only curative treatment for children and adults with end-stage liver disease. The first LT performed by Starzl in 1967 was from a deceased donor. A whole donor liver replaced the resected liver and was called an orthotopic liver transplant (OLT) . The intGeneral considerations in liver transplant ultrasound\u00a0The standard technique for perioperative Doppler ultrasound (DUS) involves using a 2-5 MHz convex transducer positioned with a probe angle < 60 degrees to the long axis of the vessel. Typically, hepatic artery measurements are made just proximal to the hepatic artery bifurcation -15. The Postoperative Doppler ultrasoundIn 1994, Dodd et al. were among the first to associate quantitative DUS findings in the postoperative period with hepatic arterial complications following a liver transplant. Their findings from a retrospective cohort identified a significant decrease in the hepatic arterial resistive index (RI) and a significant increase in systolic acceleration time (SAT) in patients that experienced arterial complications (thrombosis or stenosis). Peak systolic velocity (PSV) and absent arterial waveforms were not associated with vascular complications. The results suggested that a RI < 0.5 and SAT > 0.08 seconds were predictive of hepatic arterial complications . These fThe incidence of early hepatic artery thrombosis (eHAT), defined as hepatic artery thrombosis (HAT) within one month of transplant, is a well-documented complication following both OLT and SLT. eHAT occurs in 2-5% of adults following LT -20. A reHepatic artery stenosis (HAS) occurs later than HAT postoperatively . It occuIntraoperative Doppler ultrasoundCheng et al. demonstrated the utility of intraoperative DUS in a case series of nine patients with identified vascular complications. The subsequent intervention resulted in surgical correction at the time of transplant and 100% graft survival . Gu et aIntraoperative Doppler ultrasound has clinical impact in identifying sequelae of the hepatic artery buffer response. Blood flows into the liver through the portal vein and hepatic artery. The liver receives nearly 25% of cardiac output and performs first-pass filtration from the splanchnic circulation ,33. The Hepatic venous outflow obstruction occurs in 1-6% of OLTs due to inferior vena cava (IVC) torsion, compression, or anastomotic stenosis . TypicalAlternative ultrasound types in transplantHom et al. performed a study comparing patients who had undergone a liver transplant with contrast-enhanced ultrasound to conventional color DUS . ContrasThe literature on intraoperative DUS in liver transplants is relatively sparse despite increased use. The present case reports and case series have demonstrated the utility of qualitative DUS assessment to detect immediate graft complications. However, only a handful of single-center studies have investigated quantitative parameters that would allow for increased standardization of DUS interpretation. This review concludes that focused investigations into intraoperative DUS findings are necessary for continued liver transplant success."}
+{"text": "Indocyanine green fluorescence angiography (ICGFA) is commonly used in colorectal anastomotic practice with limited pre-training. Recent work has shown that there is considerable inconsistency in signal interpretation between surgeons with minimal or no experience versus those consciously invested in mastery of the technique. Here, we deconstruct the fluorescence signal patterns of expert-annotated surgical ICGFA videos to understand better their correlation and combine this with structured interviews to ascertain whether such interpretative capability is conscious or unconscious.n\u2009=\u200924) were quantitatively interrogated using a boutique intensity tracker (IBM Research) to generate signal time plots. Such fluorescence intensity data were examined for inter-observer correlation  at specific curve milestones: the maximum fluorescence signal (Fmax), the times to both achieve this maximum (Tmax), as well as half this maximum (T1/2max) and the ratio between these (T1/2/Tmax). Formal tele-interview with contributing experts (n\u2009=\u20096) was conducted with the narrative transcripts being thematically mapped, plotted, and qualitatively analyzed.For fluorescence signal analysis, expert-annotated ICGFA videos (excellent (ICC0.9\u20131.0) for Fmax, Tmax, and T1/2max  and moderate (0.5\u20130.75) for T1/2/Tmax (0.729). While all experts narrated a deliberate viewing strategy, their specific dynamic signal appreciation differed in the manner of description.Correlation by mathematical measures was Expert ICGFA users demonstrate high correlation in mathematical measures of their signal interpretation although do so tacitly. Computational quantification of expert behavior can help develop the necessary lexicon and training sets as well as computer vision methodology to better exploit ICGFA technology.The online version contains supplementary material available at 10.1007/s00464-022-09299-3. Indocyanine green fluorescence angiography (ICGFA) has been rapidly adopted across many surgical disciplines . It has Therefore, here we follow on the initial observer variability discovery work with a focused investigation of the interpretation and cognitive processes occurring at expert user level in that study via semi-structured interviews as well as detailed quantitative analysis of observed video signal interpretation. The purpose of our study was to evaluate factors underlying the better correlation seen between experts and to establish whether this occurs due to conscious act in order to inform how best to advance ICGFA interpretation among others.n\u2009=\u200914, 9 showing perfusion signals at the time of proximal colonic transection, five showing anastomotic/small bowel perfusion) obtained during routine laparoscopic colorectal surgery to both experienced  and inexperienced  observers via an innovative video display and annotation platform (Mindstamp: The Interactive Video Platform www.mindstamp.io). All ICGFA transection perfusion videos demonstrated the white-light tissue appearances as well as the near-infrared (NIR) appearances and an overlay, false-colored view of the NIR signal on the white-light image simultaneously using the Pinpoint Endolaparoscopic Near-infrared system (Stryker\u00a9). Using Mindstamp, observers were able to record their interpretations of the fluorescence signal of the proximal colonic segment directly onto the video segment, indicating their choice of stapler positioning across the colon based on their interpretation of the fluorescence signal. This allowed comparison of interpretations between experienced and inexperienced users and showed significant differences in interpretation between the two groups with experienced users showing higher levels of agreement in signal interpretation.This research    of four intraoperative ICG angiograms used in the prior study were analyzed using a boutique intensity tracker (IBM Research Ireland ) to genesee Fig.\u00a0 (camera max), the time required for it to rise to fifty percent of the maximum fluorescence intensity (T1/2max), and the time to achieve the full peak (Tmax), as well as the ratio of the two (T1/2/Tmax)  for one video and charted as scatter plots, with Chi-squared confidence ellipses charted to visually demonstrate expert/inexpert clustering of curve features.The generated fluorescence intensity data were recorded on Microsoft Excel v2012 . Specific curve milestones identified previously as those most clinically meaningful indicators of appropriate ICGFA perfusion signal , 11 werewww.wordclouds.com . Although not academically quantitative, this method of graphical representation groups commonest words used by size with increasing font size indicating more frequently used terms as a simple visual means of summarizing common words and terms.To understand any conscious viewing strategy applied by each experienced user in the study, each underwent formal interview conducted by teleconference using a template of open and closed questions relating to specific and general uses of ICG fluorescence with particular reference to signal interpretation (see supplementary information). Responses were recorded, transcribed, and qualitatively assessed via thematic analysis  (in shorn\u2009=\u20096) were synthesized from the ICGFA videos (n\u2009=\u20094).Six thousand forty data points per expert  levels of correlation among these experienced users regarding peak intensity (Fmax 0.925) and chronological flags (Tmax 0.938 and T1/2max 0.925) and moderate (0.5\u20130.75) correlation for the T1/2max/Tmax ratio (0.729).Once plotted, the quantitative fluorescence curves were analyzed regarding Fn\u2009=\u20092) with the former espousing the benefit of simultaneous interpretation of white-light image appearances. Minimalist systems with fewer options for signal output manipulation were favored. Among considerations other than on-screen fluorescence signal, advocacy for standardization to fixed dosing and administrative method protocols was common with less regard for exact dosing, titration to weight, or ideal signal performance. With respect to inflow signal interpretation, homogeneity of distribution and maximal brightness were prioritized criteria although there was otherwise divergence in opinions re the other proposed criteria. A single expert admitted to using the chronology of the fluorescence as a discrete transection modifying criteria, while two others actively expressed that they did not feel this to be important.Structured discussion with each experienced observer demonstrated that each use ICGFA as a confirmatory rather than directive measure with respect to sufficiency of bowel perfusion  with a focus on inflow alone and each employs a deliberate interrogative viewing strategy to do so. Furthermore, all advocated a conscious systematic approach to learning including preclinical simulation as opposed to operative experiential learning although none had done so themselves or has such a facility in their departments. The experts however described their exact methodology in a variety of ways without common precise terminology , the time to achieve this zenith (Tmax), and the threshold period at which half this incline has been achieved (T1/2max) demonstrated excellent correlation. Interestingly, compound metrics identified experimentally as prognostically sensitive for anastomotic leakage (T1/2max/Tmax) [Our experienced users showed excellent tacit agreement in their selections of bowel locations for proximal transections and their selection points were found to have highly similar curve profiles suggesting a common acquired ability to similarly dissect the dynamic signal being observed and flag the most relevant clinical location in a highly concordant fashion. Specifically, the peak intensity (Fax/Tmax)  resultedThis study\u2019s findings do suggest a method for explaining to others how best to extract the most useful information from ICGFA through its observation, perhaps in training libraries that users can study as they accrue their own clinical experience showing patterns of ICGFA signaling at different areas across a screen with indication of where an expert surgeon would choose to affect a clinical decision. Furthermore, the digital deconstruction of ICGFA methodology it uses could also be used for post hoc reflection on trials and experiences most especially those with equivocal or negative results . This stThis work so prompts further study and informs any future investigators regarding potentially useful parameters to investigate in future collaborative, multicentered work to cultivate greater datasets and a body of evidence to guide best practice and aid in surgical simulation, training, and research.This work is of course limited by the relatively small numbers involved but it does enable larger studies now to be performed to test and tease out these findings more robustly and indeed determine the usefulness of interpretation training for surgeons beginning their ICGFA use. It is possible too that actual intraoperative interpretations  differ from those made when watching isolated video alone and this also needs greater understanding (likely best through studies of inter- and intra-observer interpretations in theater versus out of theater).In conclusion, ICGFA interpretation appears to standardize with experience although at present such expertise is tacitly acquired. Computational charting of the fluorescence signal into quantitative ICGFA plots over time seems able to provide a mathematical way to understand clinical mastery in interpretation potentially allowing introduction of a standard lexicon to verbally articulate the peaks and troughs of these visible intensity fluctuations. More complete understanding of expert interpretation may also inform machine-based analysis methods to automatically provide ICGFA interpretation in the future although further work is necessary to achieve this goal.Supplementary file1 (DOCX 13 kb)Below is the link to the electronic supplementary material."}
+{"text": "Transportation needs among lower-income older adults is understudied, particularly regarding how transportation utilization is related to leisure constraints. This preliminary study included 39 adults residing in subsidized housing in North Carolina and Pennsylvania  and assessed reported modes of transportation for daily activities and perceived leisure activity constraints. Much of the sample reported driving (57.9%) or relying on others to drive (70.3%) with a significant sample reporting use of public transportation (48.6%). Transportation utilization was differentially correlated with leisure constraints. Perceived difficulties getting to/from activities in the community was associated with greater utilization of having \u2018others drive you\u2019 , but lower utilization of \u2018driving oneself\u2019 . Walking as a mode of transportation was associated with lower  perceived difficulties getting to/from activities in the housing complex. These results indicate the importance of further exploring the association between transportation and leisure needs of these lower-income older adults."}
+{"text": "After forced migration, pregnant women and new mothers face specific challenges in the host country. Little research focuses on the impact these challenges have on forced migrant (FM) women\u2019s mental health (MH). The study\u2019s aim shed light on FM women\u2019s mental wellbeing in the perinatal period.For this mixed-method study 15 individual problem-centered interviews were carried out in Arabic with FM mothers living in Germany within the postnatal period to one year postpartum. The transcripts were analysed using the Framework Analysis. In addition, structured quantitative interviews with 3070 new mothers were conducted on 3 obstetric wards in Berlin over a period of 23 months using an adapted version of the MFMCQ and the PHQ4. FM women (n = 187) were compared with immigrant (n = 1192) and non-immigrant women (n = 1673). A Kruskal-Wallis-Test was performed to compare the three groups.In the qualitative interviews mothers stated having depression and varied emotions . Most FM mothers indicated contextual factors (e.g. bad housing conditions) and structural barriers in perinatal healthcare as negatively impacting their MH. The preliminary quantitative analysis of the interviews conducted in birth clinics directly after birth showed no significant differences in the mean scores of the PHQ-4 within the compared groups .While the quantitative study part indicates that PHQ-4 scores are independent of FM experience, the qualitative part shows that FM new mothers face particular burdens in their living conditions that make them vulnerable to MH issues. Inconsistent results could be attributed to the different timing in which the structured questionnaires and qualitative interviews were conducted.\u2022\u2002To promote Mental health of new mothers, we advocate for a diversity oriented, responsive healthcare system.\u2022\u2002Effective approaches must be provided to include FM mothers in existing Early Childhood Intervention programs."}
+{"text": "Empathy is a social emotive skill that let to experience the same feelings of another person without being in the same situation. It changes during the growth becoming more over sophisticated with the involving of cognitive functions such as perspective taking . Several researches observed a correlation between empathy and psychopathologies that involve cognitive functions such as attention and executive functions  or decision-making .To investigate the impact of cognitive impairment on different empathy dimensions.80 subjects with severe neurocognitive deficit were examined. WAIS-R, neuropsychological battery and IRI test were performed.The impairment of perspective-taking dimension was significantly noticeable (=or<17/30). In addition, impairments of self-regulation process and inner-state monitoring mechanisms were also observed (=or<18/40).According to previous researches, this study confirms that empathy can be reduced when cognitive functions are compromised by psychopathologies or other medical conditions. Personal distress and perspective taking are empathy dimensions more affected in these cases."}
+{"text": "Transfemoral transcatheter aortic valve implantation (TAVI) under conscious sedation is the most widely used method of implantation. Echocardiography is used to detect complications and to assess the implantation result. The aim of this paper is to provide a time-efficient protocol when transthoracic echocardiography (TTE) is used to guide TAVI procedures.The online version contains supplementary material available at 10.1186/s44156-022-00005-6. Transfemoral transcatheter aortic valve implantation (TAVI) undertaken with conscious sedation, rather than with general anaesthesia, is the most widely practised mode of implantation in Europe. Transthoracic echocardiography (TTE) is the main form of imaging employed in these procedures and is used to detect complications, assess the result of transcatheter heart valve (THV) implantation and guide further management. We propose a time-efficient, focused protocol for echocardiographers to follow when echocardiography is used to guide transfemoral TAVI undertaken with conscious sedation. This protocol provides guidance on which key assessments are required, important pitfalls and provides examples of important complications that may arise in order to allow timely identification\u00a0and effective management. In the modern era of minimalist TAVI with transfemoral access and conscious sedation, transoesophageal echocardiography (TOE) may be preferable in a small proportion of TAVI procedures undertaken with general anaesthesia, with the benefit of continuous echocardiographic monitoring and reduced risk of contamination of the sterile field. TOE guidance may also be preferable in patients with severe renal insufficiency, particularly in conjunction with fusion imaging, to minimize contrast use and the consequent risk of renal injury.Aortic stenosis is the most prevalent valvular lesion in Europe and North America, 2. The On-table pre-procedure assessmentImmediate post THV deployment assessmentPre-cath lab exit assessmentIntraprocedural echocardiographic imaging is used principally to assess prosthetic valve function post-deployment and to allow early detection of complications. There are 3 distinct phases where TTE is employed in TAVI procedures:A rapid assessment should be made whilst preparations are underway for gaining vascular access. The value of this is to allow a baseline study for comparison with changes that may develop during the procedure. The location of optimal echocardiographic windows should be carefully noted in order to improve quality and avoid suboptimal images which may delay the procedure and hamper accurate assessment. Where necessary, slight tilting of the patient with a wedge under the right chest may be employed to improve echocardiographic image quality. Careful positioning at the start of the procedure is important as the patient may be unable to move and reposition themselves during the procedure. Additionally, image acquisition should be done with ECG-triggering as standard Fig.\u00a0A. This eImmediately post THV deployment echocardiography should be undertaken to rapidly identify complications, to assess prosthesis function and paravalvular regurgitation.The first imaging window is the subcostal region to assess for development of pericardial effusion which may indicate injury to the annular complex or LVOT 1C Right). A comparison with the immediate pre-procedure images is important to help determine new changes  and transvalvular aortic regurgitation (TAR) may be seen post THV deployment. Assessment should be made from short axis, left parasternal long axis and apical windows. TAR may be artefactually caused by the stiff catheter delivery wire. A transverse, short-axis view just below the THV in the LVOT is particularly useful in differentiating wire-induced TAR from PVR . Jet lies within the THV frame and adjacent to the delivery wire.Additional file 3: Video S3: Apical 5 chamber view showing TAR jet within the THV frame and \u2018hugging\u2019 the delivery wire.Additional file 4: Video S4: Small PVR jets at 12 o\u2019clock. Larger PVR jet at 3 o\u2019clock. PVR lies outside the THV frame.Additional file 5: Video S5: Apical 5 chamber view showing PVR jet outside the THV.Additional file 6: Video S6: Parasternal long axis view showing small VSD post deployment of balloon expandable THV.Additional file 7: Video S7: Short axis view at LVOT level showing VSD."}
+{"text": "Using thecorrected imputed genomic dataset, the average predictive abilitiesobtained across traits and model runs increased by 0.008 for thebenchmark main-effect model G-BLUP when compared to predictiveabilities obtained with the original dataset. Based on these results, theestimated effect of the error on the published genomic predictiveabilities was negligible. When repeating GWAS using the correcteddataset, differences between the original and the corrected results wereobserved. A revised Supplementary Table 3 containing a list ofsignificant marker-trait associations identified using GWAS that wasbased on the corrected genomic dataset was provided."}
+{"text": "Ecological momentary assessment (EMA) was used to understand the influence of individual differences in stress reactivity measured by the Perceived Stress Reactivity Scale (PSRS) and the cortisol awakening response (CAR) on emotional reactivity to stressors, operationalized as the within-person change in negative affect (NA) associated with stressor exposure. Five times per day for 10 days, 178 working adults ages 20-80 years old  reported in EMAs their current NA and whether they had experienced a stressor since the previous survey. During the same period, participants provided seven salivary cortisol samples per day. Samples collected at awakening and 30-minutes post-awakening were used to calculate the CAR. Steeper CARs are hypothesized to have a role in preparing individuals to cope with upcoming daily demands. Before the EMA period, participants completed the PSRS, including its Work Overload Reactivity subscale. Multilevel models revealed a significant 3-way interaction between Stressor Exposure x CAR x Work Overload Reactivity predicting daily NA. Individuals with high Work Overload generally reported greater NA, regardless of stressor exposure or the magnitude of their CAR. Individuals with low Work Overload reported lower levels of NA on days they experienced more stressors than usual and had steeper CARs. Effects remained significant after controlling for neuroticism and the Perceived Stress Scale. Findings suggest the CAR\u2019s potential role of preparing individuals for upcoming demands is moderated by work-related stress reactivity. Steeper CARs on days with more stressor exposure may provide enhanced emotional benefits for individuals low in workload reactivity."}
+{"text": "Figure 1) ruled out pulmonary embolism revealing bilateral pleural effusions and a diagnostic thoracocentesis showed a predominantly neutrophilic exudate with normal pH and quite low glucose level (71mg/dl). A high titre of rheumatoid factor in the neutrophilic exudate plus the medical history of rheumatoid arthritis set the provisional diagnosis of a rheumatoid arthritis\u2019 pleurisy and the patient was referred. Upon our clinical examination, diminished lung sounds in both lung bases were found without additional lung sounds. A new diagnostic thoracocentesis was performed which revealed surprisingly a predominantly lymphocytic exudate with normal pH but again quite low glucose level (62mg/dl). The adenosine deaminase (ADA) value was high (84 IU/L) highly suggestive of tuberculosis, mesothelioma, or lymphoma. A full body computed tomography  was performed which was negative for solid tumour, pleural thickening or enlarged lymph nodes. The Ziehl-Neelsen staining of the pleural fluid revealed an acid-fast organism and the next day the polymerase chain reaction was positive for mycobacterium tuberculosis. A three regimen antituberculosis therapy was initiated and in the follow up of the patient  bilateral pleural effusions were reduced. Pleural exudate in patients with known rheumatoid arthritis should not be always attributed to their condition, as thorough investigation might reveal tuberculosis or malignancy.An 86-year-old woman, non-smoker, with a medical history of rheumatoid arthritis for 20 years (stable at 5mg of prednisolone) was referred from a peripheral hospital to the Department of Respiratory Medicine of our tertiary hospital for further evaluation of bilateral pleural effusions with the provisional diagnosis of rheumatoid arthritis pleurisy. The patient reported frailty starting two months prior, low-grade fever, and mild small joints\u2019 arthralgias for one week and pleurodynia in her right hemithorax starting two days ago. A computed tomography pulmonary angiogram ("}
+{"text": "Knee osteoarthritis (OA) is one of the leading causes of pain in older adults. Previous studies indicated clinic-based transcranial direct current stimulation (tDCS) was effective to reduce pain in various populations, but no published studies have reported the efficacy of home-based self-administered tDCS in older adults with knee OA using randomized clinical study. Thus, the purpose of this study was to evaluate the efficacy and safety of tDCS on clinical pain intensity in adults with knee OA pain. One hundred twenty participants aged 50\u201385 years with knee OA pain were randomly assigned to receive fifteen daily sessions of 2 mA tDCS for 20 min (n = 60) or sham tDCS (n = 60) over 3 weeks with remote supervision via telehealth. Clinical pain intensity was measured by asking participants to rate their knee pain using a numeric rating scale from 0 (no pain) to 100 (worst pain imaginable). Participants  had a mean age of 66 years and the mean body mass index in the sample was 32.59 kg/m2. There have been no adverse events. Active tDCS significantly reduced pain intensity compared to sham tDCS after completion of the fifteen daily sessions . We demonstrated that home-based self-administered tDCS was safe and reduced clinical pain intensity in older adults with knee OA, which can increase its accessibility. Future studies with multi-site randomized controlled trials with various populations are needed to validate our findings."}
+{"text": "Several theories exist regarding the underlying mechanism of type V endoleaks (T5EL), which remains unclear. Torikai et al. (2018) describe sac expansion in cases with patchy heterogenous enhancement of peripheral thrombus and postulate these are due to atypical type II endoleaks (T2EL) from proliferated vasa vasora. These cases of apparent endotension pose a therapeutic challenge as continued sac expansion warrants active intervention.Retrospective review of T5EL cases was performed who underwent multidisciplinary discussion at our institution between 2020\u20132021. Clinical history and imaging were reviewed by a vascular interventional radiologist aiming to identify the underlying mechanism of sac expansion.Two cases of these specific T5ELs were identified. One patient underwent endovascular management and image-guided aspiration of intra-sac fluid whilst another underwent open surgical ligation and sac plication. In both cases, fluid re-accumulated with re-expansion of the aneurysmal sac on follow-up. Careful review of CT imaging showed subtle foci of peripheral sac enhancement, suggestive of vasa vasora causing occult T2ELs. This was not visible on single phase CTA, super-selective angiography or cone beam CT.We identified two complex cases with unexplained sac expansion following EVAR suggestive of T2ELs from proliferated vasa vasora. Transcatheter embolisation of this network of vessels although challenging has been previously considered to stunt sac expansion. We suggest this phenomenon is under-diagnosed. Nevertheless, long-term surveillance is warranted as continued sac expansion risks changes in aneurysm morphology leading to potential loss of the proximal/distal seal zones. Type V endoleaks (T5ELs) describe aneurysm sac expansion after endovascular aortic repair (EVAR) without a demonstrable type I-IV endoleak /imaging was performed and reviewed by a vascular interventional radiologist in attempts to identify a potential mechanism for sac expansion. For this type of study formal ethical approval is not required.Cases of T5EL with heterogenous appearances of the aneurysm sac that underwent multidisciplinary discussion at our tertiary referral centre between 1Two cases of the specific subtype of T5EL were identified in male patients aged 84\u201385\u00a0years. Both patients underwent elective EVAR with Zenith endografts  between 2007\u20132010 for infra-renal abdominal aortic aneurysms and later presented with persistent aneurysm sac expansion. No endoleak was identified on CTA nor were there any inflammatory changes around the aneurysm sac. Both patients underwent diagnostic catheter angiography with cone beam CT, but a cause of sac expansion could not be identified. This included super-selective catheter angiograms scrutinising the SMA/internal iliac vessels for small T2ELs.Both patients had been treated for other endoleaks in the past, prior to presentation with unexplained sac expansion. These were managed endovascularly by transcatheter embolisation of T2ELs or endograft relining with a Nellix endovascular aneurysm sealing system  in the first patient for a type IIIb endoleak.Duplex ultrasound (US) of the aneurysm sac in the first patient demonstrated a large central anechoic fluid component with peripheral echogenic thrombus and no endoleak Fig.\u00a0. Given tA T2EL endoleak from left lumbar arteries in the second patient was resistant to attempts at endovascular embolisation. Due to persistent sac expansion, the patient underwent open sac plication. Intraoperatively, T2ELs from previously embolised left lumbar arteries and the IMA were ligated. A small type IIIb endoleak from the main body was repaired with bioglue. Sac haematoma and formerly deployed embolic material was evacuated and the sac was plicated. Similarly, surveillance US found re-expansion of the sac to pre-operative dimensions without an endoleak. The sac size remained stable on surveillance. However, the patient presented a year later with aortic rupture due to disruption of the distal endograft seal zone and was treated by palliation with no further interventions.A careful review of pre and post contrast CTA in both patients showed subtle enhancement of sac thrombus adjacent to the aortic wall Fig.\u00a0, which iPatients with enlarging aneurysm sacs but no identifiable endoleaks are diagnosed as having T5ELs. These patients pose diagnostic and therapeutic challenges, as the underlying mechanism remains unclear. As T5ELs do not involve pressurised blood entering the aneurysmal sac, one could argue it carries a low rupture risk and active intervention should be reserved for symptomatic patients. The first patient we describe remains asymptomatic and under active surveillance. However, as with our second patient, continued expansion may alter the morphology of the aneurysm sac. This in turn risks disruption of the endograft seal zones and the development of secondary type I/III endoleaks.We found that despite percutaneous aspiration and surgical plication, sac re-expansion occurred to pre-treatment dimensions. Other authors also report similar challenges. Derboghossian et al.  Derbogh, describWilliams  reportedThese cases may in fact represent atypical T2ELs involving retrograde flow from the vasa vasora. Insertion of covered stents has been shown to cause proliferation of vasa vasora from the adventitia to the intima (Sanada et al. On careful review of the images in our patients, subtle peripheral foci of arterial enhancement in the aneurysm wall Fig.\u00a0 could beFurthermore, the vasa vasora are tiny vessels that do not opacify readily even on super-selective catheter angiography or cone-beam CT, as in our experience. Toriaki\u2019s group used a combination of superselective angiography and on-table CT to confirm vasa vasorum involvement and perform successful embolisation. Unfortunately, such facilities are not available in all institutions.Other reports of T5EL describe sac hygroma \u2013 a gelatinous material within the aneurysm sac (Risberg et al. Our findings suggest the specific type of T5ELs we describe above actually represent occult T2EL from vasa vasora. We propose that this obscure phenomenon may go underdiagnosed, unsurprising given the diagnostic challenges we outlined above. In addition to unenhanced and delayed phase CTA, contrast-enhanced US of peripheral sac thrombus and super-selective angiograms of lumbar/inferior mesenteric arteries may be warranted to confirm or exclude this entity as a cause of unexplained sac expansion.Long-term surveillance is essential to identify an occult source of endoleak and to maintain the original sealing zones. As for the optimal therapeutic intervention, this remains a challenge and a topic for discussion as experience accrues of this phenomenon."}
+{"text": "Regular mammographic screening can reduce breast cancer morbidity and mortality. Participation rates are suboptimal in Australia\u2019s fully funded biennial breastscreening program (BreastScreen) for women aged 50-74. Despite obesity being a well-established risk factor for post-menopausal breast cancer, cross sectional data suggests obesity may be a risk factor for non-participation in recommended screening, due to adverse screening experiences. This research aimed to ascertain the link obesity and non-participation by using data linkage of routinely collected data.Data for women age eligible for breast screening were linked between the NSW Cancer Registry and the Australian Longitudinal Study of Women\u2019s Health (ALSWH) to create a cohort of women who either participated in screening as recommended or not. Women from the 1946-1951 ALSWH birth cohort were included in the study. These women reported BMI via 8 survey waves. The primary outcome was adherence to breast screening measured by frequency of screening over the follow-up period (1998-2016). Unadjusted risk ratios were calculated using mixed-effects logistic regression for the association between BMI and screening participation.The study included 2804 linked records of age eligible women (mean age of 52.37[SD 5.47]). 22.8% of the cohort were obese (BMI>30kg/m2). Obesity was significantly associated with non-recommended screening participation (screening within 3 years of last breast screen); odds ratio 1.63 .Obesity has a significantly impact on recommended participation in a nationally provided breast screening program, despite obesity being a risk factor for post- menopausal breast cancer. Optimising participation among higher risk and under-screened women in under utilised breast cancer screening programs is warranted. Development of targeted interventions to increase screening participation among these higher risk women is needed.\u2022\u2002Women living with obesity and less likely to participate in recommended breast screening.\u2022\u2002Targeted interventions are needed to optimise participation in breast screening to ensure these higher risk women are not at higher risk of adverse outcomes due to breast cancer."}
+{"text": "Physical fitness outcomes are considered major health biomarkers to assess and monitor exercise-based interventions across the lifespan. Recent studies provide evidence that many adult and childhood chronic diseases should have their origins in gestational or fetal life. To date, a few pioneering studies have showed associations between prenatal predictors and selected physical fitness tests (strength and cardiorespiratory). Nevertheless, there is a lack of knowledge about the influence of prenatal factors on childhood performance on a comprehensive fitness test battery including speed and coordination. The innovative purpose of the current study is to analyse the relative weight of prenatal predictors on schoolchildren's physical fitness outcomes.We obtain data from1188 children (571 girls) aged 6-11 years and 1020 adolescents (495 girls) aged 12-17 years. Prenatal predictors  were self-reported from offspring's mothers. The ALPHA fitness test battery for youth was used to assess offsprin\u01f5s physical fitness . Regression analysis were performed to predict the different physical fitness outcomes.The main findings of the present study indicate that the presence of gestational anemia significantly predicted lower scores of lower-body explosive muscular strength (standing long jump) and motor fitness (4x10-m shuttle run) and predicted moderately lower scores of upper-body isometric muscular strength (handgrip strength test). . Moreover, gestational anemia better predicted lower scores of muscular strength and motor fitness in children than in adolescents  . While gestational age and length of gestation (>34- ?42 weeks) predict better cardiorespiratory fitness (20 m shuttle-run test)  and motor fitness . .This evidence suggests that preventive strategies by health-care institutions, policy makers and technicians must be two-fold: a) to effectively reduce gestational anemia in order to prevent offsprin\u01f5s predisposition to low levels of physical fitness, and b) to intervene with toddlers and children at risk to provide tailored physical activity programs and regular physical fitness evaluation."}
+{"text": "Individual Placement and Support (IPS) is an evidence-based supported employment program that helps people with severe mental illness to achieve steady meaningful employment in competitive mainstream jobs. Employment specialists are an integral part of IPS service delivery. The primary goal of an employment specialist is to help IPS users obtain competitive employment by providing targeted job development and ongoing support to workers and employers for as long as it is required.This study aims to investigate the impact of the covid-19 restrictions on the delivery of IPS services in Northern Norway and how this may have affected the employment specialists\u2019 perception their work environment.We conducted four phases of a longitudinal work environment panel survey with the IPS employment specialists in Northern Norway. Phase 1: January-February 2020 (pre-covid), phase 2: June-July 2020 (during covid) and phase 3: October-November 2020 (during covid) were not related to covid and collected data on fourteen work environment indicators. Phase 4: October 2020 was a covid specific survey and collected data about the impact of covid-19 restrictions on IPS service delivery.Employment specialists perceived that they had less collaborative engagement with clinical teams and employers after covid-19 restrictions were introduced. This was accompanied by a significant decline in four of the employment specialists\u2019 work environment indicators.The covid-19 restrictions appear to have created obstacles for IPS service delivery in Northern Norway. These challenges may have negatively impacted the employment specialists\u2019 perception of their work environment, creating job dissatisfaction and potentially increasing employee attrition.No significant relationships."}
+{"text": "Older adults who are homebound or socially isolated have high rates of loneliness and depression with fewer opportunities for treatment. Our team extended an existing psychotherapy intervention (Engage & Connect) to improve access to mental health care for older adults who are homebound. We iteratively created a tablet-based application (Engage PRISM) leveraging a user-centered design approach to provide older adults, particularly those with limited technology experience, an easy-to-use application to support social reward. Engage PRISM connects clients with the psychotherapy intervention and additional features to increase social reward exposure virtually. All eligible participants received a K92 ZTE tablet, equipped with the Engage PRISM application, internet service, Zoom, and access to Selfhelp\u2019s Virtual Senior Center. Participants were then enrolled in the 9-week Engage & Connect intervention delivered by a licensed mental health counselor via Zoom on the tablet each week. We evaluated feasibility of the intervention and preliminary effect on depressive symptoms through a weekly PHQ-9. Feasibility was assessed through participants\u2019 ability to use the tablet to access mental health treatment. We provided tablets to eight participants ages 67 to 84; participants demonstrated 100% feasibility of use of the tablet intervention. We dropped two participants from the study due to a greater level of care needed. All participants were provided with referrals prior to ending the study. Preliminary evidence indicates that four of the six remaining participants had experienced a reduction in depressive symptoms  three weeks into the study reporting over a 30% reduction on average."}
+{"text": "Background: Medical tape is used routinely for a variety of tasks across healthcare settings. The literature contains numerous publications in which common practices around medical tapes have been suspected to lead to infection transmission. Healthcare providers can turn to individually packaged single-patient-use medical tape rolls to help reduce cross-contamination risk by limiting exposure to environmental contaminants, minimizing contact with hospital surfaces and equipment, and minimizing exposure to healthcare workers\u2019 hands and other patients. Methods: We evaluated the effect of individually packaged tape on cross contamination using a controlled laboratory assay. Ceramic tiles were inoculated with microorganisms evenly spread across the surface and allowed to air dry. Using gloves, packaged and unpackaged tapes were rolled over their entire outside circumference onto the contaminated tiles to simulate cross contamination. Using new gloves, the packaged tapes were then removed from their package with minimum contact. All cross-contaminated tape rolls were placed in phosphate-buffered water and mixed in a vortexer for bacterial recovery procedures. Serial dilutions were plated on appropriate media for bacterial enumeration. The average log10 colony-forming unit (CFU) recovery was measured for comparison. We used 4 types of tapes in this study . We used 4 different microorganisms as inoculates: Staphylococcus aureus (methicillin-resistant), Enterococcus faecium (vancomycin-resistant), Klebsiella pneumoniae (carbapenem-resistant), and Clostridium difficile (spore). Each test (tape and bacteria combination) was done in 3 or 6 replicates; each bacterial enumeration was the average of duplicate plates. The detection limit for this method is 8 CFU per sample, which is equivalent to 0.9 log10. Results: The results for all tapes tested showed a statistically significant lower mean log10 recovery of each of the microorganisms tested for packaged versus unpackaged tape  to 4.64 log10 (for K. pneumoniae on Medipore H). This is equivalent to 99%\u201399.99% cross-contamination protection from the 4 organisms tested. Conclusions: Individual packaging of medical tape rolls protects them from external contaminants. Even if the packaging becomes contaminated, the tape retrieved from the package will be significantly less contaminated than it would have been from exposure to the same contaminants without packaging.Funding: 3M CompanyDisclosures: None"}
+{"text": "Clostridioides difficile infection (CDI) in observational studies (cure rates >90%) but efficacy in controlled clinical trials appears lower.Microbiota restoration is highly effective to treat recurrent We performed an updated meta-analysis to assess the efficacy of microbiota restoration for recurrent CDI in open-label registered prospective clinical trials compared to randomized controlled trials (RCTs).A systematic search of Embase, Web of Science and Scopus was performed up to June 2022 to identify studies of interest. Clinical trials of microbiota restoration for recurrent CDI with clinical resolution with one dose as the primary outcome were included. We calculated both unweighted and weighted pooled resolution rates (UPR and WPR) with 95% confidence intervals (CI).I2of 86%. Analysis of trials with a control arm (non-microbiota restoration) revealed CDI resolution in 357 of 496 patients  with microbiota restoration. Among the 9 open-label clinical trials, CDI resolution was seen in 524 of 653 patients after initial microbiota restoration . Comparison of resolution rates between RCTs and open-label trials revealed a lower cure rate in RCTs compared to open-label trials .Eighteen studies  with 1149 CDI patients were included. Of the patients treated with microbiota restoration, 881 experienced symptom resolution . There was significant heterogeneity among studies with an I2of 61%. Comparison of cure rates with microbiota restoration vs antibiotics showed higher cure rate with microbiota restoration . There were no serious adverse events reported.Analysis of the 10 trials with non-microbiota restoration revealed CDI resolution in 201 of 397 patients with antibiotics . There was significant heterogeneity among the included studies with an Microbiota restoration in a randomized controlled setting leads to lower resolution rates compared to open label and observational settings, likely due to stricter definitions and inclusion criteria. Resolution rates in open label studies were similar to observational studies.NoneNone Declared"}
+{"text": "Studies of thalamic structure and function in Progressive Supranuclear Palsy (PSP) suggest it may play a role in key aspects of the clinical syndrome. This study examined thalamic changes across PSP phenotypes investigating (i) thalamic atrophy (ii) thalamic functional connectivity and (iii) the relationship between thalamic structural and functional connectivity changes with clinical severity.Participants92 participants with PSP  and 104 age-matched controls were recruited from the Cambridge Centre for Parkinson's Plus Disorders cohort. Clinical assessments and imaging were conducted within 1 year of diagnosis.Structural AnalysisThalamic volumes (TVs) were obtained using FreeSurfer. Bayesian multiple regression  was used to model (i) mean TVs (ii) group differences in mean TVs (iii) relationships between Z-standardised clinical scores and TVs with age, gender, and total grey matter as covariates.Functional AnalysisVoxel-wise seed-based functional connectivity of the thalamus used the Functional Magnetic Resonance Imaging Expert Analysis Tool (FEAT) in FMRIB's Software Library (FSL). Inter-group differences and relationships between clinical scores and functional connectivity for each group were assessed using a general linear model with age and gender as covariates.Structural AnalysisTVs for all PSP subgroups were smaller than controls. No differences between PSP subgroups were detected. There was evidence for a relationship between TVs for the entire PSP group and Revised Addenbrooke's Cognitive Examination (ACER) scores . Subgroup analysis showed evidence for a relationship between ACER scores and TVs in PSP-RS  and PSP-cortical  phenotypes. A negative influence of TVs on total PSP rating scale scores was found for the PSP cohort a whole .Functional AnalysisPSP patients as a group showed decreased thalamic functional connectivity in higher cortical regions. Subgroup analysis revealed decreased connectivity in those areas compared to controls but in distinct distributions and magnitude. Increased thalamic connectivity with the middle temporal gyrus correlated with ACER scores for PSP patients as a group and in the PSP-cortical subtype.Thalamic volume loss is a prominent aspect of PSP and is associated with a wide network of changes in functional connectivity that may be distinct between PSP subtypes. Changes in thalamic structure and function predict clinical severity, particularly in PSP-RS and PSP-cortical subtypes."}
+{"text": "Healthcare services are primarily focusing on medical and physical treatment of COVID-19 while psychosocial and mental health needs are not considered a priority.The purpose of this study was to explore how recovered individuals with COVID-19 adapted to their psychological and social stressors during infection period.A descriptive phenomenological approach conducted using a purposeful sample of 13 individuals recovered from COVID-19 in Jordan. Data collected using unstructured interviews.Perception of being diagnosed with COVID-19 revealed to three major themes; positive learning , tolerating ambiguity , and resilience .The study indicates that there is a need to integrate psychosocial and mental health care services into healthcare plans provided to individuals with COVID-19.No significant relationships."}
+{"text": "The progeroid syndrome includes a group of rare, severe genetic disorders clinically characterized by premature physical ageing. Severe aortic stenosis has been described in progeria patients, but no previous surgical aortic valve replacement was reported. We describe a successful surgical aortic valve replacement combined with coronary artery bypass grafting in a progeria patient with severe aortic stenosis and a small aortic annulus. Progeroid syndrome (PS) includes a group of rare, severe genetic disorders clinically characterized by premature physical ageing [1]. Progeroid syndrome (PS) includes a group of rare, severe genetic disorders clinically characterized by premature physical ageing . The lifA 33-year-old woman who suffered from chest pain, dyspnoea and fatigue due to severe aortic stenosis was admitted for aortic valve intervention. The patient characteristics are presented in Table\u00a0Echocardiographic parameters are presented in Table\u00a0The operation was performed through the median sternotomy and central arterial and venous cannulation. A transversal aortotomy revealed senile degeneration of the aortic leaflets, which were meticulously removed. There was no annulus calcification or subvalvular membrane. In order to implant the mechanical prosthesis size 17 (ST Jude Regent) in a very small aortic annulus, the ascending aorta was completely transected above the sinotubular ridge. In addition, the coronary arteries were carefully mobilized and secured with rubber tapes  has a longer life expectancy, and most often, patients die of myocardial infarction in the mid-50s [The estimated prevalence of patients with PS is one in 4\u20138 million new births. 2 and projected indexed effective orifice area, there was no danger of patient-prosthesis mismatch with 17\u2009mm prosthesis size. It was previously demonstrated that prosthesis implantation using interrupted mattress sutures with the pledgets placed on the left ventricular side of the annulus (the supra-annular implantation technique) allowed the use of a larger prosthesis for a given annulus than the intra-annular implantation technique with the pledgets located above the aortic annulus. However, the pledgets placed on the ventricular side of the annulus may obstruct the left ventricular outflow tract and decrease the effective orifice area of the prosthesis . Transaortic or simple interrupted sutures placement technique could be a satisfactory alternative to the aortic root enlargement technique, which requires an advanced surgical skill level.Conflict of interest: none declared. Reviewer information: Interactive CardioVascular and Thoracic Surgery thanks Jose G. Fragata and the other anonymous reviewer(s) for their contribution to the peer review process of this article."}
+{"text": "A 9-year-old girl presented with a cough and dyspnea. Thoracic computed tomography (CT) detected a giant cystic lesion and mediastinal shift . The patEchinococcus granulosus,Hydatid cyst disease continues to be an important public problem today. The causative agent of this disease is a parasite belonging to the cestode class,"}
+{"text": "Staphylococcus haemolyticus strains isolated from a mouse fibrotic lung tissue and exhibiting proapoptotic activity on human lung alveolar epithelial cells. The genomes were obtained from a combination of Illumina MiSeq and Oxford Nanopore MinION sequencing.We report here the complete genome sequences of three  Staphylococcus and Streptococcus genera (Idiopathic pulmonary fibrosis (IPF) is a disease of unknown etiology, and the lung microbiome of IPF patients is characterized by increases in s genera . We demos genera . Tissuess genera . To isols genera  were inoStaphylococcus epidermidis) as a reference. The sequence reads from each of strains 1b and 7b were assembled by Unicycler as a single circular chromosome and three circular plasmids (Bandage assembly graph viewer) . MiSeq reads were trimmed using Trimmomatic v0.38, retaining reads longer than 30\u2009bp . Long re. MiSeq r viewer) . The rea viewer) . The 16SPRJNA707584. The Sequence Read Archive (SRA) for the raw reads and the NCBI RefSeq accession numbers are provided in The sequences have been deposited in the GenBank database under BioProject accession number"}
+{"text": "The authorship has changed: Wanawan Pragot regrettably publishedthe work that she carried out during her Ph.D. at the University ofAberdeen under the supervision of Waheed Afzal where this work hadbeen assisted by (then) post-doc Ara Carballo-Meilan and (then Ph.D.student) Lewis McDonald. Wanawan Pragot regrets her action and wantsto correct it. She notes that Chaiwat Photong helped her in proofreadingthe manuscript before she submitted. We believe that the contributionof Chaiwat Photong does not merit being the first author. The revisedorder and new additions reflect the contributions.The Acknowledgmentand Author contributions have also been revisedas given here."}
+{"text": "Teaching Point: The acute appendicitis in a context of Malone appendicostomy complication is very rare but can occur and may be challenging to diagnose due to its unusual position. Figure 1, red arrow axial image) and enlargement of the appendicostomy due to a large 30 \u00d7 10 mm appendicolith  with discrete fat stranding  and local reactional mesenteric lymph nodes. No bowel perforation was detected. The retained diagnosis was acute appendicitis, and the patient was treated conservatively with a satisfactory clinical evolution. Years later, relapsing symptoms led to surgical ablation of the appendicostomy. MA anastomoses the appendix to the deep part of the umbilicus and includes a valve mechanism allowing for antegrade colonic enema flushing without stool leakage in patients with fecal incontinence. Frequent complications of MA include stomal orifice stenosis as well as stomal infection and appendiceal perforation during catheterization [A 33-year-old male patient with a history of Malone appendicostomy (MA) for neonatal ano-rectal malformation presented with fever (40\u00b0C), increasing periumbilical pain, diarrhoea and nausea. Clinical examination revealed periumbilical cutaneous inflammation. Bloods showed only discrete increase of CRP. Abdominal computed tomography (CT) examination revealed wall thickening ("}
+{"text": "There is a limited published data on the treatment of blood stream infections (BSI) in patients receiving extracorporeal membrane oxygenation (ECMO). Traditionally, the management of only fungal and Gram-positive BSIs require follow-up blood cultures to document clearance. The presence of large retained cannulas in ECMO create concern for persistent bacteremia. This study investigates whether certain variables are predictive of blood stream infections with positive repeat cultures (BSIPRC) and if BSIPRC is associated with increased mortality.All positive blood cultures from patients receiving ECMO at Brooke Army Medical Center identified between September 2012 and October 2021 were included in this study. Blood cultures were excluded if they were determined to be contaminants by the primary team. For each positive blood culture, charts were retrospectively reviewed. Date of clearance was defined as the first negative blood culture after a positive. BSIPRC was defined as re-isolation of the same organism on repeat blood cultures following an initial positive blood culture.A total of 60 patients and 87 BSI were investigated (38.5 BSI per 1000 ECMO days). Gram-positive (GP) organisms caused a majority of BSI  followed by Gram-negative (GN)  and fungal  infections. Of the 80 (92%) BSIs who had repeat blood cultures drawn, patients had BSIPRC in 35 (44%) of cases. There were no clinical features that differentiated patients with positive repeat cultures (Table). There was no difference in survival to discharge for patients with BSIPRC as compared to single day BSI (20 (58%) vs. 28 (63%), p=0.78). In 6 patients with BSIPRC with Gram-negative organisms, two (33%) died before clearance and five (83%) died before decannulation.Characteristics of patients and all blood stream infections.There were no clinical findings that differentiated patients with BSIPRC from those who had a single day of positivity. BSIPRC was associated with high mortality in patients with Gram-negative bacteremia. In the absence of clear predicative factors in demonstrating clearance of BSI, repeat blood cultures may be necessary. Future studies are needed to determine why Gram-negative BSIPRC are associated with a high mortality.All Authors: No reported disclosures."}
+{"text": "In chronic total occlusion (CTO) intervention, it has been determined that it is impossible to create a reentry from a subintima to a true lumen with regular guidewire manipulation. Therefore, antegrade dissection and reentry (ADR) using Stingray system  was developed. In the present case, ADR using a Stingray balloon failed to create a reentry. Intravascular ultrasound (IVUS) observation revealed the damaged part of the wall by ADR. We could create a reentry at the damaged part by an exact vertical directional puncture using the tip detection method with an AnteOwl WR-IVUS  .A 74-year-old man suffered from effort angina pectoris due to a CTO lesion in the left anterior descending coronary artery because of occlusion of bypass grafting to it. Computed tomography and angiography showed severe calcification in the CTO Fig.\u00a0A, B. An Supplementary file1 Intravascular ultrasound images during the puncture of the true lumen using the tip detection method. (MP4 22361 KB)Below is the link to the electronic supplementary material."}
+{"text": "Clustering algorithms are commonly used to identify disease clusters. New Clustering algorithms are benchmarked on synthetic data to assess their accuracy. These datasets lack the complexities of real electronic health record (EHR) producing a partial assessment of the algorithm. We developed a synthetic EHR cluster generator for benchmarking clustering algorithms.We have created a synthetic EHR cluster generator, clustEHR, based on Synthea, a synthetic EHR generator that produces datasets (with parameterized noise and cluster separation) of known clusters and with clinically relevant patient outcomes. We evaluated clustEHR by generating multiple datasets of variable cluster separation and percentage of noise variables to reflect easy and hard clustering problems. We used a linear model to assess the relationship between these parameters and cluster problem difficulty. K-means accuracy was used as a proxy to measure cluster problem difficulty.We have developed a tool for generating synthetic EHR cluster data with clinically relevant outcomes based on the rate of decline of medical observations (e.g. blood pressure). The following parameters are supported: a) number of clusters, b) number of patients in each cluster, c) number and data type of features, d) separation through defining clusters as either diseases such as COPD or dementia (high separability) or inter-disease conditions such as emphysema and chronic bronchitis within COPD (low separability), and e) noise variables through identifying variables not predictive of true cluster outcomes random forest feature importance metric. We show that high cluster separation significantly increases k-means accuracy (coefficient of 0.33). Smaller percent of noise variables increase accuracy though not significantly (coefficient 0.42).ClustEHR offers realistic mixed data types as well as outcomes which are frequently used to evaluate clusters when subtyping diseases. The evaluating results suggest that the difficulty of the cluster data can be user determined. The tool can be used to create realistic datasets for evaluating clustering approaches."}
+{"text": "A(ii) the first three lanes for the actin loading control were mistakenly duplicated in the last three lanes of the image panel. A representative data from several repeated experiments is now provided in corrected Figure\u00a03A(ii). The revised figure shows results obtained with new NIK antibody because initial antibody is no longer available. In two cell lines (BEAS2B and H358) the new antibody revealed better NIK expression than it was shown with original antibody. This observation does not affect the conclusions of the manuscript that some melanoma cell lines exhibit a higher-level NIK protein and a higher level of NIK protein associated with IKK than normal human epidermal melanocytes (NHEMs).In the original version of Figure\u00a03NIK expression in various cell lines. Whole-cell extracts were harvested in RIPA buffer and 40 ug of total protein for each cell line were loaded for Western blot. After proteins were transferred to nitrocellulose membrane, the membrane was cut between 50 KD and 75 KD. The upper part was blotted with anti-NIK antibody  and signal was detected with Enhanced Chemiluminescence (ECL) method. The lower part of the blot was developed with anti-\u03b2-actin antibody  and signal was detected with fluorescence method (LI-COR). Wild type mouse mammary fibroblast (NIK WT MEF) and NIK knock-out mouse mammary fibroblast (NIK WT MEF) were used as positive and negative controls for the NIK antibody."}
+{"text": "As the use of antiretroviral therapy (ART) increases, the issue of treatment failure is still a global challenge, particularly in a resource limited settings including Ethiopia. The results of former studies in Ethiopia were highly variable and inconsistent across studies. Thus, this systematic review and meta-analysis intended to provide the pooled estimation of treatment failure and associated factors among children on antiretroviral therapy.2 test and Cochrane Q test statistics. We run Begg\u2019s regression test to assess publication bias. A random-effects meta-analysis model was performed to estimate the pooled prevalence of treatment failure.We searched international databases  during the period of February 30 to April 7, 2021. All identified observational studies reporting the proportion of treatment failure among HIV positive children in Ethiopia were included. Heterogeneity of the studies was checked using IThe estimated pooled prevalence of treatment failure among children in Ethiopia was 12.34 . Subgroup analysis of this review showed that the highest prevalence was observed in Addis Ababa (15.92%), followed by Oromia region (14.47%). Poor ART adherence , advanced WHO clinical staging , and opportunistic infections (AOR = 2.64 CI: 2.19, 4.31 were found to be significantly associated factors with childhood treatment failure.This study revealed that treatment failure among children on ART was high in Ethiopia. Poor ART adherence, advanced WHO clinical staging, opportunistic infections, and low level of CD4 cell counts increased the risk of treatment failure. Acquired immune deficiency syndrome (AIDS) is a viral disease caused by human immunodeficiency virus (HIV) that weakens the immune system and makes the body susceptible to opportunistic infections . The HumAntiretroviral therapy (ART) is crucial to decrease progress of HIV/AIDS by suppressing viral replication which in turn reestablishes the immune function of HIV-infected individuals ,7. In adThe current guidelines recommend that, virological failure is more informative to assess treatment failure . The JoiIn Ethiopia, studies were conducted to estimate the magnitude as well as to identify associated factors of treatment failure among HIV-infected children \u201327. ThesAdditionally, there was no a country wide data which represents a national treatment failure and its associated factors among HIV positive children. Hence, the aim of this systematic review and meta-analysis was to estimate the pooled prevalence and associated factors of treatment failure among children on ART using available studies in Ethiopia. The findings of this systematic review and meta-analysis will highlight the prevalence and associated factors of TF with implications to improve health care workers\u2019 interventions, assist decision makers and other concerned stakeholders to design, implement and evaluate interventions to improve level of ART adherence. Furthermore, the findings will enable the country to sustain treatment successes and to hasten the decline of childhood treatment failure in Ethiopia.The result of this systematic review and meta-analyses was prepared and reported using the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guideline . The proWe carried out a systematic review and meta-analysis to estimate the pooled prevalence of TF and associated factors among HIV-positive children in Ethiopia which is located in east Africa. To find potentially relevant articles, a comprehensive search was carried out on PubMed, Web of Science, Google Scholar, Scopus, and Cochrane Library databases. To find unpublished relevant literatures to this study, some online repository library centers were searched. Besides, gray literatures were searched from review of reference lists and input of content experts. MeSH , Boolean operators and all fields within records were used to search in the advanced PubMed search engine. Search terms or phrases used were: children, child, pediatrics, treatment failure, antiretroviral therapy, prevalence, and associated factors.The advanced PubMed database search strategy was performed using the following key terms (((((((Children(tw) OR child(tw) OR pediatrics(tw))) OR ((\"child\"[MeSH Terms] OR \"child\"[All Fields] OR \"children\"[All Fields]) AND tw[All Fields] OR (\"child\"[MeSH Terms] OR \"child\"[All Fields]) AND tw[All Fields] OR (\"paediatrics\"[All Fields] OR \"pediatrics\"[MeSH Terms] OR \"pediatrics\"[All Fields]) AND tw[All Fields]))) AND (((Treatment failure(tw) OR immunological failure(tw) OR clinical failure(tw) OR virological failure(tw))) OR ((\"treatment failure\"[MeSH Terms] OR (\"treatment\"[All Fields] AND \"failure\"[All Fields]) OR \"treatment failure\"[All Fields]) AND tw[All Fields] OR  AND tw[All Fields] OR  AND tw[All Fields] OR  AND failure[All Fields]) AND tw[All Fields]))) AND (((ART(tw) OR antiretroviral therapy(tw) OR ARV(tw) OR antiretroviral(tw) OR HAART(tw))) OR ((\"art\"[MeSH Terms] OR \"art\"[All Fields]) AND tw[All Fields] OR  OR \"anti-retroviral agents\"[All Fields] OR \"antiretroviral\"[All Fields]) AND (\"therapy\"[Subheading] OR \"therapy\"[All Fields] OR \"therapeutics\"[MeSH Terms] OR \"therapeutics\"[All Fields])) AND tw[All Fields] OR \"arv\"[All Fields] AND tw[All Fields] OR  OR \"anti-retroviral agents\"[All Fields] OR \"antiretroviral\"[All Fields]) AND tw[All Fields] OR  OR \"highly active antiretroviral therapy\"[All Fields] OR \"haart\"[All Fields]) AND tw[All Fields]))) AND  OR proportion(tw) OR magnitude(tw) OR risk factors (tw) OR associated factors(tw) OR predictors(tw))) OR  AND tw[All Fields] OR proportion[All Fields] AND tw[All Fields] OR magnitude[All Fields] AND tw[All Fields] OR (\"risk factors\"[MeSH Terms] OR (\"risk\"[All Fields] AND \"factors\"[All Fields]) OR \"risk factors\"[All Fields]) AND tw[All Fields] OR (associated[All Fields] AND factors[All Fields]) AND tw[All Fields] OR predictors[All Fields] AND tw[All Fields]))) AND ((Ethiopia(tw)) OR ((\"ethiopia\"[MeSH Terms] OR \"ethiopia\"[All Fields]) AND tw[All Fields])). The search was done between March 3 and April 27, 2021. All papers published up to April 27, 2021 were included. Endnote X8 software manager was used to cite references and manage the searched literatures.This review has two main outcome variables. The first outcome is HIV/AIDS treatment failure which was defined as immunological, clinical, and virological treatment failure . The secStudy area: Only studies conducted in Ethiopia were included to produce single estimate of common effects.Study design: All observational study designs reporting the prevalence of TF were eligible for this meta-analysis.Population: All HIV-positive children on antiretroviral treatment.Language: Only articles reported in English language were incorporated.Publication condition: Both published and unpublished studies were considered.Conference reports and articles without full text access were excluded. Exclusion of these studies is because of the inability to check the quality of articles in the absence of full text.The required data from included articles were extracted by two authors (BG and LD) using a standardized data extraction format, adapted from the Joanna Briggs Institute (JBI). Any disagreements during screening were undertaken through discussion. The reviewer contacted the first author(s) of primary research for additional information. The first author name, follow up years, publication year, region, study area, study design, sample size, response rate, and prevalence with 95% CI were included the data selection form.The qualities of included articles were evaluated by four investigators  using Newcastle-Ottawa Scale quality assessment tool for observational studies . The too2 = 94.7%, p<0.001), hereafter, a random-effects meta-analysis model was performed to estimate the pooled prevalence. Subgroup analysis was conducted to adjust random variation between point estimates of original study and investigate how failure fluctuates across subgroup participants. Outlier within the included articles was checked using sensitivity analysis. Publication bias across studies was assessed using funnel plot and egger\u2019s regression test. The Begg\u2019s regression test results at 5% significance level were not statistically significant for publication bias https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at\u00a0figures@plos.org. Please note that Supporting Information files do not need this step.While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool,\u00a0 2 Dec 2021Reviewer #1 Comments to the AuthorThe authors of this systematic review and meta-analysis have presented useful data to determine the pooled national burden of childhood HIV/AIDS treatment failure as well as its associated factors in Ethiopia. Conversely, there are specific comments that the reviewer would like the authors to address so as to further improvement of the manuscript.Authors\u2019 response: we are very glad to the reviewer\u2019s appreciation of our efforts; and we have just given our respective responses to each of the specific reviewer comments as detailed below.1. Is the manuscript technically sound, and do the data support the conclusions?Thank you very much for your insightful comment. Yes. We have a conclusion which is supported by the data analysed and presented in this study . 2. Has the statistical analysis been performed appropriately and rigorously?We acknowledge the reviewer\u2019s concern regarding to statistical analysis for this study. Yes. We have carried out all the necessary statistical analysis properly and presented our finding accordingly in the main documents of this study.3. Have the authors made all data underlying the findings in their manuscript fully available?Yes. Comments have been taken and we have made the necessary correction accordingly . For detail please see the supporting information file.4. Is the manuscript presented in an intelligible fashion and written in standard English?Great thanks. We have carefully reviewed the manuscript based on your suggestion and some typographic error has been also updated .5. It will be worthwhile to do a subgroup/sensitivity analysis of cohort and cross-sectional analysis. As, in you may exclude cross-sectional studies and check for the estimates in cohort studies. Repeat it for cross-sectional and compare whether there is a difference. You may also look at Urban/rural population. Any variable for meta-regression?Absolutely! We have taken the given comment and sensitivity analysis was already done accordingly. However, the result indicated that there is no single study unduly influenced the overall estimates of treatment failure and there is no significant variability for meta-regression. We have done subgroup analysis based on study design, and giving a prevalence of 12.14 in cohort which is nearly the same in cross-sectional study 13.43  . NB. Generally, we have tried to revise our manuscript according to the requirement of PLOS ONE template.AttachmentResponse to Reviewers.docxSubmitted filename: Click here for additional data file. 7 Dec 2021Prevalence and associated factors of treatment failure among children on ART in Ethiopia: a systematic review and meta-analysisPONE-D-21-32599R1Dear Dr. Gelaw,We\u2019re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.Within one week, you\u2019ll receive an e-mail detailing the required amendments. When these have been addressed, you\u2019ll receive a formal acceptance letter and your manuscript will be scheduled for publication.http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at onepress@plos.org.If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they\u2019ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact Kind regards,Frank T. SpradleyAcademic EditorPLOS ONE 10 Jan 2022PONE-D-21-32599R1 Prevalence and associated factors of treatment failure among children on ART in Ethiopia: a systematic review and meta-analysis Dear Dr. Gelaw:I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department. onepress@plos.org.If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact plosone@plos.org. If we can help with anything else, please email us at Thank you for submitting your work to PLOS ONE and supporting open access. Kind regards, PLOS ONE Editorial Office Staffon behalf ofDr. Frank T. Spradley Academic EditorPLOS ONE"}
+{"text": "Acute myocardial injury is common after noncardiac surgery and associated with mortality. Impaired intraoperative cardiovascular dynamics are a risk factor for acute myocardial injury. Optimizing intraoperative cardiovascular dynamics may thus reduce acute myocardial injury. We aimed to investigate the effect of intraoperative personalized goal-directed hemodynamic management on the incidence of acute myocardial injury. We hypothesized that personalized goal-directed hemodynamic management reduces the incidence of acute myocardial injury compared to routine hemodynamic management in high-risk patients having major abdominal surgery. We performed a post-hoc secondary analysis of a randomized clinical trial including 180 high-risk major abdominal surgery patients that were randomized to personalized goal-directed hemodynamic management or routine hemodynamic management. We compared the incidences of acute myocardial injury\u2014defined according to the Fourth Universal Definition of Myocardial Infarction (2018)\u2014between patients randomized to personalized goal-directed hemodynamic management or routine hemodynamic management by calculating the relative and absolute risk reduction together with 95% Wald confidence intervals and P values. Acute myocardial injury occurred in 4 of 90 patients (4%) in the personalized goal-directed hemodynamic management group and in 12 of 90 patients (13%) in the routine hemodynamic management group . In this post-hoc secondary analysis, intraoperative personalized goal-directed hemodynamic management reduced the incidence of acute myocardial injury compared to routine hemodynamic management in high-risk patients having major abdominal surgery. This needs to be confirmed in larger prospective trials.The online version contains supplementary material available at 10.1007/s10877-022-00826-0. Acute myocardial injury is common in patients having noncardiac surgery and associated with postoperative mortality \u20135. AcuteIntraoperative hypotension\u2014reflecting impaired intraoperative cardiovascular dynamics \u2014is a modIn a recent randomized controlled clinical trial, we showed that intraoperative personalized goal-directed hemodynamic management reduces the incidence of postoperative clinical complications compared to routine hemodynamic management in high-risk patients having major abdominal surgery . HoweverWe thus now conducted a post-hoc secondary analysis of the original trial  to invesThe original trial and the present study were approved by the ethics committee  on 4 August 2015 and 2 December 2020 and all patients provided written informed consent.We performed a post-hoc secondary analysis of a randomized clinical trial  that wasAdult high-risk patients scheduled for major abdominal surgery expected to last at least 90\u00a0min or cause blood loss exceeding 1000\u00a0ml were enrolled into the original trial . PatientPatients were randomized to intraoperative personalized goal-directed hemodynamic management (targeting baseline cardiac index measured non-invasively one day before surgery) or to routine hemodynamic management . In patiBlood samples were collected before the induction of general anesthesia and three days after surgery. After centrifugation, serum aliquots were separated into Eppendorf tubes and stored at\u2009\u2212\u200980\u00a0\u00b0C until transfer to our central laboratory for batched analysis. Serum troponin I was measured using the Siemens Atellica IM High-Sensitivity Troponin I Assay . The 99th percentile of a reference population for this assay is 38.6\u00a0ng/l for women and 53.5\u00a0ng/l for men . Serum NWe defined acute myocardial injury according to the definition of \u201cmyocardial injury and infarction associated with non-cardiac procedures\u201d set forth in the Fourth Universal Definition of Myocardial Infarction (2018)  as a posDescriptive results are presented as medians with 25th percentiles and 75th percentiles for continuous data and as absolute frequencies and percentages for categorical data.Incidences of acute myocardial injury in the personalized goal-directed hemodynamic management and the routine hemodynamic management group are illustrated using stacked bar charts. We compared the incidences of acute myocardial injury between patients randomized to personalized goal-directed hemodynamic management or routine hemodynamic management by calculating the relative risk  and the absolute risk reduction together with 95% Wald confidence intervals (CI) and P\u00a0values (Chi-squared test).To illustrate preoperative and postoperative troponin I and NT-proBNP concentrations in patients randomized to personalized goal-directed hemodynamic management and routine hemodynamic management we computed spaghetti plots and violin plots with overlaying boxplots. We compared relative changes in troponin I and NT-proBNP concentrations in patients randomized to personalized goal-directed hemodynamic management and routine hemodynamic management using the Wilcoxon rank-sum test with continuity correction.We used R version 3.5.3  for statistical analyses.We excluded 8 of the 188 patients included in the original trial because blood samples were missing. Therefore, we included 180 patients  in this post-hoc secondary analysis  in the personalized goal-directed hemodynamic management group and in 12 of 90 patients (13%) in the routine hemodynamic management group   relative change in postoperative NT-proBNP concentrations compared to baseline NT-proBNP concentrations was 227% (96% to 664%) in patients in the personalized goal-directed hemodynamic management group and 430% (143% to 851%) in patients in the routine hemodynamic management group (P\u2009=\u20090.046) Below is the link to the electronic supplementary material."}
+{"text": "High grade serous ovarian cancer (\u201cHGSOC\u201d) is the seventh most common cancer worldwide among women. The disease has no unique symptoms and often women are diagnosed in advance stages. The World Health Organization estimates that 225,500 women are diagnosed and 140,200 will die of this disease per year. In the United States, the 5-year survival rate is 43%, and 85% of all HGSOC patients experience recurrence despite aggressive treatment. More efficacious drug combination treatments are needed. Recently it was found that platinum drugs are inactivated in dimethyl sulfoxide (DMSO). Thus drug discovery platforms that use it as a solvent are not able to study platinum drugs in combination with other drugs easily. Advances in Echo technology at the National Center for Advancing Translational Sciences (NCATS) enabled acoustic transfer of platinum drugs in aqueous solutions. This allows us to find novel small molecule/platinum drug combinations that can be tested in clinical trials.We ran single-agent dose-response experiments to correctly estimate the dose-ranges needed for the matrix screens utilizing the OVCAR8 human carcinoma cell line. Then, we conducted our pilot matrix screen with compounds that are commonly combined with cisplatin for HGSOC treatment. Lastly, we spotted cisplatin against the Mechanism Interrogation PlatE drug library to identify novel combinations for clinical use against HGSOC. Compounds that show synergistic cell killing will give insight into novel drug combinations to treat HGSOC.Several synergistic and antagonistic effects were found. These results were refined with smaller-scale screening and tested in other HGSOC cell lines.The novel combinations discovered will allow chemotherapy patients to receive lower dosages of platinum drugs while maintaining or improving efficacy of cytotoxicity of cancer cells. This will help alleviate the side-effects of platinum drugs experienced by HGSOC patients."}
+{"text": "As Congress considers renewing the Acute Hospital Care At Home (AHCaH) waiver, which provides a full hospital payment for Hospital at Home (HaH) care, evaluating uncertainty around the future of HaH payment is critical. Our qualitative study explored HaH leaders\u2019 experiences with implementing HaH  from 14 new and pre-existing programs across the U.S. We conducted semi-structured interviews with HaH programs diverse by size, urbanicity, and geography. We analyzed transcripts using a thematic approach. Participants across settings and regions wanted greater clarity about the waiver\u2019s future. Lack of clarity affected staffing (nurses reluctant to take temporary jobs) and investment in establishing programs . Programs adapted to uncertainty in multiple ways: 1) operating parallel waiver and non-waiver programs; 2) seeking to determine/ calculate the HaH value for their institution; 3) determining which patients would benefit most from HaH; and 4) seeking additional health system financing options beyond the CMS reimbursement (new programs) or relying on existing contracts with payers (existing programs). Implementing HaH is a complex and resource intensive process. Greater clarity from CMS regarding the waiver\u2019s future state will encourage programs to invest the resources that they need to establish their programs long-term. Waiver extension/ permanence would also enable programs to develop and test measures of value, making rigorous evaluations possible to optimize different HaH components."}
+{"text": "Clustering algorithms are commonly used to identify disease clusters. New Clustering algorithms are benchmarked on synthetic data to assess their accuracy. These datasets lack the complexities of real electronic health record (EHR) producing a partial assessment of the algorithm. We developed a synthetic EHR cluster generator for benchmarking clustering algorithms.We have created a synthetic EHR cluster generator, clustEHR, based on Synthea, a synthetic EHR generator that produces datasets (with parameterized noise and cluster separation) of known clusters and with clinically relevant patient outcomes. We evaluated clustEHR by generating multiple datasets of variable cluster separation and percentage of noise variables to reflect easy and hard clustering problems. We used a linear model to assess the relationship between these parameters and cluster problem difficulty. K-means accuracy was used as a proxy to measure cluster problem difficulty.We have developed a tool for generating synthetic EHR cluster data with clinically relevant outcomes based on the rate of decline of medical observations (e.g. blood pressure). The following parameters are supported: a) number of clusters, b) number of patients in each cluster, c) number and data type of features, d) separation through defining clusters as either diseases such as COPD or dementia (high separability) or inter-disease conditions such as emphysema and chronic bronchitis within COPD (low separability), and e) noise variables through identifying variables not predictive of true cluster outcomes random forest feature importance metric. We show that high cluster separation significantly increases k-means accuracy (coefficient of 0.33). Smaller percent of noise variables increase accuracy though not significantly (coefficient 0.42).ClustEHR offers realistic mixed data types as well as outcomes which are frequently used to evaluate clusters when subtyping diseases. The evaluating results suggest that the difficulty of the cluster data can be user determined. The tool can be used to create realistic datasets for evaluating clustering approaches."}
+{"text": "Psychiatric illnesses are common among older adults and are associated with increased mortality and physical comorbidities. It is suggested that patients with frailty have a higher prevalence of depressive symptoms. (1) The eFI (electronic Frailty Index) is a tool used to assess the severity of frailty in elderly frail patients using a cumulative deficit model based on routine interactions with their GP.Patients were selected for annual frailty assessments by searching the electronic clinical system (SystmOne) using the eFI tool. Patients were assessed using the Comprehensive Geriatric Assessment (CGA) framework. In addition, all patients were screened for coexisting anxiety and depression using the Patient Health Questionnaire (PHQ-9) and Generalized Anxiety Disorder (GAD-7) questionnaire.Of the 118 patients who ranged from mild to severe frailty, we found there was a positive correlation of the frailty severity eFI scores with increased rates of anxiety and depression evidenced by higher scores on the PHQ-9 and GAD-7 scoring tools. We found a positive correlation of the eFI with the PHQ-9 depression scores of (r = 0.819 p < 0.001). Within the same data set, we found correlation coefficients of eFI and anxiety GAD-7 scores (r = 0.651 p < 0.001). Increasing frailty was found to be associated with a higher rate of depression and anxiety.We found in this study higher (eFI) electronic frailty indices are associated with higher rates of anxiety and depression. We would recommend annual frailty assessments in patients with high electronic frailty indices and this should include screening for mental health deterioration. Early detection of deterioration will enable patient centered supportive measures and targeted treatment strategies. Health maintenance programs should ensure patient centered holistic assessment of both physical and mental health needs for early identification to avoid deterioration of both physical and mental health."}
+{"text": "A 55-year-old female presented with bilateral lower limb swelling and facial swelling along with a decreased frequency of micturition. Baseline investigations revealed an elevated serum creatinine and blood urea nitrogen.\u00a0Subsequent investigations revealed a positive antinuclear antibodies (ANA) +++  and positive anti-double-stranded DNA (dsDNA) testing.\u00a0A detailed ophthalmic evaluation was performed. Her visual acuity was 6/36 improving to 6/18 in either eye. The near vision was found to be N36 without any further improvement. A dilated fundus examination revealed multiple yellowish lesions throughout the posterior pole consistent with pockets of subretinal fluid in the right eye. A swept-source optical coherence tomography (OCT) was performed that revealed the presence of fluid in both\u00a0the intraretinal and subretinal spaces. A bacillary layer detachment, with the accumulation of fluid in the intraretinal space, was noted. Similar fundus findings were seen in the left eye.\u00a0A decision was made to employ plasmapheresis (PLEX) along with her routine thrice-weekly hemodialysis. Additionally, the systemic steroids were continued. At her third follow-up (day 22), her vision had improved to 6/9 unaided bilaterally and to N6 with the appropriate correction. There was a near-complete regression of the exudative retinal detachments bilaterally with pigmentary changes. The OCT scans revealed significant regression of the serous retinal and retinal pigment epithelium (RPE) detachments with a thin rim of residual subretinal fluid. Fundus examination and OCT studies established the diagnosis of systemic lupus erythematosus (SLE) choroidopathy and guided its further management with systemic immunosuppression, hemodialysis and plasmapheresis. There was a rapid resolution of the retinal and choroidal findings with visual recovery over the next month. Systemic lupus erythematosus (SLE) is a common autoimmune disease characterized by the development of autoantibodies to nucleic acid-containing cells. Systemic findings include lupus nephritis, dermatological, musculoskeletal or hematological manifestations . CommonlA 55-year-old female presented to her local physician with a recent two-month history of bilateral lower limb swelling which had increased since the last three days, facial swelling and red facial rash along with a decreased frequency of micturition.\u00a0Her previous significant medical history included systemic hypertension and hypothyroidism currently being treated. Baseline investigations revealed a fasting blood glucose of 73.8 mg/dl , an elevated serum creatinine of 2.56 mg/dl  and a blood urea nitrogen of 59.71 mg/dl . An abdominal ultrasound showed slightly altered renal cortical echotexture suggestive of medical renal disease. Mild fullness of the bilateral pelvicalyceal system and entire ureter was noted along with mild urothelial thickening noted along the entire pelvicalyceal system and ureters. Following a urological consult, she underwent a cystoscopy with urethrotomy with bilateral retrograde ureteropyelography (RUP) for suspected hydronephrosis.A nephrologist\u2019s opinion was sought, and subsequent investigations revealed a positive antinuclear antibodies (ANA) +++ test  and positive anti-double-stranded DNA (dsDNA) testing , and glomerular basement membrane (GBM) antibody testing was negative with equivocal test results for perinuclear antineutrophil cytoplasmic antibodies (P-ANCA)\u00a0(myeloperoxidase (MPO))  and negative results for cytoplasmic ANCA (c-ANCA) antibodies .\u00a0A needle biopsy of the kidney revealed focal necrotizing, diffuse proliferative and crescentic glomerulonephritis with diffusely thickened capillary walls featuring predominantly cellular crescents over 3/36 of sampled glomeruli and tuft necrosis in 4/36 glomeruli. Direct immunofluorescence (DIF) studies revealed glomerular capillary and mesangial immune complex deposits (immune-mediated crescentic and diffuse proliferative glomerulonephritis). Patchy acute tubular injury is noted. A clinical diagnosis of type IV lupus nephritis with activity and chronicity was made.At this time, an ophthalmic opinion was sought for her 15-day history of bilateral gross visual loss. Records reveal a visual acuity of 6/18 bilaterally with a diagnosis of bilateral multiple exudative retinal detachments.\u00a0An optical coherence tomography (OCT) scan at the time reported retinal pigment epithelium (RPE) and serous retinal detachments bilaterally.\u00a0Based on a confirmed diagnosis of systemic lupus erythematosus with lupus nephritis, she was treated with systemic steroids (prednisolone 60 mg/day) and intravenous cyclophosphamide . Hemodialysis was initiated for persistent anuria and a raised serum creatinine of 6.4 mg/dl . She was administered three doses of methylprednisolone 500 mg intravenously, and she was transferred to our center.3; normal: 4,000-11,000/mm3) with a predominant neutrophilic response . Her serum creatinine was 4.35 mg/dl .\u00a0As she was mildly febrile, blood and urine cultures were sought, which grew Escherichia coli. The presence of a bloodstream infection precluded the use of further immunosuppression in the form of rituximab or calcineurin inhibitors.On examination, she was pale with gross anasarca and bilateral pitting edema of the lower limbs. Vital parameters including her blood pressure (140/70 mmHg), heart rate (92/min) and oxygen saturation (98%) were normal. Examination of her respiratory and cardiovascular systems was normal.\u00a0She was comprehensively investigated with routine hematological tests, renal and liver function tests. Relevant findings included mild anemia  and leukocytosis  revealed her near vision to be N36 without any further improvement. A slit-lamp examination of either eye was normal as were her intraocular pressures and pupillary reactions. No evidence of anterior uveitis (cells/flare) or vitreous cells was detected. A dilated fundus examination revealed multiple yellowish lesions throughout the posterior pole consistent with pockets of subretinal fluid in the right eye Figure . A sweptVascular access was re-established via a right-sided internal jugular tunnel cuffed catheter (TCC), and a decision was made to employ plasmapheresis (PLEX) along with her routine thrice-weekly hemodialysis. Additionally, the systemic steroids were continued with the addition of hydroxychloroquine (200 mg/day) and cilnidipine (10 mg/day).\u00a0She was monitored with visual acuity assessment, slit-lamp examination, dilated fundus examination and OCT scans weekly. At her third follow-up (day 22)\u00a0following five sessions of plasmapheresis and continued immunosuppressive treatment, her vision had improved to 6/9 unaided bilaterally and to N6 with the appropriate correction. There was a near-complete regression of the exudative retinal detachments bilaterally with pigmentary changes Figures ,\u00a02C. TheSystemic lupus erythematosus (SLE) is a multisystem autoimmune disease with protean manifestations. Several phenotypes exist, and patients may present with numerous clinical manifestations ranging from a mild dermatological involvement to severe multiorgan disease.\u00a0The pathogenesis is complex and is currently thought to be due to the activation of autoimmunity in genetically susceptible patients. The underlying pathogenetic mechanism is an activation of T and B cells which then leads to cytokine release, complement activation and autoantibody production . Lupus aSystemic manifestations include dermatological , musculoskeletal (arthritis), hematological (cytopenia), cardiovascular , central nervous system  and renal (lupus nephritis).\u00a0SLE can affect virtually every tissue of the eye. Commonly described findings include as follows: A) Orbital manifestations: This includes a vasculitis that manifests as proptosis, painful orbital areas, defective vision and restriction of extraocular movements. Nonperfusion of the globe and extraocular muscles is common and may lead to optic nerve ischemia. Myositis may present similarly and is best diagnosed on computed tomography or ultrasound as an enlargement of one or several extraocular muscles. B) Ocular surface manifestations: The commonest ocular manifestation of SLE is keratoconjunctivitis sicca which occurs in the majority\u00a0and is usually due to an aqueous layer deficiency. C) Scleral/corneal manifestations: These include a mild episcleritis or a phenotype of scleritis which typically presents with higher degrees of pain and may potentially be sight-threatening. Phenotypes of scleritis reported include anterior and posterior scleritis. D) Retinal manifestations:\u00a0These may be seen in up to 29% of patients with active disease. Retinal microangiopathy consisting of small intraretinal hemorrhages and cotton wool spots is the commonest manifestation. Mechanisms of causation include immune complex deposition in the vessel wall with subsequent inflammation. A subset of patients present with retinal vasculitis with retinal venular or arteriolar inflammation. This is closely linked to the presence of antiphospholipid antibodies including anticardiolipin.\u00a0Several reports have highlighted central retinal artery/vein occlusions or retinal ischemia as important causes of visual morbidity. E)\u00a0Optic nerve lesions in the form of optic neuritis or ischemic optic neuropathy have been reported [Lupus choroidopathy is a rare ocular manifestation with approximately 40 patients described till date in the literature . In a reNguyen and co-workers described the management of three cases of SLE choroidopathy and included a literature review which included 25 previously published papers . These iJabs et al. described their experiences with six patients who presented with serous detachments of the retinal pigment epithelium and retina in a multifocal pattern that had its fluorescein angiographic correlates in several areas of late hyperfluorescence within the sensory retinal detachments . Good syThese reviews were described prior to the widespread adoption of OCT in retinal practices. Kouprianoff et al. described the systemic, clinical and OCT findings of a 16-year-old female with SLE . OCT revThe patient we describe is a 55-year-old woman with a previous diagnosis of SLE, who developed lupus nephritis and bilateral severe gross visual loss. She was treated with immunosuppressives, hemodialysis and plasmapheresis (PLEX). PLEX probably works in several ways: it may remove autoantibodies and circulating immune complexes or may replace abnormal proteins. PLEX has so far been used to treat patients with severe neurological manifestations of SLE including psychosis or acute myelopathy. Available literature for the use of PLEX in the ocular manifestations of SLE is limited. Papadaki and co-workers have described the successful treatment of two patients with retinal vasculitis who were treated with PLEX and immunosuppression .www.pubmed.gov) using the search terms \u201cbacillary layer detachment\u201d and \u201csystemic lupus erythematosus\u201d returned no results and suggests that our findings constitute a novel finding and that the spectrum of bacillary layer detachment is expanded to include SLE choroidopathy.Clinical findings included RPE detachments, sub- and intraretinal fluid and bacillary detachments. A widespread choroidal vasculitis with consequent leakage into the subretinal and intraretinal space appears to account for our observed findings.\u00a0Bacillary detachments are a novel OCT sign recently described that may denote a split between the myoid and ellipsoid layers of the inner photoreceptor segment usually following outer retinal lesions or infections/inflammations of the choroid. It has been reported in numerous conditions including toxoplasmic retinochoroiditis, Vogt-Koyanagi-Harada disease and chronic serous chorioretinopathy . In our The patient we describe had classic clinical and investigational findings of SLE. The development of lupus nephritis with the consequent choroidal lesions led to a profound visual loss. Fundus examination and OCT studies established the diagnosis of SLE choroidopathy and guided its further management with systemic immunosuppression, hemodialysis and plasmapheresis. There was a rapid resolution of the retinal and choroidal findings with visual recovery over the next month.SLE choroidopathy is an infrequently reported complication of SLE.\u00a0Limited cases have been reported in the literature with the vast majority presenting with multifocal exudative retinal detachments with findings of intraretinal and subretinal fluid collections. Appropriate treatment usually results in good anatomical and visual recovery.\u00a0The relatively new modality of OCT permitted us a good characterization of the retinal/choroidal disease and allowed us to describe a novel finding of bacillary layer detachment in this patient. Serial follow-up allowed us to monitor the resolution of the disease."}
+{"text": "High-quality social contacts are important for older adult\u2019s emotional well-being whereas narcissism, characterized by self-centeredness, may undermine the quality of personal relationships. Narcissism may be associated with poorer quality relationships because narcissistic adults are more self-centered in their daily social interactions. The current study examined the associations between linguistic features of conversation throughout the day and narcissism using a machine learning approach. Older adults aged 65\u201389  wore an unobtrusive electronically activated recorder (EAR) throughout the day for 4 to 6 days. The EAR was activated 30 seconds every 7 minutes to capture conversations occurring in a natural setting. The sound files that contained participant\u2019s speech  were transcribed verbatim. We used Linguistic Inquiry and Word Count (LIWC) to extract linguistic features from the transcriptions . Linguistic features were analyzed using random forest algorithm which is a supervised machine learning method that can evaluate features\u2019 performances in predicting older adult\u2019s narcissism. The model reached an accuracy of 62% and results showed that total word count, more auxiliary verbs , more swear words , and less assent  were the most powerful predictors of narcissism. Drawing on sound files collected from real-life interactions, findings indicate higher usage of aggressive and disagreeable words among more narcissistic individuals, which probably leads to poorer quality relationships with social partners. Interventions aiming to improve contact quality and emotional well-being may consider individuals\u2019 word use in daily interactions."}
+{"text": "Antiphospholipid syndrome (APS) is a rare autoimmune multisystem disease characterised by thrombosis and pregnancy morbidity in the presence of persistently elevated titres of: lupus anticoagulant, anticardiolipin and/or anti-glycoprotein 1. It may be primary  or secondary ). Recent publications highlighted clinical criteria limitations for children and raised awareness of the burden and prevalence of non-criteria manifestations in this population. This case report adds further weight to the need to raise multi-specialty awareness of non-criteria manifestations to aid recognition and treatment of this rare condition with potentially severe sequelae.13-year-old female with SLE diagnosed aged 8 in India with bilateral optic neuritis occurring two months later. ANA positive at diagnosis with low complement and thrombocytopenia. Treated with prednisolone and hydroxychloroquine. Patient moved to the UK aged 9; initial abnormal bloods: mildly positive ANA (ENA negative), thrombocytopenia, strong lupus anticoagulant. As serology not strongly suggestive and optic neuritis rare in lupus diagnosis questioned. Ophthalmology review confirmed bilateral optic atrophy without evidence of previous vasculitis. There was debate whether the post-retinal demyelination was due to antiphospholipid syndrome or a primary demyelinating condition. Hydroxychloroquine stopped and azathioprine started. Following normal neurology investigations  concluded if patient developed new APS-related symptoms or worsening visual evoked potentials anticoagulation would be discussed. Patient remained stable over four years with chronic thrombocytopenia and ESR persistently elevated. Azathioprine changed to Mycophenolate mofetil (MMF) due to side effects.Routine medication monitoring bloods in 2022 showed ESR 97, CRP 78, Platelets 61. Review identified vasculitic rash on soles of both feet with palpable nodules and normal pulses. Further investigation confirmed antiphospholipid antibody triple positivity. Aspirin commenced, hydroxychloroquine restarted, MMF dose increased and rituximab administered. Left foot rash settled but right progressed with toe discolouration and numbness. Skin biopsy considered but not performed due to skin integrity concerns. Foot pulses remained present and normal. Bilateral lower limb doppler reported as normal; increased symptoms resulted in CT angiogram which revealed bilateral non-occlusive popliteal thrombus and left pulmonary embolus. Subsequent echocardiogram was normal. Patient was anticoagulated with low molecular weight heparin followed by warfarin. Vascular surgical team advocated medical management and patient received seven infusions of Iloprost followed by Sildenafil. She achieved near total resolution of skin changes to toes with only minimal loss of skin over tip of right great toe. Patient will now require long-term anticoagulation.APS was considered in initial differential diagnosis but patient did not meet current clinical criteria as no past evidence of thrombosis. Lupus anticoagulant was consistently strongly positive and anticardiolipin repeatedly negative. As anti-B2 glycoprotein 1 antibody is not routinely tested and must be verbally requested, it was only checked once (negative) prior to discovery of triple positivity.ANA reported as strongly positive at time of SLE diagnosis but reviewing original notes from India titre was 1:100 and therefore not highly convincing. ENA negative and complement and white cell count normal on repeat testing since. Therefore, it is probable that this patient has primary APS as opposed to secondary APS in association with SLE. However, it is possible that this patient may develop more symptoms of SLE over time.When this patient presented with foot rash there were high numbers of children presenting with varying severity of painful, itchy toes coined \u2018covid toes\u2019 due to suspected link to SARS-CoV-2 infection. Patient had exposure history, and COVID antibody serology was difficult to interpret due to recent vaccination. Dermatology found appearance to be consistent with \u2018covid toes\u2019 and advised supportive treatment. The triple APS antibody positivity result provided probable aetiology. Providing evidence of thrombus was problematic with false reassurance from apparently normal lower limb arterial doppler when actually popliteal arteries were not checked in view of the presence of normal flow proximally at the groin and distally in the feet.This case highlights the need to continue to search for thrombus in presence of high titres antiphospholipid antibodies and particularly in the case of triple positivity as although patient presented with colour change to toes, she was entirely asymptomatic from her PE and her left foot improved spontaneously despite a left popliteal thrombus also being present.Non-criteria manifestation of thrombocytopenia (occurs in 25% paediatric APS patients) was present throughout and patient had past history of haematuria . A paediatric specific APS criteria including these may have resulted in earlier detection of triple antiphospholipid antibody positivity and thus earlier treatment escalation and possible avoidance of thrombus.It has been reported that a high proportion of children with positive antiphospholipid antibodies don\u2019t develop a thrombus. However, it is interesting that our patient was entirely asymptomatic from her pulmonary embolus which was an incidental finding on her CT angiogram. This prompts a discussion about how much imaging should be performed in those with high levels of persistent positive antiphospholipid antibodies.Rituximab resulted in normalisation of platelet count and ESR for the first time since initial presentation. Anticardiolipin antibodies normalised, lupus anticoagulant decreased from strong to moderate and anti-B2 glycoprotein levels decreased but remained positive. Rituximab is a recognised treatment for catastrophic antiphospholipid syndrome (CAPS) but not routinely used in APS. The consistently raised ESR in an apparently clinically well patient is a reminder to continue to search for causes of inflammation. As the CRP was largely in normal range, this demonstrates the unique value of the ESR.In view of anti-B2 glycoprotein 1 antibody requiring to be verbally requested, discussions are ongoing with the laboratory department regarding the possibility of electronic request and a comment with recommendation to check other two antiphospholipid antibodies following one positive antibody result.As a result of this case, a plan will be put in place to ensure annual screening of antiphospholipid antibodies in all juvenile SLE patients in our care.It is hoped that this case report promotes discussion amongst the paediatric rheumatology community regarding further research required for development of paediatric specific APS criteria and management."}
+{"text": "Older adults with cognitive disability are worse off with being up-to-date with preventive care and routine dental care is not considered a clinical preventive visit covered by insurance for this population. I examine disparities in access to dental and clinical preventive services  in the past year in 28,068 older adults with cognitive disability using the nationally representative Medical Expenditure Panel Survey from 2009-2016. I conduct multivariate logistic regressions and find older adults with cognitive disability vs. no disability have higher odds of receiving annual blood pressure check  but lower odds for having an annual dentist visit  with only one-tenth of those with cognitive disability report having dental insurance. These findings have implications for integrated community-and-clinical care partnerships for closing the gap for routine dental care services among older adults with cognitive disability."}
+{"text": "Student training was suspended in most post-acute settings in the United States due to the COVID-19 pandemic. Through a collaborative partnership between a university and a healthcare organization we offered a virtual telehealth clinical experience to prepare student physical therapists for practice in a skilled nursing facility (SNF) setting. 35 students engaged virtually for 80 hours with two clinical instructors. The curriculum included eight virtual learning modules along with four telehealth patient encounters that exposed students to interdisciplinary teams in the SNF context. Students completed a retrospective pre/post Self-Perception of Learning Survey. Results demonstrated students\u2019 self-perception of learning was significantly increased implying an improved ability to practice in the SNF setting. This approach advanced student learning in patient care management, interprofessional practice, and telehealth practice in the SNF setting. Future work is planned to expand the program to include 20 physical therapy, occupational therapy, and speech and language pathology students."}
+{"text": "Communications Biology 10.1038/s42003-021-02966-6, published online 11 January 2022.Correction to: The original version of this Article was missing data accessions (SRR19134783 and SRR19134809) in the Data Availability statement.\u201cAll genome sequence data are available at the GenBank under the Accession number JABETM000000000. Raw sequence data are available at the NCBI SRA site with the accession numbers SRR15444039 and SRR15254972.\u201dThis error has been corrected in the HTML and PDF versions of the Article, as follows:\u201cAll genome sequence data are available at the GenBank under the Accession number JABETM000000000. Raw sequence data are available at the NCBI SRA site with the accession numbers SRR15444039, SRR15254972, SRR19134783 and SRR19134809.\u201d"}
+{"text": "Life-threatening bleeding after oocyte retrieval is unusual. We report a case of massive vaginal bleeding requiring transcatheter arterial embolization (TAE) after transvaginal US-directed follicle aspiration for oocyte retrieval and provide a brief review of cases in which the pseudoaneurysm of the injured artery was managed with a TAE approach. A 40-year-old woman presented massive vaginal bleeding after transvaginal ultrasonography-directed follicle aspiration for oocyte retrieval. Contrast-enhanced computed tomography revealed active bleeding from the uterine ostium. Transcatheter arterial embolization was performed for a pseudoaneurysm of the right pudendal artery to manage the hemorrhage. Potentially life-threatening bleeding should be recognized as a rare complication after oocyte retrieval to promptly establish the diagnosis and preserve the uterus. In vitro fertilization (IVF) is a common treatment worldwide for people who cannot conceive naturally. IVF is generally very safe, and those undergoing IVF rarely experience any health or pregnancy-related problems associated with the procedure . TransvaHere, we report a case of massive vaginal bleeding requiring transcatheter arterial embolization (TAE) after transvaginal US-directed follicle aspiration for oocyte retrieval and review the relevant literature. A 40-year-old woman with a history of primary infertility for three years was transferred using emergency transportation from another hospital. She presented massive vaginal bleeding. Her vital signs were as follows: heart rate, 135 bpm; blood pressure, 80/65 mmHg; and respiratory rate, 25 breaths/min. The hemoglobin level was 6.1 g/dL. The patient became hemodynamically unstable and had hypotension. She had undergone transvaginal US-directed follicle aspiration to retrieve oocytes 6 h earlier at another hospital. This was her second attempt at oocyte retrieval.The patient had no history of surgical intervention. Her left ovary with a chocolate cyst due to a history of endometriosis adhered to the uterus and was unsuitable for oocyte retrieval. Further, the right ovary was firmly fixed behind the middle uterine segment. Her physician assessed the difficulty in obtaining oocytes with conventional follicle aspiration through the vaginal fornix from the right ovary because the right ovary was malpositioned. In addition to conventional follicular aspiration through the vaginal fornix, transmyometrial oocyte retrieval was performed for the right ovary under US guidance using a 19-gauge aspiration needle. To perform transmyometrial puncture, an aspiration needle was inserted obliquely through the lower uterine segment to reach the right ovary. Color Doppler was used to check blood flow around the follicles and myometrium. Three oocytes were retrieved. 10 min after the procedure, Pulsatile vaginal bleeding and pain persisted after the procedure. Gauze packing did not stop the vaginal bleeding. She was transferred to our hospital using emergency transportation because she became hemodynamically unstable and developed hypotension with gauze packing alone.Contrast-enhanced computed tomography (CT) on admission revealed active bleeding from the uterine ostium suggesting a ruptured pseudoaneurysm . TAE wasIVF is an established treatment modality for infertility worldwide. In assisted reproduction, US-guided retrieval of oocytes through the vaginal fornix is now accepted as a safe and well-tolerated method involving a low overall complication rate . AlthougIn our case, transmyometrial oocyte retrieval was performed in addition to conventional follicular aspiration through the vaginal fornix. This might have increased the risk of hemorrhage because vascular penetration with aspiration can cause myometrial trauma .Very rare cases require TAE to stop bleeding associated with oocyte retrieval. We searched PubMed and Google Scholar to review the available literature (published until April 2022) on massive vaginal bleeding requiring TAE after transvaginal US-directed follicle aspiration for oocyte retrieval using the key terms \u201coocyte retrieval,\u2019\u2019 and \u201carterial embolization\u2019\u2019. There were six cases (including our case) requiring TAE after transvaginal US-directed follicle aspiration for oocyte retrieval due to pseudoaneurysm . MoreoveThe management of pseudoaneurysms based on the fertility of the case may be controversial . TAE hasIn conclusion, it is important to recognize pseudoaneurysm as a rare complication after IVF to achieve a prompt diagnosis and enact uterus-preserving management for this potentially life-threatening disorder. Both the fertility specialist and general obstetrician/gynecologist should be aware of this to ensure better counseling of their patients and effective treatment."}
+{"text": "Limits to in-person social interaction increased the risk of loneliness during the Covid-19 pandemic. This study examines how gender and previous information communication technologies (ICT) experience could stratify how ICT-mediated social interactions related to loneliness during the COVID-19 pandemic. We employed National Health & Aging Trends Study data collected in 2018 and 2020-2021  to examine how the email and video call use before and during the COVID-19 pandemic was associated with loneliness and how the degree of impact differed by gender and previous ICT experience. In total, 35% reported feeling lonely some days or more frequently during the COVID-19 pandemic. Preliminary analysis showed older adults using video calls during the COVID-19 pandemic were 1.24 times more likely to report loneliness. This association was stronger among men than women and those who did not use ICT preceding the pandemic than those who used."}
+{"text": "Fragmented communication between care partners, health care providers, and adult day centers around the needs of persons living with dementia (PLWD) contributes to avoidable health care utilization. CareMOBI, is a user-centered mobile application that streamlines information exchange around datapoints relevant to the care of PLWD. CareMOBI facilitates team-based communication around emerging clinical problems by uniquely integrating the knowledge and day-to-day observations of adult day center staff and care partners. We present a stakeholder engaged approach to iteratively designing and validating an initial prototype. Through interviews and focus groups with adult day center staff (n=31), primary care providers (n=22), and family caregivers (n=13) we identified barriers to communication across settings. We then visually mapped the domains of a future app which we subsequently validated and refined with end-users (n=25). We present our current prototype which synthesizes these findings and addresses key barriers to information exchange across community settings serving PLWD."}
+{"text": "A 74-year-old man with a history of retrosternal oesophageal reconstruction was referred for surgical treatment of mitral valve regurgitation and coronary artery disease. He underwent mitral valve replacement combined with coronary artery bypass grafting through a left thoracotomy. Combined mitral valve replacement and coronary artery bypass grafting through a left thoracotomy were feasible in this patient with a retrosternal neo-oesophageal conduit. Cardiac surgery in patients with a history of retrosternal oesophageal reconstruction remains challenging. Cardiac surgery in patients with a history of retrosternal oesophageal reconstruction remains challenging. We report a successful mitral valve replacement (MVR) combined with coronary artery bypass grafting (CABG) through a left thoracotomy in a patient with a retrosternal neo-oesophageal conduit.A 74-year-old man was referred for surgical treatment of mitral valve regurgitation and coronary artery disease. He underwent oesophageal surgery for oesophageal carcinoma with retrosternal gastric tube reconstruction through a right thoracotomy 11\u2009years ago. Transthoracic echocardiography showed severe mitral valve regurgitation due to a flail mitral valve posterior leaflet and mildly reduced left ventricular systolic function with an ejection fraction of 43%. Coronary angiography revealed occlusion of the left anterior descending artery. Computed tomography revealed that the neo-oesophageal conduit was located just beneath the upper and lower parts of the sternum Fig.\u00a0a. The oret al. reported 8 cardiac surgical cases after extra-anatomic oesophageal reconstruction   . They peet al. reported a case series of 16 patients who underwent the left thoracotomy approach for multiple redo mitral valve operations (Mitral valve surgery through a left thoracotomy is rarely performed in selected patients. Suzuki erations . All proIn this case, mitral valve repair was not performed mainly because the intraoperative transoesophageal echocardiography could not be used. In addition, when complex mitral valve repair was needed, the time required for CPB and aortic cross-clamping might have been extended because of our inexperience with this approach. Ultimately, we could perform MVR and CABG through a left thoracotomy without any difficulty. Combined MVR and CABG through a left thoracotomy was feasible in a patient with a retrosternal neo-oesophageal conduit."}
+{"text": "Bipolar disorder is one of the most frequent psychiatric disorders among suicidal patients. A large part of patients with bipolar disorder (30\u201350%) will attempt suicide. Suicidal ideation being a major risk factor of suicidal act, it is crucial to better characterize patients with suicidal bipolar depression . The aim of this study was to characterize suicidal bipolar depressed patients in comparison with non-suicidal depressed patients in terms of clinical characteristics, evolution of depression and suicidal ideation course over time, and risk of suicide attempt during follow-up.Among patients with bipolar disorder recruited from the network of FondaMental expert centres for bipolar disorder between 2009 and 2017, we selected patients with at least mild depression and without current manic symptomatology at baseline (N = 938). Suicidal depression was defined by a baseline score \u2a7e2 for item 12 of the QIDS-SR (28.9%). A subsample of about 300 patients  was followed up for 2 years.Baseline clinical features  were more severe in patients with without suicidal depression. Suicidal patients tended to remain more suicidal throughout the followup .Depressed bipolar disorder patients reporting suicidal ideation had more severe clinical features and were more prone to report persistent suicidal ideation during the follow-up, independently of thymic state. Clinicians should closely monitor this subgroup of patientsNo significant relationships."}
+{"text": "We describe a case of epipericardial fat necrosis.Epipericardial fat necrosis is an inflammatory condition in which the pericardial fat pad necrotizes resulting in surrounding inflammation. This condition mimics more ominous pathology in clinical presentation and radiographic findings. Management is supportive with oral analgesics. A 39-year-old male presented to the emergency department (ED) for three days of right-sided, pleuritic chest pain. The patient denied any preceding trauma or illness. Examination revealed no overlying skin changes or reproducible chest wall tenderness, although lung sounds were noted to be diminished near the right lung base. His vital signs were as follows: temperature of 98.2\u00b0 Fahrenheit; respiratory rate of 17 breaths per minute; pulse oximetry of 95% on room air; blood pressure of 135/82 millimeters of mercury; and heart rate of 92 beats per minute.Chest radiograph revealed a right pleural effusion with right base consolidation suspicious for pneumonia . Based oEpipericardial fat necrosis is a rare benign condition5CPC-EM CapsuleWhat do we already know about this clinical entity?Epipercardial fat necrosis is a self-limited, inflammatory condition which often causes chest pain and radiographic findings suggestive of more ominous pathologies.What is the major impact of the image(s)?These images demonstrate the characteristic fat pad changes in combination with radiographic findings that may also be present with more ominous pathologies.How might this improve emergency medicine practice?Early recognition of this etiology may reduce excessive imaging and aid in the initiation of appropriate management."}
+{"text": "The low prevalence of some genetic neuro-developmental syndromes associated to psychiatric disorders requests to be integrated in human genome-phenome databases from which pleiotropy can be compiled from by systematic integration of phenotypes associated with genetic loci using phenomic inference tools. Williams-Beuren syndrome (WBS) is a neurodevelopmental disorder related to elastin gene at 7q11.23. Anxiety, depression and attention problems are the main behavioral problems found in WBS with no gender differences. Significant differences between cohorts are reported in particular regarding somatic complaints and aggressive behavior.Here, we report a Tunisian cohort of WBS patients for whom clinical behavioral phenotypes as well as genetic features are detailed.Sixteen patients from Sfax, Tunisia were referred for genetic assessment due to a suspected WBS syndrome.Genetic evaluation using fluorescent in situ hybridization confirmed 7q11.23 microdeletion in only eight patients. Comparison of detailed behavioral phenotypes revealed differences between age groups, gender groups and genetic groups. Anxiety and depression were recorded in the two older male patients and aggressive behavior was recorded in only two boys. The severity of behavioral features were dependent to familial environment and to parental socio-economic and educational levels.A more complete understanding of phenomic space is critical for elucidating genome-phenome relationships mediating neurodevelopmental disorder associated to psychiatric diseases for assessing and managing psychiatric and behavioral risks in young syndromic children.No significant relationships."}
+{"text": "MUC2 mucin, produced by colonic goblet cells, forms a mucus bilayer that provides a physical barrier between potential pathogens in the lumen and the underlying epithelial cells. Mucus is thus the first line of innate host defense in the gastrointestinal (GI) tract. Many GI diseases including inflammatory bowel disease and colon cancer affect the glycosylation of mucus. Goblet cells produce a variety of proteins that are associated with the mucus layer. Of these proteins, FCGBP is of significant interest due to its structural similarities to MUC2 mucin with unknown functions. In this study, we investigated how a missense mutation in FCGBP altered the glycosylation of goblet cell MUC2 and affected its barrier functions.Hypothesis: A missense mutation in FCGBP results an impaired mucus layer by the altering glycomic profiles of goblet cell mucins. Specific aims:1) To determine mechanistically how FCGBP impeded the structural integrity of the mucus layer2) To quantify MUC2 glycoprotein modifications in the altered mucus layerTo investigate whether FCGBP impaired mucus barrier functions, two cell types were investigated: wildtype LS174T (WT) MUC2 mucus-producing goblet cells and LS174T cells with a missense mutation in FCGBP (FCGBP MS). To determine if FCGBP MS led to loss in barrier function in the mucus layer, the penetration of 0.2, 1, and 2 \u03bcm fluorescent beads (to mimic bacteria) through the mucus layer were quantified. To determine if the differences in penetrability were caused by differences in MUC2 glycosylation in the goblet cell lines, sensitive glycomic analyses were performed by high-performance liquid chromatography-mass spectrometry (HPLC-MS) and capillary electrophoresis with laser-induced fluorescence detection (CE-LIF). Both intact cells and isolated MUC2 mucin granules were analyzed. To determine if differences in the glycomic profiles was caused by differences in glycotransferases, RT-PCR was performed on over 30 human glycosyltransferases.FCGBP MS cells exhibited significant loss in MUC2 mucus barrier function as quantified by fluorescent beads penetration through the mucus layer in a temporal manner. FCGBP MS cells exhibited an altered glycomic profile with a notable increase in sialylated glycans as quantified by HPLC-MS. The increase in sialylated glycans was associated with a significant increase in sialyl-transferase expression in FCGBP MS cells.These data demonstrate that a single missense mutation in FCGBP altered the penetrability of the mucus layer associated with an increase in sialylated proteins, a signature hallmark of numerous colonic diseases. FCGBP was critical in providing structural integrity of the mucus layer and maintenance of goblet cell glycosylation profiles.CIHRNone Declared"}
+{"text": "Aging is a complex biological process associated with progressive loss of physiological function and susceptibility to several diseases, such as cancer and neurodegeneration. As senescence burden increases with aging and becomes a risk factor for many age-related diseases we are specifically interested in senescence-derived aging signatures. We use cutting-edge proteomic workflows to investigate both the senescence-associated secretory phenotype (SASP) in tissue cultures. We are subsequently examining exosome proteins as well as lipid cargo in plasma from human young (20\u201326 yrs) and old cohorts and old (60\u201366 yrs) individuals. We will also present current work assessing senescence markers in cartilage and bone targeting underlying mechanisms and options for intervention for osteoarthritis. Overall, our focus is specifically directed towards senescence-derived biomarkers of aging."}
+{"text": "Stenosis is a common complication of haemodialysis arteriovenous accesses. Endovascular approaches with percutaneous transluminal fistuloplasty have largely replaced open surgical approaches as first line treatment. Vessel rupture is an uncommon complication of fistuloplasty and most reports describe venous rupture. Stent-graft deployment can salvage this, however, its use requires careful assessment of the distal vasculature. Arterial rupture with fistuloplasty has rarely been described in the literature. This is a novel case describing the use of a BeGraft coronary stent-graft to manage juxta-anastomotic arterial rupture and pseudoaneurysm complicating fistuloplasty.A 77\u2009year old female with end stage renal failure secondary to systemic amyloid light chain type amyloidosis was referred for a suspected radio-cephalic arteriovenous fistula stenosis after difficulty cannulating with poor flow during dialysis and clinical reduction in the fistula thrill. Both Doppler ultrasound and intravenous fistulography confirmed a venous stenosis 2\u2009cm distal to the anastomosis. The stenosis was treated by fistuloplasty, however, this was complicated by a rupture of the juxta-anastomotic arterial segment intraoperatively. Intermittent balloon tamponade was used to minimise extravasation although a pseudoaneurysm formed within the damaged arterial segment. The patient\u2019s distal neurovascular status was assessed using the Barbeau test and we sonographically confirmed adequate retrograde arterial flow via a complete palmar arch directing blood from the ulnar artery. After discussion with the renal transplant team, a 4\u2009mm BeGraft coronary stent-graft was deployed to control haemorrhage and bypass the pseudoaneurysm until adequate haemostasis and fistula flow was achieved. Follow-up 3\u2009months post-procedure reported the patient continued with haemodialysis using the stented fistula with no further complications.To our knowledge, this is the first case report describing the application of BeGraft coronary stent-grafts to salvage fistuloplasty of a radio-cephalic arteriovenous fistula stenosis complicated by juxta-anastomotic arterial rupture and pseudoaneurysm formation. We demonstrate the safety and short-term efficacy of this technology. Fistuloplasty, or percutaneous transluminal angioplasty (PTA), remains the first-line treatment of arteriovenous fistula (AVF) stenosis with a technical success rate of 90%  type amyloidosis on long term haemodialysis was referred to the interventional radiology department following difficulty in cannulating her AVF and clinical reduction in the palpable fistula thrill. Her significant medical comorbidities include type 2 diabetes mellitus, hypertension, hypercholesterolaemia and a pacemaker for Mobitz type 2\u2009second degree atrioventricular block.Doppler ultrasound revealed a stenosis 2\u2009cm distal to the anastomosis. With systemic heparinisation, we performed fistulography under intravenous sedation  and local anaesthetic (10\u2009ml 1% Lidocaine). Glyceryl trinitrate (800\u2009\u03bcg) and Amlodipine (10\u2009mg) were administered during the procedure due to a systolic blood pressure of\u00a0over 200\u2009mmHg on a background of known hypertension. This controlled the systolic pressure to 150\u2009mmHg.Under ultrasound guidance, retrograde puncture of the fistula was performed. A 5F sheath was inserted and the catheter and wire were successfully passed across the stenotic lesion. The initial venogram confirmed a single juxta-anastomotic venous segment stenosis Fig.\u00a0.Fig. 1AnThis was initially dilated with a 4\u2009mm Sterling balloon (Boston Scientific) which resulted in suboptimal reduction of the stenosis after which a 5\u2009mm Sterling balloon was used to overcome the tight stenosis. To achieve optimal dilatation of the affected vessel, a short segment of the balloon was positioned and inflated within the arterial segment to attain adequate vessel patency and to prevent migration of the balloon proximally due to arterial-flow back pressure. This was complicated by rupture at the juxta-anastomotic radial artery segment which immediately presented as pain and swelling in the patient\u2019s forearm and was confirmed by fistulography Fig.\u00a0.Fig. 2ShIntermittent balloon tamponade was maintained with a 3\u2009mm balloon at the level of contrast extravasation. To ensure safety of the distal limb whilst the balloon was inflated, the neurovascular status of the patient was clinically assessed together with ultrasound of the radial artery distal to the fistula which demonstrated adequate retrograde blood flow from the complete palmar arch via the ulnar artery. This was further confirmed with a Barbeau test which showed no dampening of the pulse oximeter waveform on the ipsilateral thumb with balloon inflation. Confirmation of the above allowed for prolonged balloon tamponade for a total duration of 30\u2009minutes without concern for neurovascular compromise to the distal limb.Whilst intermittent balloon tamponade minimised extravasation, a small pseudoaneurysm subsequently formed within the short arterial segment Fig.\u00a0. After dThe completion fistulogram demonstrated excellent flow through the fistula with no evidence of active bleeding and complete exclusion of the pseudoaneurysm Fig.\u00a0. There wThe patient recovered well post-procedure and was admitted overnight for monitoring and neurovascular observations. Her post-operative haemoglobin levels were within normal limits . The forearm swelling improved significantly, and no neurovascular complications were noted the following morning. The patient was reviewed in haemodialysis clinic 3\u2009months later and successfully continued with haemodialysis through the stented fistula, reporting no further complications.PTA induced arterial rupture is a rare but serious complication in percutaneous coronary intervention and has also been reported for femoral, popliteal, iliac and renal artery interventions  covered Cobalt-Chromium stent-graft, to manage juxta-anastomotic arterial rupture and pseudoaneurysm complicating fistuloplasty for a radio-cephalic AVF stenosis.Whilst BeGraft is commonly used in coronary intervention, a small number of studies have reported application of a BeGraft coronary stent-graft within a comparable non-coronary context such as in traumatic or iatrogenic injury to the anterior tibial artery and other small vessels including the renal, gluteal and ascending cervical arteries  or Fluency Plus (Bard), both self-expanding ePTFE covered Nitinol stent-grafts, would not have met these requirements due to their larger profiles. Furthermore, balloon-expandable stent-grafts allow for more precise positioning as they do not require stepwise deployment, making the BeGraft coronary stent-graft the most suitable option for this application.Sufficient segments of proximal and distal landing zones were identified for stent-graft placement to adequately exclude the pseudoaneurysm without crossing the anastomosis. Had an adequate distal arterial landing zone not been present, it would have been feasible to cross the anastomosis with the stent-graft as we had demonstrated adequate retrograde flow from the ulnar artery via the intact palmar arch. This alternative placement would have been suboptimal as the angulation of the anastomosis would have increased the risk of stent fatigue. Both explant and in silico data demonstrate that pulsatile fatigue-related damage of stent-grafts concentrate in areas of severe angulation and bending (Dalbosco et al. Irrespective of the approach used to treat AVF arterial rupture and pseudoaneurysm, whether balloon tamponade or stent-graft deployment is used or the positioning of the stent-graft, it is vital to assess for adequate retrograde blood flow via the palmar arch from the ulnar artery. This can be clinically proven by neurovascular assessment, the Barbeau test and sonographically by ultrasound of the distal vasculature. If necessary, prolonged tamponade in arterial rupture and stent-grafting across the anastomosis can be safe with confirmation of the above.Despite the high technical success rate demonstrated by stent-grafts in both AVF vessel rupture and pseudoaneurysms, there are a few limitations. Covered stent-grafts are not designed for repeat cannulation which means once deployed, the area must be marked to avoid cannulation over that site as in our patient.In conclusion, juxta-anastomotic arterial segment rupture is a rare complication of fistuloplasty that can be managed with endovascular stent-graft deployment. Clinical assessment of the neurovascular status and adequate retrograde palmar arch flow via the ulnar artery are key to ensuring safe balloon tamponade and stent-graft deployment. We demonstrate that the BeGraft coronary stent-graft is safe and effective in the short-term. Its long-term success in salvaging failed or complicated fistuloplasty of AV accesses requires further investigation."}
+{"text": "Understanding the impact of multi-drug resistant organism (MDRO) acquisition on renal transplant recipients (RTR) mortality and allograft function is paramount to mitigating deleterious outcomes. Prior studies have been limited by lack of control groups and sample sizes. We aimed to the assess whether the detection of an MDRO or a susceptible organism during the early post-transplant period was associated with increased mortality and allograft failure among RTRs.We performed a retrospective cohort study of RTRs at the Emory University Transplant Center between 2005\u20132022. Early post-transplant culture positivity was defined as a positive culture within 30 days of renal transplant. The primary outcome was a combined composite of one year- allograft loss and/or mortality following renal transplant. A Kaplan\u2013Meier survival analysis was performed, and differences between survival curves for RTRs with an early post-transplant positive culture (stratified by susceptibility status) and negative control RTRs were assessed using the log-rank test. Multivariable cox proportional hazard and a competing risk analysis were performed.& 2. One hundred and forty-nine (5%) RTRs experienced the composite outcome, this was experienced more frequently among RTRs with an MDRO detected  compared to RTRs with a susceptible organism defected  and negative controls  (Table\u00a03). Significant difference between time from transplantation to the composite outcome when comparing negative controls, MDRO and susceptible organisms RTRs was observed (log rank p < 0.001) . Early post-transplant culture positivity  and MDRO detection  were significantly associated with the composite outcome (Table\u00a04).Among 3,233 RTRs, 259 (8%) had a susceptible organism detected and 35 (1%) had an MDRO detected . Demographic and microbiology characteristics are summarized in Table\u00a01 MDRO as well as susceptible organism acquisition during the early post-transplant period was associated with increased mortality and allograft loss highlighting the need for increased infection prevention efforts within this vulnerable population.All Authors: No reported disclosures."}
+{"text": "Cervical carotid dissection is one of the causes of ischemic stroke in young people. Most of the patients with carotid dissection do not have connective tissue diseases . It seems that dissection may occur without an obvious cause or may follow environmental injuries like vigorous neck movements, chiropractic manipulation, emesis, severe coughs, and some infections. We present a case of bilateral carotid dissection in a patient following coronavirus infection and severe coughs.A 38-year-old right-handed man presented with recurrent episodes of transient right hemiparesis and aphasia. He had a history of coronavirus infection and severe persistent, nonproductive cough 7 days before the onset of his symptoms. Carotid angiography showed tapered flame-like appearance in proximal segment of left ICA starting about 2 cm distal to the carotid bulb caused complete occlusion of left ICA and in right CCA angiography there is pseudo aneurysm in right cervical ICA just before the Petrous segment. In 3 months in follow up DSA there is evidence of complete occlusion of right pseudo aneurysm and recanalization of left ICA without stenosis. COVID-19 may have role in the processes that eventually led to CAD Cervical carotid dissection (CAD) is one of the causes of ischemic stroke in young people . AccordiA 38-year-old right-handed man presented to our center complaining of recurrent episodes of transient right hemiparesis and aphasia. The patient had a history of coronavirus infection and severe persistent, nonproductive cough 7 days before the onset of his symptoms. The right-sided symptoms had been occurring two times, each time lasting 10 minutes. His medical history was negative for hypertension, and smoking or recent trauma. On physical examination, the patient was normotensive, intact neurological examination, and no carotid bruits were detectable. Bilateral peripheral pulses were normal and equal. Routine laboratory tests were normal. A computed tomographic (CT) scan and magnetic resonance imaging of the brain was normal. The patient with diagnosis of transient ischemic attack (TIA) was immediately treated with intravenous heparin and oral antiplatelet agents. Carotid angiography showed tapered flame-like appearance in cervical portion of left internal carotid artery (ICA) starting about 2 cm distal to the carotid bulb caused complete occlusion of left ICA . These fLeft vertebral artery angiography revealed collateral circulation to bilateral ICA from bilateral posterior communicating arteries. We decided to treat the patient with simultaneous bilateral carotid artery stenting as he was symptomatic despite receiving medical treatment. A femoral artery approach was obtained and selective bilateral carotid angiogram was performed. The 8F guiding catheter was put to the left CCA and the PILOT 150 micro-guidewire was passed from occluded segment of left ICA after that (8\u00d740 mm) self-expanding carotid stent  was deployed in the ICA. Post-stenting angioplasty was performed with inflation (5\u00d720 mm) NC balloon (Medtronic). We decided to put a stent in right ICA. There was a pseudo-aneurysm in distal cervical portion of ICA. The 8F guiding catheter was introduced to the right CCA and the lesion was crossed by PILOT 150 micro-guidewire and the stent was deployed in the distal cervical portion of ICA.There were no neurological complications. After 3 months in follow up catheter angiography there is evidence of complete occlusion of right pseudo aneurysm and recanalization of left ICA without stenosis .The patient introduced in this case report had spontaneous bilateral cervical carotid dissection with frequent TIA symptoms. It is generally believed that spontaneous dissection occurs in the context of underlying vascular wall structure disorders although no definite arteriopathy is found in many cases . CongeniA positive history of a recent coronavirus infection may be a risk factor for vascular dissection . Two proSome studies found an association between pertussis and CAD. Although difficult to prove, it seems that severe coughs due to pertussis play a role in dissection , 8. Acco Bilateral cervical ICA dissection with sudden onset more probably compromise hemodynamic than atherosclerotic lesions because the collateral circulation has not sufficiently developed. The indication of carotid artery stenting (CAS) for carotid artery dissection is the following situations: (a) symptoms persist or worsen under medical therapy; (b) significant hemodynamic compromise or (c) There is contraindications for antithrombotic therapy . Our pat"}
+{"text": "The association between family-related life events  and unsustainable working life in terms of unemployment, sickness absence and disability pension (SA/DP) are rarely studied from a life-course perspective although having public health importance. We investigated trajectories of unsustainable working life, and the associations between change in family-related life events and unsustainable working life trajectories by controlling for familial factors.This is a prospective cohort study of 37,867 Swedish twins aged between 20-40 years on 31st December 1994. Data on trajectories of annual unemployment, SA/DP, and a combined measure of unsustainable working life months was collected from the Swedish national registers. The trajectories over a 23-year period were analysed by group-based trajectory modelling. Associations of change in family-related life events with trajectory groups in the whole sample were estimated by multinomial logistic regression and in discordant twin pairs  with conditional models.Most participants had no or low levels of unemployment, SA/DP or combined unsustainable working life during 1994-2016. Individuals who were stably married or changed from being single living without children to married living with children had a decreased risk of unsustainable working life compared to individuals with stable family-related life events. The risk of unsustainable working life months over time was higher among individuals who changed from married to single status regardless of having children (range of HRs:1.31-4.44).Family-related life events such as maintaining the relationship or getting married and having children decreases the risk of unsustainable working life while divorce is a risk factor for unsustainable working life. From a public health perspective, actions to support family formation or life would consequently promote a sustainable working life.\u2022\u2002Unsustainable working life was less likely among married and among those who changed from single living without children to married with children compared to those with stable family life events.\u2022\u2002Individuals who changed from being married to divorced status had an increased risk of unsustainable working life over time and therefore being potentially an important group for public health."}
+{"text": "Aortic dissection is one of the most common emergency condition leading to internal organs or lower limb ischemia and aortic rupture. Herein, we described a reverse \u201ccheese wire\u201d endovascular fenestration repair (CWFER) in a patient with complicated abdominal aortic dissection which had never been reported.A 62-year-old male presented abdominal tear-like pain and acute ischemia of the right lower extremity during the endovascular treatment of celiac trunk aneurysms. Computed tomography angiography (CTA) and digital subtraction angiography (DSA) showed abdominal aortic type B dissection with acute ischemia of the right lower extremity preoperatively. After a detailed preoperative examination, the patient then was performed a reverse CWFER. So far, the patient has been followed-up for 6\u2009months, postoperative CTA demonstrated good stent-graft expansion and perfusion of bilateral common iliac arteries; also, no endoleak was detected.The right iliac artery in this patient supplied by false lumen, which lead to acute ischemia of the right lower extremity, needed to be treated as an emergency and dealt with promptly. CWFER is a very high-risk treatment that requires the rich experience of vascular surgeon and accurate assessment of aortic dissection. After interventional treatment, the patient recovered uneventfully after 6\u2009months\u2019 follow-up.The online version contains supplementary material available at 10.1186/s12893-022-01581-4. B-type aortic dissection is one of the most common emergent conditions affecting the aorta \u20134. CliniA 62-year-old male presented abdominal tear-like pain and acute ischemia of the right lower extremity during the endovascular treatment of celiac trunk aneurysms. Computed tomography angiography (CTA) and digital subtraction angiography (DSA) showed abdominal aortic type B dissection with acute ischemia of the right lower extremity preoperatively Figs.\u00a0 and 2, aThis patient provided prior informed consent to this intervention, as well as the publication of the relevant data. Anticoagulation therapy  was prescribed before the patient underwent the procedure. The endovascular repair of abdominal aortic dissection was performed under general anesthesia. The orientation of the puncture was guided by fluoroscopy. The percutaneous access of both femoral arteries was created by placing a 6\u00a0F short sheath (Terumo). The gooseneck snare was introduced into the false lumen of the lower abdominal aorta from the left femoral artery under the guidance of the path map. A 0.035-inch guidewire (Terumo) was introduced into the false lumen from the right femoral artery and captured by the gooseneck snare, an additional movie file shows this in more detail (see Additional file A gentle upward bilateral pull was maneuvered using a \u2018\u2018cheese wire\u2019\u2019 technique to shear the flap of the mid-abdominal aorta from the distal tear of the left common iliac artery dissection up to the proximal end Fig.\u00a0. This opAngiography confirmed the patency of the bilateral common iliac arteries and adequate visceral perfusion with no evidence of endoleak or arterial rupture Figs.\u00a0 and 4. TThe open surgery of type B aortic dissection is still associated with significant morbidity and mortality . The AorThis patient had symptoms of acute right iliac artery occlusion, such as severe pain in the right lower extremity and no pulse. Previous studies demonstrated the feasibility of using intravascular fenestration of dissection flap for treating poor perfusion secondary to acute aortic dissection \u201310. ChalThis would establish the true-false-true through wire access by maintaining the Lunderquist wire and sheath access to the true lumen on both sides. Completion angiography demonstrated excellent technical results with no evidence of endoleak and a satisfactory apposition of the graft to the aortic wall at the proximal neck. Also, the 6-month follow-up did not show an endoleak on CT angiography, and the patient reported to be feeling well. Taken together, the cheese-wire technique is a useful maneuver that facilitates endovascular arterial dissection repair. Adequate proximal or distal fixation could be conducted by endovascular fenestration. Nonetheless, sufficient experience is necessary for interventional therapy; also, total percutaneous approach is considered feasible for treating some sophisticated aortic dissections.Additional file 1. The procedure of reverse \u201ccheese wire\u201d endovascular fenestration repair.Additional file 2. Angiography confirmed the patency of the bilateral common iliac arteries and adequate visceral perfusion."}
+{"text": "DNA methylation at the fifth position of cytosine (5mC) is one of the most studied epigenetic mechanisms essential for the control of gene expression and for many other biological processes including genomic imprinting, X chromosome inactivation and genome stability. Over the last years, accumulating evidence suggest that DNA methylation is a highly dynamic mechanism driven by a balance between methylation by DNMTs and TET-mediated demethylation processes. However, one of the main challenges is to understand the dynamics underlying steady state DNA methylation levels. In this review article, we give an overview of the latest advances highlighting DNA methylation as a dynamic cycling process with a continuous turnover of cytosine modifications. We describe the cooperative actions of DNMT and TET enzymes which combine with many additional parameters including chromatin environment and protein partners to govern 5mC turnover. We also discuss how mathematical models can be used to address variable methylation levels during development and explain cell-type epigenetic heterogeneity locally but also at the genome scale. Finally, we review the therapeutic implications of these discoveries with the use of both epigenetic clocks as predictors and the development of epidrugs that target the DNA methylation/demethylation machinery. Together, these discoveries unveil with unprecedented detail how dynamic is DNA methylation during development, underlying the establishment of heterogeneous DNA methylation landscapes which could be altered in aging, diseases and cancer. In mammOver the last years DNA (de)methylation has been widely investigated thanks to high throughput technological advances, thus allowing methylome profiling of a large panel of biological samples. Accumulating evidence suggest that DNA methylation is a highly dynamic mechanism driven by a balance between methylation and demethylation processes. However, although the distribution of DNA methylation in the genome is now well-documented at steady state, the dynamics of the underlying mechanisms requires more attention. In this review article, we will first give an overview of the latest advances highlighting DNA methylation as a dynamic cycling process with a constant turnover of cytosine modifications. We will also discuss how variable methylation levels could explain the epigenetic heterogeneity observed during early embryo development in mammals and might influence cellular differentiation.Arabidopsis thaliana, active replacement of 5mCs by unmodified cytosines is initiated by the glycosylase activity of Demeter (DME)/repressor of silencing 1 (ROS1) enzymes from the base excision repair (BER) machinery  and the BER machinery during estrogen receptor-mediated transcription activation . HoweverDNMT1 is responsible for the maintenance of DNA methylation patterns during DNA replication. The multifunctional protein UHRF1 has been reported to act as an important cofactor of DNMT1 in DNA maintenance methylation . UHRF1 iImpairment of DNA maintenance methylation reduces global DNA methylation and results in passive demethylation characterized by a progressive dilution and loss of 5\u00a0mC marks during successive DNA replication cycles. Several processes can be involved in replication-dependent passive DNA demethylation including the downregulation of DNMT1/UHRF1 complex , the impDNA methylation patterns are essential for cell fate decisions during mammalian development and act as epigenetic barriers by limiting the developmental potential of cells and restricting their differentiation to avoid a regression into an undifferentiated state. Although DNA methylation landscapes are stably maintained in somatic cells, the genome undergoes a dynamic two-step genome wide reprogramming . First, de novo methylation and demethylation, and the functions of the regulators have been largely studied using mouse and human embryonic stem cells (mESCs and hESCs) as powerful model systems for both in vivo and in vitro assays. Both mESCs and hESCs derive from the inner cell mass of blastocyst-stage pre-implantation embryos but hESCs reflect a later phase in development than mESCs in addition to having distinct biological properties methylation dynamics plays a key role in the spatio-temporal regulation of gene expression, the maintenance of genome stability and embryonic development . The delde novo methylation during development is also observed in DNMT3s DKO mESCs as well as in mouse early embryos deficient in both of DNMT3A and DNMT3B, which leads to embryonic lethality  to form the fundamental unit of chromatin: the nucleosome . Each nuDynamic DNA methylation landscapes are shaped by a local competition between TETs and DNMTs for CGI association as well as other proteins partners such as TFs. Actually, DNA methylation and TFs binding act in a synergistic manner to regulate the spatio temporal expression of genes and chromatin remodeling, leading to local DNA methylation changes. Zinc finger cysteine-X-X-cysteine (ZF-CXXC) domain-containing proteins specifically target unmethylated CpGs at CGIs which are commonly hypomethylated and where they have chromatin-modifying activities . The firEmerging evidence suggest the existence of long non-coding RNA (lncRNA)-mediated DNA methylation. LncRNAs are transcripts with a length over 200 nucleotides which have been shown to interact with DNMTs and TETs through different mechanisms . Methylade novo and maintenance DNMTs. These models were then further improved by Genereux et al.  involved in establishing cell-type specific heterogeneity. A classical model of methylation dynamics has been first proposed by Otto and Walbot  and Pfeix et al.  and assupG dyads , they espG dyads . By usinpG dyads . Numeroun levels .The developed mathematical models explained the dynamics underlying steady state DNA methylation levels. For years, bulk cell measurements approaches used the average DNA methylation level of a cell population to define the methylation state of CpGs without considering that each CpG may exist in a dual state (methylated or unmethylated). The development of high-resolution single-cell approaches and especially single cell whole genome Bisulfite Sequencing (scBS-Seq) largely contributed to unravel DNA methylation variations in differentiating cells, at the genome scale. Using whole genome scBS-Seq, several studies demonstrated the emergence of methylation heterogeneity in mESCs. Howeverin vitro and in vivo methylation enzymes revealed highly dynamic methylation changes in early development both  in vivo . The co- in vivo . By cons in vivo .de novo methylation  resulting in their silencing as well as proto-oncogenes overexpression are also frequently observed. Aberrant DNA methylation leads to the formation and/or progression of cancer including hematological malignancies and solid tumors  and methWithin the last years, based on the reversible nature of epigenetic marks, small molecules referred to as epidrugs were developed to target epigenetic regulators . Aberranl-tryptophan 1 (RG108)) were designed to improve cancer treatments. MG98 is an antisense oligonucleotide targeting DNMT1 messenger RNA (mRNA) but, despite specifically downregulating DNMT1 in a dose-dependent manner, controversial responses have been observed in different (pre)clinical trials  promotes DNA demethylation by TETs which makes it a promising therapeutic agent that could be used to increase 5\u00a0mC turnover through TET activation. Indeed, Vitamin C is a well-studied antioxidant known to work as a co-factor for Fe(II) 2-oxoglutarate dioxygenase enzymes like TET enzymes . By reduIn silico screening of natural products as potential TET inhibitors further identified compound 35 (C35), a catechol containing small molecule targeting the catalytic core of TETs and thus blocking their enzymatic activity  reprogramming by Yamanaka et al., in 2006, allowed to generate pluripotent cells from differentiated somatic cells . Indeed, studies . AltogetFor the last decades, emerging high-throughput technological advances and mathematical modelling largely contributed to unravel DNA methylation oscillations at both local and genome scales. DNA methylation has been highlighted as a dynamic cycling process regulated by a balance between DNMTs and TETs and associated with a constant turnover of cytosine modifications. These variable steady state DNA methylation levels generate heterogenous DNA methylation patterns in healthy cells but also in cancer cells. Driven by DNA methylation dynamics, tumor heterogeneity can act as a barrier in cancer treatment by supporting tumor cells progression. Within the last years, DNA methylation has been increasingly investigated as a potential biomarker and therapeutic target for human cancer treatment. DNA methylation-based epigenetic clocks have been developed as diagnostic tools and age prediction biomarkers, while transient reprogramming strategies reinforced our comprehension of DNA methylation dynamics to design new therapies. Several molecules targeting methylating (DNMTs) and demethylating (TETs) enzymes were identified as potential anticancer drugs through modulations of DNA methylation dynamics. While some epidrugs are currently used alone or in combination with other therapies for cancer treatment, one of the main challenges remains to reduce side effects and cytotoxicity to ensure a positive outcome for patients."}
+{"text": "A 69-year-old man with non-ischemic cardiomyopathy and permanent atrial fibrillation underwent a pacemaker upgrade to a cardiac resynchronization therapy (CRT) defibrillator several years earlier. He experienced multiple inappropriate ICD shocks due to lead fracture and underwent a lead extraction with insertion of a new ICD lead performed at an outside hospital. Following the lead revision, the patient developed worsening heart failure, as well as intermittent pocket stimulation. An echocardiogram demonstrated a left ventricular (LV) ejection fraction of 35%, which was markedly reduced from the prior echocardiogram. He presented 1\u00a0year later for an elective defibrillator generator replacement due to battery depletion. His chest X-ray showed a rightward and inferior displacement of the ICD lead as compared to the pacemaker leads (panel A in Fig.\u00a0This case illustrated a spectacular complication of a trans-arterial placement of the ICD lead into the aortic arch and a unique cause of CRT failure, with epicardial and endocardial pacing across the lateral LV wall. Although inadvertent arterial puncture can occur during routine access using the subclavian or proximal axillary vein , an LV l"}
+{"text": "Apical hypertrophic cardiomyopathy (ApHCM) is a clinical challenge when presenting with symptoms of angina plus shortness of breath. An appropriate diagnosis of concurrent coronary artery disease (CAD) is needed for proper diagnosis, risk stratification, and management. We present a case of a 64-year-old gentleman with a history of ApHCM and CAD\u00a0with previous percutaneous intervention presenting with recurrent angina. A repeat coronary angiography showed no new obstructive lesions. A stress cardiac magnetic resonance imaging was performed, which showed perfusion defect in the apex with apical scarring likely secondary to microvascular disease. The patient was managed medically with the improvement of symptoms. Diagnosis and management of CAD in patients with ApHCM are challenging. Multiple diagnostic modalities may be required for delineating the underlying pathology. Patients should be managed initially with medications. If symptoms are not controlled with medical management, a heart team approach with referral to an advanced center experienced in apical myectomy should be considered. One of the rare variants of hypertrophic cardiomyopathy is apical hypertrophic cardiomyopathy (ApHCM) which mainly affects the left ventricular apex. Most patients with this morphology present with midventricular obstruction rather than left ventricular outflow tract obstruction (LVOTO). Based on some research studies, it has been found that ApHCM is mostly\u00a0prevalent in the East Asian population ,2. ApHCMA 64-year-old male with a past medical history of coronary artery disease (CAD) and ApHCM presented to the cardiology clinic with recurrent exertional chest pain. He had undergone coronary angiography 10 months previously for angina, which documented 80% stenosis of the first posterolateral branch of the right coronary artery (RCA) with the subsequent percutaneous intervention of the lesion. Symptoms of chest pain initially improved but recurred in the four months before his clinic follow-up and were described as central non-radiating chest discomfort on minimal exertion that typically resolved with rest. Repeat electrocardiogram (ECG) showed left ventricular (LV) hypertrophy with deep T wave inversion in V3, unchanged from previous ECG and attributed to known ApHCM  was noted to have a mild diffuse plaque with maximal 30% stenosis and to be shorter compared to the diagonal Figure . RCA shoLeft ventricular end-diastolic pressure was elevated (21 mmHg), and the left ventriculogram showed typical findings of ApHCM Figure .Subsequent stress cardiac magnetic resonance imaging (MRI) confirmed severe apical hypertrophy Figure  and multGiven MRI findings, his angina symptoms were attributed to microvascular ischemia of the apex secondary to severe ApHCM. The patient was given pharmacological treatment with beta-blockers (BB) and calcium channel blockers (CCB) and showed subsequent improvement.ApHCM is a variant of hypertrophic cardiomyopathy (HCM) characterized by isolated hypertrophy of the LV apex. ApHCM accounts for 3-10% of all HCM in the United States\u00a0compared to 25% of all HCM cases in Japan . The resThe evaluation includes an ECG and an echocardiogram, which show high QRS voltage and symmetrical deep T waves in the left precordial leads and increased apical wall thickness of more than 15 mm . CoronarMedical management is similar to therapy for HCM. BBs are the backbone of the treatment . CCBs arSome patients have shown improved symptoms with the novel surgical technique of apical myectomy ,16. AlcoPatients with ApHCM can present with angina, which poses a diagnostic dilemma of whether symptoms are caused by concomitant coronary disease. Careful patient evaluation with angiography and perfusion imaging helps delineate the underlying pathology and permits more specific treatment and risk stratification because patients with concurrent CAD have a worse prognosis."}
+{"text": "Culex mosquito populations near (10 m) and far (150 m) from each coop location for the peak WNV transmission season (Jul-Sep 2019). We also monitored serum IVM levels in treated chickens and tested for WNV antibodies in all chickens throughout the study. RESULTS/ANTICIPATED RESULTS: Since IVM impacts only mosquitoes that live long enough to take a bloodmeal from a treated chicken, we do not expect to find a marked difference in adult Culex abundance between the two treatment arms, but we expect to find a reduction in WNV infection prevalence and a shift in female mosquito age structure towards younger, uninfected individuals at treated coops. We also anticipate seroconversions in treated chickens to occur at lower rates versus untreated control chickens indicating a reduction in WNV transmission intensity at treated coops. We observed no negative health outcomes from the long-term ingestion of IVM by study chickens. A pathological investigation is underway to compare histological findings between treated and untreated chickens. DISCUSSION/SIGNIFICANCE OF IMPACT: IVM provides the potential for targeted mosquito control. Reduced WNV transmission dynamics here is a stepping stone to a commercial WNV control strategy; IVM-treated feed for wild birds for homeowners\u2019 use to combat WNV transmission in their neighborhoods.OBJECTIVES/GOALS: We conducted a randomized field trail to evaluate the efficacy and safety of a novel vector control strategy that involves treating urban backyard chickens with ivermectin (IVM), a widely used antiparasitic and mosquitocial drug. The goal was to reduce vector mosquito populations and West Nile virus (WNV) transmission. METHODS/STUDY POPULATION: We placed eight flocks\u2014four treated and four untreated control\u2014of six Lohmann brown chickens (16 month-old) each in backyard coops across Davis, CA and administered IVM in feed daily at treated coops (200 mg IVM/kg feed) for eleven weeks. We monitored entomological indices weekly  in"}
+{"text": "Anodal capture can provide a resynchronization effect on biventricular pacing. However, evidence of such an effect remains unclear in left bundle branch pacing (LBBP). We report a patient with a baseline sinus rhythm with complete atrioventricular block and a ventricular escape rhythm with a right bundle branch (RBB) block QRS morphology and left axis deviation who received LBBP for cardiac resynchronization therapy (CRT), and its anodal capture stimulation (ANS) rendered a near-normal QRS morphology. The resolution of the RBB pattern during bipolar pacing in this patient resulted from a fusion of LBBP and right ventricular septal capture from ANS. In conclusion, CRT can be achieved during LBBP by ANS in patients who do not have retrograde RBB activation. Left bundle branch (LBB) pacing (LBBP) is increasingly being performed, especially in patients with high-grade degree atrioventricular block (AVB), to avoid complications related to non-physiologic ventricular depolarization from pure myocardial pacing. Anodal capture has been demonstrated to have beneficial effects on cardiac resynchronization therapy (CRT) with biventricular pacing. However, there is still a lack of data on the effect of anodal capture in LBBP.. His-bundle lead placement was attempted but was unsuccessful due to the absence of the His-bundle potential. LBBP lead placement was then performed as described by Wu et al.1A 67-year-old woman presented for an elective upgrade from a dual-chamber pacemaker to a cardiac resynchronization therapy defibrillator (CRT-D) due to pacing-induced left ventricular (LV) systolic dysfunction. Her past medical history was significant for her complete heart block status after a dual-chamber permanent pacemaker implant, coronary artery disease status after coronary artery bypass graft surgery, and hypertension. Her baseline electrocardiogram (ECG) showed normal sinus rhythm with complete heart block. She had an escape rhythm with a right bundle branch (RBB) block morphology with a QRS duration of 121 ms and a left axis deviation (LAD) at a rate of 30 bpm Figure 1 shows a set of surface ECG tracings from baseline to pacing at different sites during lead advancement. Her baseline ventricular escape rhythm most likely originated either from the left posterior fascicle or LBB with underlying left anterior fascicular block given the absence of the His-bundle potential and right bundle branch (RBB) block\u2013LAD QRS morphology. Unipolar pacing at the target site for the LBB on the right ventricular (RV) septal area demonstrated a typical \u201cW\u201d pattern in V1 . The lead was rapidly rotated clockwise until the tip penetrated the septal surface and reached the mid-septal area. The paced QRS morphology at this site demonstrated that the notch in lead V1 moved toward the end of the QRS complex . Further lead advancement resulted in a more prominent R-wave on the paced QRS morphology in lead V1. As the tip of the lead reached the LBB area , the paced QRS morphology showed an RBB pattern with LAD , which was similar to the baseline QRS morphology indicating LBB or left posterior fascicle capture. There were no changes in QRS morphology during decremental unipolar pacing at this site, starting from 5.0 V at 0.5 ms to complete loss of capture at 0.8 V at 0.5 ms. After the delivery sheath was pulled back and the ring electrode was exposed, a repeat decremental pacing in a bipolar configuration was performed at 5.0 V at 0.5 ms. Paced QRS morphology at a high output resulted in a narrower QRS width and the resolution of the RBB pattern . As the pacing output was decreased to 3.0 V at 0.5 ms, the QRS morphology changed to an RBB pattern with a wider QRS width similar to the baseline QRS morphology and unipolar paced QRS morphology.2 which is the ring electrode in this bipolar configuration. Capture usually occurs at the tip electrode (cathode) and requires a lesser pacing output than ANS. ANS can also be observed in CRT devices that allow pacing from the LV lead electrode as a cathode to the RV lead ring or coil as an anode. ANS from the RV lead electrode can result in biventricular capture during LV pacing alone or triple-site ventricular capture during biventricular pacing.4 In summary, CRT can be achieved during LBBP by ANS in patients who do not have retrograde RBB activation. However, the benefit of CRT from ANS in LBBP is unclear and requires more clinical studies.CRT with a near-normal QRS complex can be achieved during LBBP by a retrograde RBB activation in some patients. However, this patient did not have a retrograde RBB activation as demonstrated by there being no resolution of RBB block morphology during unipolar pacing. The narrow QRS morphology with a near-normal QRS morphology during bipolar pacing in this patient resulted from a fusion of LBBP and RV septal capture from anodal stimulation (ANS). ANS is defined as a capture at the anode,"}
+{"text": "Branch vessel occlusion is a major cause of stroke in parent artery sacrifice (PAS) for vertebral artery dissecting aneurysms (VADA). There is now an increasing trend towards preservation of branch vessels during PAS. Stents are commonly employed to achieve this but bring with it the attendant risks of future thrombosis and lifelong antiplatelet use. Although a microcatheter protection technique has been utilised in branch artery protection of wide-necked saccular aneurysms, it has rarely been described in PAS for VADAs. We describe the use of a dual microcatheter technique in the protection and remodelling of the posterior inferior cerebellar artery (PICA) during PAS of the vertebral artery, which also served as a temporary scaffold to support placement of the coils during the embolisation process. Parent artery sacrifice (PAS) for vertebral artery dissecting aneurysms (VADAs) is a well-established technique ; the priA microcatheter protection technique is one of the described assisted techniques used to preserve parent or branch arteries in endovascular embolisation of wide-necked saccular aneurysm; however, this technique is rarely employed in embolisation of VADAs.\u00a0We describe the technique of microcatheter protection of the PICA during PAS of a VADA resulting in complete occlusion of the vertebral artery while simultaneously preserving the adjacent PICA, without the use of a stent or flow diverter.\u00a0A 57-year-old woman presented with a World Federation of Neurosurgical Societies Grade III, Modified Fisher Grade IV subarachnoid haemorrhage. Computed tomographic angiography (CTA) showed a right VADA affecting the proximal V4 segment.Catheter digital subtraction angiogram confirmed a 5.3 x 11.5 mm (diameter x length) dissecting aneurysm Figure\u00a0 involvinA right transfemoral approach was used to insert a 6-Fr guiding catheter into the cervical vertebral artery. After choosing the best working projection by using a biplane angiography unit (GE innova 3131-IQ), a roadmapping technique was done.A 1.7-Fr microcatheter  was advanced to the right vertebral artery aneurysm. A 2.3-Fr microcatheter  was then inserted in tandem, and was used to cannulate the PICA Figure\u00a0. Under sFollow-up CTA Figure\u00a0 showed cThe technique of microcatheter protection of the PICA has been described in angioplasty of atherosclerotic intracranial lesions  and in tIn our case, preservation of the PICA to minimize complications of side branch occlusion was important because of its larger-than-normal calibre and presumed larger vascular territory. Moreover, there was angiographic absence of collateral supply either from an ipsilateral AICA-PICA complex or contralateral bihemispheric PICA disposition. Its larger-than-normal calibre also facilitated temporary cannulation with a microcatheter to enable reconstruction of the PICA into an end vessel while the parent artery was being occluded.\u00a0This technique avoids the use of stents, reducing costs and obviating the need for periprocedural and lifelong antiplatelet therapy. The risk of delayed stent occlusion in the PICA is also eliminated. Cannulation of the PICA also serves as a means of remodelling for the reconstruction of the PICA origin and provides mechanical stabilisation to enable better packing of the coils in the dissected segment, reducing the risk of recurrence. This is achievable even with the higher coil mass needed for parent artery occlusion.Branch artery protection without the use of stents is feasible in selected cases where the vessel origin is just adjacent to (but not within) the diseased segment. This ameliorates the morbidity of procedure-related infarcts while eliminating stent-related complications. This technique is also applicable in VADAs proximal to the PICA origin where the microcatheter can be introduced via the contralateral vertebral artery."}
+{"text": "The growth of solo living has important implications for the rising \u201cloneliness epidemic\u201d among older adults. This study considers whether two forms of social connectedness\u2014extra-household core discussion networks and formal social participation\u2014buffer the loneliness associated with living alone. Our study uses data from two surveys  encompassing 20 developed Western countries in 2009/2010 and 2015/2016 . Harmonizing measures across data sets, we estimate survey-specific and pooled linear regression models with interaction terms. Results indicated that high levels of social connectedness only moderately buffer the loneliness associated with living alone in later life. Findings were largely consistent across regions of Europe and the United States, though the buffering patterns were most robustly identified for widowed solo dwellers. Taken together, the results suggest that extra-household connections are partial compensators, but do not seem to fully replace the ready companionship afforded by residential co-presence in later life. Future research is needed to understand whether the efficacy of compensatory connections differs by gender, race/ethnicity, and across more diverse global regions."}
+{"text": "The authors should be congratulated on reporting their findings in a large radical cystectomy cohort for muscle-invasive (MIBC) and metastatic bladder cancer . The man"}
+{"text": "Millions of older adults living in close communal contact in senior housing communities remain vulnerable during the COVID-19 pandemic. Approximately 30% of Lifestyle Leaders currently live in senior housing. This presentation will cover the unique challenges these participants have encountered, including experiences with and the impact of changing norms and pandemic-related policies within communities over time. In March 2020, 75% of Lifestyle Leaders rated the response of their senior housing community to COVID-19 as \u201cExcellent\u201d or \u201cVery Good.\u201d In August 2020, they reported they believed they were less likely to contract COVID-19 living in senior housing compared to people not living in senior housing (80%). Interview data revealed Lifestyle Leaders in these environments held favorable views toward their communities. This presentation will further discuss how the Lifestyle Leaders who do not live in senior housing perceive senior living and how these perceptions have shifted during the pandemic."}
+{"text": "Ovis dalli dalli) are important herbivores in the mountainous ecosystems of northwestern North America, and recent declines in some populations have sparked concern. Our aim was to improve capabilities for fecal metabarcoding diet analysis of Dall\u2019s sheep and other herbivores by contributing new sequence data for arctic and alpine plants. This expanded reference library will provide critical reference sequence data that will facilitate metabarcoding diet analysis of Dall\u2019s sheep and thus improve understanding of plant-animal interactions in a region undergoing rapid climate change.Dall\u2019s sheep (rbcL gene of 16 arctic-alpine vascular plant species that are known to comprise the diet of Dall\u2019s sheep. These sequences contribute to a growing reference library that can be used in diet studies of arctic herbivores.We provide sequences for the chloroplast The online version contains supplementary material available at 10.1186/s13104-021-05590-z. Ovis dalli dalli) are endemic to alpine ecosystems of northwestern North America, and their populations have been declining in recent decades [Dall\u2019s sheep  were paired upon import, then quality trimmed with BBDuk trimmer . Sequences were normalized, then aligned and assembled using the de novo assembly tool (Geneious Prime). Assembled contigs were uploaded and annotated using BankIt, then submitted to GenBank  Table 11.Table 1We sequenced one DNA extraction from each plant species.The sequencing project was funded through a grant to train new users on Illumina Nextera sequencing.The following are limitations for these data files:Additional file 1. Table of information about the plant specimens used for rbcl sequencing."}
+{"text": "Genome-wide association studies have identified thousands of genetic susceptibility loci associated with cancer as well as other traits and diseases. Mapping germline variation in identified genetic susceptibility regions to alterations in nearby gene expression nominates candidate genes potentially related to disease risk for further functional investigation. We developed LDexpress as an online resource that integrates population-specific linkage disequilibrium data from the 1000 Genomes (1000G) project and tissue-specific expression data from the Genotype-Tissue Expression project to better study regional germline variation impacting gene expression. LDexpress is a publicly available web tool designed to be easy to use, flexible to conduct a wide range of variant queries, and quick to efficiently investigate dozens of query variants across multiple tissue types. We demonstrate the utility of LDexpress using example genomic queries and anticipate this tool will accelerate understanding of disease etiology by uncovering associations of regional germline variation to nearby gene expression. Genome-wide association studies (GWAS) have made tremendous advances in identifying germline genetic variation associated with disease risk . IdentifA common approach for selecting nearby candidate genes for functional investigation is by performing an expression quantitative trait locus (eQTL) analysis. eQTL analyses identify germline variants associated with local gene expression by testing for a relationship between variant genotype and gene expression levels \u20134. Whilehttps://ldlink.nci.nih.gov/?tab=ldexpress) is a new open access web-based tool that seamlessly integrates LD patterns estimated from the 1000G project with gene expression data from GTEx v8 to investigate correlations between genotype and regional gene expression.GTEx is an excellent resource for eQTL information but lacks information on local linkage disequilibrium patterns. Linkage disequilibrium (LD) is the nonrandom distribution of alleles at nearby loci in a defined population . Germlinhttps://ldlink.nci.nih.gov/?tab=ldexpress) asks the user to input information for the desired query including a list of RefSeq (RS) numbers or genomic positions of query variants, the 1000G population of interest, the GTEx tissue or tissues of interest, threshold options for LD metrics , GTEx eQTL p-value, and genomic window of interest. The calculate button submits the form data to the LDexpress Python flask server which pulls phased VCF data  for the 1000G population of interest and calculates LD measures for sequenced variants in the selected window surrounding the query variants. LD measures are calculated as previously described in LDlink [https://storage.googleapis.com/gtex_analysis_v8/single_tissue_qtl_data/GTEx_Analysis_v8_eQTL.tar, accessed 8/19/2020) indexed by variant position for rapid retrieval. eQTL associations that match the user defined GTEx tissue of interest and meet the user provided p-value significance value are returned to the LDexpress web interface. Most variant queries take less than 10\u00a0seconds to complete.LDexpress is designed to be accessible to a wide range of genomic investigators interested in disengangling tissue- and population-specific eQTL associations. The landing page for accessing LDexpress (n LDlink . Varianthttps://ldlink.nci.nih.gov/?tab=apiaccess) using the options described above to allow batch queries.LDexpress organizes query results into a menu of clickable links for each query variant that has an eQTL association in LD within a selected GTEx tissue. The variant links will direct the user to a searchable and sortable table that provides details on variants in LD that have eQTL associations in GTEx. The table displays information on variant RS number, position and LD measures with the query variant as well as provides details on the eQTL association including gene symbol, Gencode ID, tissue type, effect size and p-value. Custom links are also generated to dbSNP, NCBI Gene, Ensembl and GTEx where further details and plots on the variants, genes and eQTL association are provided. Variants with no eQTL associations in LD in GTEx will be displayed as warnings. All LDexpress returned results can also be downloaded in a tab-delimited text file for further investigation. LDexpress web content is programmed in HTML5 for cross platform compatibility. The LDexpress web tool is available and fully supported for two full years following publication and does not require mandatory registration to use the resource. LDexpress can also be accessed through the LDlink API  that were associated with altered expression of SF3A3, INPP5B, and FHL3 in transverse and sigmoid colon tissues. The second example query is from a recent cutaneous melanoma GWAS [ITGB3BP gene in skin tissue , a tumor suppressor gene. CSR1 binding leads to migration of SF3A3 to cytoplasm and reduces splicing efficiency of epidermal growth factor receptor and platelet-derived growth factor receptor [http://www.proteinatlas.org) also suggested that the expression of SF3A3 protein might be a prognostic factor in liver cancer [INPP5B is a member of inositol polyphosphate-5-phosphatase family which regulates calcium signaling. The expression of INPP5B protein is prognostic for renal, head and neck, and pancreatic cancers in The Human Protein Atlas. Finally, FHL3 has been shown to modulate SOX4 expression leading to abrogation of self-renewal and epithelial-mesenchymal transition in cancer cells [We showcase the utility of LDexpress by identifying eQTLs with receptor . The Humr cancer . INPP5B er cells , 14.ITGB3BP) suggest this transcriptional coregulator that binds to and enhances the activity of members of the nuclear receptor families could be important for melanoma risk at 1p31.3. Functional studies in breast cancer cells indicates ITGB3BP induces apoptosis through a caspase 2-mediated signaling pathway.In the melanoma example, LDexpress demonstrated ancestry and tissue-specific identification of eQTLs by finding variants in linkage disequilibrium at 1p31.3 with the tagging rs670318 variant. The ancestry-specific population groups in the 1000 Genome Project sequencing data used by LDexpress enables cancer researchers to further disentangle potential differences in cancer risk based on genetic ancestry. The identification of an eQTL with integrin subunit beta 3 binding protein  were White. Previously, population-biased eQTL (pb-eQTL) were examined in GTEx across 31 tissues and discovered only 178 pb-eQTL suggesting that ancestry likely accounts for a limited proportion of all eQTLs . DespiteOur example LDexpress queries showcase the convenience and potential etiologic insights LDexpress can add to post-GWAS analyses that is not easily accomplished with simple GTEx queries, which are unable to perform comprehensive population-specific searches for proxy variants in LD. We anticipate LDexpress to be a useful tool for researchers that assists with identifying potential genes relevant for disease risk for future functional investigation."}
+{"text": "Liver cancer is considered one of the deadliest diseases with one of the highest disease burdens worldwide. Among the different types of liver cancer, hepatocellular carcinoma is considered to be the most common type. Multiple conventional approaches are being used in treating hepatocellular carcinoma. Focusing on drug treatment, regular agents in conventional forms fail to achieve the intended clinical outcomes. In order to improve the treatment outcomes, utilizing nanoparticles\u2014specifically lipid based nanoparticles\u2014are considered to be one of the most promising approaches being set in motion. Multiple forms of lipid based nanoparticles exist including liposomes, solid lipid nanoparticles, nanostructured lipid carriers, microemulsion, nanoemulsion, phytosomes, lipid coated nanoparticles, and nanoassemblies. Multiple approaches are used to enhance the tumor uptake as well tumor specificity such as intratumoral injection, passive targeting, active targeting, and stimuli responsive nanoparticles. In this review, the effect of utilizing lipidic nanoparticles is being discussed as well as the different tumor uptake enhancement techniques used. Liver cancer is the sixth highest cancer in terms of incidence rate and the third highest cancer in mortality rates. The world health organization (WHO) estimates the occurrence of 905,677 new cases in the year 2020 with 830,180 new deaths during the same year  score, and HKLC (Hong Kong Liver Cancer) staging . HoweverOther classification systems have been employed based on the molecular signature of HCC. These classification systems include G1-G6 (gene-signature based classification), iHCC 1\u20133 (metabolic classification), immune-high, immune-mid and immune-low  and poorly polyploid and highly polyploid  .Current conventional HCC therapies include liver resection, liver transplantation, local ablative therapy, transarterial therapy, and systemic therapies (tyrosine kinase inhibitors). However, regular chemotherapeutic agents such as doxorubicin (DOX) and gemcitabine show limited success due to the high ability of HCC to possess drug resistance both intrinsic and acquired .Liver resection is the process by which part of liver is removed. The extend of partial removal is governed by the tumor extension as well as the histological change of the underlying parenchyma. However, liver transplantation possesses the ability to completely remove both detectable, un-detectable nodules, preneoplastic lesions as well as treating the underlying cirrhosis . ChoosinLocal ablative therapy is considered to be the go-to therapy for early stage, unresectable tumors . LocallyTransarterial therapy can be classified into transarterial embolization, transarterial chemoembolization (TACE), and transarterial radioembolization (TARE) . TransarGenetic mutations in cancer setting result in dysregulating tyrosine kinases . TyrosinDespite multiple approved drugs, drug treatment of unresectable, advanced HCC still does not meet the intended outcomes. These insufficient outcomes can be attributed to multiple reasons including low drug bioavailability, and nonspecific drug delivery which lead to high risk of side effects with low drug concentration in the target tissue . One of Nanoparticles are defined recently by the British Standards Institution as 3D nano-objects with 3 external dimensions in the nano range with the nano range extending between 1 and 1000\u00a0nm . NanoparLipidic nanoparticles are biocompatible, non-toxic, and well tolerated nanoparticles formulated mainly of physiological lipids . Using lThis review article is constructed with the aim of elucidating the huge potential of using lipidic nanoparticles Fig.\u00a0 to delivLipidic nanoparticles possess the ability to improve the encapsulated drugs bioavailability and permeability, as well as enhance the payload stability through providing protection against physiological barriers . These eLiposomes are considered to be one of the most studied nanoparticles . LiposomLiposomes have been extensively studied as an approach to HCC treatment. Yang et al. prepared liposomal formulation entrapping docetaxel. The prepared liposomes composed of soy phosphatidylcholine, 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC), or 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC). HepG2 and SMMC-7721 cells were used to assess the efficacy of drug encapsulation in liposomal formulation as well as the safety of different liposomes forming materials. In both cells, soy phosphatidylcholine was the safest liposome forming material at both 24 and 48\u00a0h except for SMMC-7721 cells at 48\u00a0h, DMPC was the safest option. In HepG2 cells, drug loaded DOPC liposomes exhibited the highest cytotoxicity. While in SMMC-7721, drug loaded soy phosphatidylcholine liposomes had the highest cytotoxicity. It is also worth mentioning that in both cell lines, combining free drug with blank liposomes demonstrated higher cytotoxicity than drug encapsulated liposomes. Drug loaded soy phosphatidylcholine liposomes were able to decrease lactate dehydrogenase leakage, alleviate drug induced intracellular malondialdehyde (MDA) production, while increasing superoxide dismutase activity compared to free drug in HepG2 cells .1/2 compared to chitosan coated PLGA nanoparticles and free drug. Nanoerythrocytes coated chitosan coated PLGA nanoparticles also had higher drug accumulation in the liver [Chitosan can be applied as a coat to increase the liposomes stability and minimize its aggregation . Quagliahe liver .50 compared to blank nanoparticles and free drug. Pharmacokinetic testing demonstrated that drug loaded liposomes were able to accumulate more in the plasma and liver compared to free drug while the free drug and drug loaded liposomes were both not toxic to the N-nitrosodiethylamine rats\u2019 vital organs. Drug loaded liposomes therapeutic and protective effects were assessed in which the prepared liposomes exhibited the highest therapeutic and cancer preventive effect in comparison to free drug. Resveratrol loaded cationic liposomes also showed lower number of nodules as well as lower liver marker enzymes [Due to conventional chemotherapeutics agents\u2019 drawbacks such as toxicity and cancer recurrence, there is an ongoing search for new compounds with anti-cancer activity. One of the most explored options is the usage of phytochemicals . Phytoch enzymes .50 respectively, which the authors attributed to the easier availability of the drugs to the cancerous cells. Yet, the authors also stated that these results may indicate longer action time of the prepared liposomes resulting in higher anti-proliferative effect. In vivo testing was done on H22 tumor bearing mice on which the prepared formulation showed the lowest tumor volume as well as the lowest tumor weight, while decreasing SOR exposure to normal tissue [Combination therapy has been extensively used in cancer therapy. Combination therapy utilizes the pharmacological actions of two or more pharmaceutical agents in either an additive or a synergistic manner in order to combat the heterogenic nature of cancers . Employil tissue . Wang etl tissue . Sarfrazl tissue Another approach for combination therapy is combining a chemotherapeutic agent with other forms of therapy such as microwave ablation and radiotherapy. Wu et al. prepared DOX loaded liposomes and utilized it in combination with microwave ablation. The liposomal formulation consisted of 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), cholesterol, and DSPE-PEG2000. Drug loaded liposomes exhibited higher cellular uptake and cytotoxicity in HepG2 and Huh7 cells compared to free drug. Applying microwave ablation enhanced the cytotoxic efficacy compared to microwave ablation alone or drug loaded liposomes alone. Combining microwave ablation with drug loaded liposomes showed the highest reduction in tumor volume and weight in HepG2 tumor bearing mice compared to the free drug, microwave ablation alone and a combination of both. Microwave ablation also possessed the ability to enhance the cellular uptake of both drug loaded liposomes and free drug both in vitro and in vivo with drug loaded liposomes showing higher uptake . Shin etRSG), and remote loading with hypertonic loading (LRHG)-. The liposomal formulations were composed of DPPC, cholesterol, and DSPE-PEG2000. Utilizing the different combination of loading techniques significantly enhanced the entrapment efficiency of gemcitabine compared to passive loading technique. Incorporating gemcitabine in both liposomal formulations enhanced the cellular uptake in Huh7 cells resulting in lower IC50 compared to free drug. LRSG and liposomal DOX were chosen to assess the in vivo efficacy in Huh7 tumor bearing mice. LRSG combined with liposomal DOX significantly delayed tumor growth time while enhancing the animals\u2019 survival time compared to free drug combination and control group [Tamam et al. explored a new loading approach to increase gemcitabine entrapment\u00a0entitled hypertonic loading. The new loading approach depends on admitting a high osmotic pressure which forces the water molecules including the drug through lipid bilayer. The authors prepared two gemcitabine loaded liposomes combining different loading techniques\u2014remote loading with small volume loading  and did not cause cell lysis in hemolysis assay. The authors also stated that both formulations increased the bioavailability of SOR. Multiple cell lines  were used to assess the cytotoxicity effect of the prepared NLCs. Drug loaded NLCs containing Captex\u00ae 355 EP/NF showed higher cytotoxicity than the free drug. Drug loaded Miglyol\u00ae 812 NLCs showed dose dependent cytotoxic effect in HepG2, Huh7 and PLC/PRF/5 cells, and no cytotoxic effects in Hep3B cells . The samVarshosaz et al. prepared ASGPR targeted NLCs through chemically binding lactobionic acid to stearyl amine. The prepared NLCs composed of glyceryl monostearate, lecithin, oleic acid or Labrafac\u00ae, and tween 80 or Solutol\u00ae HS15. The prepared NLCs were used to entrap 5-fluorouracil. The optimized targeted, drug loaded formula which contained oleic acid and Solutol\u00ae HS15 was assessed in vitro using HepG2 cells. The results showed that the prepared NLCs had higher cytotoxicity as well as higher cellular uptake than untargeted NLCs .As mentioned earlier, HCC is considered to be one of the most resistant cancers to treatment. Liu et al. explored the ability of NLCs to overcome drug resistance through the utilization of 10-hydroxycamptothecin resistant HepG2 cells. The authors entrapped 10-hydroxycamptothecin in NLCs composed of soya oil, tween 80 and used xyloglucan as a coat to target ASGPR. The prepared NLCs were compared against microemulsion containing 10-hydroxycamptothecin and the free drug. NLCs showed the highest cytotoxicity and the highest cellular uptake. Also, in in vivo drug resistant xenograft model, NLCs showed longer residence time in the blood, higher accumulation in the liver, improved drug safety by increasing the lethal dose in comparison to free drug, as well as higher tumor inhibition rate . Zhao et50 when tested on HepG2 cells in comparison to the free drug as and other NLCs containing other liquid lipids. NLCs containing coix seed oil also showed the highest anti-tumor effect and inhibition rate in HepG2 tumor bearing mice [The process of formulating NLCs -as well as other drug delivery systems- requires the addition of pharmaceutical excipients alongside the active pharmaceutical ingredient. Excipients are defined by the International Pharmaceutical Excipients Council as \u201csubstance(s) other than the active pharmaceutical ingredient that are included in a drug delivery system to enhance the attributes of the overall safety and effectiveness of the drug delivery system during storage or use.\u201d . Excipieing mice .50 when assessed on HepG2, Huh7, and human colorectal carcinoma (HCT-116) [Another new advancement in designing drug delivery systems is the utilization of ion pair amphiphile (IPA). IPAs are cheap, lipid like alternative to phospholipids . They arHCT-116) .Microemulsions are bi-continuous dispersions of oil droplets in water that are thermodynamically stable, optically isotropic. These droplets exist in a diameter larger than swollen micelles .Ma et al. prepared and assessed the effectiveness of microemulsions in entrapping tanshinone  and tansTrepanier et al. incorporated CRV431  in self-microemulsifying drug delivery system. The prepared formulation consisted of vitamin E, Maisine\u00ae CC, propylene glycol, Transcutol\u00ae, and Cremophor\u00ae RH40. The prepared drug loaded nanoparticles exhibited high drug accumulation in the liver in healthy rats. The prepared drug loaded nanoparticles also exhibited higher Cmax and significantly larger AUC in healthy human subjects compared to Neoral\u00ae  .Nanoemulsions consist of oil, water and an emulsifier that form an emulsion with droplet size ranging from 20 to 500\u00a0nm . They diTabassum et al. incorporated the extract from five-day sprout of nigella sativa in nanoemulsion. Sefsol\u00ae 228, tween 80, and ethanol were used for the nanoemulsion formulation. The prepared drug loaded nanoemulsion was able to induce cytotoxicity in HepG2 while being non-toxic to normal human liver (WRL-68) cells. Treated HepG2 cells with drug loaded nanoemulsion showed increased levels of internal reactive oxygen species (ROS) which is hypothesized to be the utilized pathway for apoptosis by the prepared drug loaded nanoemulsion . NigellaSweed et al. formulated self-nanoemulsifying drug delivery system incorporating rosuvastatin calcium. Peceol\u00ae, tween 80, and Transcutol\u00ae P were used to construct the self-nanoemulsifying drug delivery system. Blank nanoparticles exhibited almost no toxicity in HepG2 cells indicating the safety of the prepared formulation. Drug loaded nanoparticles enhanced the cytotoxic effect of free drug in HepG2 cell as well as increased the apoptotic cells percentage .Ahmad et al. prepared nanoemulsion formulation composed of Sefsol\u00ae 218, Kolliphor\u00ae RH40, and PEG400 that was used to encapsulated silymarin. Drug loaded nanoemulsion exhibited cytotoxic effect as well as apoptotic signs in HepG2 cells compared to untreated control. The prepared drug loaded nanoemulsion also promoted intracellular release of ROS to which the authors attributed the generated apoptosis. Pharmacokinetic study in healthy rats demonstrated the ability of encapsulating the drug in nanoemulsion in improving the pharmacokinetic parameters of the free drug. The prepared drug loaded nanoemulsion exhibited higher Cmax, shorter Tmax, and larger AUC compared to free drug .Despite the phytochemicals robust pharmacological actions and their success in vitro. Their clinical use is limited due to their poor in vivo absorption. One of the suggested strategies to deliver phytochemicals is the usage of phytosomes . PhytosoFreag et al. assessed phytosomes ability to enhance the intestinal absorption of diosmin. The research group prepared lyophilized complex of soy phosphatidylcholine and diosmin with the aim of the in vitro formation of phytosomes upon exposure to the gastrointestinal tract aqueous media. The pure drug was not able to penetrate intestinal membrane in vitro. However, drug loaded phytosomes were able to penetrate intestinal membrane and allow the drug presence in significant amount in the dissolution medium .Komeil et al. prepared genistein loaded phytosomes using three different phospholipids namely Lipiod\u00ae S100, Phosal\u00ae 53 MCT, and Phosal\u00ae75 SA. The prepared phytosomes  exhibited the ability to enhance the drug accumulation in the liver, blood, and intestinal serum lipoproteins in healthy rats. These results indicate the ability of the phytosomal preparation to enhance lymphatic uptake as well as protecting the drug from intestinal degradation. The prepared drug loaded phytosomes  exhibited lower cytotoxic effect than free drug initially then had higher cytotoxic effect later on in HepG2 cells with Lipiod\u00ae S100 phytosomes exhibiting higher cytotoxic than Phosal\u00ae75 SA phytosomes. The authors attributed these results to the longer time necessary for the phytosomal preparation to exert their cytotoxic effect due to the complex structure between the drug and phospholipid. In DEN model in rats, both drug loaded Lipiod\u00ae S100 and Phosal\u00ae75 SA phytosomes exhibited higher caspase-8 expression with lower VEGF expression compared to free drug and untreated control. Drug loaded Lipiod\u00ae S100 phytosomes exhibited the highest improvement in alanine aminotransferase and aspartate aminotransferase. Drug loaded Phosal\u00ae75 SA phytosomes exhibited the highest AIF, and caspase-3 expression as well as lower MMP9 expression . LoadingCoating nanoparticles can be defined as the introduction of a material on the surface of nanoparticles . Shao etKhan et al. prepared lipid coated, pH sensitive calcium carbonate nanoparticles entrapping cisplatin and oleanolic acid. The lipids used in the coating layer are HSPC, cholesterol, and DSPE-PEG2000. The prepared nanoparticles exhibited higher in vitro release in pH 5.5 compared to pH 7.4. Co-loaded nanoparticles exhibited higher cytotoxic effect compared to single drug loaded nanoparticles in HepG2 cells. Co-loaded nanoparticles were also able to ameliorate cisplatin\u2019s induced liver toxicity resulting in higher hepatoprotection . Liu et Nanoassemblies are core\u2013shell structure nanoparticles that form due to the presence of a hydrophobic and hydrophilic portion co-existing together . If one Hanafy et al. prepared bromopyruvic loaded nanoassemblies composed of oleic acid conjugated chitosan. The prepared nanoassemblies were coated with folic acid conjugated bovine serum albumin in order to target folic acid receptor. Drug loaded nanoparticles exhibited higher cytotoxic effect on HLF cells compared to free drug with minimal cytotoxic effect caused by blank nanoparticles . MonajatIn order to increase the treatment efficacy, prodrug nanoassemblies have been developed. Prodrug nanoassemblies utilize both prodrug and nanoparticles through modifying the active constituent structure with another moiety rendering the structure amphiphilic . Zuo et Nanoparticles face multiple biological barriers that limit their ability to greatly accumulate in the tumor tissue . Upon reChemotherapeutic agents lack the ability to solely affect cancerous cells. This inability to discriminate between normal and cancerous cells significantly lowers the treatment efficiency . To addrRen et al. evaluated the effect of intratumoral injection of free and liposomal DOX on the pharmacokinetics, biodistribution, and anti-tumor effect in H22 tumor bearing mice. The prepared drug loaded liposomes were able to decrease the drug concentration in the plasma and healthy organs (except for liver and spleen) while exhibiting lower toxicity and lower mortality rates. Drug loaded liposomes also significantly enhanced the tumor tissue concentration compared to the free drug. The free drug showed lower anti-tumor effect compared to drug loaded liposomes .Emulsomes are a type of nanoparticles which consist of a phospholipid layer surrounding a solid lipid core . Xu et aFu et al. prepared paclitaxel and DOX co-loaded liposomes. The prepared liposomes were loaded into thermoresponsive nanocomposite gel for intratumoral delivery. The prepared gel exhibited sol phase at 4\u00a0\u00b0C and gel phase at 37\u00a0\u00b0C with limited corrosion when incubated in phosphate buffer solution at 37\u00a0\u00b0C. The prepared liposomes showed no toxicity on three different cell lines  while exhibiting enhanced cellular uptake and internalization in SMMC-7221 cells. Intratumoral injection of the prepared liposomal gel significantly enhanced the accumulation in the tumor site while minimizing accumulation to other organs in SMMC-7721 tumor bearing mice. In vivo results also demonstrated the possible ability of the prepared gel to delay the payload release .Irreversible electroporation is an emerging cancerous tissue ablation technique. It depends on the delivery of strong, short pulses of electric field that result in killing tumor cells as well as creating membrane defects . It was For the tumor cells to grow, excessive supply of oxygen and nutrients must be attained by the tumor cells. This need for oxygen and nutrients promote the tumor angiogenesis process through which new blood vessels supplying the tumor with its needs are formed . The newZhao et al. prepared Fasudil loaded pegylated liposomes using DSPE-mPEG2000. The prepared liposomes showed significantly higher accumulation in the tumor tissue as well as in the liver, spleen, stomach, and kidney in Hep3B xenograft tumor model when compared to free Fasudil . Huang em which resulted in lower drug leakage and slower drug release [Another approach that can be used to enhance targeting is altering the composition of nanoparticles . Li et a release .As previously mentioned, passively targeted nanoparticles possess higher blood circulation time. However, one common limitation of this targeting approach is the possible premature release of the active payload . NanoparpH responsive nanoparticles respond to changes in pH through two main pathways: protonation/ionization of functional groups and removal of acid-labile bonds . In protGuo et al. prepared liposomal formulation containing DOX and MDM2 inhibitor MI-773. The liposomal formulation was coated with carboxymethyl chitosan as a pH sensitive coat. The prepared coated nanoparticles exhibited negative charge in pH 7.4 which converted into positive charge at lower pH indicating the dissociation of the carboxymethyl chitosan coat. Coated liposomes also exhibited higher in vitro drug release at pH 6.5 compared to pH 7.4. Cellular uptake in HepG2 cells was assessed in pH 6.5 and 7.4. Coated liposomes showed improved uptake in pH 6.5 compared to pH 7.4 due to the charge reversal from negative to positive .Duan et al. synthesized N-acetylgalactosamine modified and pH sensitive DOX prodrug. This prodrug was co-encapsulated with SOR in lipid nanoparticles for the treatment of HCC. The prodrug gained pH sensitive capabilities due to the presence of hydrazine functional group. pH sensitive modified nanoparticles exhibited higher in vitro drug release in pH 5.5 compared to pH 7.4. The authors this increase in DOX release to the cleavage of hydrazone bonds in lower pH. They also stated that these results indicate that DOX will be released more easily in the tumor lower pH environment .The tumor redox microenvironment is controlled by nicotinamide adenine dinucleotide phosphate (NADP) -NADPH/NADP\u2009+-and glutathione. It was reported that glutathione levels in tumor tissue is significantly higher (4 folds) than in normal tissue. Glutathione exerts its reducing effects mainly through fragmenting disulfide bonds . DisulfiZhou et al. encapsulated DOX in redox responsive liposomal nanohybrid cerasomes through the incorporation of disulfide bond. Redox responsive nanoparticles exhibited higher in vitro release in glutathione rich release medium compared to glutathione deprived release medium. While glutathione addition showed no impact on regular nanoparticles. Redox responsive nanoparticles exhibited cytotoxic effects on SMMC-7721 cells and human breast cancer cells (MCF-7) while showing minimal effect on human embryonic kidney cells (293) .Utilizing ultrasound as a trigger for payload release is coupled with the usage of ultrasound contrast agents micro/nanobubbles. Micro/nanobubbles compose of gas-filled inner core (such as fluorocarbon) that allows the particles to oscillate at high speed when exposed to ultrasound field resulting in its destruction . EmployiZhu et al. prepared liposomal microbubble entrapping DOX using perfluoropropane as the gaseous core. Drug loaded liposomal microbubbles had a significant cytotoxic effect on H22 cells in the presence of ultrasound. However, drug loaded liposomal microbubbles had limited cytotoxicity in the absence of ultrasound. Drug loaded liposomal microbubbles enhanced the tumor ultrasound signals with high nanoparticles signals around the tumor in H22 tumor bearing mice. Tumor blood flow also increased after nanoparticles destruction indicating liposomal microbubbles\u2019 ability to enhance blood flow inside the tumor .Guo et al. used perflenapent as the gaseous core in formulating arginine-glycine-aspartic acid (RGD) modified liposomal nanobubbles loaded with fingolimod and superparamagnetic iron oxide nanoparticles. In vitro release of drug increased from the prepared liposomal nanobubbles when ultrasound was applied. The enhancement in drug releases was directly proportional to the ultrasound power applied. Cellular uptake of the prepared nanoparticles in HepG2 cells improved when ultrasound was applied compared with no ultrasound application. This improvement was attributed by the authors to the cavitation process .For nanoparticles to gain responsiveness to magnetic field, materials possessing magnetic behavior must be included. One of the most commonly used materials is iron oxide nanoparticles . UtiliziGrillone et al. prepared SOR and superparamagnetic iron oxide nanoparticles loaded solid lipid nanoparticles. The prepared solid lipid nanoparticles enhanced cellular uptake in HepG2 cells when magnetic field was applied. Magnetic field application was able to focus the cytotoxic effect in the desired tumor tissue as a result of magnetically driven tumor accumulation .Chen et al. encapsulated DOX with superparamagnetic iron oxide nanoparticles in PEG stabilized liposomes. The in vitro release of the entrapped drug significantly increased upon the application of magnetic field. Drug loaded nanoparticles cytotoxicity significantly improved upon applying magnetic field compared to its absence in Huh7 cells .Liu et al. formulated DOX loaded thermosensitive liposomes. Radiofrequency responsive manganese and zinc doped superparamagnetic iron oxide nanoparticles were used in mixture with the liposomal formulation. The combination was used to induce hyperthermia allowing the release of the encapsulated payload. The authors utilized a strong static gating field containing a sharp zero point superimposed on the radiofrequency field. This modification allowed radiofrequency waves to affect only nanoparticles at zero or near zero point. Thus, increasing the resolution of the targeted release. In vitro release of DOX increased with increasing the temperature of the dissolution medium. DOX in vitro release also increased with the presence of magnetic nanoparticles. Liposomal formulation in combination with magnetic nanoparticles exhibited higher cytotoxic effect in Huh7 cells in the presence of magnetic field compared to its absence .Increasing the tumor tissue temperature to 40\u201343\u00a0\u00b0C is termed hyperthermia . As mentDirect tumor killing using microwave ablation by heat generation was explored by Zhou et al.. Sodium chloride that is used as a thermo-seed was encapsulated in liposomal formulation. Liposomes loaded with sodium chloride exhibited better heat conversion than blank liposomes and free sodium chloride. Sodium chloride loaded liposomes exhibited the highest cytotoxic effect on HepG2 cells while showing hemocompatibility on the application of microwave. The in vivo efficacy of the prepared liposomes was assessed in both HepG2 xenograft animal model and MHHC97H orthotropic animal model. In both models, the prepared nanoparticles exhibited the highest anti-tumor effect while applying microwave compared to the usage of free sodium chloride, microwave ablation alone, and the prepared nanoparticles alone without applying microwave .Guo et al. prepared icaritin loaded microemulsion with coix seed oil as an unconventional liquid phase. The prepared microemulsion was entrapped in thermosensitive liposomes. In vitro release of the entrapped drug was slow at 37\u00a0\u00b0C. However, in vitro release was significantly higher at 42\u00a0\u00b0C. The prepared microemulsion and thermosensitive liposomes exhibited enhanced cellular uptake in HepG2 cells compared to free drug using clathrin-mediated internalization pathway. Applying mild hyperthermia enhanced the prepared nanoparticles cytotoxicity. The prepared liposomes enhanced tumor uptake and exhibited higher tumor penetration in HepG2\u2009+\u2009LX-2 desmoplastic 3D tumor spheroids before hyperthermia application. Hyperthermia application enhanced the in vivo anti-tumor effect of the thermosensitive liposomes compared to the anti-tumor effect in the absence of hyperthermia in HepG2\u2009+\u2009LX-2 tumor bearing mice .Zhu et al. modified iron oxide nanoparticles with oleic acid. These modified magnetic particles were encapsulated alongside hydroxycamptothecin to obtain thermosensitive magnetic liposomes. Drug in vitro release was enhanced when the release media was heated to 42\u00a0\u00b0C compared 37\u00a0\u00b0C confirming the thermosensitive characters of the prepared nanoparticles. The prepared drug loaded nanoparticles enhanced tumor treatment in Huh7 tumor bearing mice when magnetic strips and external heating source (42\u00a0\u00b0C water bath) were applied compared to the anti-tumor effect in their absence .Multiple clinical trials were conducted validating the efficacy of DOX loaded thermosensitive liposomes as an adjuvant therapy to radiofrequency ablation , 211.1O2) upon activating a photosensitizer. The generated 1O2 is responsible for killing cancer cells [Phototherapy is described as the utilization of light (preferably near-infrared light) through activating phototherapeutic agents. These agents should possess low toxicity in the dark as well as the ability to kill cancer cells under light activation without affecting normal cells . Photother cells . Payloader cells .Youssef et al. encapsulated hypericin in solid lipid nanoparticles. The encapsulated photosensitizer exhibited lower degradation when compared to free photosensitizer. Both free and encapsulated photosensitizer exhibited no significant effect on HepG2 cells in the dark. However, upon light exposure, both free and encapsulated photosensitizer exhibited significant cytotoxicity. The free photosensitizer exhibited higher cytotoxic effect. These results were attributed by the authors to the possible quenching deactivation of the photosensitizer as a result of the solid lipid nanoparticles compact and thick structure .3Na)4ZnPc)- was synthesized by Abdel Fadeel et al.. The prepared photosensitizer was evaluated for its photodynamic efficacy after being loaded into liposomes and transferosomes [A new photosensitizer -thiophenyl sulfonated zinc phthalocyanine  in thermosensitive liposomes. Encapsulating the photosensitive agent in liposomal formulation enhanced its photostability compared to free agent. The drug in vitro release from the prepared thermosensitive liposomes increases significantly upon light application. The prepared nanoparticles were able to attain more cellular uptake in Hep3B cells upon light activation. This enhancement in cellular uptake was attributed by the authors to the production of ROS and the generation of thermal effect which promoted cellular uptake. The cytotoxic effect of the prepared nanoparticles on Hep3B cells significantly improved upon light activation compared to the cytotoxic effect in absence of light. The prepared nanoparticles also had higher anti-tumor effect in Hep3B tumor bearing mice upon light activation compared to its absence .One of the potential risks of phototherapy is the induction of severe hypoxia as a result of oxygen consumption in generating ROS. This may result in a rise in cancer metastatic risk . Yang etHigher understating of disease progression and molecular targets has allowed the development of nanoparticles that actively target the tumor tissue on a cellular level limiting nanoparticles unspecific binding to healthy organs and tissues . Active ASGPR is a C-type lectin composed of 48\u00a0kDa (ASGPR-1) and 40\u00a0kDa subunits (ASGPR-2) that is responsible for clearing glycoproteins that terminate with a galactose or N-acetylgalactosamine moiety . ASGPR iPathak et al. utilized arabinogalactan conjugated to cholesterol as the targeting moiety for DOX loaded liposomes. Non-targeted drug loaded liposomes showed comparable cell inhibition on HepG2, breast cancer (MCF7), colon cancer (HT-29), and lung cancer (A549) cells. While targeted liposomes showed higher uptake in HepG2 cells. In vivo biodistribution was conducted on healthy mice through radiolabeling the formulated nanoparticles. Both liposomal formulations were able to accumulate in the liver and spleen with minor amounts being present in the bladder. These results indicate the ability of both nanoparticles to mitigate DOX mediated nephrotoxicity. In vivo analysis in HepG2 tumor bearing mice exhibited smaller tumor volume when compared to free drug . Bansal In a research done by Ding et al., the effectiveness of three different ligands was assessed in enhancing cellular uptake of 10-Hydroxycamptothecine loaded liposomes. Galactose and di-galactose were bound to stearic acid targeting ASPGR while galactose and biotin were co-bound to stearic acid targeting both ASPGR and biotin receptors. Galactose-biotin liposomes showed the highest cellular uptake in HepG2 cells followed by di-galactose liposomes then galactose liposomes. Cellular uptake studies also exhibited low uptake in A549 (lung cancer cells), Hela , and SGC-7901 (gastric cancer cells). All targeted liposomes also exhibited lower cellular uptake in LO2  than HepG2 cells .Qu et al. synthesized Octanoyl galactose ester as a targeting ligand for HCC which was used to provide active targeting capabilities to formulated microemulsion. Targeted microemulsions showed higher uptake than non-targeted microemulsion in HepG2 cells. Cellular uptake studies also showed that targeted microemulsion uptake decreased significantly when HepG2 cells were pre-treated with galactose. Targeted microemulsion exhibited higher localization in tumor site with longer retention time when compared to non-targeted microemulsion in HepG2 tumor bearing mice. The authors also stated that there was no\u00a0difference in pharmacokinetics between orally administered targeted and non-targeted microemulsion which the authors attributed to the lack of effect on galactosylation modification on oral absorption .Wei et al. utilized both passive and active targeting approaches in enhancing the delivery of DOX. DSPE-PEG2000 was used to convert the liposomes into pegylated liposomes as well as conjugating the targeting moeity which was Lactoferrin. Targeted liposomes showed higher cellular uptake in ASPGR positive HCC cell lines HepG2, BEL7402, and SMMC7721. However, both targeted and non-targeted liposomes showed no difference in cellular uptake in ASPGR negative mouse embryonic fibroblast cell line NIH 3T3. DOX showed the highest cellular uptake in all cell lines which the authors attributed to DOX ease of diffusion into the cells while nanoparticles accumulate in the cell using receptor mediated and non-receptor mediated endocytosis .1/2. Huh7 orthotopic tumor xenograft model in mice as well showed higher accumulation for targeted liposomes in the tumor area [The possibility to tackle both MDR as well as active targeting to HCC using mitoxantrone loaded liposomes was explored by Zhang et al.. The research group synthesized galactosyl conjugated Pluronic P123 utilizing P123 ability to reverse MDR while targeting ASPGR using the galactosylated moiety. The ability of P123 to reverse MDR was validated using BCRP-overexpressing Madine-Darby Canine kidney cell line. P123 exhibited dose dependent enhancement in the drug accumulation while galactosylated P123 showed comparable effect indicating that galactosylation possesses limited effect on MDR reversal. Targeted liposomes and P123 modified liposomes showed comparable enhancement in mitoxantrone uptake when compared to conventional liposomes. Conventional liposomes also improved mitoxantrone uptake compared to free drug which the authors attributed to the ability of liposomes to bypass efflux transporters. Targeted liposomes showed higher cellular uptake in ASPGR positive Huh7 cells when compared to P123 modified liposomes and conventional liposomes. Liposomal formulations were able to improve free drug pharmacokinetics with targeted liposomes showing the highest AUC and longest Tmor area .A summary of other approaches targeting ASPGR is provided in Table GA is the aglycon derivative of the widely present in licorice roots glycyrrhizic acid . GA is oCellular uptake and clearance mechanism of both free GA and GA modified liposomes in HepG2 cells were evaluated by Sun et al.. Free GA showed both concentration and temperature dependent uptake with higher uptake achieved in higher concentrations and higher temperature. Different proteins showed varying effects on GA uptake. Bovine serum albumin showed no interference in GA uptake. Fetal bovine serum and cytoplasm protein slightly decreased GA uptake while cytomembrane protein showed the highest decrease in GA uptake. GA coupled liposomes showed time dependent uptake with higher uptake achieved with longer incubation time. GA coupled liposomes showed higher dependence on active transport, endocytosis, and caveolae-dependent endocytosis cellular uptake mechanisms while clathrin-dependent endocytosis and micropinocytosis were not significantly utilized by GA coupled liposomes. Free GA clearance best fitted exponential decay kinetics while GA coupled liposomes best fitted second order kinetics . The samChu et al. coupled GA to DSPE-PEG2000 and used it as a targeting moiety for curcumin loaded NLCs. Varying concentrations of GA were used to assess whether cellular uptake increases with increasing the targeting ligand concentration on HepG2 cells. The results showed that with increasing the ligand concentration, the cellular uptake increases until reaching a certain limit then decreases. The authors attributed these results to the overabundance of ligands which may result in stearic hinderance which may result in blocking ligand-receptor interactions. Targeted NLCs with the best ligand concentration exhibited higher cellular uptake in HepG2 in comparison to free drug, conventional NLCs, and pegylated NLCs .Docetaxel loaded liposomes were modified by Li et al. through synthesizing 3-succinyl-30-stearyl GA. Non-targeted liposomes showed no difference in cellular uptake in L02 cells and hepatic nonparenchymal cells (LX-2) while targeted liposomes showed enhanced uptake in L02 cells through receptor mediated endocytosis. Targeted liposomes had enhanced pharmacokinetic profile compared to non-targeted liposomes when assessed in healthy rats. However, the difference was not significant between the two groups. The authors attributed these results to the inability of hydrophilic succinic anhydride to overcome the hydrophobicity of GA. This led to rapid MPS uptake of hydrophobic targeted and non-targeted liposomes .1/2 and higher elimination rate for targeted liposomes which the authors ascribed to the targeted liposomes\u2019 ability to distribute quickly to the tissues as well as quick recognition by GAR and ASPGR. Targeted liposomes were able to significantly enhance liver targeting compared to non-targeted liposomes. The results also demonstrated that targeted liposomes accumulated mainly in the liver and kidney with higher amount in the kidney [Zhou et al. explored the potential of synthesizing a single ligand that has the ability to target two receptors simultaneously. The authors synthesized 3-Galactosidase-30-stearyl deoxyglycyrrhetinic acid  which has the ability to target both GAR and ASPGR. The synthesized ligand was used to modify cantharidin loaded liposomes. In vivo testing in healthy rats exhibited lower Te kidney . Double e kidney .Folate Receptor (FR) is a family of proteins that are classified into FR\u03b1, FR\u03b2, FR\u03b3 and FR\u03b4. They are a group of glycoproteins where FR\u03b1, FR\u03b2, and FR\u03b4 are glycosyl-phosphatidylinositol anchored cell surface proteins while FR\u03b3 is a secreted protein with no anchor . Folate Folic acid was conjugated to DSPE-PEG2000 by Liu et al. and they used this conjugation to modify diacid metabolite of norcantharidin loaded liposomes. Biodistribution study in H22 tumor bearing mice demonstrated high accumulation of targeted and pegylated liposomes in the tumor, liver, and spleen. This accumulation was significantly higher than the free drug accumulation. Targeted liposomes were able to further enhance pegylated liposomes\u2019 ability to target the tumor. However, targeted liposomes showed significantly higher accumulation in the kidney compared to pegylated liposomes. The authors stated that this higher accumulation in the kidney requires further safety evaluation for targeted liposomes containing diacid metabolite of norcantharidin due to higher risk of kidney toxicity . Liu et 1/2 with lower clearance in B16 tumor-bearing mice. Targeted nanosuspensions improved tumor targeting efficiency compared to free drug while pegylated nanosuspensions showed intermediate improvement in targeting efficiency. Both nanosuspensions were accumulated in the liver and spleen more than free drug while decreasing the free drug concentration in the heart, lung, and kindey [Wang et al. prepared docetaxel lipid based nanosuspensions modified using folic acid conjugated DSPE-PEG2000. Targeted and pegylated nanosuspensions showed comparable cytotoxic effect on FR negative HepG2 cells. However, targeted nanosuspensions showed significantly more cytotoxic effect than pegylated nanosuspensions on FR positive B16 cells. Both nanosuspensions improved the cytotoxic effect of free drug on both cell lines. Both targeted and pegylated nanosuspension improved the pharmacokinetic parameters of free drug with higher residence time, and Td kindey .EGFR is a single chain transmembrane glycoprotein . EGFR  to be used as the targeting moiety. EGFR Fab\u00b4 conjugated nanoparticles showed higher cellular uptake when compared to non-modified nanoparticles. This improvement in cellular internalization was observed in SMMC-7721 (high expression of EGFR), HepG2 (moderate expression of EGFR) and Huh7 (low expression of EGFR) cells. However, the enhancement in cellular uptake in Huh7 was moderate. EGFR Fab\u00b4 conjugated nanoparticles enhanced tumor tissue uptake in SMMC-7721 tumor bearing mice when compared to non-modified nanoparticles. Non-modified nanoparticles exhibited low cellular internalization in the tumor tissue. However, EGFR Fab\u00b4 conjugated nanoparticles demonstrated high cellular internalization in a pattern consistent with receptor mediated endocytosis .Low density lipoprotein receptor (LDLR) composes of several domains, most importantly class A repeat and class B repeat. Class A repeat consists of three pairs of cysteines in each seven or eight repeat moieties. Each seven or eight repeat moieties consist of approximately 40 amino acids. Class B repeat contains four-amino-acid sequence of Tyr-Trp-Thr-Asp. Domains containing class B repeat typically consist of both class B repeats and epidermal growth factor repeats. The class B repeats form a structure called \u03b2-propeller . Among LApo B was explored as a targeting ligand for LDLR by Wang et al.. The research group utilized Apo B as a targeting ligand for lipid nanoparticles entrapping both SOR and dihydroartemisinin. The prepared nanoparticles were able to enhance the cellular uptake in LDLR\u2009+\u2009ve HepG2 cells compared to non-targeted nanoparticles. This enhancement in uptake was mediated through receptor mediated endocytosis .Alanazi et al. explored the ability to target LDLR conjugating cholesterol to an active pharmaceutical ingredient. This exploration was based on the theoretical knowledge that this conjugation will result in a cholesterol ester which is a natural component of LDLR. The research group conjugated 5-fluorouracil to cholesterol and incorporated this conjugation into both liposomes and LDL nanoparticles. Drug conjugation to cholesterol was able to enhance drug partitioning into LDL core due to its hydrophobic nature compared to non-conjugated drug. When comparing conjugated and non-conjugated drug loaded liposomes in healthy rats, conjugated drug loaded liposomes significantly enhanced the drug accumulation in liver. Conjugated drug loaded liposomes also were able to accumulate in LDL while non-conjugated drug loaded liposomes failed to accumulate in LDL .LDL nanoparticles packed with docosahexaenoic acid targeting LDLR were explored by both Ou et al.  and YangCD are cell surface glycoprotein that are used to immunophenotype cells. There are more than 350 CD markers that exhibit various functions including cell adhesion, cell activation, and cell inhibition . MultiplCD13  protein is a 150\u00a0kDa metalloprotease characterized by the presence of a catalytic domain oriented toward the extracellular matrix. It plays a vital role in multiple processes including cytokines activity regulation through cleaving the present N-terminals as well as regulating inflammatory mediators . Pang etCD90  protein is 25 to 37\u00a0kDa glycophosphatidylinositol anchored protein with heavy N-glycosylation on two sites in human and three sites in mouse. CD90 exerts roles in cell\u2013cell and cell\u2013matrix interactions . Yang etd, and t1/2 compared to free drug in healthy rats. Huh7 tumor bearing mice demonstrated higher ability for targeted liposomes to accumulate in the tumor as well as liver and spleen with lower accumulation in heart, lung, and kidney. In vivo evaluation also confirmed the ability of targeted liposomes to enhance tumor uptake compared to non-targeted liposomes and free drug [CD147  protein is a type-1 transmembrane glycoprotein that exerts functions in intercellular recognition. CD147 can be present in either a 27\u00a0kDa unglycosylated form or a 43 to 66\u00a0kDa glycosylated form , 273. Waree drug .Peptides are low molecular weight protein fragments that compose of two or more amino acids linked together using peptide (amide) bond . PeptideRGD is a peptide that has the ability to bind to integrin receptors  which arWang et al. formulated SOR and quercetin loaded lipid coated PLGA nanoparticles and used RGD conjugated DSPE-PEG as the targeting moiety. Targeted nanoparticles exhibited higher cellular uptake in HepG2 cells when compared to non-targeted combination loaded nanoparticles, non-targeted SOR loaded nanoparticles, and free drugs both the combination and SOR alone .RGD conjugated DSPE-PEG was used by Fei et al. to modify arsenic trioxide loaded liposomal shell-mesoporous silica core hybrid nanoparticles. In vitro study was conducted in \u03b1v\u03b23 positive HepG2 and \u03b1v\u03b23 negative MCF-7 and L02. Targeted nanoparticles exhibited significantly more uptake in HepG2 than MCF-7 and L02. Non-liposome shell mesoporous silica nanoparticles showed lower uptake due to the nanoparticles aggregation on cell surface impeding their uptake. Targeted and non-targeted nanoparticles exhibited enhanced bioavailability and prolonged residence time than non-liposome shell mesoporous silica nanoparticles and free drug due to lower drug leakage in healthy rats. H22 tumor bearing mice showed higher accumulation in tumor tissue by all nanoparticles. Targeted nanoparticles exhibited the highest accumulation in the tumor tissue .iRGD peptide (CRGDK/RGPDC) is a combination between RGD sequence motif and cryptic CendR motif . This seSP94 (SFSIIHTPILPL) is an HCC targeting peptide that was identified using phage display technique . It was Wu et al. enhanced targeting ability of DOX and vinorelbine co-loaded liposomes using SP94 conjugated to DSPE-PEG-N-hydroxysuccinimide(NHS). The ability of SP94 to enhance targeting was explored using DOX alone as the model drug. Targeted liposomes showed improved cellular uptake in SK-HEP\u20111 cells when compared to pegylated liposomes. Targeted liposomes exhibited higher tumor accumulation while showing similar uptake to pegylated liposomes in normal organs in Mahlavu tumor bearing mice .The effectiveness of SP94 modification was compared to the effectiveness of galactose modification in enhancing the targeting effect by Jiang et al.. SP94 or galactose was conjugated to DSPE-PEG2000 to modify C14 alkyl chain norcantharimide derivative loaded liposomes. Both galactose and SP94 modified liposomes were able to enhance cellular uptake in HepG2 cells compared to conventional liposomes. However, SP94 modification showed completely different uptake pattern than galactose modified liposomes. SP94 modified liposomes were able to internalize within the cells at a much faster rate than galactose modified liposomes and then decline over time. While galactose modified liposomes showed increased accumulation over time. The authors ascribed SP94 faster uptake to its possible ability to allow the ligands to bind to multiple binding sites through the enhancement of clustering and mobility of ligands. This effect is attributed to the SP94 binding to peg-terminal \u201cbrush\u201d on the fluid lipid membrane. SP94 modified liposomes were able to enhance drug concentration in the tumor tissue while decreasing its accumulation in normal organs in H22 tumor bearing mice .To assess the efficacy of different peptides in targeting HCC, Wu et al. conjugated L-peptide, SP94 peptide, and PC5-52 peptide to liposomal iron oxide nanoparticles and DOX loaded liposomes. L-peptide, which is an anti-cancer cell membrane, SP94 peptide, and PC5-52-peptide, which is anti-tumor endothelia. L-peptide and SP94 showed comparable cellular uptake in HepG2 and Huh7. Cellular uptake increased when combining the two peptides. L-peptide was also able to avoid binding to normal hepatocytes, same as SP94. Drug loaded liposomes showed some toxicity signs in the liver, kidney, and spleen. However, L-peptide or SP94 or both peptides modified drug loaded liposomes showed no signs of toxicity in HepG2 tumor bearing mice. The in vivo model also demonstrated the ability to enhance the chemotherapeutic effect of DOX when PC5-52-peptide modified drug loaded liposomes is co-administered with either L-peptide or SP94 modified drug loaded liposomes. The authors concluded from the in vivo results that combining anti-tumor and anti-endothelial peptide is more effective than a combination of two anti-tumor peptides .TAT (GRKKRRQRRRPPQ) is the transcriptional activator protein in HIV-1. It is a cationic cell penetrating peptide which consists of arginine and lysine residues . TAT -liMei et al. formulated multistage liposomes composed of cleavable PEG, RGD, and TAT. Long chain cleavable PEG was employed as the first stage to achieve passive targeting. The second stage composed of RGD conjugated to medium chain PEG to recognize and bind to HCC cells. The third and inner stage is TAT conjugated to short chain PEG to enhance cellular internalization. Cellular uptake was assessed using HeLa cells (low expression of integrin receptors) and HepG2 cells (high expression of integrin receptors). RGD modification improved cellular uptake in HepG2 compared to HeLa cells. TAT co-modification showed synergistic effect in improving cellular uptake in HepG2 cells. Cysteine addition to cells  exhibited higher cellular uptake for cleavable PEG liposomes suggesting that the removal of the outer PEG layer exposed the targeting ligands and enhanced cellular uptake. Multistage liposomes exhibited high dependence on clathrin-dependent uptake pathway. HepG2 tumor bearing mice demonstrated the ability of PEG coating to allow the liposomes to evade the reticuloendothelial system (RES). The in vivo model exhibited higher ability of multistage liposomes to internalize into the tumor tissue with higher stability .Zhao et al. prepared phase-transformation lipid nanoparticles entrapping 10-hydroxycamptothecin and coated with liquid perfluoropentane. The prepared nanoparticles possess the ability to transform into lipid microbubbles upon exposure to external ultrasound radiation with a specific intensity. The prepared nanoparticles were modified using cysteine flanked TAT (CG-TAT-GC) to enhance cellular internalization as well as hyaluronic acid to add target cellular specificity through binding to CD44. Double modified nanoparticles were able to adhere to SMMC-7721 cells which overexpress CD44. However, cysteine flanked TAT modified nanoparticles were not able to adhere to SMMC-7721 cells. SMMC-7721 tumor spheroid showed the ability of the double modified nanoparticles to penetrate the 3D tumor. Yet, hyaluronic acid modified nanoparticles were not able to penetrate the 3D tumor efficiently. SMMC-7721 tumor bearing mice were used to assess the targeting ability in vivo. Double targeted nanoparticles exhibited higher accumulation in the tumor site when compared to non-targeted nanoparticles as well as cysteine flanked TAT modified nanoparticles .Aptamers are defined as nucleic acid molecules that have the ability to bind to specific targets through folding into complex 3D structures that mimic antibodies . Ding etOther less explored active targeting approaches using lipidic nanoparticles are summarized in Table HCC is considered to be one of the most challenging diseases worldwide with less-than-optimal treatment outcomes using chemotherapeutic agents. Lipidic nanoparticles gained significant attention due to their stability, biocompatibility, and their ability to decrease undesirable side effects. Utilizing lipidic nanoparticles significantly enhances the cytotoxic activity of the used anti-neoplastic agents. Further enhancements in the efficiency of lipid based nanoparticles can be achieved through various targeting techniques. Targeting approaches drastically enhance the tumor uptake of the intended anti-neoplastic agents while minimizing the effect on normal tissues. Lipid based nanoparticles hold great promise in improving the treatment outcomes of anti-neoplastic agents for HCC. However, further improvements are required to achieve higher number of clinically approved medications. A special focus should be directed toward decreasing the possible risk of toxicity. Alternatives to the possibly toxic cationic lipids as well as solutions to achieve the encouraging effects of positively charged lipidic nanoparticles without the associated toxicity risk should be attained to further enhance the safety profile of the prepared formulations. Another area of focus to further increase bench to bedside translation is the methods of preparation used. Novel, green, and ecofriendly methods of preparation that do not depend on organic solvents will further improve the scalability of production and decrease production costs while eliminating the risk of the presence of toxic residuals."}
+{"text": "Inflammatory Bowel Disease (IBD) is a challenging medical condition that is driven by various genetic and environmental factors. Therapeutic opportunities for this disease remain limited due to the lack of in-depth understanding of the pathogenetic mechanisms and actionable targets driving the disease. Analysis of telomere dysfunctional mice and patients with genetic defects in telomere maintenance unexpectedly revealed phenotypes mirroring those observed in IBD. Molecular characterization of this model identified a pathway driven by telomere DNA damage-mediated activation of the ATM/cABL/YAP1 pathway, which directly regulates genes central to IBD pathogenesis and amenable to therapeutic intervention. This review summarizes the evidence correlating telomere dysfunction with IBD and colitis-associated cancer and proposes therapeutic opportunities for such inflammatory conditions targeting this newly identified pathway. Inflammatory bowel disease, mainly comprised of Crohn\u2019s disease and ulcerative colitis, is a challenging condition associated with both genetic and non-genetic drivers. The mechanisms that drive IBD are not well understood, making it difficult to identify therapeutic targets of pathogenetic relevance . In courTelomeres are nucleoprotein structures at the ends of chromosomes that protect and maintain chromosomal integrity together with the shelterin protein complex. During cell division, chromosomes must be replicated; however, the replication machinery cannot fully copy to the very end of linear human chromosomes. Telomerase Reverse Transcriptase (TERT) and its RNA component (TERC) act in a coordinate manner to elongate telomeres to solve the end replication problem, where TERC provides the RNA template for telomere repeat synthesis . GeneticA systematic phenotypic and histological analysis of the telomere dysfunctional mouse model  revealed a significant inflammatory phenotype specific to the large intestine with remarkably negligible effect on the small intestine [in silico analysis of the promoter for pro-IL18 revealed various transcription factor binding sites. In particular YAP1 caught our attention given a recent report on a SNP associated with TEF binding element in IBD patient epithelium [In vivo treatment of telomere dysfunctional mice with inhibitors for YAP1 (verteporfin) or caspase-1 (Ac-YVAD) or with broad spectrum antibiotics (trimethoprim-sulfa) ameliorated disease burden and suppressed the ATM/YAP1/IL18 axis revealing cooperation between the two axes telomere dysfunction mediated DNA damage and the microbiome activated inflammasome pathway in driving inflammatory response and highlighting YAP1 as a common orchestrator. Interestingly, we found that DNA damage (irradiation) could also activate this pathway. This study also establishes the important role of intestinal epithelial cells in driving such diseases that may cooperate with the immune cells in exacerbating the disease and driving relapse. To summarize, telomere dysfunction can initiate an inflammatory response through DNA damage mediated activation of the YAP1/pro-IL18 axis in the presence of the gut microbiome , a condition known to be associated with telomere dysfunction and aid in identifying viable therapeutic targets for such chronic conditions with limited therapeutic options."}
+{"text": "These findings change the field of FSH-FSHR biology, call for paradigm shift, explain FSHR expression on cancer cells in multiple organs and provide straightforward explanations for various existing conundrums including extragonadal expression of FSHR.Follicle stimulating hormone (FSH) is secreted by the anterior pituitary and acts on the germ cells indirectly through Granulosa cells in ovaries and Sertoli cells in the testes. Extragonadal action of FSH has been reported but is still debated. Adult tissues harbor two populations of stem cells including a reserve population of primitive, small-sized, pluripotent very small embryonic-like stem cells (VSELs) and slightly bigger, tissue-specific progenitors which include ovarian stem cells (OSCs) in ovaries, spermatogonial stem cells (SSCs) in testes, endometrial stem cells (EnSCs) in uterus and hematopoietic stem cells (HSCs) in the bone marrow. Data has accumulated in animal models showing FSHR expression on both VSELs and progenitors in ovaries, testes, uterus and bone marrow and eventually\u00a0gets lost as the cells differentiate further. FSH exerts a direct action on the stem/progenitor cells via alternatively spliced FSHR-3 rather than the canonical FSHR-1. FSH stimulates VSELs to undergo asymmetrical cell divisions to self-renew and give rise to the progenitors that in turn undergo symmetrical cell divisions and clonal expansions followed by differentiation into specific cell types. Excessive self-renewal of VSELs results in cancer and this explains ubiquitous expression of embryonic markers including nuclear OCT-4 along with FSHR in cancerous tissues. Focus of this review is to compile published data to support this concept. FSHR expression in stem/progenitor cells was confirmed by immuno-fluorescence, Western blotting, in situ hybridization and by quantitative RT-PCR. Two different commercially available antibodies  were used to confirm specificity of FSHR expression along with omission of primary antibody and pre-incubation of antibody with immunizing peptide as negative controls. Western blotting allowed detection of alternatively spliced FSHR isoforms. Oligoprobes and primers specific for Fshr-1 and Fshr-3 were used to study these alternately-sliced isoforms by in situ hybridization and their differential expression upon FSH treatment by qRT-PCR. To conclude, stem/progenitor cells in adult tissues express FSHR and directly respond to FSH via FSHR-3.  Existing dogma that FSH action is limited to Granulosa cells in ovaries and Sertoli cells in the testes needs an urgent revision.Two populations of stem cells exist in multiple adult tissues including quiescent VSELs and slightly bigger, tissue-specific progenitors including OSCs in ovaries, SSCs in testes, EnSCs in the uterus, HSCs in the bone marrow and so on\u00a0in other adult organs as well. These stem/progenitor cells express FSHR which eventually gets degraded as cells differentiate further into tissue-specific mature cell types. FSH acts directly on the VSELs that exist in all adult tissues including ovaries, testes, uterus and bone marrow. FSH exerts a direct effect on the stem/progenitor cells and promotes asymmetrical, symmetrical divisions and clonal expansion. FSH effects on extragonadal tissues including uterus and bone marrow stem/progenitor cells is clearly delineated in this review.In addition to the existing dogma that FSH exerts an indirect action on the germ cells via Sertoli cells in testes or granulosa cells in the ovaries, FSH directly affects testicular and ovarian stem cells.FSH action on the stem/progenitor cells is mediated via Fshr-3 which is alternately spliced, growth factor type-1 receptor that acts via calcium signaling and the ERK/MAPK pathway.Stem cells are involved in both endometrial regeneration and hematopoiesis in bone marrow and FSH has a potential role in both these processes.Expression of FSHR on VSELs and OSCs in the ovaries explains why commercially available ovarian cancer cell lines when treated with FSH do not show increase in cAMP. Gonadotropin theory with a potential role of stem cells in the OSE could possibly explain initiation of ovarian cancer.Our findings explain extragonadal expression of FSHR in the uterus. FSH exerts direct action on both endometrial and myometrial stem cells. Various uteropathies have a stem cell basis and this explains FSHR expression in clinical samples of endometriosis, endometrial cancers as well as myomas.Several folds increased Fshr-3 in testicular cancer samples is intriguing and suggests a role of FSH in initiating testicular cancer similar to gonadotropin theory that exists for ovarian cancer.It is textbook information, after almost 90\u2009years of research since follicle-stimulating hormone (FSH) was first reported in 1930s, that FSH is secreted by the anterior pituitary and acts on granulosa cells in the ovarian pre-antral follicles and on Sertoli cells in the testes , 3. PublPresent review is a compilation of the work published since 2013 suggesting that FSHR are expressed on the tissue-resident stem/progenitor cells in multiple organs including bone marrow and reproductive tissues ovaries, testes and uterus. These results call for a paradigm shift in the field since evidently FSH exerts a direct action on the stem cells via Fshr-3 rather than the canonical Fshr-1 isoform. Tissue-resident stem cells that exist in adult tissues are the very small embryonic-like stem cells (VSELs) and were recently reviewed \u20138. FSHR It is widely believed and textbook information that FSH acts on Granulosa cells in the ovaries and Sertoli cells in the testes . HoweverWe published an article in 2012 . These rThese findings of FSH action on the OSE cells become more intriguing since ovarian stem cells are reported to reside in the OSE. Presence of stem cells in adult ovaries were initially reported by Tilly\u2019s group  in adultIn a review describing various aspects of the ovarian stem cells , we haveStem cells located in sheep OSE cells, collected by gentle scraping, were found to express FSHR (besides stem cell markers) whereas the epithelial cells remained distinctly negative Fig.\u00a0 24]. Ex. Ex24]. Immuno-localization studies were carried out further for FSHR expression in sheep ovarian sections as well as by confocal microscopy on sheep OSE cell smears Fig.\u00a0. FSHR exFSH stimulates stem cells proliferation and clonal expansion. It was intriguing to note how stem cells story which was main focus of our lab research gradually got intertwined with FSH-FSHR biology. Further experiments revealed that when sheep OSE cell smears . The chemoablated ovaries were removed and cultured in vitro with and without FSH (5mIU) for 7\u2009days and later studied for the effect of FSH on stem cell markers and proliferation was marked by studying BrdU uptake. An increased expression of stem/progenitor cells  was observed along with proliferation in OSE evidenced by BrdU uptake. This was accompanied by the formation of germ cell nests  and expression of Scp3 which was not detected in chemoablated ovaries without FSH treatment [Fshr-3 transcripts have been detected in mice OSE cells and not canonical Fshr-1 . Studiesreatment .Fig. 8EfThis is entirely a new and novel FSH-FSHR biology within the mammalian ovaries and delineated by our group for the first time. FSHR are expressed on the OSE cells, to be more precise on the stem cells that reside in the OSE whereas the epithelial cells remain distinctly negative. Since cancer involves selective expansion of stem cells, FSHR has been reported on ovarian cancer stem\u00a0cells. FSH acts via Fshr-3 on the stem cells via ERK/MAPK to bring about proliferation of stem cells.To conclude, stem cells residing in the mouse, rabbit, marmoset, sheep and human ovarian surface epithelium express FSHR. Besides acting on the granulosa cells, FSH acts directly on the ovarian stem cells and stimulates them to undergo proliferation, asymmetrical, symmetrical divisions and clonal expansion to form germ cell nests and this action is mediated via Fshr3 in mice, sheep and human ovaries. FORKO mice discussed above  developeFSHR isoforms have been reported in sheep  and humaWe have recently reported a simple and robust protocol to enrich both the populations of stem cells from mice testes along with their detailed characterization . FSHR exTesticular stem cells smears were prepared from chemoablated testes. Fig.\u00a0As shown in Fig.\u00a0Further Western blotting experiment on proteins extracted from Sertoli cells and intact testes after FSH treatment when hybridized with Abcam FSHR antibody showed presence of 75\u2009kDa band for canonical FSHR-1 in Sertoli cells but in intact testis, two bands of 75 and 40KDa were detected. 75\u2009kDa band was not detected in intact testes after FSH treatment because as such the protein amount may be too less but we clearly observed the band in protein extracted from Sertoli cells. However, FSH treatment affected stem/progenitor cells and FSHR-3 and other isoforms showed increased expression and were detected by Western blot Fig.\u00a0.Fig. 13WExpression of FSHR on the stem cells was also confirmed by in situ hybridization using oligoprobes. Both Fshr-1 and Fshr-3 were found expressed on the stem cells. FSH treatment resulted in active transcription of Fshr-3 on dividing stem cells compared to Fshr-1 mRNA Fig.\u00a0.Fig. 14FExpression of Fshr1 and Fshr3 were also studied by qRT-PCR in different treatment groups Fig.\u00a0. It was Fshr1 and Fshr3 was studied on D100 by qRT-PCR  or diethylstilbestrol (2\u2009\u03bcg/pup/day on days 1\u20135) and later studies were undertaken on D100 of adult life. Treatment affected the testicular stem cells and resulted in pathologies including disrupted spermatogenesis, reduced sperm counts, infertility and tumor-like changes were observed in DES treated group . ExpressPCR Fig.\u00a0. Fshr-3 The results compiled above are intriguing since FSHR expression is expected only on the Sertoli cells as per existing understanding . Resultsfunctional expression of FSHR in endometriotic lesions. FSHR is reported in uterine myomas also [Uterus is considered as an end organ for the steroid hormones estrogen (E) and progesterone (P) to act. These hormones are secreted by the ovaries under the influence of pituitary gonadotropins and thus it is generally believed that FSH exerts an indirect effect on the uterus. However, few reports have challenged this existing dogma in the field. Increased expression of FSHR was reported in the secretory phase human endometrium compared to proliferative phase , 60. Latmas also . This bomas also , 11 who Our group has reported two populations of stem cells including VSELs and slightly bigger EnSCs in adult mouse uterus and recently published a robust protocol to enrich them from mice uterus . VSELs sMyometrium was atrophied after bilateral ovariectomy and both perimetrium and myometrium were clearly visualized in the ovariectomized uterus along with small spherical stem cells Fig.\u00a0, arrow. A careful scrutiny of the H&E stained sections of atrophied endometrium Fig.\u00a0 after biFSH treatment exerted a marked effect on the endometrial epithelial cells which showed hypertrophy and hyperplasia Fig.\u00a0. Small sUterine stem cells can be enriched by spinning at 1000\u2009g and visualized after H&E staining . The steThe stem cells enriched from adult uterus were used to prepare smears and studied for expression of PCNA and FSHR Fig.\u00a0. Two disTo conclude, two populations of stem cells exist in adult mouse uterus which express FSHR and FSH exerts direct effect on the uterine stem cells similar to in the ovaries and testes. Early differentiating progenitors express embryonic markers as well as FSHR. We have recently shown that neonatal endocrine disruption affects uterine stem cells differentiation and progenitors increase in numbers associated with increased FSHR expression . MoreoveHematopoietic system also harbors two populations of stem cells including VSELs and hematopoietic stem cells (HSCs) , 70, altFunctional studies were reported in vivo by our group on adult mice bone marrow showing a direct effect of FSH on hematopoiesis . TreatmeEffect of FSH treatment was also studied on stem cells in bone marrow cell smears. For this 5-FU treated mice were further treated with FSH (5\u2009IU) on days 4 & 5 and sacrificed on Day 6. Bone marrow was flushed out and used to make cell smears Fig.\u00a0. One couSimilarly, VSELs in mouse prostate are regulated by FSH and only Fshr3 is expressed in adult prostate and not the canonical Fshr1 (unpublished data by our group). These results are in contradiction with recent scRNAseq study  which neIn view of the research findings compiled in this review, it becomes imperative to appreciate a wider landscape for FSH action which is so far limited to Sertoli cells in testes and Granulosa cells in ovaries."}
+{"text": "Sarcoidosis is a common disease with the incidence of cardiac involvement varying. Cardiac sarcoidosis should be kept on the differential when young patients present with acute heart failure, conduction abnormalities or new arrhythmia. Cardiac involvement in sarcoidosis must be diagnosed early and treated aggressively. Here we present a patient who presented with shortness of breath and was found to have significant heart failure with reduced ejection fraction caused by sarcoidosis with cardiac involvement. She was treated with optimization of medical therapy for heart failure and eventually required implantable cardioverter defibrillator (ICD) placement. Sarcoidosis is a rare inflammatory disorder of unknown etiology involving multi-organ systems. The cardiovascular system is affected rarely. A key feature of the disease is formation of noncaseating granulomas in the affected organs. In patients with systemic sarcoidosis, it is estimated that about 5% have symptomatic cardiac sarcoidosis (CS) . AdvanceA 40-year-old female with no prior medical history presented to her primary care physician (PCP) for shortness of breath (SOB) on exertion that had progressively worsened over the previous few months. She had a prior CT of her abdomen and it showed multiple pulmonary nodules at the lung bases. This led to further evaluation with CT chest which showed cardiomegaly and numerous scattered pulmonary nodules with the largest being 11 mm  of 30%, mild mitral and tricuspid regurgitation and moderate pulmonary hypertension Figure .One month later she presented to the emergency department for worsening heart failure symptoms including worsening shortness of breath and lower extremity edema. She was symptomatic with New York Heart Association (NYHA) class III heart failure symptoms. Her electrocardiogram (EKG) showed right bundle branch block (RBBB) and first-degree atrioventricular (AV) block Figure .Transthoracic echocardiogram was repeated, and her EF dropped to 14%. Cardiac MRI revealed severe cardiomyopathy with reduced EF estimated at 14% along with a patchy transmural fibrosis. A stress test did show abnormal left ventricular perfusion in a left circumflex distribution. Left heart catheterization was performed and showed no coronary artery disease. She then had a cardiac biopsy that was consistent with cardiac sarcoidosis showing dense interstitial fibrosis with non-necrotizing granulomas with mild inflammation composed of lymphocytes, macrophages and multinucleated giant cells, some containing asteroid bodies  technique. Recently published guidelines acknowledge LGE on Cardiac MRI as a diagnostic criterion .Cardiac involvement can be assessed with endomyocardial biopsy. However, due to patchy myocardial involvement in CS, diagnostic yield of endomyocardial biopsy is only about 20%. Thus, in most cases, diagnosis of CS is made when the patient demonstrates histologically confirmed extracardiac sarcoidosis and has non-histologic clues of CS . HoweverOral corticosteroid is standard treatment. Immunosuppressive combination therapy with methotrexate or azathioprine is considered second-line treatment. A combination of leflunomide and mycophenolate mofetil can be contemplated if the patient does not tolerate first-line treatment due to side effects .Early diagnosis and aggressive treatment of CS are essential in preventing the complications mentioned above, including sudden\u00a0cardiac\u00a0death .\u00a0This case highlights the importance of including CS in the differential diagnosis of a young and otherwise healthy patient presenting with signs and symptoms of new onset heart failure and non-ischemic cardiomyopathy. Optimal medical management of heart failure should also be initiated. These patients are typically started on a prednisone taper and should strongly be considered for automated ICD when left ventricular dysfunction is present. In the case of persistent symptoms despite glucocorticoid therapy, immunosuppressive agents may be of benefit in symptom management."}
+{"text": "Providing time and money to adult children may enhance perceived usefulness and consequently the subjective well-being (SWB) of older parents. However, non-reciprocal relationships with children and conflicts with leisure activities could negatively affect parents\u2019 SWB. It was hypothesized that a substantial amount of support to children would be associated with lower SWB when older parents (a) had a low expectation of receiving long-term care from the children, and (b) were engaged in hobbies/learning activities. Life satisfaction and depressive symptoms measured as SWB were predicted based on the Generalized Estimating Equations, using panel data (2012-2017) with a nationwide representative sample of Japanese adults aged 60 years and older . Providing child-rearing support  of 30 hours or more per month was positively associated with SWB regardless of conditions (a) and (b). Hypothesis (b) was partially supported: providing financial support enhanced depressive symptoms among older adults with hobbies/learning."}
+{"text": "Healthcare workers have experienced a significant burden of COVID-19 disease. COVID mRNA vaccines have shown great efficacy in prevention of severe disease and hospitalization due to COVID infection, but limited data is available about acquisition of infection and asymptomatic viral shedding.Fully vaccinated healthcare workers at a tertiary-care academic medical center in Omaha Nebraska who reported a household exposure to COVID-19 infection are eligible for a screening program in which they are serially screened with PCR but allowed to work if negative on initial test and asymptomatic. Serial screening by NP swab was completed every 5-7 days, and workers became excluded from work if testing was positive or became symptomatic. Of the 94 employees who were fully vaccinated at the time of the household exposure to COVID-19 infection, 78 completed serial testing and were negative. Sixteen were positive on initial or subsequent screening. Vaccine failure rate of 17.0% (16/94). Healthcare workers exposed to household COVID positive contactHigh risk household exposures to COVID-19 infection remains a significant potential source of infections in healthcare workers even after workers are fully vaccinated with COVID mRNA vaccines especially those with contact to positive domestic partners. All Authors: No reported disclosures"}
+{"text": "Chromosomal localization and estimated duplication times illustrated that genes in TIP4 formed a tandem array on the short arm of chromosome 1, resulting from pepper-specific expansion after its divergence with Solanaceae species. Transcriptome analyses under various abiotic stress conditions revealed that transport-, photosystem-, and thylakoid-related genes were generally enriched in expression clusters containing AQP genes in pepper. These results provide valuable genomic resources and insight into the evolutionary mechanism that generate genomic diversity of the AQP gene family in pepper.Aquaporins (AQPs) are known to have a vital role in water transport in all living organisms including agriculturally important crops, but a comprehensive genomic study of AQPs in pepper has not been implemented. Here, we updated previous gene annotations and generated a total of 259 AQP genes from five plants, including pepper. Phylogenetic and motif analyses revealed that a large proportion of pepper AQP genes belong to the specific subgroup of  Th. Th44]. Chromosomal distribution of the re-annotated AQP genes was visualized using MapChart v2.32 . Gene naWe estimated the divergence times of the AQP genes by first identifying duplicated gene pairs with DupGen_Finder pipeline . Next, tTo examine expression profiles of pepper AQP genes, we collected RNA-Seq data for leaf tissues under various abiotic stress  at different times generated from a previous study . We firsp value \u2264 0.05 were clustered using the Mfuzz program [https://www.biobam.com/omicsbox/ (accessed on 5 January 2021)), and enriched GO terms were determined by Fisher\u2019s exact test .We performed expression clustering of the differentially expressed genes (DEGs) in the whole annotated pepper genome, including the newly annotated AQP genes. Expression clustering was calculated from log2 transformation of fold changes between the FPKM values measured in plants under stress conditions and unstressed control plants. The DEGs that had a  program  in an R"}
+{"text": "Physical activity may preserve cognitive functioning in older adults. This study examined associations between objectively measured physical activity and cognitive functioning. We recruited participants  with (N=26) and without (N=181) cognitive impairment from the University of Kansas Alzheimer\u2019s Disease Center (KU-ADC). We collected cognitive data representing verbal memory, attention, and executive function. Accelerometers (Actigraph GT9X) were used to measure physical activity 24 hours a day for 7 days in a free-living environment. Physical activity was categorized as moderate to vigorous physical activity (MVPA) based on the Freedson (2011) Adult Vector Magnitude cut points. The association between cognitive functioning and total MVPA was evaluated by using multiple regression. We used factor analysis to create three composite scores  from 11 individual cognitive tests. Compared to verbal memory and attention, results indicate that total MVPA was more strongly associated with executive function . These findings are consistent with the literature suggesting that executive function in older adults may benefit from physical activity. Future research should investigate the physiological mechanisms by which MVPA benefits executive function in contrast to types of activity that might benefit verbal memory and attention."}
+{"text": "In March 2020 the Centers for Medicare & Medicaid Services (CMS) announced restrictions on visitors and nonessential personnel in nursing homes to protect residents and facilities from SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) outbreaks. At the time, these measures were \u201ctemporary\u201d but they continued well into 2021 resulting in a prolonged pause on in-person study activities in a palliative care clinical trial in 12 nursing homes. This session will address the impact of this pause and decisions made to overcome the potential failure of the trial. Of utmost importance was respecting nursing homes rapidly changing context, continued communication with the site leadership, transitioning to phone and video-conference study activities, and designing a retrospective study using existing data to answer a different but similar research question. As clinical researchers move forward implementing trials and complex interventions in nursing homes, we must use the lessons learned to design flexible trial protocols."}
+{"text": "Benign anastomotic intestinal strictures are difficult to manage as there may be limited response to dilation.\u00a0Fully covered self-expanding metal stents have been utilized in small case series; however, stent suturing is required due to the high risk of stent migration.\u00a0Lumen-apposing metal stents (LAMS) are fully covered and have a novel dumbbell shape that prevents stent migration.\u00a0Initial reports identify low migration rates and good clinical success rates. This is the first report of perforation following treatment of an ileosigmoid stricture in a 52-year-old female, three weeks after LAMS placement. Lumen-apposing metal stents (LAMS) are fully covered dumb-bell shape stents with flanged ends that were originally designed to drain pancreatic fluid collection .\u00a0IntestiA 52-year-old female had a past medical history of ischemic pancolitis with transmural necrosis of the splenic flexure, status post subtotal colectomy with end ileostomy and subsequent takedown with ileosigmoid anastomosis.\u00a0She presented with abdominal pain, nausea and vomiting. CT of the abdomen showed small bowel obstruction at the ileosigmoid anastomosis level Figure . FlexiblThree weeks later, the patient presented to the emergency room with severe abdominal pain. CT of the abdomen showed small bowel obstruction with multiple foci of intraperitoneal air concerning for perforation Figure  and a 6 Anastomotic strictures often present a management challenge. Endoscopic balloon dilation with or without steroid injection is typically the first-line therapy for gastrointestinal (GI) anastomotic strictures. Temporary placement of fully covered SEMS has been utilized for the treatment of upper intestinal tract anastomotic strictures; however, endoscopic suturing of the stent to the intestinal wall to prevent stent migration is required . FrequenYang et al identified a clinical success rate of 64% in a retrospective study of 30 patients treated with LAMS for benign gastrointestinal strictures . Irani eAlthough LAMS placements are well-tolerated procedures, they are not free of complications. Adverse events with LAMS included abdominal pain with subsequent ulceration identified at the time of stent removal from the site of gastrojejunal anastomotic strictures, in two of 25 patients, one to three weeks after stent placement . In anotAdditional adverse events reported in extensive review analysis of the literature available until 2017 were bleeding, vomiting, stent migration, death, and formation of new strictures proximal to the LAMS. In this review, they also included one study in which a perforation happened immediately after the procedure requiring surgery that they considered a technical failure . Here weManaging anastomotic strictures\u00a0often present a great challenge. Endoscopic balloon dilation with or without steroid injection is first-line therapy. Temporary placing fully covered SEMS is another option; however, has its own limitations and complications. On the other hand, lumen-apposing metal stents (LAMS) provide another approach to manage gastrointestinal strictures. It has great therapeutic potential with its novel dumbbell shape; however, ulceration and perforation are major concerns that require\u00a0further consideration of the optimal design of the stent design for this indication."}
+{"text": "There is limited data on how endurance training can impact cardiac function and arrhythmogenesis. Intense endurance training has been\u00a0associated with pathological remodeling of the right ventricle (RV) that can act as a substrate for fatal ventricular arrhythmias in older athletes. A previously healthy 63-year-old female marathon runner presented with symptomatic monomorphic ventricular tachycardia (VT) while exercising. Transthoracic echocardiogram (TTE) demonstrated no structural or functional abnormalities. Electrophysiology study (EPS) with three-dimensional mapping and programmed electrical stimulation was performed demonstrating significant scarring of the RV, including RV outflow tract and RV free wall.\u00a0VT ablation was successfully performed. Unfortunately, exclusion of arrhythmogenic right ventricular cardiomyopathy (ARVC) was limited due to the lack of cardiac magnetic resonance imaging (MRI). Therefore, a single chamber implantable cardioverter defibrillator (ICD) was placed for secondary prevention. Currently, the clinical significance of exercise-induced ventricular arrhythmias in trained athletes without cardiovascular disease is still unknown. This case highlights the need for investigation with larger studies and longer follow up to help us understand the mechanism of exercise-induced scar formation and standardize our management regarding screening, exercise recommendations, and ICD placement in older athletes. There is limited data on how endurance training can impact cardiac function and arrhythmogenesis. Intense endurance exercise predominantly affects the right ventricle (RV) and may induce chronic structural changes and pathological remodeling that can act as a substrate for fatal ventricular arrhythmias . ManagemA previously healthy 63-year-old woman, who is an avid runner and still trains for and participates in marathons, presented with symptomatic wide complex tachycardia while exercising Figure . Her symOur case showed an unusual substrate for VT localized into the\u00a0RVOT, inferior and free wall in an older athlete without a prior history of underlying structural heart disease or cardiovascular risk factors. Currently, the clinical significance of exercise-induced ventricular arrhythmias in trained athletes without apparent cardiovascular disease remains unknown. In contrast to our case, in a large consecutive cohort of young and highly trained athletes, ventricular tachyarrhythmias induced by exercise testing were found in 7% . The undFurthermore, this case suggests that EPS and 3D mapping can be important to guide us to the possible underlying mechanism and formulate further treatment plans for similar patients. This was illustrated by a recent study that described a novel clinical entity of an isolated subepicardial RVOT scar as a substrate for fast VT in high-level endurance athletes that can be successfully treated by ablation . Of inteOur observations posit a few important questions. Is endurance\u00a0training the only exposure to form VT substrate or should we consider genetic testing in all these patients?\u00a0What is the optimal method to screen asymptomatic older athletes who wish to continue high-intensity exercise? Is there any benefit to defibrillator therapy in this population? What are the best recommendations for symptomatic older athletes post ablation therapy? There is not enough data in the literature to answer these questions. This case highlights the need for investigation with larger studies and longer follow up to help us understand the mechanism of exercise-induced scar formation and standardize our management regarding screening, exercise recommendations, and ICD placement in older athletes."}
+{"text": "Only about three million people in France have so far received at least one dose of a Covid-19 vaccine. Those aged over 75 are offered either Pfizer or Moderna vaccines in a vaccination center. Older people with pre-existing conditions can now get AstraZeneca's Covid-19 vaccine. We will provide detailed information later. The symposium has experts from 8 countries. We will use an interview and dialog format, instead of presentations (please refer to the program overview)."}
+{"text": "Conventional fluoroscopic guidance can provide enough information to precisely insert an occipital screw in ordinary cases. However, the occipital screw creates a potential risk of dural venous sinus injury or thrombosis.\u00a0In some cases, with dural sinus variation, surgeons must especially be cautious to avoid its injury. We present a rare case of proper occipital screw placement using a navigation system for a pathological odontoid fracture with a high risk of dural venous sinus injury because of anatomical variations in the transverse and occipital sinuses. A 60-year-old man who underwent thyroidectomy at the age of 37 years for thyroid carcinoma developed acute neck pain and quadriparesis due to falling out of bed. He urgently underwent closed reduction and temporary immobilization with a halo-vest for a pathological odontoid fracture and atlantoaxial dislocation. Preoperative contrast-enhanced CT showed an absent right transverse sinus and a prominent occipital sinus as variations of the dural venous sinuses. Occipito-C7 fusion surgery was performed without intraoperative active venous bleeding or postoperative brain disorder by using a navigation system for the occipital screw placement to avoid injury to the dural sinus. Postoperative computed tomography showed bi-cortical occipital screw placement avoiding the prominent occipital sinus. The patient\u2019s postoperative course was uneventful. In this case, although rigid occipito-cervical fixation using bi-cortical occipital screws was needed for the pathological odontoid fracture, the variation of the occipital sinus created a high risk of injury during occipital screw placement with conventional fluoroscopic guidance. There is an anatomical variation of the dural venous sinuses between individuals. Prominent occipital sinus injury may notably cause fatal complications such as massive bleeding or occlusion. Thus, we safely inserted the occipital screws using a navigation system that enabled us to avoid occipital venous sinus injury. Occipital screw placement with a navigation system can be a better option to prevent dural venous sinus injury in cases where there is variation in the dural venous sinuses, such as with a prominent occipital venous sinus. Recent advances in navigation systems for spinal fusion surgery have increased the safety of screw insertion. Navigated pedicle screw insertion has greater accuracy compared to non-navigated insertion for all spinal regions ,2. HowevA 60-year-old man underwent thyroidectomy at the age of 37 years for thyroid carcinoma. He was found to have metastases to the odontoid process and multiple lung metastases on positron emission tomography/computed tomography (PET/CT) one month before surgery. Lenvatinib and radiation therapy were planned because he initially had no neck pain. However, he developed acute neck pain and quadriparesis after falling from bed and was urgently referred to our department. The patient, whose preoperative neurologic loss was graded at modified Frankel C1, exhibited neck rotatory deformity and severe muscle weakness  of the upper and lower limbs bilaterally. CT\u00a0revealed a pathological odontoid fracture and atlantoaxial dislocation. He urgently underwent closed reduction and temporary immobilization with a halo-vest under general anesthesia and was scheduled to undergo occipito-cervical fusion surgery for definite stabilization. Contrast-enhanced CT after closed reduction showed an absent right transverse sinus and a prominent occipital venous sinus  due to variation of the occipital venous sinus that could cause its injury during occipital screw placement Figure .\u00a0PreoperPostoperative CT showed bi-cortical occipital screw placement avoiding the prominent occipital venous sinus and no intracranial hematoma Figure .His motor weakness improved to the MMT 4-5 level, and he could walk with one crutch six months after surgery.In this case, occipital screw placement using a navigation system during occipito-cervical fusion surgery avoided injury to the occipital venous sinus that could have been fatal. Occipito-cervical fusion surgery is usually performed for high cervical instability\u00a0. ImplantOn the other hand, it has been recognized that there are some possible risks such as dural injury, CSF leakage, dural venous sinus injury or thrombosis, and sub- or epidural hematoma during occipital screw placement\u00a0. Nadim eIn this case, the absent right transverse sinus and the prominent occipital venous sinus as an idiopathic anatomic variation were found on preoperative contrast-enhanced CT. Although rigid occipito-cervical fixation using bi-cortical occipital screws was needed for this pathological odontoid fracture, the variation of the occipital venous sinus created a high risk of its injury during occipital screw placement with conventional fluoroscopic guidance. Thus, we safely inserted the occipital screws using a navigation system that enabled us to avoid injury to the occipital venous sinus. The postoperative course was uneventful without any implant failure. In ordinary cases, conventional fluoroscopic guidance can be enough to precisely insert the occipital screw because navigation needs extra time for registration. However, using a navigation system may be a safe option for variations of the occipital venous sinus, possibly preventing injury during occipital screw placement.There is a great anatomical variation of the dural venous sinuses between individuals. Variations of the dural venous sinus, such as a prominent occipital venous sinus, require attention to the location of the occipital screw. Prominent occipital sinus injury may notably cause fatal complications such as massive bleeding or occlusion. Occipital screw placement with a navigation system can be a better option to avoid dural venous sinus injury in those cases."}
+{"text": "Prior research on the causality and directionality between disease and functional limitations is ambiguous. The current study used longitudinal monozygotic twin data to test both directions linking disease burden and functional limitations in middle-aged and older adults, controlling for genetic and familial factors. We also examined potential moderation by psychological well-being. The Twins sub-sample from the first two waves of the longitudinal Midlife in the United States (MIDUS) study was used . Only monozygotic twins (N = 713) were included in analyses. In separate multi-level models, we examined disease burden at MIDUS 2 predicted by functional limitations at MIDUS 1 and MIDUS 2 functional limitations predicted by disease burden at MIDUS 1. Disease burden and functional limitations at MIDUS 2 varied substantially within families. There was no within-family association of earlier functional limitations with change in later disease burden , but there was a within-family association such that the twin with higher baseline disease burden had a greater increase in functional limitations than his/her co-twin . Well-being was not a moderator in either model. We found support for a potentially causal association between earlier disease burden and later increases in functional limitations, consistent with the Disablement Process Model. Sensitivity analyses confirm the detected within-family effect. Possible mechanisms linking disease burden and functional limitations are discussed as potential targets for future research."}
+{"text": "A 40-year male presented to the emergency department with the complaints of fatigue that had progressively worsened over the period of 3 months. He had recently emigrated from Mexico, where he worked on a farm and eaten raw watercress. Clinical examination revels pallor of oral mucosa. Laboratory findings showed an increased in absolute eosinophil count of 1400 cells per cubic millimeter (reference range 0-400). Ultrasonography of the abdomen reveled intrahepatic biliary ductal dilatation and magnetic resonance cholangiopancreatography revealed a hilar stricture. Endoscopic retrograde cholangiopancreatography was then performed and large flatworm were visualized emerging from major duodenal papilla."}
+{"text": "Adverse childhood experiences (ACEs) may predict markers of neurocognitive performance  and brain health/plasticity . This pilot examined the magnitude of effects between: 1) ACES and EF performance, 2) ACEs and BDNF levels, and 3) EF performance and BDNF levels. We hypothesize that higher ACEs will be associated with poorer EF scores and lower BNDF levels and that lower EF scores will be associated with lower BDNF levels. Given the pilot nature of the study, an emphasis is placed on effect size vs. significance. Participants were 36 middle-aged women enrolled in the NICE SPACES trial . ACES were quantified using the 10-item Adverse Childhood Experiences Scale. EF was measured using the fluid cognition composite from the NIH Toolbox \u2013 Cognition Battery. BDNF was estimated using proBDNF levels estimated from serum collected via venipuncture. Higher ACEs levels were not directly associated with EF scores ; but did show a meaningful negative beta coefficient with BDNF levels . EF scores and BDNF showed a positive coefficient that did not reach significance . In a modest pilot of middle-age women, higher ACEs were associated with lower BDNF, indicating greater adversity in childhood is linked to lower neurotrophins levels in adulthood. The lower BDNF levels may help explain poorer performance on cognitive tasks. Larger follow-up studies in more powered samples are warranted given the size of detected coefficients."}
+{"text": "The aim for this study was to provide information about how community paramedicine home visit programs best \u201cnavigate\u201d their role delivering preventative care to frequent 9-1-1 users by describing demographic and clinical characteristics of their patients and comparing them to existing community care populations.z-tests.Our study used secondary data from standardized assessment instruments used in the delivery of home care, community support services, and community paramedicine home visit programs in Ontario. Identical assessment items from each instrument enabled comparisons of demographic, clinical, and social characteristics of community-dwelling older adults using descriptive statistics and Data were analyzed for 29,938 home care clients, 13,782 community support services clients, and 136 community paramedicine patients. Differences were observed in proportions of individuals living alone between community paramedicine patients versus home care clients and community support clients . We found higher proportions of community paramedicine patients with multiple chronic disease  and mental health-related conditions .When using existing community care populations as a reference group, it appears that patients seen in community paramedicine home visit programs are a distinct sub-group of the community-dwelling older adult population with more complex comorbidities, possibly exacerbated by mental illness and social isolation from living alone. Community paramedicine programs may serve as a sentinel support opportunity for patients whose health conditions are not being addressed through timely access to other existing care providers.ISRCTN 58273216.The online version contains supplementary material available at 10.1007/s43678-021-00153-4. Clinician\u2019s capsuleWhat is known about the topic?Community paramedicine programs are designed to improve access to care for vulnerable patient groups but case finding remains a challenge.What did this study ask?We investigated who community paramedicine patients are and how they compare to clients receiving community care using identical assessment items.What did this study find?Community paramedicine patients have higher proportions of multiple chronic disease and mental health-related conditions than others who receive community care.Why does this study matter to clinicians?Community paramedicine programs support older patients with complex comorbidities and mental illness by offering improved access to collaborative care.Community paramedicine programs address barriers to care faced by community-dwelling older adults (\u2265\u200965\u00a0years of age) or other vulnerable patient populations who may otherwise resort to calling an ambulance or visiting an emergency department (ED) \u20134. CommuWhether community paramedicine home visit programs represent a duplication of community-based services requires further exploration , 25, 26.Our study proposed to identify characteristics of existing community paramedicine home visit patients across multiple jurisdictions and compare them to clients from other community-based care providers. We hypothesized that patients in community paramedicine home visit programs represent a distinct subset of community-dwelling older adults with complex needs and a limited social support structure that contributes to their enrolment in these programs.Our study used routinely collected de-identified secondary data about individuals assessed for their eligibility of home care services or as part of the delivery of community support services or community paramedicine programs across Ontario. We used identical variables from each data set to compare the home care and community support services client populations to those enrolled in community paramedicine home visit programs. This study was approved by Hamilton Integrated Research Ethics Board (#1650D).Information about home care clients included all individuals assessed using the interRAI Home Care (HC) assessment , betweenInformation about clients receiving community support services was obtained from individuals who had been assessed using the interRAI Community Health Assessment (CHA) assessment instrument , betweenData about individuals enrolled in community paramedicine home visit programs were obtained from paramedic services that implemented a standardized assessment instrument as part of the Common Assessments for Repeated Paramedic Encounters (CARPE) study ISRCTN 58273216). Several paramedic services participated in development of the CARPE assessment instrument through a process including literature review 8273216. , and an Six paramedic services implemented the CARPE assessment instrument voluntarily as part of a quality improvement process within existing community paramedicine home visit programs. All paramedic services had similar patient enrollment criteria: diagnoses of Congestive Heart Failure (CHF), Chronic Obstructive Pulmonary Disease (COPD), or diabetes, and health system utilization that included at least three 9-1-1 calls, two ED visits, or one hospital admission in the preceding year , 38. ComData were analyzed using descriptive statistics  for each identical item from the respective assessment instruments . For reporting purposes, items were grouped by domain and collapsed into dichotomous variables to identify presence of disease, health deficits, or indicators of impairment (according to the nature of the respective assessment item). Comparative analysis for each assessment item tested proportions of responses using z-test (with\u2009\u221d\u2009\u2009=\u20090.05) to investigate differences between the community paramedicine patients and the other cohorts of community-dwelling older adults according to identical fields from the respective assessment instruments. Analysis was completed using SAS 9.4  and excluded incomplete or partial assessments.Table Community paramedicine patients demonstrated higher proportions of COPD, coronary artery disease, diabetes, or CHF  and they displayed higher proportions of associated symptoms \u2014all of which were statistically significant differences. A higher proportion of community paramedicine patients would meet the criteria for further assessment of their mental health, 29.4% when compared to 12.4% in community support services clients. More community paramedicine patients indicated that they had experienced a major life stressor or a decline in social activities in the past 90\u00a0days (52.2% compared to 22.5% in home care clients and 25.7% in community support services clients).When comparing community paramedicine patients to community support services clients, little evidence of difference was observed in the proportions of individuals who had difficulty communicating or functional deficits for some Activities of Daily Living and Instrumental Activities of Daily Living  . But the home care client group displayed statistically significant differences, with higher proportions of dependence for all functional items when compared to community paramedicine patients.We found that patients in community paramedicine home visit programs likely represent a distinct sub-group of the community-dwelling older adult population because of numerous differences observed between our cohort groups. Our data suggests that the proportion of individuals with mental health needs, complex co-morbidities, and ongoing health conditions or symptoms are often different between community paramedicine programs and home care and community support services agency populations. Higher proportions of health needs in community paramedicine patients suggests they are a complex patient group who could benefit from more integrated care that includes an interface between multiple care providers\u2014reinforcing a characteristic of many community paramedicine home visit programs , 17. By Duplication of services with other existing community-based health care services is a critique of community paramedicine programs  but, to The inferences drawn from our comparisons should be made cautiously because they are based on a small convenience sample of community paramedicine patients assessed using a prototype assessment instrument. Community paramedicine programs remain relatively small in comparison to the number of clients seen through other established programs delivering community-based care. While the sizes of the sample cohorts present a limitation to the inferences, they are reflective of the differences in sizes of the patient populations and were large enough to power statistical analyses. To further strengthen our analysis, we excluded small counts (<\u200910) of observations from the community paramedicine cohort.Opportunity exists for further collaboration between community-based support services agencies and home care providers, community paramedicine home visit programs, and other parts of the healthcare continuum\u2014particularly primary care providers\u2014to improve coordination of care to medically complex community-dwelling older adults , 10, 39.Anonymized data were obtained for our study meaning that analysis of cross-membership between cohorts was not possible. It is possible that a handful of patients could have been represented in all three groups and questions remain about the likelihood of this. High levels of cross-membership between groups would have lessened the likelihood of observing differences in our analysis. Future research should aim to provide a complete analysis of health system utilization amongst community dwelling older adults.High proportions of mental health-related conditions were identified in community paramedicine patients. Other research has demonstrated that mental health and social isolation can contribute to repeated 9-1-1 use , 15, 40.Our analysis showed that community-dwelling older adults in community paramedicine home visit programs may represent a distinct patient group with a greater proportion of mood symptoms, ongoing health conditions, and complex comorbidities than comparable patient populations that receive home care or community support services. Enrolment into a community paramedicine home visit program may be indicative of a combination of inadequate social support structures or clinical instability and decline of a patient\u2019s condition. Community paramedicine home visit programs may provide a sentinel support opportunity for community-dwelling older patients whose health conditions are not otherwise being addressed through timely access to other existing care providers.Supplementary file1 (DOCX 16 kb)Supplementary file2 (DOCX 24 kb)Below is the link to the electronic supplementary material."}
+{"text": "A best evidence topic has been constructed using a described protocol. The three-part question addressed was: In patients undergoing laparoscopic appendicectomy is Hem-o-lok clip safer than Endoloop ligature for closure of appendiceal stump?The search has been devised and 6 studies were deemed to be suitable to answer the question. The outcome assessed was the safety and cost effectiveness of Hem-o-lok clip (Polymer ligation) versus Endoloop ligature for appendiceal stump closure during laparoscopic appendicectomy. We concluded that Hem-o-lok clip is a safe and feasible tool for appendiceal stump closure. It's also a cost-effective way and could be a cheaper option compared to other measures. A BET p2In performing laparoscopic appendicectomy, which technique is the best for appendiceal stump closure? Is it Endoloop ligature or Hem-o-lok clip? Are there any downsides for using either one of them? Therefore, we decided to conduct a systematic review to look for an evidence-based answer to these questions.3In [patients undergoing laparoscopic appendicectomy] is [Hem-o-lok clip] [Polymer clip] safer than [Endoloop ligature] for [closure of appendiceal stump]?4The search was conducted as following:Embase 1974 to 2021 and MEDLINE\u00ae 1946 to November 2021 using the OVID interface.[Laparoscopic appendicectomy OR appendicectomy] AND [ Hem-o-lok clip OR Polymer clip OR Polymeric clip] AND [closure of appendiceal stump] AND [Intraoperative complications OR Postoperative complications OR Leak OR abscess].The search was limited to English language and human studies.5250 articles were found. Out of these 6 deemed to be suitable and met the criteria of our search after removing the duplicate and excluding the irrelevant articles. We only included articles which compared these two methods for appendiceal stump closure and excluded studies which compared other methods.1Conference abstracts2Studies not comparing both techniques3Absence of full-text articles4Low evidence papersExclusion criteria:6.8Four randomized clinical trials and two retrospective studies proved that Hem-o-lock is safe and feasible tool for appendiceal stump closure. It's also a cost-effective way and could be a cheaper option compared to other measures.Not applicable.None.SA: devised the idea of the study, conducted literature search and wrote the paper.TS: assisted in literature search and collecting the data.MO: assisted in literature search and writing the paper.RI: assisted in literature search editing and writing the paper.1.Name of the registry: Not applicable2.Unique Identifying number or registration ID: Not applicable3.Hyperlink to your specific registration (must be publicly accessible and will be checked):Sabry Abounozha (SA), Tamer Saafan (TS), Munzir Obaid (MO), Rashid Ibrahim (RI).Not Applicable.None."}
+{"text": "We aimed to examine the usefulness of cystoscopic findings to guide mesh tension adjustment during laparoscopic sacrocolpopexy (LSC) to promote better repair of pelvic organ prolapse (POP) and prevent de novo stress urinary incontinence (SUI). In this technique, the bladder wall was observed using a cystoscope when various traction pressures were applied by pulling the mesh arm with forceps before fixation to the promontory during LSC. Adjustment was performed on 20 patients, and postoperative outcomes of POP repair and development of de novo SUI were evaluated. When excessive traction was applied on the mesh arm, a bladder neck opening and a cord-like elevation in the center of the trigone and posterior wall were observed in all cases. The tension was gradually loosened, and precisely when the above-mentioned cystoscopic finding  disappeared, an anatomically appropriate elevation of the vaginal apex was achieved; the mesh arm was fixed to the promontory. At 6\u00a0months after LSC, anterior wall recurrences were diagnosed in four patients (beyond the hymen in one) with few symptoms, while no occurrence of de novo SUI. Cystoscopic findings during mesh tension adjustment in LSC could be useful in achieving improved POP repair.The online version contains supplementary material available at 10.1007/s00192-021-04791-1. Laparoscopic sacrocolpopexy (LSC) is considered an excellent option for apical vaginal prolapse owing to its superior correction rates in treating pelvic organ prolapse (POP) . HoweverA greater reduction in point Aa increased the risk of de novo SUI . Since nKato et al. recently reported an unusual cystoscopic finding in a woman with severe mixed urinary incontinence following LSC . A cord-Twenty women with symptomatic stage 3\u20134 POP according to the Pelvic Organ Prolapse Quantification (POP-Q) system underwent LSC with mesh tension adjustment under cystoscopic guidance at our center from July 2019\u2013April 2020. The POP-Q was used for objective prolapse assessment before and 3 and 6\u00a0months after surgery. Prolapse recurrence was defined as retreatment (pessary use or surgery) or POP-Q stage \u2265 2 prolapse. Prolapse Quality of Life Questionnaire (P-QOL)  was usedThe study was conducted as per the principles of the Declaration of Helsinki and approved by the Institutional Review Board . Informed consents were obtained from all patients.All surgical procedures were performed by two senior surgeons according to the procedure by Wattiez et al. . A polytTable Table Cystoscopic findings along with laparoscopic images are shown in Fig.\u00a0The CR finding and bladder neck opening were observed in all patients when excessive traction was applied on the mesh arm. An anatomically appropriate vaginal apex elevation was achieved precisely when the findings disappeared.Even after decreasing the pneumoperitoneum pressure, no significant change was observed in the cystoscopic finding, although the mesh tension had slightly diminished.POP-Q was measured at 3 and 6\u00a0months after surgery. Although four patients 20%) were diagnosed with anterior wall recurrences, retreatment was not required because the degree of anterior prolapse was POP-Q stage 2  with few symptoms and the apex was sufficiently elevated (point C\u2009\u2265\u2009\u20135) in all four patients. In the other 16 patients, all compartments were well repaired . Seven patients had no preoperative SUI symptoms and a negative stress test. Postoperative de novo SUI did not occur in those seven patients"}
+{"text": "Select kynurenine pathway interventions extend lifespan in invertebrate models and are of interest in treating age-associated diseases. Kynurenine pathway activity is responsive to inflammatory signaling, and we are evaluating the potential for these interventions to increase pathogen resistance and curtail age-associated immune decline in Caenorhabditis elegans and mammals. The kynurenine pathway facilitates the catabolism of tryptophan to nicotinamide adenine dinucleotide (NAD). Our lab has found that supplementing the kynurenine metabolite 3-hydroxyanthranilic acid (3HAA) or inhibiting the enzyme 3HAA dioxygenase (HAAO) extends lifespan in C. elegans. 3HAA has demonstrated pro/anti-inflammatory properties in mammals, suggesting a potential role in immune function. C. elegans have a primitive immune system that lacks an adaptive element, but it recapitulates aspects of innate immune signaling and pathogen response. I hypothesize kynurenine pathway interventions that impact C. elegans\u2019 lifespan similarly improve pathogen resistance and immunity. Interventions within the kynurenine pathway are capable of differentially impacting pathogenesis and lifespan of C. elegans challenged with Psuedomonas aeruginosa. C. elegans subjected to select lifespan-extending kynurenine pathway interventions fared better when challenged with P. aeruginosa at older ages. Additionally, fluorescent infection tracking has displayed decreased infection rates in worms with elevated 3HAA. Our data suggests pro-immune activity is facilitated by 3HAA acting downstream of the dbl-1 pathway in addition to directly inhibiting bacterial growth. Our goal is to discover the mechanism(s) through which the kynurenine pathway interacts with immune function in animals and identify potential targets for clinical therapy in aging populations."}
+{"text": "Threatening stimuli seem to capture attention more swiftly than neutral stimuli. This attention bias has been observed under different experimental conditions and with different types of stimuli. It remains unclear whether this adaptive behaviour reflects the function of automatic or controlled attention mechanisms. Additionally, the spatiotemporal dynamics of its neural correlates are largely unknown. The present study investigates these issues using an Emotional Flanker Task synchronized with EEG recordings. A group of 32 healthy participants saw response-relevant images  flanked by response-irrelevant distracters . We assessed behavioural and ERP responses drawn from four task conditions  and subjected these responses to repeated-measures ANOVA models. When presented as response-relevant targets, threatening images attracted faster and more accurate responses. They did not affect response accuracy to targets when presented as response-irrelevant flankers. However, response times were significantly slower when threatening images flanked objects than when neutral images were shown as flankers. This result replicated the well-known Emotional Flanker Effect. Behavioural responses to response-relevant threatening targets were accompanied by significant modulations of ERP activity across all time-windows and regions of interest and displayed some meaningful correlations. The Emotional Flanker Effect was accompanied by a modulation over parietal and central-parietal regions within a time-window between 550-690ms. Such a modulation suggests that the attentional disruption to targets caused by response-irrelevant threatening flankers appears to reflect less neural resources available, which are seemingly drawn away by distracting threatening flankers. The observed spatiotemporal dynamics seem to concur with understanding of the important adaptive role attributed to threat-related attention bias. When attention is drawn by co-occurring threatening and non-threatening stimuli, it biases towards the former. This processing bias, which has been previously called the threat or anger superiority effect \u20133 is conUsing fMRI, Cisler & Koster  showed tFrom a behavioural perspective, a task derived from Biased-Competition Models seems appropriate to investigate the interplay of attentional mechanisms involved in the attentional bias to threats , 24, 25.Such a proposal has been recently supported by a study designed to address this hypothesis . Parra eThe spatiotemporal dynamics of the neurocognitive mechanisms underpinning this adaptive response are still not well understood. For instance Carreti\u00e9, 2014  could noPublications contributing evidence on covert/overt attention mechanisms, which are the most relevant to the present study, reported the use of a variety of stimuli including IAPS Images \u201338, ChinWe followed a component-free approach to unveil the neural correlates of this effect. This approach avoids selection biases of time-windows and electrodes from electroencephalographic (EEG) recordings when contrasting the experimental conditions. Such an approach has been recommended for new tasks or tasks that have not been previously subjected to ERP studies . It alloThe influence of other attention orienting functions such as shifting and engagement, which are necessary to monitor conflict and allocate attentional resources , would lWe predict that if the effect induced by Threatening Flankers does reflect interference occurring during the orienting stages of disengaging attention, early ERP modulation should be observed over the posterior attentional network , 55. MorThirty-two healthy undergraduate students participated in the experiment . Their mean age was 20.2 years old (SD = 2.7) with a mean educational level of 13.9 years (SD = 2.3). This paper builds upon data from the research project: \u201cEmotional processing and its modulation in people reinserted from the Colombian armed conflict, belonging to the high council of the presidency of the Republic of Colombia, Antioquia region\u201d approved by the Ethics Committee of the research unit of the University of Antioquia . This study was conducted in accordance with the ethical standards stated in the Declaration of Helsinki . All parThis task is the one reported in Parra et al.   or a \u201cThreatening Scene/Living Object\u201d (key \u201cn\u201d with a red sticker). There was then an inter-trial interval of 2000 ms during which responses were still recorded see .2 = 0.21, \u03b2 = 0.20] and had no impact on the key interaction reported. That led them to collapse responses across these stimuli and refer to them as \u201cObject\u201d. We followed the same approach. Trials and blocks were fully randomized across participants. We computed accuracy and response time when threatening and neutral stimuli were presented either as Targets or as Flankers.As our key hypotheses concerned effects driven by real-life emotional images , we followed a 2x2 design: at Central Position\u2013Threat/Neutral as Target (TC-2.A/NC-1.A) and at Peripheral Position\u2013Threat/Neutral as Flanker (TP-2.B/NP-1.B). The living/non-living categories of objects were response irrelevant and were only used to add attentional demands and increase competition. This explains why we did not dichotomize the objects but only the emotional dimension . In fact, Parra et al.  reportedThe Flanker task was synchronized with EEG recording. A 64 electrodes NeuroScan Ltd. system with a 10\u201310 configuration easy-cap was used for acquisition. The signal was recorded with the software Scan 4.5 using a sampling rate of 1000 Hz. Impedance was kept below 10 k\u2126. The assessment was conducted within a Faraday chamber with dimmed lights. Participants were seated 60 cm away from a 17\u201d standard PC monitor where stimuli were presented. The total duration of the testing session was approximately 1 hour.The assessment was carried out in a single session. After completing the Emotional Flanker Task, we carried out an emotional screening procedure using a task that asked participants to rate in the two evaluated dimensions  each IAPS image previously seen using a 5-point Likert scale. This procedure was undertaken to ensure that the perceived valence matched the one reported by Lang et al. .runica  and jader  which are a part of the default EEGLAB. The maximum number of rejected independent components was 5%. A maximum of two trials per condition were discarded during further visual artefact rejection after ICA. Then, we applied a low-pass filter at 30 Hz and epoched the data. Blocks were epoched  with a time window between -200 ms pre- and 800 ms after-stimuli presentation. A baseline correction using the -200 to 0 ms window was applied. Only correct trials entered the ERP analysis. The average number of trials useful for analysis was always above 80%  as implemented in EEGLAB. We rejected components informing high frontopolar activity, which are associated with oculomotor artifacts; as well as other non-ocular signals based on neurophysiological criteria. Following recommendations by Luck , we elimThe Emotional Flanker Task has not been previously used in ERP studies. This would make it difficult to rely on specific ERP components to investigate the electrophysiological correlates of the attentional bias to threat found with such a test. As Kappenman and Luck  acknowlestatcond. We focused on the key contrasts which have previously revealed the Flaker Effect . Threatening images received more correct responses than Neutral Images . Emotion position also yielded a significant effect . Target objects (with flanking IAPS images) attracted more correct responses than Target IAPS images (with flanking objects) . The Emotion type x Emotion position interaction was significant . This reflected an emotion-related discrepancy when IAPS images were presented as targets, whereby Threatening images attracted more correct responses than Neutral images . Such a discrepancy was not observed when IAPS images were presented as flankers .The repeated-measures ANOVA model revealed a main effect of Emotion type . Threatening images yielded faster responses than Neutral Images . Emotion position also yielded a significant effect . Target objects (with flanking IAPS images) attracted faster responses than target IAPS images (with flanking objects) . Crucially, the Emotion type x Emotion position interaction was significant . This indicates that Threatening images presented as Targets were identified faster than Neutral images . However, when Threatening images were presented as flankers, they slowed the detection of Target objects more significantly than when Flankers were Neutral images .The repeated-measures ANOVA model revealed a main effect of Emotion type  or Emotion position . The Emotion type did significantly interact with Emotion position . A post hoc analysis shows that threatening images as targets yielded larger positive amplitudes than neutral images as targets . Such a discrepancy was not observed when images were presented as Flankers .The repeated-measures ANOVA model revealed non-significant effects of Emotion type  or Emotion position . The Emotion type x Emotion position interaction was significant . A post hoc analysis shows that threatening images as targets yielded larger negative amplitudes than neutral images as targets  with the inverted pattern observed when images were presented as flankers .The repeated-measures ANOVA model revealed a non-significant main effect of Emotion type  and Emotion position . The Emotion type x Emotion position interaction was significant . A post hoc analysis shows that threatening images as targets yielded larger negative amplitudes than neutral images as targets . Such an effect was not found for images presented as flankers .The repeated-measures ANOVA model revealed significant main effects of Emotion type  or Emotion position . The Emotion type x Emotion position interaction was significant . The post hoc analysis shows that threatening images as targets yielded larger amplitudes than neutral images as targets . The contrast between images presented as flankers was non-significant . In The repeated-measures ANOVA model revealed a non-significant main effect of Emotion type [Finally, a correlation analysis informed that the amplitude of the activity elicited over parietal and central-parietal regions in the 300 \u2013 400ms time window significantly correlated with reaction time data from the Threat-Central condition, whereby larger amplitudes were associated to slower RT  . Interestingly, a pattern compatible with the behavioural dissociation previously reported using the flanker task was only found over parietal and central-parietal regions in a late time window (550 \u2013 690ms). Our results also reveal that electrophysiological activity correlates with behavioural responses seemingly linked to endogenous attention resources deployed to process response relevant stimuli.The aim of the present study was to investigate whether combined behavioural and ERP evidence would shed new light on the spatiotemporal dynamics of the threat-related attentional bias observed with the Emotional Flanker Task. The literature review undertaken to support the rationale of this study confirmed the relevance of further exploring hypotheses linked to Biased-Competition Models of attention combining behavioural responses drawn from tasks akin to the flanker paradigm with the analysis of electrophysiological responses. Our key findings were: i) Threatening images presented as targets were detected faster and more accurately than Neutral images; however, the same images presented as flankers significantly slowed responses to targets; ii) The behavioural discrepancy observed for responses to Threatening Targets relative to Neutral Targets was accompanied by significant ERP discrepancies over extended brain regions involving frontal, central, parietal, and occipital regions, which expanded from 300ms to 700ms; iii) Contrary to our predictions, ERP discrepancies for Threatening Flankers relative to Neutral Flankers were only observed over parietal and central-parietal regions in a late time window. We now discuss each of these findings.The flanker effect reported by Horstmann et al.  relying Additionally, we found faster and more accurate responses during Threatening Target trials , 67\u201371 aControlled activity seems to be also underpinned by late ERP activity widely spreading from central and central parietal regions (as denoted by activations found during the late time window over these regions) to frontal and parietal-occipital regions. Activity occurring within a similar time window  has been linked to the encoding of emotional and motivational aspects of images in rich sensory contexts \u201375 and mOn the other hand, in support to a potential automatic nature of the mechanisms sub-serving the interference effect observed during Threatening Flanker trials, we found slower responses to response-relevant targets when they were flanked by response-irrelevant Threatening images. However, our prediction that ERP modulations during early time widows would underpin such an effect was not supported by our data. We predicted that if the effect induced by Threatening Flankers does reflect automatic interference occurring during the orienting stages of disengaging attention, early modulation of relevant ERP activity  would be observed , 37. InsThreat-related stimuli seem to activate two complementary processes supported by the attentional network. Parra et al.  suggesteWe may suggest that the modulation observed within our earlier significant time window over central-parietal regions when Threatening targets were presented, and the modulation observed over the same regions within a late time window when Threatening flakers appeared may be indexing similar mechanisms. The former would be linked to endogenous processes quickly triggered to uptake information presented in the focus of attention, whereas the latter would reflect processes in charge of widely scanning the environment searching for potential threats when they are imminent, and the circumstances allow to do so. From this perspective, the attentional bias to threat could be a process exogenously triggered and endogenously kept .The fact that we have observed such an attentional bias to threat under subliminal stimulus presentation conditions (200 ms) suggests that triggering such an adaptive response does not need long exposures. An alternative account could be that the sources of neural activity triggering the threat-related bias to response-irrelevant stimuli  are too deep in the brain to be recorded via scalp EEG .It is striking that the function of such a sophisticated attentional system can be disrupted if response-irrelevant threat-related subliminal or supraliminal stimuli appear in the visual field outside the focus of attention , 85. TheThere are some limitations to the present study which we would like to acknowledge. First, although we have previously found that response-key mappings would unlikely explain the patterns of results reported with the Emotional Flanker Task , future The results presented in this study lead us to suggest that the attentional mechanisms involved in adaptive responses to threat-related stimuli seem to operate under different spatiotemporal dynamics. The saliency of threatening stimuli will bias attention whether they fall within or outside the focus of attention. The attention system spares resources that can be quickly deployed towards threat-relevant stimuli. Such a monitoring system operates through controlled processes responsible for extracting information from endogenously attended stimuli  and spares resources to explore salient environmental signals through a feed-forward dynamic mechanism with potential survival value. This functional dynamic associated to threat detection grants our attentional system with an important evolutionary function , 88 and S1 File(DOCX)Click here for additional data file.S1 Data(XLSX)Click here for additional data file."}
+{"text": "The authors present a study that included patients treated for CABG procedures, in which CAS and VAS were identified by magnetic resonance angiography. Cerebral magnetic resonance imaging was performed to identify new post-operative subclinical cerebral lesions. Associations between CAS/VAS post-operative cerebral lesions were investigated. Forty-six patients were included in the study. Thirteen percent had significant CAS and 11% had significant VAS. Thirty-five percent had new cerebral infarction postoperatively. The authors found a significant association between the presence of cerebral vessel stenosis and acute cerebral infarction. In this letter to the editor, we emphasize that intraoperative management and monitoring during CPB could be crucial, in particular for patients with CAS and VAS who need urgent cardiac surgery. The optimal management of such patients remains controversial. Gold et al.  showed that high mean arterial pressure (MAP) during CPB reduces the overall incidence of combined cardiac and neurological complications. Johnsson et al.  did not show an increased incidence of perioperative neurologic events with a MAP >70 mmHg during CPB in patients with significant bilateral CAS. Maintaining cerebral regional oxygen saturation index (rSO2) in preoperative range reduces the incidence of postoperative cognitive dysfunction and general morbidity. Near-infrared spectroscopy (NIRS) allows assessment of cerebral oxygen delivery and the demands ratio to the frontal cortex. Routine use of cerebral rSO2 monitoring during cardiac surgery may improve patient\u2019s outcome and shorten hospital stay. Cerebral monitoring using NIRS can identify otherwise unrecognized cerebral hypoperfusion during aortic surgery as well. NIRS has been extensively used in patients undergoing cardiac surgery to find an association between the measurements of cerebral oxygenation and postoperative outcome . Several studies have found an association between intraoperative cerebral oxygen desaturation and postoperative cognitive dysfunction, stroke, and prolonged hospital stay . There is no evidence base for the management of patients with asymptomatic CAS and VAS requiring urgent cardiac surgery. Only a large multicenter international randomized study can provide an evidence base for the management of these patients.Carotid artery stenosis (CAS) and vertebral artery stenosis (VAS) are associated with cerebral infarction after cardiopulmonary bypass (CPB). We read with great interest the article \u201cCerebral Lesions in Patients Undergoing Coronary Artery Bypass Grafting in Relation to Asymptomatic Carotid and Vertebral Artery Stenosis\u201d, by Wiberg et al."}
+{"text": "Married and cohabiting couples have important influences on one another\u2019s stress and well-being. Pandemic-related stress may influence the extent to which couples' stress levels are coregulated. This study examined the experience of nonspecific stress and pandemic-related stress and the moderating role of closeness among couples aged 50 and over in which at least one member had hypertension. A total of 30 couples reported their feelings of closeness to one another in a baseline interview and their feelings of nonspecific stress and pandemic-related stress every three hours for 5 days. There was no difference in closeness and nonspecific stress between husbands and wives. Wives reported greater pandemic-related stress than husbands. Actor-partner interdependence models revealed that wives\u2019 nonspecific stress predicted husbands\u2019 nonspecific stress  and that husbands\u2019 nonspecific stress predicted wives\u2019 nonspecific stress in each three hour period  and these associations were not moderated by closeness. Coregulation in pandemic-related stress among husbands and wives was moderated by wives\u2019 feelings of closeness such that when wives\u2019 feelings of closeness were lower, greater husband pandemic-related stress predicted lower pandemic-related stress for wives  whereas when wives\u2019 feelings of closeness were higher, greater husband pandemic-related stress predicted greater pandemic-related stress for wives . These findings indicate that closeness may have detrimental effects especially when considering emotional coregulation in couples regarding the pandemic."}
+{"text": "This cohort study analyzes milk samples from lactating mothers to determine if COVID-19 vaccine\u2013related messenger RNA was detectable in human milk after vaccination. The World Health Organization recommends that breastfeeding individuals be vaccinated and does not advise cessation of breastfeeding following vaccine administration.5 The Academy of Breastfeeding Medicine states that there is little plausible risk that vaccine nanoparticles or mRNA would enter breast tissue or be transferred to milk,6 which could theoretically result in priming of infant immune responses that could alter childhood immunity. However, there are no direct data. To address this knowledge gap, we analyzed milk samples to determine if vaccine-related mRNA was detectable in human milk after vaccination.Messenger RNA (mRNA) vaccines against COVID-19 were recently approved under an emergency use authorization.The institutional review board of the University of California, San Francisco, approved the study. Written informed consent was obtained from all study volunteers in the COVID-19 Vaccine in Pregnancy and Lactation (COVIPAL) cohort study from December 2020 to February 2021. Clinical data were collected by questionnaires. Self-collected milk samples were kept on ice or immediately frozen (at home) until arrival in the laboratory. Samples were collected prior to vaccination and at varied time points up to 48 hours after vaccination. Total RNA was isolated from milk components using the RNeasy Mini Kit (Qiagen). We performed real-time quantitative polymerase chain reaction assay targeting the mRNA used in the COVID-19 mRNA-based vaccines. The BNT162b2 (Pfizer) and mRNA-1273 (Moderna) vaccines were separately inoculated into prevaccination milk samples, which were processed by the same protocols and used as positive controls for this assay  volunteered for this study . Their cVaccine-associated mRNA was not detected in 13 milk samples collected 4 to 48 hours after vaccination from 7 breastfeeding individuals. These results provide important early evidence to strengthen current recommendations that vaccine-related mRNA is not transferred to the infant and that lactating individuals who receive the COVID-19 mRNA-based vaccine should not stop breastfeeding. In addition, any residual mRNA below the limits of detection in our assay would undergo degradation by the infant gastrointestinal system, further reducing infant exposure. Limitations of this study are the small sample size and few participants who received the mRNA-1273 vaccine. In addition, milk storage conditions may affect mRNA stability. Clinical data from larger populations are needed to better estimate the effect of these vaccines on lactation outcomes."}
+{"text": "ABSTRACT IMPACT: This work has the potential to identify targetable pathways conveying resistance to PARP inhibitors that may improve ovarian cancer patient outcomes. OBJECTIVES/GOALS: High grade serous ovarian cancer is the deadliest gynecologic malignancy. PARP inhibitors are an FDA approved targeted therapy that is being used more and more frequently in the clinic. It is vital to understand mechanisms driving resistance to this therapy in order to develop treatments to improve patient responses. METHODS/STUDY POPULATION: RNA-sequencing and transcription factor analysis was used to identify pathways of interest. An AP-1 transcriptional reporter assays was used to confirm results of the transcription factor analysis. An unbiased lentiviral shRNA screen was used to identify AP-1 subunits promoting PARP inhibitor resistance. Lentiviral transduction allowed for the knockdown ATF6. Comet assays and two-plasmid systems were used to determine levels of DNA damage and levels of DNA damage repair respectively. RESULTS/ANTICIPATED RESULTS: PARP inhibitor resistant cell lines have increased WNT signaling which promotes to increased DNA damage repair. PARP inhibitor resistant cell lines also have increased AP-1 transcriptional activity, ATF6 expression, and active p38. ATF6 knockdown and p38 inhibition is sufficient to resensitize cells to PARP inhibition. Upon treatment with PARP inhibitors, ATF6 knockdown as well as p38 inhibition lead to increased DNA damage in PARP inhibitor resistant cell lines. RNA-sequencing reveals a signifcant overlap in downregulated genes in cells treated with a \u03b2-catenin inhibitor and cells with an ATF6 knockdown. DISCUSSION/SIGNIFICANCE OF FINDINGS: Due to the increasing prevalence of PARP inhibitors in the clinic, it is vital to uncover mechanisms contributing to resistance. This work has the potential to identify targetable pathways conveying resistance to PARP inhibitors that may improve ovarian cancer patient outcomes."}
+{"text": "The COVID-19 pandemic has disrupted older adults\u2019 in-person healthcare services. Many individuals rely on remote communication with their healthcare providers for non-urgent health or mental health issues. The present study investigated the effects of technology learning and depressive symptoms on new adoption of telehealth  to communicate with healthcare providers during the COVID-19 pandemic. A sample of 1,500 Medicare beneficiaries aged 65 or older was selected from the National Health and Aging Trend Study. A series of logistic regressions were performed. Results showed that older adults who learned a new online technology during the COVID-19 outbreak were more likely to adopt telehealth. Also, older adults with a higher level of depressive symptoms were more likely to start using telehealth. The findings highlight the importance of technology training to help older adults go online. Telehealth can be an important coping tool for depressive symptoms during the pandemic."}
+{"text": "Aortoenteric fistula is a life-threatening emergency and is associated with high morbidity and mortality. Prompt surgical intervention before the aneurysm ruptures lowers the mortality rate to about 50%. Potential imaging mimics for aortoenteric fistula include retroperitoneal fibrosis, mycotic aortic aneurysm, and infectious aortitis. Secondary aortoenteric fistula has relative higher incidence compared to primary and is more common with open aortic repair versus endovascular stent graft repair. Ectopic gas in the aneurysm sac and extravasation of enteric contrast into the aneurysm sac is diagnostic for aortoenteric fistula. However, enteric contrast is not recommended for routine evaluation of aortoenteric because the aforementioned finding is extremely rare. More common imaging findings include bowel loop appearing adherent to aneurysm sac with associated inflammatory stranding and foci or ectopic gas within the aneurysm sac or interposed between the bowel and aneurysm sac. Here we present a case of 52-year-old male who presents with incidental primary aortoenteric fistula. Aortoenteric fistula is defined as an abnormal communication between the aorta or aortoiliac tree with the gastrointestinal tract and presents as catastrophic gastrointestinal bleeding with annual incidence of primary aortoenteric fistula reported at 0.007 per million (with 250 cases reported in literature) Aortoenteric fistula present as minor \"herald\" gastrointestinal bleeding followed by later catastrophic life-threatening gastrointestinal hemorrhage Here, we present a case of aortoenteric fistula who underwent open resection of abdominal aortic aneurysm with a right axillary to bifemoral bypass graft.A 52-year-old Caucasian male presented to the outside facility emergency department following a syncopal episode and dysthymia. On arrival his vital signs were within normal limits. No leukocytosis. Chest radiograph and unenhanced CT brain were normal. CT abdomen and pelvis with contrast was performed which showed infrarenal abdominal aortic aneurysm measuring 8.9\u00a0\u00d7\u00a010.3 cm .Fig. 1CTAdditionally, on retrospect, the loop of jejunum appeared adherent to aneurysm sac, with ectopic air within the partially thrombosed aneurysm sac tracking to and in continuity with intraluminal bowel gas. Findings compatible with primary aortoenteric fistula .Fig. 2AdPatient underwent endovascular aortobiiliac stent graft placement on the same day at outside facility . FluorosFive days following the procedure patient reported bright red blood per rectum with stable vitals and hematocrit. CT angiogram of the abdomen and pelvis was performed which showed normal positioning of aortobiiliac stent graft and no evidence of endoleak. The size of the excluded aneurysmal sac was stable from prior exam. There was interval worsening of ectopic air within the excluded aneurysmal sac. Findings were compatible with known aortoenteric fistula .Fig. 4FiAdditionally, prior to transfer at our facility, CT abdomen and pelvis without intravenous contrast was performed which showed enteric contrast into the excluded aneurysmal sac, confirming known aortoenteric fistula .Fig. 5PrPatient was transferred to our facility for further management. Patient underwent resection of abdominal aortic aneurysm with a right axillary to bifemoral bypass utilizing bifurcated ringed Polytetrafluoroethylene, Aortoenteric fistula was first described in 19th century by a British surgeon Sir Astley Cooper CT findings of primary aortoenteric fistula includes presence of ectopic gas within the excluded aneurysmal sac and/or presence of enteric contrast in the aneurysm sac. Lack of fat plane between the vessel and bowel lumen may be early sign for developing aortoenteric fistula. Ancillary findings for secondary aortoenteric fistula includes peri-graft soft tissue inflammation, and adjacent bowel wall thickening Potential imaging mimics of aortoenteric fistula includes retroperitoneal fibrosis, mycotic aortic aneurysm, and infectious aortitis No patient identifiers are disclosed in current report."}
+{"text": "The impact of immune system and inflammation on organ homeostasis and tissue stem cell niches in the absence of pathogen invasion has long remained a conundrum in the field of regenerative medicine. The paradoxical role of immune components in promoting tissue injury as well as resolving tissue damage has complicated therapeutic targeting of inflammation as a means to attain tissue homeostasis in degenerative disease contexts. This confound could be resolved by an integrated intricate assessment of cross-talk between inflammatory components and micro- and macro-environmental factors existing in tissues during health and disease. Prudent fate choice decisions of stem cells and their differentiated progeny are key to maintain tissue integrity and function. Stem cells have to exercise this fate choice in consultation with other tissue components. With this respect tissue immune components, danger/damage sensing molecules driving sterile inflammatory signaling cascades and barrier cells having immune-surveillance functions play pivotal roles in supervising stem cell decisions in their niches. Stem cells learn from their previous damage encounters, either endogenous or exogenous, or adapt to persistent micro-environmental changes to orchestrate their decisions. Thus understanding the communication networks between stem cells and immune system components is essential to comprehend stem cell decisions in endogenous tissue niches. Further the systemic interactions between tissue niches integrated through immune networks serve as patrolling systems to establish communication links and orchestrate micro-immune ecologies to better organismal response to injury and promote regeneration. Understanding these communication links is key to devise immune-centric regenerative therapies. Thus the present review is an integrated attempt to provide a unified purview of how inflammation and immune cells provide guidance to stem cells for tissue sculpting during development, organismal aging and tissue crisis based on the current knowledge in the field. Immune response to injury determines the outcome of the healing process and efficient restoration of organ functions. Thus integrating inflammation and immune system targeted strategies to regenerative therapies is an interesting proposition. Knowledge of how immune system components and inflammatory signals interface with stem cells and progenitor cells in tissue niches is key to develop novel immune-centric regeneration therapies. An inverse relationship between efficient regeneration and immune competence exists as we go up the evolutionary ladder. In mammals as development proceeds injury responses proceed from being regenerative to reparative which resonates with the development of an intricate and complex immune system. A shift in scarless wound healing and regeneration in neonates to imperfect repair in adult mammals is mainly attributed to emergence of an intricate adaptive immune system through development. Primitive immune cells emerging from hematopoietic waves before definitive hematopoiesis have important developmental roles in shaping organogenesis, these cells later co-occupy organ specific niches along with stem cells and adapt to tissue specific functions. However the precise relevance of immune system and their roles in tissue regeneration and homeostasis are only being appreciated recently.versus acute inflammation) 2) timing  3) tissue of interface (immune privilege status) 4) complex niche specific micro-environmental factors  and systemic components . The present review evaluates current knowledge on how immune perturbations and innate immune functions impact stem cell fate decisions and how alarm signals from endogenous niche components including stem cells and their differentiated progeny impact immune-responses in tissue microenvironments in health, aging and disease.Contemporary advancement in technology to fate map cells and availability of precise tools to analyze tissue niches has renewed awareness on the role of immune system in tissue regeneration beyond its traditional role in pathogen immunity. Immune-mechanisms orchestrating repair and/or regeneration from tissue stem/progenitor cells depend on the 1) quality of immune resolution . A vicious loop of DAMP signaling and sterile inflammation if unresolved can drive tissue degenerative processes impacting stem cell functions and regeneration. DAMPs include diverse molecules like uric acid, mtDNA, extracellular ATP, HSPs, amyloid \u03b2, S100, HMGB1, and ECM proteins .Drosophila implicated developmental roles of TLRs in establishment of dorsal-ventral axis specification, synaptogenesis and axonal guidance apart from roles in anti-microbial defense (Evolutionarily conserved Pattern Recognition Receptor pathways (PRRs) recognizing altered patterns on microbes, viruses or endogenous danger signals lying at the helm of endogenous tissue surveillance mechanisms guide stem cell fate decisions and are key alarmin sensors . Out of  defense . Since t defense . Balance defense . Similar defense . The ces defense . Endosom defense  and TLR3 defense . Since n defense  it wouldSterile inflammatory signaling seems to be evolutionarily conserved in regulating Hematopoietic stem cell (HSC) production during embryonic development. Studies on HSC emergence in zebrafish and mouse indicate that tonic innate immune cell signaling in the absence of microbial challenge can contribute to HSC orchestration and control of cell numbers much before the development of a functional adaptive immune system. Known IFN\u03b3 target genes have been shown to be expressed in human fetal HSCs. Intra-arterial Hematopoietic cluster cells (HCC) emerging from the hemogenic endothelium exhibited an innate immune gene signature with enrichment of TLR pathways and IFN target genes indicating existence of sterile immune signaling networks in both mouse and human fetal HSCs . A combiIn addition to differentiated blood cells both mouse and human HSCs express most TLR family members and their downstream adaptor proteins . Stimulavia endogenous repetitive elements which are specifically expressed during endothelial to hematopoietic transitions during HSC emergence in zebrafish models  are integral constituents of Hematopoietic niches and express a wide range of TLR receptors. Minor variations in TLR expression patterns are noted based on species and their tissue of origin . Triggere defect . Thus TLe defect . Aberranh as EGF . The inah as EGF . Howevervia purinergic cell surface receptors. Autocrine eATP is noted from several cells and eATP levels peak during cellular stress. eATP is an evolutionarily conserved DAMP from mammals, fish, insects and plants. In mammals, eATP is known to bind to cell surface P2 receptors expressed on many tissues throughout the body. P2 receptors are categorized into two major classes: ligand-gated ion channels P2X1-7 receptors and metabotropic G protein-coupled P2Y receptors  of fetal liver hematopoiesis. Further functional diversification in tissues to ILC-1, -2 or -3 is guided by signals as diverse as microbiota, dietary lipids and integrated tissue specific inputs during the perinatal period. However their migratory routes during development and during tissue injury in the adult is still elusive. Coincidently ILC2s co-inhabitate stromal tissue niches and were shown to modify epithelial barriers and affect tissue health. These cells could oscillate between different tonic functional states brought in to play by the functional needs of the tissue when challenged by microbial as well as physiological stresses and can thus function as immune tissue alarms  lack antigen-specific receptors but nonetheless exhibit a broad functional spectrum like adaptive T cells and analogous to the T helper subsets are named as ILC1, ILC2 and ILC3. Despite presence of ILCs in SCID mice as well as immune-deficient humans the conventional immune responses to infection are severely compromised underscoring their role in microbial immunity. Data from mice studies indicate that developmentally they originate from a common innate lymphoid precursor (CILP) which do not possess T and B cell differentiation abilities and then finally infiltrate to different tissue e alarms . Based oe alarms . Addressreg cells) resulted in reduction in HSC pool  or the low-grade constitutively activated alternative pathway which begins with the activation of C3. However, all these three pathways merge at C3 which is subsequently converted to C3a, an anaphylatoxin, and C3b, an opsonin. Further activation of C3 components depends on context specific versatile recognition molecules and receptors on cell and pathogen surfaces such as MBL, C1q and Ficolins. Despite low activation of the alternative pathway as a part of immune-surveillance, surface of healthy cells have complement regulators which prevent further nucleation  decreased ability of HSCs for lymphopoiesis, myeloid biased differentiation, decrease in quiescence and increase in HSC pools 2) mesenchymal progenitor cell in the niche are biased towards adipogenesis  and exhihigh HSCs from aged mice into irradiated young niches resulted in skewed myeloid differentiation from these cells. Further P-selectin high aged HSCs exhibited higher cycling  mice are incapable of bone marrow reconstitution post-irradiation exaggerating the importance of autophagy processes in maintenance of HSC integrity  levels concomitant with metabolic/protein stress. These events are driven by breach of organelle quality control checks and loss of proteostasis which exaggerates intrinsic aging of quiescent HSCs . Disruptntegrity . It is s\u2212/\u2212 precursor cell into wild type mice impaired HSPC homing and engraftment efficiencies. Interestingly, it has been proposed that NLRP3 regulates HSC migration by facilitating incorporation of CXCR4 into membrane lipid rafts  signature in the absence of a prevailing infection. Interestingly, HSCs are unresponsive to Interferon due to high thresholds of ISGs. Surprisingly, differentiated derivatives of HSC have a narrow spectrum of ISGs but acquire IFN responsiveness indicating an adaptation of bone marrow microenvironment to protect exhaustion of LT-HSCs but at the same time engage progenitor responsivity to viral challenges . Endogenid rafts . Thus, NSome interesting evidence in the literature indicate inflammatory memory imprinted in the HSC genome due to a previous encounter which is passed on to their differentiated progeny. BCG induced a sustained reprogramming of HSCs and epigenetic modifications were passed on to macrophages/myeloid progeny which induced more protective immunity to virulent mycobacterial infection than na\u00efve macrophages  Cell. SiAged Mesenchymal progenitor cells in the bone marrow as well as other tissues exhibit a senescent phenotype marked by loss of clonogenicity and breakdown of DNA repair responses. Exosomes secreted by senescent stromal cells communicate aberrant instructions to stem cells altering their decisions . Exposurin vivo , in adult mice had been shown to induce \u03b1 cells to transdifferentiate into beta cells to compensate the loss and rescue the need for exogenous insulin for at least 6\u00a0months after \u03b2 cell ablation . A similA classic example of developmental trans-differentiation is emergence of HSCs directly from hemogenic endothelium . Surpris\u2212/\u2212 mice fed with western diet atherosclerotic lesions were observed in aortic roots with a concomitant increase in HDAC3. Even in human patients arteriosclerotic lesions in inflammatory areas were associated with HDAC3. HDAC3 inhibition alleviated EndMT by modulating inflammatory response indicating an intimate link between inflammatory triggers and EndMT in context of arteriosclerosis (In fact EndMT serves as the link between inflammatory factors and plaque growth in atherosclerosis. In ApoEclerosis . Inflammin vivo therapeutic applications. Major bottlenecks include epigenetic instability, functional immaturity of the differentiated cells and subsequent immune rejection and engraftment upon transplantation. Further faithful mimicking of the ultrastructural and intricate functional components of endogenous tissues is a complicated task in vitro. Thus tissue niche based targeting approaches to aid endogenous repair and regeneration is an interesting strategy. Designing rational niche targeting strategies requires adequate knowledge of micro- and macro-environmental factors influencing stem cell decisions in their tissue habitats. Dynamic two-way interactions of stem cells with stromal components and resident or systemically recruited immune system players are pivotal in reshaping tissue response patterns to duress. Fetally patterned immune niches in most tissues are subjected to life-long sculpting in a demand driven process. In this premise inability of stem cells and/or immune niches to detect danger signals and eliminate or constructively adapt to crisis are central to aging, stem cell exhaustion and aberrant trans-differentiation events driving progressive degenerative disease. Thus breaking noxious iterative communication networks at stem cell-immune interfaces would be key for constructive regeneration. This would require identification of major molecular players at aberrant stem cell-immune interfaces to unravel novel immune-centric regenerative therapeutic possibilities which could also serve as biomarkers to detect early degeneration. Niche based targeting approaches would require a holistic understanding of tissue and organismal aging and degenerative processes. Since organismal aging is intimately associated with sterile bone marrow centric inflamm-aging, uncoupling these networks at the organismal levels in degenerative disease contexts could also be one possibility to reestablish tissue homeostasis and recovery. In addition, since innate immune system is ubiquitous in most organs finding unique components and interactors in tissue immune niches would be important to establish tissue directed targeting approaches in specific tissue pathologies without compromising overall immune fitness.Recent technical advancements in iPSC generation, PSC derived organoid cultures and gene editing have opened up new avenues in drug screening and disease modelling in a dish. However the potential clinical applications have not caught pace with the technical knowhow due to limitation of usage of these cells for"}
+{"text": "Dear Editor,NHS England reports that 4.7 million people are awaiting an operation in England, the highest in a decade. Healthcare systems are seeking methods to limit an accumulating impact on services. Clinical pathways can be used to improve patient outcomes when recovery is relatively predictableIn conjunction with national guidanceTableS1. Patients were split into two cohorts; those admitted before  and during  the pandemic (Table 1). Compliance with 14 ERAS pathway factors, spanning 3 days after the operation and shown to be influential on postoperative outcomesTableThe effect of the COVID-19 pandemic on colorectal ERAS pathway adherence and patient outcomes was explored. Complete methodology and demographics can be found in U test analysis revealed an increase in colorectal surgery ERAS pathway compliance during the pandemic (P\u2009<\u20090.001) compared with before . The 30-day post-discharge mortality rate remained at zero in both groups and no patients tested positive for SARS-CoV-2 PCR swabs during admission.Mann\u2013Whitney The colorectal surgery ERAS pathway has passed the ultimate stress test; it is safe, straightforward and improves outcomes. It should form part of the post-pandemic recovery with the aim to clear waiting lists.Disclosure. The authors declare no conflicts of interest.BJS online.znab208_Supplementary_DataClick here for additional data file."}
+{"text": "Pseudomonas aeruginosa deploys a triggerfactor to hijack the lysogenic to lytic switch of a polylysogenic Staphylococcus aureus strain causing the selective productionof only one of its prophages. Fractionating extracts of P. aeruginosa identified the phenazine pyocyaninas a highly potent prophage inducer of S. aureus that, in contrast to mitomycin C, displayed prophageselectivity. Mutagenesis and biochemical investigations confirm theexistence of a noncanonical mechanism beyond SOS-response that iscontrolled by the intracellular oxidation level and is prophage-selective.Our results demonstrate that human pathogens can produce metabolitestriggering lysogenic to lytic conversion in a prophage-selective manner.We anticipate our discovery to be the starting point of unveilingmetabolite-mediated microbe\u2013prophage interactions and layingthe foundations for a selective small molecule controlled manipulationof prophage activity. These could be for example applied to controlmicrobial communities by their built-in destruction mechanism in anovel form of phage therapy or for the construction of small molecule-inducibleswitches in synthetic biology.Bacteriophages havemajor impact on their microbial hosts and shapeentire microbial communities. The majority of these phages are latentand reside as prophages integrated in the genomes of their microbialhosts. A variety of intricate regulatory systems determine the switchfrom a lysogenic to lytic life style, but so far strategies are lackingto selectively control prophage induction by small molecules. Herewe show that  This is even more surprising since bacteriophages,viruses infecting bacteria, are the most diverse and abundant biologicalentities on our planet.Microorganisms engagein an enormous diversity of ecological interactionsthat are largely controlled by small molecule metabolites.5 Altered phage compositionin the gut has been linked with human diseases,8 and phages maycontribute to maintenance of intestinal immune functions.9 The vast majority of phages in the human gutare residing integrated as prophages in the genomes of their respectivemicrobial hosts.10 These prophages canbe induced under certain conditions to resume a lytic lifestyle resultingin the production of virus particles (virions) and the destructionof the host cell.11 This typically involvesinactivation of a prophage repressor via the SOS-response.12 Genotoxic agents like mitomycin C trigger thisSOS-response through DNA damage prompting the expression of multiplegenes encoding repair pathways.13 Althoughphages during the lytic cycle destroy their host, a prophage confersvarious fitness benefits to its microbial host.15 These include for example the introduction of toxins and other virulencerelated factors encoded by the prophage,17 protection from superinfection by other phages, and serotype conversionby modulating the structure of lipopolysaccharide O-antigens.19 For bacterial populations, liberated phage particles of spontaneouslysis events of individual cells also may serve as a form of bacterialwarfare against nonlysogenized competitors.14 Thus, prophages are not only a bacterium\u2019s Achilles heelbut also important mutualistic traits and possibly even a key forcontrolling microbial communities.The human body and its microbiota harboran enormous diversityof phages. These phages drive microbial evolution and dynamicallyshape microbial communities.20 and the internalregulation of the lysis-lysogeny decision of prophages via quorumsensing signals of the bacterial host21 or its phages.23The chemistry of microbe\u2013phageinteractions still remainsunderexplored, although recent work has reported defense compoundspreventing lytic infectionsHere we expand the repertoireof small-molecule-mediated microbialinteractions by the discovery of a cross-species prophage inducingmetabolite and prophage-selective trigger factor.Staphylococcus aureus usinga plaque assay. Mitomycin C is used as standard agent for phage induction,24 which causes DNA damage and induces phages byeliciting the bacterial SOS-response.13 Phage particles were quantified as plaque forming units (PFU) onagar plates with the phage-susceptible S. aureus reporterstrain RN4220. Staphylococcus aureus strain ATCC6341 gave a strong prophage induction with mitomycin C and was consequentlyused for a screening of solid phase extracts of culture supernatantsof human commensals and pathogens that are frequently occupying thesame niches  To explore this possibility, we firsttested the inducibility of prophages by the antibiotic mitomycin Cin five human isolates of e niches 1a. Whileagnitude 1b. We thSupporting Information Figure S1). High resolution mass spectrometry resulted in an m/z of 211.08635 indicating a molecularformula of C13H10N2O . Structureelucidation by 1D and 2D NMR spectroscopy ultimately identified pyocyaninas the active compound .The characteristicblue coloration of the active fraction suggested that the inducermay be a phenazine. The active compound was obtained by activity-guidedfractionation by liquid\u2013liquid extraction with subsequent HPLC-purificationto homogeneity .The activity of the isolatedcompound was identical with commercial pyocyanin and led to concentrationdependent prophage induction with up to 1.7 \u00d7 10phzM transposon mutant of P. aeruginosa which maintains an intact phenazine gene cluster but is unable toperform the N-methylation step in the biosynthesis of pyocyanin: incontrast to metabolite fractions of wild type P. aeruginosa, those of the \u0394phzM mutant did not causephage induction . In order to gain a moredetailed understanding of prophage induction by pyocyanin, we usedsingle-molecule real-time sequencing (PacBio) of the entire genomeof S. aureus ATCC 6341. Analysis of the assembledgenome with Phaster25 identified six prophage-likeregions (PLR I\u2013VI). Two of them (I and VI) were Staphylococcusaureus pathogenicity islands (SaPImbl1 and SaPImbl6), one(V) was tentatively characterized as incomplete prophage, and threeregions  were identified as Siphoviridae (phiMBL2-4) . Production of phage particles was investigated by PCR analysis.We hereby took advantage of the fact that DNA packed in capsids iswell protected from nucleases and can thus be differentiated fromfree genomic DNA of disrupted bacterial cells. The cell-free supernatantsof induced cultures were DNase treated to digest genomic DNA of lysedcells, whereas DNA packed inside phage particles would remain intact. DNasewas then inactivated and the capsids were disrupted by a heat denaturationstep.Mitomycin C causeda maximum of phage induction at 1.5 \u03bcM, while at higher concentrationseffective phage production was probably prevented by increasing celltoxicity. Remarkably, the effectiveness of pyocyanin in prophage inductionof Supporting Information Figure S6b).Subsequently, diagnostic fingerprint regions were amplifiedby PCR using sequence-specific primers. All of the six prophage-likeregions could be detected after induction with mitomycin C, whileonly one (phiMBL3) was found with pyocyanin .In order to test which of these were further infectious tophage-sensitive S. aureus phage phiJB (99.5% at 68%coverage). TEM experiments confirmed a phage with Siphoviridae morphology with a tail length of 180 nm and a head diameter of 60nm . Pyocyanin is known to interfere with the electron transportchain in S. aureus and to cause oxidative stress.27 Using a 2\u2032,7\u2032-dichlorofluorescein diacetate (DCF-DA)fluorescent sensor for reactive oxygen species (ROS), we confirmeda strong increase of ROS in S. aureus ATCC 6341 upontreatment with pyocyanin at concentrations used for prophage induction. Wethus investigated if scavengers of reactive oxygen species would protectcells from pyocyanin-mediated prophage induction. Indeed, N-acetylcysteine significantly reduced the production ofthe phage in concentration dependence by more than 2 orders of magnitude,suggesting that the oxidative environment rather than any direct interactionof pyocyanin with a host protein is responsible for prophage induction.To investigate whether any type of ROS or electron transport chaininhibition would cause phage induction at levels and selectivity comparableto pyocyanin, we tested hydrogen peroxide and trans-\u03941-NQNO treatment compared to pyocyanin . More importantly, whilepyocyanin was selective for phage phiMBL3, both hydrogen peroxideand trans-\u03941-NQNO led to productionof multiple phages . Similar to mitomycin C, also hydrogen peroxide is knownto elicit the SOS-response in S. aureus by oxidativeDNA damage29 and quinolone N-oxides may indirectly cause the same effect.30 These results suggest that the mechanism of induction bypyocyanin relies on a high level of ROS production but strictly differsfrom that of other oxidants and electron transport chain inhibitors.This low responsiveness matchedconsiderably lower ROS levels thatwere measured for hydrogen peroxide and R) mutants of S. aureus ATCC 6341over several days of continuous exposure. These pyoR mutantsexhibited MIC values for pyocyanin of 150\u2013200 \u03bcM correspondingto up to 4-fold enhanced tolerance compared to the wild type. In comparisonto the wild type, pyoR mutants displayed identical phageinduction with mitomycin C but approximately 2 orders of magnitudelower response to pyocyanin, confirming the different induction mechanismsof both compounds  in the NAD(P)/FAD-dependentoxidoreductase gene as the only shared feature (Supporting Information Table S4). Mutation of the oxidoreductase likely limited redoxcycling of pyocyanin and thereby decreased oxidative stress and henceprophage induction. We suspected that the mechanistic differencesfor the induction of the prophages may be reflected by different typesof prophage repressors.With the aim to gain further insights into the mechanism and itsconnection to prophage induction, we selected three pyocyanin resistant. While phiMBL2 and phiMBL4 use the standard CI-likerepressor, which is typically inactivated by SOS-response mediatedRecA-dependent autoproteolytic processing, phiMBL3 exhibits a C-terminallytruncated CI*-like repressor lacking the protease domain . Consequently, the phiMBL3repressor cannot be derepressed by RecA-mediated self-cleavage. Consistentwith these findings, a phylogenetic analysis revealed that the CI*-likerepressor of phiMBL3 clustered with Stl repressors of pathogenicityislands (SaPIs) which are typically derepressed by other proteinsinstead of being cleaved .Comparing the sequences of all prophage-likeelements in the genomeof S. aureus phage phiMBL3 by pyocyaninraised the question of how its producer P. aeruginosa might benefit from this selectivity. We speculated that a broadspectrum SOS-response inducing compound would also induce residentprophages in the genome of P. aeruginosa which wouldbe self-destructive.The selectiveinduction of P. aeruginosa. Indeed, while mitomycin C caused prophageinduction, pyocyanin had no such effect , pyocyanindid not lead to induction even at concentrations up to the MIC valueof 200 \u03bcM and in contrast even slightly reduced PFU counts inconcentration dependence (P. aeruginosa or E. coli. We next aimedto explore if induction of prophages significantly contributes tocell lysis. We thus compared the colony forming units (CFU) of S. aureus ATCC 6341 with the prophage-cured strain RN4220upon pyocyanin treatment. Strain ATCC 6341 showed significantly reducedviability at prophage-inducing pyocynanin concentrations comparedto RN4220. These results suggest that prophage induction may activelycontribute to killing of cells probably due to phage-related celldisruption and indicate that prophage induction may be a suitablestrategy for P. aeruginosa to controlpopulation density of competing bacteria . The mechanism responsible for the selectivityof pyocyanin consequently operates independently from the SOS-response.Pyocyanin-mediated prophage induction depends on high-level productionof reactive oxygen species and is controlled by the intracellularoxidation level. The truncated CI*-like repressor of phiMBL3 resemblesStl-repressors of SaPIs, which are known to be induced by multiplediverse and unrelated proteins of helper phages. It can thus be speculatedthat the repressor of phiMBL3 may be specifically derepressed in anoxidative cellular environment by binding of an oxidative stress orredox state-induced or -activated protein which still needs to bediscovered. In E. coli oxidative stress is knownto activate the transcription factor OxyR, which efficiently repressesprophage induction.38 This effect may beresponsible for the nonresponsiveness of Gram-negative bacteria topyocyanin. In addition, some Gram-negative bacteria have potent detoxificationmechanisms such as efflux pumps that can reduce effective exposureto pyocyanin.39 In a sense, species selectivitypossibly entails prophage selectivity, and since most bacteria harborprophages, secreting metabolites with nonselective activity wouldbackfire on their producers. P. aeruginosa may benefitfrom lysis of a subpopulation of a particular S. aureus strain but also from the cascade effect that phage production mayhave on other nonlysogenized competitors. Phage particles may eventrigger a maladaptive antiviral immune response that prevents clearanceof a bacterial pathogen and aid the infection process in mammalianhosts.40 Pyocyanin has many important biologicalfunctions including mediating cell death of P. aeruginosa during biofilm formation, promoting anaerobicsurvival, and acting as virulence factor against the human host.43 Our finding that pyocyanin also serves as a selective prophage induceradds to the long list of remarkable activities of this metabolite.Prophage induction mediated by the SOS-responsehas been shown,for example, for Vibrio dependingon cell density,21 and it was found thata peptide-based signal called arbitrium enables communication betweenlysogenic phages.23 Also Streptomyces metabolites have been described acting as a chemical defense systemto block replication of lytic phages via intercalating DNA.20Recent discoveries have increasingly contributed to a picture ofsmall molecules driving microbe\u2013phage interactions within aspecies. For example, a quorum sensing signal was identified thatguides the lysogenic to lytic decision of We now demonstrated that microbial metabolitescan be potent cross-speciesprophage inducers and furthermore exhibit selectivity on a prophagelevel in polylysogenic hosts. Our results not only challenge the understandingof metabolite-mediated interactions within microbiota by adding anadditional layer of complexity but also open up an entirely new fieldfor manipulating these interactions. Selective prophage inducers couldallow exploitation of a built-in destruction mechanism of microbesleading to controlled lysis. Triggering lysogenic to lytic conversionin a selective way may allow active restructuring of microbial communitiesand may offer an alternative solution to phage therapy. On the otherhand, it also has not escaped our notice that the selective inductionof prophage-like sequences could be repurposed for the constructionof small molecule controlled molecular switches for synthetic biology.Pseudomonas aeruginosa is a trigger factor that hijacks the lysogenic to lytic switch ofa polylysogenic Staphylococcus aureus strain andleads to the selective production of only one of its prophages. Weprovide evidence that this potent and prophage-selective inductionis controlled by a mechanism that differs from the typical SOS-response.We have shown that pyocyanin produced by"}
+{"text": "A best evidence topic has been constructed using a described protocol. The three-part question addressed was: In patients with Infrarenal abdominal aortic aneurysm (AAA), Does endovascular abdominal aortic repair (EVAR), AS compared to open surgical repair (OSR), has higher Survival rates? The outcomes assessed were the overall survival rates in both techniques. The best evidence showed that there is no statistically significant difference between EVAR and OSR in survival rates. \u2022Endovascular abdominal aortic aneurysm repair is inferior to open surgical repair regarding the secondary rupture rates.\u2022Long term outcomes of the open surgical repair are better than the Endovascular repair.\u2022Secondary rupture is more common in endovascular repair than the open surgical repair of abdominal aortic aneurysm. This fo2While discussing the management options of 65 years old patient with Infrarenal abdominal aortic aneurysm (AAA) of 6.5\u00a0cm, one of the junior doctors asked which has better long term survival rate (>5 year); open surgical repair (OSR) or endovascular abdominal aortic repair (EVAR)?\u2022\u2022[Which modality of treatment has higher long term overall survival rates];\u2022[EVAR or OSR]?Three Parts Question:3AEmbase 1974 to June 2021 using the OVID interface:B.Medline using the PubMed interface:[AAA OR Abdominal Aortic Aneurysm]AND [Open repair OR open surgical repair OR OSR] AND [EVAR OR Endovascular Repair] AND [Survival rate].[AAA OR Abdominal Aortic Aneurysm]AND [Open repair OR Open surgical repair OR OSR] AND [EVAR OR Endovascular Repair] AND [Survival rate].\u2022Inclusion criteria: all original articles that review Survival rate among patients with AAA who underwent open surgical repair vs Endovascular Repair.\u2022Exclusion criteria: case reports, systematic reviews, letters to the editor, conference abstracts.The results were limited to English articles and human studies.4A total of 1741 papers were found using both search engines. We excluded 960 articles because they were irrelevant based on the titles and the abstracts. Seven hundred eighty-one full-text articles were screened and assessed for eligibility. From these, six papers were identified to provide the best evidence to answer the question. see 56EVAR is no being considered as standard treatment for AAA because of the initial promising results .However,In this article, we reviewed the best studies which compared the two modalities of AAA repair to evaluate which techniques have higher survival rates.Only one study in our review showed a statistically significant difference between EVAR and OSR in survival rate in favor of the OSR group; this study was conducted by Huang et al. . This stIn contrast, there are another five trials, three of them were Randomized controlled trials which were conducted by Lederle FA et al. , Van Sch7According to the above articles, the best evidence shows no statistically significant difference in long-term overall survival rate among patients with open surgical repair of abdominal aortic aneurysm compared to endovascular repair.Ahmed Abdel Rahim (AA): Conducted the literature search and wrote the paper.Rashid Ibrahim (RI): Assisted in the literature search and Writing of paper.Lu Yao(LY): Editing of writing.Ahmed Khalf (AK): Assisted in writing of paper.Mohammed Ismail (MI): Assisted in the literature search and writing of paperEthical approval was not required.No source of funding.1. Name of the registry:2. Unique Identifying number or registration ID:3. Hyperlink to your specific registration (must be publicly accessible and will be checked):Ahmed Abdel Rahim.Ethics committee approval was not required as the study was review of previously done studies.No conflicts of interest."}
+{"text": "Methanoperedenaceae was a predominant group under closed-circuit conditions.Information about sediment microbiota affected by sediment microbial fuel cells (SMFC) is limited. A laboratory-scale SMFC was applied to a eutrophic lake sediment under closed-circuit/open-circuit conditions. We analyzed the prokaryotes in the sediment adhering to the anode material. The archaeal family  Sediment microbial fuel cells (SMFC) can generate electrical energy using an anode embedded in the sediment and a cathode submerged in the overlying water . In thisThe SMFC column configurations have been described previously . BrieflyMethanoperedenaceae was the only group that showed a significant difference with the circuit condition , compared to OC conditions  (P\u2009<\u20090.005 by Student's t test). These data imply that this archaeal group may contribute to the bioelectrogenesis of the SMFC in eutrophic lake sediments.The archaeal family ondition . MethanoPRJNA767541 (The sequences were submitted to the NCBI Sequence Read Archive (SRA) under the BioProject accession number NA767541 ."}
+{"text": "Infectious respiratory-track pathogens are a common trigger of healthcare capacity strain, e.g. the COVID19 pandemic. Patient risk stratification models to identify low-risk patients can help improve patient care processes and allocate limited resources. Many existing deterioration indices are based entirely on structured data from the Electronic Health Record (EHR) and ignore important information from other data sources. However, chest radiographs have been demonstrated to be helpful in predicting the progress of respiratory diseases. We developed a joint EHR and chest x-ray (CXR) model method and applied it to identify low-risk COVID19+ patients within the first 48 hours of hospital admission. All COVID19+ patients admitted to a large urban hospital between March 2020 and February 2021 were included. We trained an image model using large public chest radiograph datasets and fine-tuned this model to predict acute dyspnea using a cohort from the same hospital. We then combined this image model with two existing EHR deterioration indices to predict the risk of a COVID19+ patient being intubated, receiving a nasal cannula, or being treated with a vasopressor. We evaluated models\u2019 ability to identify low-risk patients by using the positive predictive value (PPV). The image-augmented deterioration index was able to identify 12% of 716 COVID-19+ patients as low risk with 0.95 positive predictive value in the first 48 hours of admission. In contrast, when used individually, the EHR and CXR models each identified roughly 3% of the patients with a PPV of 0.95.Predicting Low Risk PatientsAggregated predictions for COVID19 positive patients within the first 48 hours of admission, shown with exponential weight moving average and 95% CIs. Each plot shows the number of patients flagged as low-risk by lowest aggregated prediction and the resulting accuracy for that fraction of patients. The bottom plot compares the MCURES fused model to the MCURES model. The top plot compares the EDI fused model to the EDI model.Our multi-modal models were able to identify far more patients at low-risk of COVID19 deterioration than models trained on either modality alone. This indicates the importance of combining structured data with chest X-rays when creating a deterioration index performance for infectious respiratory-track diseases.All Authors: No reported disclosures"}
+{"text": "To the editor:Drug-related bradycardia (DRB) is a common conundrum in clinical practice and is often an adverse effect of a desired effect. However, it can result in multiple hospital admissions, particularly for older adults.Over a three-month period, we identified 100 hospitalised patients aged over 70 years with 2 or more documented episodes of bradycardia during admission . These constituted 4.32% of total admissions. Syncope was the most common presenting symptom and occurred in 23 patients. Causality assessment via Naranjo algorithm demonstrated a definite causal association between the administration of rate-limiting medications and bradycardia (score of 9) [Although our study did not report any in-hospital death, during the 12-month follow-up period 30 patients had deceased, 14 patients were re-admitted with DRB and 5 patients underwent permanent pacemaker implantation. Neither an admission with DRB or a background of AF were significant predictors of mortality.Patients initially diagnosed with AF often have a rapid ventricular response and require rate limiting medications such as beta-blockers and non-dihydropyridine calcium channel blockers drugs to mediate their heart rate As AF progresses there is electrical remodelling and changes in the expression of ion channels within the cardiomyocytes leading to myocardial fibrosis This in turn slows conduction through cardiomyocytes and leads to delayed ventricular response or \u201cslow AF\u201d This process occurs over many years and can remain clinically silent ,3 We susWithout pharmacovigilance older adults may continue taking rate-limiting drugs despite a gradual reduction in their heart rate. Another point to underscore, is that many older adults are underweight and sarcopenic  which can result in prescription errors based on weight and size. Caution should therefore be exercised when initiating and up-titrating rate-limiting medications in older patients, and those with AF should undergo regular review of their heart rate and ECG surveillance. Holter monitoring may be a valuable tool within in this context and should be routinely employed."}
+{"text": "P. aeruginosa (PSA) coverage if locally validated risk factors are present. They further recommend obtaining local data on CAP pathogens to quantify risk factors and help guide clinical decision-making. To comply with the current guideline recommendations and to determine which patients may benefit from empiric anti-pseudomonal therapy, we aimed to characterize our institution\u2019s local risk factors for CAP caused by PSA. The 2019 ATS/IDSA community-acquired pneumonia (CAP) guidelines recommend empiric This is a retrospective single-center matched cohort study of patients admitted to our institution with a CAP diagnosis and a positive respiratory culture who received antibiotic treatment in the past 19 years. Multivariate logistic regression was performed to assess the relationship between PSA and the following risk factors: severe or very severe COPD (FEV1 < 50% predicted), requiring invasive mechanical ventilation or vasopressor support in the first 24 hours of admission, history of PSA infection/colonization in the previous year, tracheostomy, bronchiectasis, long-term care facility residence and admission with receipt of IV antibiotics in the previous 90 days.A total of 343 patients were screened and 213 were included. Patients were mostly male (99%) with a median (IQR) age of 70 (63-76) years. Long-term care facility residence was removed from the model to prevent it from being over fit as it was related tracheostomy. In the multivariate analysis the only independently associated risk factor for PSA CAP was evidence during the prior year of PSA infection or colonization . Other risk factors that did not reach statistical significance but may be clinically significant included severe or very severe COPD  and tracheostomy .The results of this study provide valuable data to help guide empiric CAP treatment at our institution. Based on these results, patients with PSA infection or colonization in the past year are appropriate to provide empiric anti-pseudomonal therapy for CAP. Further evaluation of severe or very severe COPD and tracheostomy would be beneficial to better characterize their role in PSA CAP.All Authors: No reported disclosures"}
+{"text": "Fluorescence Tracker App downloadable via MATLAB\u00ae file exchange). Statistical analysis of FI-time plots compared tumours  against control during FI curve rise, peak and decline from apex. Early kinetic FI signal measurement delineated discriminative temporal signatures from tumours  offering rich data for analysis versus delayed spot measurement (n\u2009=\u200910 cancers). Malignant lesion dynamic curves peaked significantly later with a shallower gradient than normal tissue while benign lesions showed significantly greater and faster intensity drop from apex versus cancer. Automated tracker quantification efficiently expanded manual results and provided algorithmic KNN clustering. Photobleaching appeared clinically irrelevant. Analysis of a continuous stream of intraoperatively acquired early ICG fluorescence data can act as an in situ tumour-identifier with greater detail than later snapshot observation alone. Software quantification of such kinetic signatures may distinguish invasive from non-invasive neoplasia with potential for real-time in silico diagnosis.As indocyanine green (ICG) with near-infrared (NIR) endoscopy enhances real-time intraoperative tissue microperfusion appreciation, it may also dynamically reveal neoplasia distinctively from normal tissue especially with video software fluorescence analysis. Colorectal tumours of patients were imaged mucosally following ICG administration (0.25\u00a0mg/kg i.v.) using an endo-laparoscopic NIR system  including immediate, continuous in situ visualization of rectal lesions transanally for up to 20\u00a0min. Spot and dynamic temporal fluorescence intensities (FI) were quantified using ImageJ  and by a bespoke MATLAB\u00ae application that provided digitalized video tracking and signal logging at 30fps ( Improved intraprocedural tissue characterisation could allow better in situ primary tumour profiling and confirmation/exclusion of metastatic deposits acuminating cancer outcomes and healthcare efficiency2.Direct visualization by endoscopy is an early component of clinical pathways for many patients with visceral cancer that directs subsequent care. At operation, direct inspection assists quantification of overall cancer burden especially in areas poorly seen by non-invasive workup and impacts surgical strategy. However, determination of tissue nature by operator judgement alone or indeed by traditional biopsy  is imperfect3. Such capacity can help characterise tissue intraoperatively with most clinical application thus far for tissue perfusion assessment using the non-selective fluorophore indocyanine green (ICG)6. For this, the NIR-ICG visualization is dynamic, occurring within seconds of agent administration, fitting current surgical practice very well. In contrast, NIR cancer identification strategies have concentrated on advanced preprocedural fluorophore administration with visual interrogation planned for many hours or days later at a time when tissue agent concentrations are relatively static7.Surgical colorectal cancer care is ideally suited for digital advance with both endoscopy and laparoscopy embedded in its diagnosis and therapy. Its endolaparoscopic systems are capable of providing multispectral illumination including tissue-penetrating near-infrared (NIR) spectral vision9. Their irregular vascular architecture and lack of a lymphatic recovery system leads to the tumoritropic accumulation of macromolecules such as albumin in solid tumours 10. Such characteristics mean even a chemically non-selective perfusate, such as ICG, could functionally discriminate cancer at any site allowing in situ optical delineation. However, when applied simply by preoperative administration and later snapshot observation, high false positive rates pertain 11.Malignant tumours distinguish from normal tissue and benign neoplasia by hallmark metabolic behaviours including their neovascularization (angiogenesis) as well as cell\u2013cell and host-tumour interstitial interactions12. As the processes being visualized are more complex than perfusion alone and non-tumour background noise may manifest, video-based analytics could de-risk image interpretation permitting greater interpretative clarity and even potentially a \u2018digital tissue biopsy\u2019 through software. Herein we pilot the use of systemic NIR-ICG as a licensed available-now agent for endoscopic colorectal neoplasia perfusion interrogation with the goal of identifying discriminant tissue characterisation features. The automated operative perfusion quantification methodology developed and used for this study is available for download so others may test and add to this exploratory work while we continue to expand our clinical series on a collaborative basis.We hypothesized that kinetic characterisation of the evolving dynamic fluorescence intensity (FI) signature at and within cancer deposits could provide discrimination of cancer versus non-cancer even with a passive, non-targeted fluorophore such as ICGThis clinical experience involved adult patients already undergoing endolaparoscopic diagnostic or therapeutic procedures for colorectal neoplasia under general anaesthesia. Informed consent was obtained from all participants in accordance with relevant guidelines and, regulations and with institutional  ethics approval . ICG is licensed internationally for tissue perfusion characterisation and has an excellent safety profile. NIR Endoscopic Systems are commercially available with the one used in this study  being capable simultaneous white light and NIR display. Therefore, no experimental agents or devices were used and no clinical care decisions changed based on NIR-ICG appearances.Patients with colorectal tumors were administered ICG intravenously at a dose of 0.25\u00a0mg/kg intraprocedurally. The endoscopic NIR system was used to directly visualise rectal tumours continuously transanally for up to 20 subsequent minutes and enabled a video recording to be made of endoscopic white light and NIR appearances simultaneously. Ex vivo resection specimens from a separate cohort also receiving the same dose of ICG systemically were opened and their mucosal surfaces examined post-operatively with the same camera for still image analysis. In addition, to examine for photobleaching effects in tissue, two opened specimens were examined continuously postoperatively for 20\u00a0min at the site of neoplasia and the recording analysed similarly to the in situ rectal recordings (see below).The videos along with similar high-resolution photographs of the opened mucosal surface of any resected specimens ex vivo underwent post-hoc fluorescence intensity (FI) analysis. All imagery contained both the neoplastic lesion and some adjacent normal tissue. Patient demographics and reactions possibly related to ICG usage were recorded prospectively along with the routine pre and postoperative pathological and radiological reports to capture cancer-relevant details.13 after annotation of regions of interest (ROI) on the endomucosal surface regions representing the tumour and adjacent normal tissue (control) avoiding obvious areas of surface blood by a surgeon. Spot mean FI in 25\u2009\u00d7\u200925 pixel areas in the tumour were contrasted with normal mucosa \u00ae, Galway, Ireland . This allowed in-app surgeon-ROI-annotation for tumour and control areas from the white-light (RGB) images prior to the onset of non-zero fluorescence intensities in the NIR images with automatic detection and frame-by-frame tracking of surface feature points in the white light images  to account for the changing pixel locations of these areas due to camera movement. By continuously tracking in the white-light image, the app maps FI in the corresponding pixels of the complimentary NIR image for the ROIs throughout the video duration. Also, following surgeon annotation of tumour versus control ROI, the software can group the dynamic intensity results using K-Nearest Neighbour (KNN) algorithm , a surgeon again postoperatively annotated ROIs as above also avoiding those areas only variably seen over time in the movies. Post-hoc kinetic plotting of FI dynamic patterns of in situ lesions over time, was initially performed using Image-J on grayscale still image stacks serially sampled at one frame per second (fps) from the time of fluorescence signal onset to video end. Thereafter fluorescence measurement was digitalized and automated through the creation of a bespoke, standalone Fluorescence Tracker App (FTA), developed in collaboration with MathWorkssee Fig.\u00a0. For aut17. An intensity rise of 5 grey units was marked as the end of the latency period and the starting block for the incline. Following the rapid inflow period, the point of maximum fluorescence intensity (Fmax), time to achieve this summit (Tmax) and respective gradient (Fmax/Tmax) were calculated along with the time taken (T\u00bdmax) to achieve half the maximum (F\u00bdmax) intensity. Following peak intensity, fluorescence clearance from the target tissue was flagged at 100\u00a0s (T100) from the start of the descent  and SPSS Software  version 26 with statistical significance ascribed to p-values less than 0.05. Spot ex vivo FI measurements and dynamic mean values were compared from tumours versus control tissue using Mann\u2013Whitney U. FI signals from in vivo videos were plotted against time and examined for distinctions regarding specific curve milestones and variables adapted from previously described methodologiesIn total, thirty-two patients were recruited into the study (see Table With respect to spot ex vivo intensity measurement (n\u2009=\u200910) late after ICG administration, mean (\u00b1\u2009standard deviation) cancer intensity was non-significantly raised 57.0\u2009\u00b1\u200961.3) compared with control (36.0\u2009\u00b1\u200928.3) (Mann\u2013Whitney U) with considerable overlap of scores suggesting poor discrimination of cancer by single point in time analysis even some hours after ICG administration , were analysed manually by Image J (1 fps) and both these and the next twelve were analysed using the automated FTA. Both manual Image J analysis n\u2009=\u20098) and automated FTA analysis (n\u2009=\u200920) of lesions in situ being dynamically profiled displayed potentially discriminative statistical differences between cancers and benign tumours from their FI temporal signature kinematics. Figure\u00a0 and automax comparisons showed that the cancer intensity curve zenith (Fmax 202\u2009\u00b1\u200935.68) was significantly higher than for both the benign tumours  and control tissue  (Mann\u2013Whitney U). With respect to the FTA graphs, three-way analysis using Kruskal\u2013Wallis comparison of cancer, benign and control regions showed significant differences in upslope (gradient from baseline to Fmax p\u2009=\u20090.039) and for both the downslope and fall between Fmax and T100 (p\u2009=\u20090.046 for each). Direct comparison with Mann\u2013Whitney U between cancers and control regions showed that cancers peaked significantly later, took significantly longer to rise from baseline to maximum and exhibited a shallower gradient to the peak. This resulted in a significantly later T100. Skew for cancers was further to the right (\u2212\u00a01.69\u2009\u00b1\u20091.17 vs \u2212\u00a00.41\u2009\u00b1\u20091.37 p\u2009=\u20090.04). In comparing cancers with benign lesions, there were also significant differences by T100 in terms of both fall and downward gradient. There was no statistically significant difference in these measures between all lesions together and benign lesions alone compared with the controls.Tables time to rise\u2019 demonstrated on neoplastic tissue (p\u2009=\u20090.041) versus control when these were manually grouped.Within the group analysed by FTA, six cancer cases underwent application of the KNN classification algorithm. With surgeon ROI (lesion and control) selection, the algorithm was able to cluster the data into two groups segregating cancer from normal tissue automatically, in a fashion not significantly different to the manually segregated data (Wilcoxon signed rank resting). However, the automated classification was unable to reproduce the significantly raised \u20183. Notably, it is already impacting decision-making and step-sequencing in reconstructive surgery both of the gastrointestinal tract18 and other tissues19. As well as a means to demarcate watersheds between perfused and non-perfused intestine, other uses include critical boundary identifications such as ureters21 and fascial planes22 by direct instillation. For cancer and draining lymph node identification, ICG has been placed peritumorally submucosally by endoscopic tattoo25. In situ revelation of cancer including tumour margination however requires labelling pathology rather than physiology. While cancerous tissue can retain fluorescent agents, there remains a significant issue with false positive findings27. Because of this lack of sensitivity, most research groups are now focusing on development of new cancer-selective agents although accuracy remains problematic30. Given that cancers likely act to accumulate agents in their vicinity differently to other areas that trap agents more passively, we thought to observe dynamically the processing of ICG by tumours under continuous direct observation different to others who have focused on single point in time observations.Fluorescence-guided surgery is proposed as the next progressive iteration in cancer surgery, especially endo-laparoscopic operations31 but one that seems less relevant in vivo due perhaps to protective effect of tissue and dynamic turnover of dye in the ROI in situ). This desktop post-hoc based assessment of the curve metadata has demonstrated possible discriminative flow milestones and timepoints related to the early phase behaviour of the dye in the peritumoral environment that preludes late stage appearances. While additional distinguishing parameters may also exist and could be identifiable via longer videos enabling analysis of dye processing and efflux patterns and/or by using more sophisticated analytical methods, this initial work is encouraging .In this experience, digital FI quantitative assessment of tumour perfusion angiograms has been demonstrated, controlling too for potential impact due to photobleaching . Such a distinct FI signature could be visually noticed in both grey-scale, composite and threshold modes and could be quantified with post-hoc image data analysis. Manual intensity quantification allowed mathematical comparisons of the FI time patterns although such data generation was labour-intensive while episodic sampling (even at 1fps) made smoothing of data difficult and background noise impaired statistical analysis. Automating feature detection, tracking and quantification enabled higher sampling rates (30fps) and so provided richer data for analysis with processing time being a function of computational ability rather than human labour.32. In lesions where biopsy is still indicated, the fluorescent signal profile could indicate the site of most relevant yield re cancer detection. With regard to visible lesions, the key issue to discriminate is cancer versus not cancer and so benign tumor behaviour being similar to normal tissue fits the clinical paradigm re lesion management.While further work needs to be done these findings are of great potential clinical relevance. The ability to optically characterize neoplasia through its biological hallmark behaviours could help optimize clinical diagnostic pathways by immediately indicating the nature of lesion and facilitate, in cases of benign aetiology, immediate local excision (or conversely caution such an approach in lesions with benign appearances but containing an invasive focus). Avoidance of biopsy is increasingly advocated in these cases as such an act can introduce architectural distortion in the samples and induce fibrosis in the residual lesion 33. Detailed region by region biopsy collated to continuous FI perfusion criteria may too yield digital tumour margin delineation and heterogeneity appreciation. Greater patient numbers is of course needed too and, with early proof of principle now provided, a larger clinical study is now ongoing to develop and validate these findings 32 while AI methods are also being developed to enable real-time deployment34.To be maximally useful however this work of course necessitates future effort translating our dataset into a classifier which would allow validation against a gold standard such as histopathology. In this regard, KNN clustering showed encouraging discriminative abilities and which may be refined with further artificial intelligence methodologies37. As ICG can be seen in this experience to passively concentrate in tumours, it seems likely that so too will, at least in part, a \u201ccancer-specific\u201d agent. Such internalisation mechanisms could prove advantageous in performance over cell-surface or ligand-specific agents which could be limited in applicability due to variance in intra and inter-tumour target expression. It is likely also that the ICG uptake mechanisms through cancer pathophysiology seen here are shared across other common cancers and could extend to sites of regional spread and metastatic disease.Cell-specific targeting remains of great interest for future advances in this area but a deep understanding of tumoural functional characteristics is necessary to best inform the purpose and level of probe engineering needed. ICG accumulates quickly and can be effectively imaged with a variety of commercial cameras and so there is much to be learned from this study for new agent development. Its non-specific tumour uptake mechanisms include enhanced permeability and retention (EPR), aberrant gap junctions and dysregulated pinocytosis38 or injury will equally be prone to incidental, unintended probe accumulation. This indicates that a relatively high rate of false positive findings may continue despite any additional tumour targeting features. Rigorous preclinical and clinical study controls are required to minimize heuristic mechanistic targeting assumptions. While long-in-advance (24\u201348\u00a0h) administration of the fluorophore has been proposed to offset non-cancer signalling , a significant downside exists with respect to the unpredictability of operative timing and patient-to-patient pharmacokinetic variances.While cancer cell selectivity can be engineered in cell culture, tumour imaging in vivo encompasses a variety of host:cancer interactions as well as additional cell signalling and response pathways. Furthermore, additional unrelated sites of inflammation39.An inbuilt synchronous and continuous dynamic quantification algorithm and screen display can be of use to all fluorescence imaging agents and could even enable synchronous use of multiple probes of different wavelength colours. Addition of cancer-specific targeting could still accelerate agent accumulation at the ROI following systemic distribution, enabling short-window observations with the greatest sensitivity and specificity possible within minutes. This would be of use for the operator more akin to episodic perfusion assessment with the added biochemical, biological and imaging complexity hidden. \u201cOff\u2013on\u201d fluorogenic compounds are especially attractive for this purpose as their signalling only switches on when they arrive at the appropriate microenvironment40. Furthermore, while other surgical camera manufacturers offer similar systems for ICG visualization by NIR, camera design and performance investigation has shown previously significant inter-manufacturer variation between signal and ICG concentration (including the tendency of some systems to boost the images for human interpretation) which limits the generalizability of these findings until further (ongoing) validation is performed41. While selection of the specific timepoints for analysis (e.g. 100\u00a0s post-peak timepoint) is somewhat arbitrary, they do provide milestones for statistical analysis enabling comparisons between lesions and adjacent healthy tissue as control. Statistical curve analysis is currently not calculated in real time and is limited to one curve per ROI. Simultaneous synthesis and dissection of multiple curves may further discern tumour heterogeneity. Although the automatic classifier diminished the differentiation ability of our metrics when compared to surgeon-based classification, better classification algorithmic methods may to some extent replace operator input. Other tracking algorithms exist and further software development may address field of view interruptions.This study is of course limited by the small cohort studied although has the strength that patients were recruited into the study without arbitary preselection. Fluorescence data is also dependent on the recording of the detected fluorescence signal. Video stability, suctioning, instrumentation and tumour oozing/desloughing impaired continuous tracking and required further user interaction. The distance and angulation of the camera as well as the depth of ICG have been found to influence the signal and need consideration in further protocols42.This endeavour has nonetheless shown the feasibility of ICG with NIR-illumination for continuous quantitative FI assessment. Software assessment of these perfusion curves has yielded metadata which could potentially be used to identify cancer in human patients. The previous focus on spot readings may alleviate the need for concurrent injection and recording but has overlooked the potential for incorporating dynamic ICG flow patterns to improve confidence of interpretation. Equally incorporation of computer-assistance can help and even potentially replace the need for human observer visualization promising near real-time assessment of lesions during procedures with minimal user interaction as a \u2018digital biopsy\u2019 enabled through advances in computer processing, artificial intelligence and broad cloud-based datasets"}
+{"text": "Background: Activation of the mTOR signaling pathway is ubiquitous in cancers and a favourable therapeutic target. However, presently approved mTOR inhibitor monotherapies have modest benefits in labeled indications while poor outcomes have been reported for mTOR inhibitor monotherapy when administered in a label-agnostic setting based on univariate molecular indications. The present study aimed to determine whether patient-specific combination regimens with mTOR inhibitors and other anticancer agents selected based on multi-analyte molecular and functional tumor interrogation  yields significant treatment response and survival benefits in advanced or refractory solid organ cancers.Methods: We evaluated treatment outcomes in 49 patients diagnosed with unresectable or metastatic solid organ cancers, of whom 3 were therapy na\u00efve and 46 were pre-treated in whom the cancer had progressed on 2 or more prior systemic lines. All patients received mTOR inhibitor in combination with other targeted, endocrine or cytotoxic agents as guided by ETA. Patients were followed-up to determine Objective Response Rate (ORR), Progression Free Survival (PFS) and Overall Survival (OS).Results: The Objective Response Rate (ORR) was 57.1%, the disease Control rate (DCR) was 91.8%, median Progression Free Survival (mPFS) was 4.9 months and median Overall Survival (mOS) was 9.4 months. There were no Grade IV treatment related adverse events (AEs) or any treatment related deaths.Conclusion: Patient-specific combination regimens with mTOR inhibition and other anti-neoplastic agents, when selected based on multi-analyte molecular and functional profiling of the tumor can yield meaningful outcomes in advanced or refractory solid organ cancers.Trial Registration: Details of all trials are available at WHO-ICTRP: https://apps.who.int/trialsearch/. RESILIENT ID CTRI/2018/02/011808. ACTPRO ID CTRI/2018/05/014178. LIQUID IMPACT ID CTRI/2019/02/017548. Since at cancer . Likewist cancer  owing tot cancer .It is accepted that tandem therapeutic targeting of multiple signaling pathways can lead to improved outcomes in cancer . The mTOAlthough the potential benefits of Everolimus in combination with chemotherapy agents have been hypothesized in various cancers, the benefits of such regimens in a refractory setting has not yet been demonstrated. Further, selection of chemotherapy agents for such combination regimens have been largely derived from Randomized Clinical Trials (RCT) or Standard of Care (SoC) guidelines rather than via patient-specific evaluation of drug resistance or sensitivity in respective tumors. The benefits of the latter approach lie not only in identifying relevant drugs with higher antitumor activity  but alsode novo combination treatment regimens has been previously demonstrated  for identifying vulnerabilities in advanced refractory cancers (ARC) and their targeting with personalized nstrated . Here, wThis manuscript reports data from a subset of patients from three prospective interventional phase II/III trials, including RESILIENT (CTRI/2018/02/011808), ACTPRO (CTRI/2018/05/014178) and LIQUID IMPACT (CTRI/2019/02/017548) who received mTOR inhibitor-based treatments. The primary outcome data for the RESILIENT Trial has already been published . The outBetween Jan 2018 and Jun 2019, 37 patients with advanced solid organ cancers received treatments with mTOR inhibitors in combination with other systemic anticancer agents as part of various prospective interventional clinical trials conducted by the study sponsor. All study participants were previously counseled regarding study objectives, potential benefits and potential risks and provided signed written informed consent for participation in the trial and for publication of deidentified data. Between Jan 2018 and Dec 2018, 12 patients underwent ETA as a commercial service to inform precision systemic therapy options for advanced broadly refractory solid organ tumors and received treatments with mTOR inhibitors in combination with other systemic anticancer agents. Treatment outcomes were available in these patients and were hence considered for analysis. All patients consented for analysis and publication of deidentified data. Outcome data for these patients are reported.in vitro chemoresponse profiling (CRP) of viable tumor tissue derived cells (TDCs) or Circulating Tumor Associated Cells (CTACs) from peripheral blood. Both cytotoxic anticancer agents as well as mTOR inhibitors were evaluated by CRP where viable TDCs/CTACs were treated in vitro with standardized concentrations of anti tumor agents and the proportion of cell death was measured. Next Generation Sequencing (NGS) analysis of tumor tissue DNA or peripheral blood circulating tumor DNA (ctDNA) using a targeted gene panel (452 or 411 genes) was performed to identify molecular alterations in the mTOR pathway genes that are known to be indicative for selection of mTOR inhibitor as well as molecular alterations to select appropriate targeted and endocrine agents. Finally, Immunohistochemistry (IHC) profiling of tumor tissue was used to determine expression of Estrogen Receptor (ER) and Androgen Receptor (AR) for selection of Endocrine agents. ETA findings were integrated to generate patient specific treatment recommendations which were shared with the treating oncologist.The process of ETA and generation of patient specific therapy recommendations have been described previously  and is aAll patients received individualized combination regimens with mTOR inhibitors and other targeted, endocrine or cytotoxic drugs which were informed by ETA findings. Among 39 patients where the combination regimen included \u22651 cytotoxic agents, the choice of single or multiple cytotoxic agents was based on reported safety information (AE profiles) of each individual cytotoxic agent (labeled toxicity), as well as phase I trial data of safety and toxicity of combinations. This safety information was used to anticipate/predict patient-wize expected AEs which was referred to while determining the appropriate starting dose as well as dose escalation in each patient. In all patients, the treatment agents were initially administered at lower (\u226450%) doses, and were escalated based on an individualized dose escalation schedule. Other factors which guided patient-specific dosage and schedule included institutional guidelines and protocols as well as clinical assessment of the patients\u2019 health. As per the treatment plan in the trials, patients were to be administered treatments until progression or death or dose limiting toxicity. Patients who showed durable response were maintained with suitable dose reduction as decided by the treating clinician. For non-trial patients, schedule and duration were determined by the treating clinician based on clinical assessment of patients\u2019 health.Treatment response was assessed in all patients based on a baseline and follow-up radiological imaging (CT/PET-CT) as per RECIST 1.1 criteria  to deterPatients were followed up until study termination or patient exclusion  or until December 2020, to determine Progression Free Survival (PFS) as well as Overall Survival (OS). Post completion of study, patients were followed-up every 6 months for OS only. Patients who were not part of the clinical trials underwent follow-up imaging scans at intervals specified by the treating clinicians.Treatment related AEs were prospectively obtained for trial patients during the trial. Treatment-related AEs for non-trial patients were obtained from patients\u2019 clinical records which were provided by the treating clinician. All AEs were graded according to NCI-CTCAE v5  and repoThe present manuscript reports outcomes in 49 patients  who received mTOR inhibitor-based treatment regimens informed by ETA . This con = 20), cytotoxic and other targeted/endocrine agents (n = 19), or \u22651 targeted or endocrine agents (n = 10). In this cohort, seven patients were AR+, three patients were ER+ and two patients were AR+, ER + by IHC. All anticancer drugs in the combination treatments were approved by the United States FDA for use as antineoplastic agents. Selection of all treatment agents (including mTOR inhibitors) was agnostic to the respective labeled indications. Patient-wize drugs and regimens are provided in All patients were administered mTOR inhibitors as part of multi-drug regimens where the combinations included either \u22651 cytotoxic agent  showed Complete Response (CR), 27 (55.1%) showed Partial Response (PR), 17 (34.7%) showed SD and 4 (8.1%) patients showed PD. The Objective Response Rate (ORR) in this sub-cohort was 57.1% and disease Control Rate (DCR) was 91.8%. Patient outcomes are summarized in Among 20 patients who received mTOR inhibitors in combination with cytotoxic agents (mTOR_C), PR was observed in 10 patients (50%). Among 29 patients, the combination regimen included an additional targeted or endocrine agent  for tandem blockade of other signaling pathways; 18 of these patients (62.1%) showed PR. Within these 29 patients, PR was observed in 6/10 (60%) patients where AR/ER was targeted in tandem with mTOR, 5/9 (55.5%) patients where the VEGF signaling pathway was a tandem target and in 6/9 (66.7%) patients where the EGFR/ERBB2 pathway was targeted along with mTOR.n = 49) reported median PFS (mPFS) and median OS (mOS) of 4.9\u00a0months (95% CI: 3.6\u20136.2) and 9.4\u00a0months (95% CI: 6.6\u201312.2) respectively. The PFS rate and OS rate at 12 and 24\u00a0months were \u223c60 and \u223c35% respectively. The mPFS, PFS rates, mOS and OS rates in the various regimen subtypes are summarized in The study patients (The molecular landscape of mTOR pathway associated genes in the study cohort as determined by NGS is depicted in There were no grade IV treatment related Adverse Events (AEs) or any treatment related deaths. Grade III treatment related AEs were seen in 34 patients. The most common grade III treatment related AEs were Fatigue (27%), Anorexia (11%) and Oral Mucositis (8%) which were managed by administration of standard treatment modalities Hyperglycemia which has been previously reported in mTOR regimens was observed in one patient. Patient-wize AEs are provided in The study outcomes support the hypotheses of the study that ETA-guided combination regimens of mTOR inhibitors with other anti-neoplastic agents can achieve meaningful response in advanced refractory cancers especially when such combinations include other targeted/endocrine agents for tandem blockade of other tumor-associated signaling pathways. While PFS rates were higher in combination regimens that included another targeted agent , the OS rates were similar across all therapy regimen subtypes indicating that mTOR inhibitors in combination regimens offer OS benefits while tandem targeting of additional tumor pathways yields PFS benefits as well apart from to OS benefits. It is generally accepted that subsequent lines of anticancer treatments are associated with decreasing probability of success. However. among patients who received ETA-guided combination regimens, there was an almost doubling of the PFS (PFS2:PFS1 ratio) indicating significant therapeutic benefit to patients. The authors acknowledge that the instances of censored PFS may underrepresent the actual extent of benefit. However, the recorded data indicate a significant median advantage despite censored observations; since therapy was ongoing in several patients, eventual improvements to these ratios are anticipated. We hence conclude that ETA guided combination regimens can provide significant PFS improvements even in heavily pre-treated populations. The response and survival benefits indicate the ability of ETA guided combination treatments to exploit known targetable vulnerabilities as well as to overcome known resistance variants. The present outcomes are remarkable in context of the PFS and ORR reported for the mTOR arm in the SHIVA trial , as welln = 24, 48.9%), loss of PTEN gene function via SNV or CNA . Deleterious SNV/CNA in multiple mTOR pathway genes were also observed in some patients . The present study does not aim to establish the predictive efficacy of these mTOR pathway variations for mTOR inhibitor selection or treatment response; the profile of (detected and undetectable) molecular variants in the known mTOR pathway genes suggests the role of additional hitherto unidentified genes and gene-variants linked to resistance or response toward mTOR inhibitors. Molecular alterations (SNV and CNV) of unknown significance in mTOR pathway genes were detected in 9 cases. These variations are speculated to be probable indications, which may be confirmed based on future insight into the phenotypic consequence (gain/loss of function) of these variations.Presently, apart from Alpelisib, selection of other mTOR inhibitors is not based on molecular indications. Prior attempts to match variations in mTOR pathway genes with label-agnostic mTOR blockade  have reported largely discouraging outcomes. Several variations are associated with mTOR activation such as alterations in the AKT (1/2/3), PIK3CA and PTEN genes besides the mTOR gene itself . Among tin vitro CRP of cell lines or primary tumor cellsy  with in vitro and largely in vivo response to mTOR inhibition, but where the tumor harbored no known alterations indicative of mTOR activation.Prior attempts to identify potentially synergistic and safe anticancer drug combinations  as well r cellsy  reflect de novo drug combinations. The safety profile of multi-drug anticancer regimens especially those with combinations of targeted and cytotoxic agents has been discussed at length in prior meta analyses (de novo (targeted and cytotoxic) drug combinations in most patients with manageable profiles of adverse events (AEs). It is generally agreed that although the actual profile of Adverse Events (AEs) in any given patient cannot be accurately predicted, the commonly occurring AEs associated with each drug or combinations can be anticipated. The profile of AEs shows that even though this heavily pretreated cohort was at an inherently higher risk of AEs due to cumulative toxicities from prior treatments, ETA guided therapies were generally well tolerated with a manageable toxicity profile  heavily pretreated cohort of patients with acceptable toxicity profile.We demonstrate that patient-specific combination regimens which achieve mTOR blockade and tandem targeting of other tumor vulnerabilities not only lead to favourable outcomes in advanced refractory cancers but also had manageable toxicity profiles. While prior attempts to expand the scope of mTOR inhibitor monotherapy in an organ agnostic setting based on univariate molecular profiling have been largely successful, we show that personalized combination regimens based on multi-analyte tumor profiling can yield significant and meaningful treatment benefits in various solid organ cancers. This is a viable pan-cancer treatment strategy since it overcomes the limited efficacy of mTOR inhibitors as well as the drug-resistance associated with activation of mTOR."}
+{"text": "Scientific reports 10.1038/s41598-021-97868-2, published online 15 September 2021Correction to: The original version of this Article erroneously included preview URL in Data availability section.http://proteomecentral.proteomexchange.org) via the jPOST partner repository (https://jpostdb.org) with the data set identifier PXD021851 . The other datasets generated during or analyzed during this study are available from the corresponding author on reasonable request.\"\"The MS raw data and analysis files have been deposited in the ProteomeXchange Consortium  via the jPOST partner repository (https://jpostdb.org) with the data set identifier PXD021851. The other datasets generated during or analyzed during this study are available from the corresponding author on reasonable request.\"\"The MS raw data and analysis files have been deposited in the ProteomeXchange Consortium (The original Article has been corrected."}
+{"text": "Repetitive transcranial magnetic stimulation (rTMS) is a promising approach for post-stroke rehabilitation but there lacks a rationale strategy to plan, execute, and monitor treatment. We present a case of targeted rTMS using the Omniscient Infinitome software to devise targets for treatment in a post-stroke patient and describe the functional connectomic changes after treatment. A 19-year-old female with no medical history presented 19 months after suffering a left middle cerebral artery (MCA) superior division ischemic stroke, resulting in language impairment and diminished right upper extremity motor function.\u00a0She underwent a resting-state MRI (rsMRI) with tractography and images were processed using the Omniscient Infinitome software. Analysis using the anomaly detection within the software enabled us to identify three targets for rTMS . These areas were treated with 25 sessions of intermittent Theta Burst Stimulation (iTBS) over five days at 80% of motor threshold concomitantly with targeted physical therapy and speech therapy. At five months follow-up, her language and right upper extremity functions significantly improved. Her connectomic analysis revealed substantial neural changes, including normalization of the sensorimotor network, substantially thicker callosal fiber bundle connecting the two hemispheres, and increased cortical recruitment in her language network.\u00a0We present the first description of robust connectomic alterations in a post-stroke patient following targeted rTMS treatment. Further studies on the use of rTMS with an emphasis on functional connectomics are warranted. Ischemic strokes are a leading cause of disability in the world . The socRepetitive transcranial magnetic stimulation (rTMS) has been investigated as a treatment adjunct to hasten neurorehabilition ,4. It isWe report a case of rTMS used for post-stroke neurorehabilitation in a young female in conjunction with a novel, cloud-based software (Omniscient Infinitome) that provides detailed network maps of her functional connectomes. We demonstrate the utility of this software in selecting rationale rTMS targets and demonstrating changes in fiber tracts after intervention.The patient was a 19-year-old right-handed female without any past medical history who suffered an ischemic stroke, resulting in extensive cystic encephalomalacia and gliosis in the territory of the cortical branches of the superior division of the left middle cerebral artery (MCA)  chosen as targets in the same fashion using the abnormality detector with the goal to further improve her right upper extremity dexterity (functional outcome in Figure Repetitive TMS has shown promise in improving functional outcomes in patients struggling to recover from ischemic strokes over conventional therapy alone . In the Neuroplasticity associated with the recovery and associated changes in tractography have been previously demonstrated in post-stroke patients . Tract iOutside of the confines of a single case report, we acknowledge the fact that this patient had several advantages that may have positively influenced her outcome. Aside from her young age and presumably more robust neuroplasticity, her relative independence allowed her to participate in therapy . FurtherWe report a case of robust connectomic alterations in a chronic post-stroke patient following rTMS treatment. It suggests that individualised iTBS treatment guided by anomaly detection algorithms could be a successful modality to improve speech and motor outcomes long-term, even in stroke patients who have seen no improvement in their condition for over a year.\u00a0Further studies on the use of rTMS with an emphasis on functional connectomics are warranted."}
+{"text": "Angiographically confirmed complete surgical excision of brain arteriovenous malformations (bAVMs) is conventionally considered curative. Recurrence in adults is rarely encountered; only 18 cases have been reported in the English literature over the past 30 years. The potential for recurrence and consequent need for routine long-term follow-up are important considerations in the management of these lesions. We report\u00a0a case of a 23-year-old female with a recurrent bAVM discovered incidentally on routine imaging three years after complete surgical excision. We review the existing literature and discuss the options for surveillance and management. Brain arteriovenous malformations (bAVMs) are congenital anomalies of dysplastic blood vessels with direct connections between arteries and veins without intervening capillaries which form a tangle of abnormal dilated channels called a nidus. Most of these lesions are discovered incidentally during imaging for other indications; symptomatic bAVMs most commonly present with haemorrhage and seizures\u00a0-3. bAVM A 23-year-old right-handed lady with no medical history presented in April 2017 to a district general hospital with acute onset left brachiofacial hemiparesis. A computed tomography (CT) scan of the brain showed a right frontal intraparenchymal haematoma Figure  and CT aShe was taken to theatre emergently for decompressive craniectomy, evacuation of the haematoma and excision of the bAVM. Intra-operative indocyanine green (ICG) angiography revealed two main arterial feeders on the cortical surface and one main draining vein to the superior sagittal sinus. The bAVM was excised en-bloc and post-excision ICG showed no remnant which was confirmed on immediate post-operative DSA Figure .She was transferred to our rehabilitation centre 19 days after surgery. While undergoing rehabilitation she had a generalised seizure attributed to scar epilepsy which was controlled with levetiracetam. She recovered well; her Functional Independence Measure (FIM) score improved from 28 to 108, and she had a cranioplasty implant four months later. She remained clinically well on six-monthly follow-up apart from another seizure in June 2018. A non-enhanced CT showed no haemorrhage and she had no further seizures after the dose of levetiracetam was increased. A routine CTA in August 2020 showed partial recanalization of the same bAVM nidus, now supplied via tiny right middle cerebral artery (MCA)  cortical branch(es) with venous drainage towards the superior sagittal sinus Figure .In light of her age and good functional status, repeat surgical resection was recommended although the option of stereotactic radiosurgery was also offered. After consulting with a radiosurgeon, she decided to proceed with surgical resection. A stereotactic CTA repeated in February 2021 showed stable size of the bAVM. She underwent resection of the recurrent AVM in March 2021 with stereotactic navigation via CTA. Intra-operatively, small cortical feeders were seen which were taken circumferentially; no large draining vein was identified. Post-operative day 1 CTA showed no remnant bAVM Figure . She hadbAVM recurrence in adults after angiographically demonstrated complete excision is a rare phenomenon. Only sporadic case reports/series exist; just 18 cases have been reported in the English literature over the last 30 years  have been found in adult samples , and higThere is little evidence to guide the duration, schedule and modality of follow-up imaging in adult patients after complete surgical resection; there is no consensus even in the paediatric literature ,31. BaseThe appropriate treatment strategy is similarly poorly established, and the risk of re-rupture of these recurrent bAVMs is unknown. Just over half the adult recurrences were treated by surgical excision, stereotactic radiosurgery (SRS) was the next most common option. A systematic review in 2018 that included paediatric cases found that surgery (59%) and SRS (37%) were the most common methods of treatment  and a rebAVM recurrence in adults after complete surgical resection is a rare but potentially important phenomenon. Routine follow-up imaging over an extended duration may be warranted, especially in cases with one or more risk factors for recurrence. New or progressive clinical manifestations should similarly trigger vascular imaging. Non-invasive imaging modalities may be a viable alternative to DSA for surveillance. Repeat surgical excision and SRS were the most common methods of treatment."}
+{"text": "METHODS/STUDY POPULATION: Lysates were prepared from BAL cells isolated from horses with no, mild/moderate and severe EAS. Relative MARCKS protein levels were determined using equine specific MARCKS ELISA (MyBioSource). Cultured BAL cells were pretreated with a MARCKS inhibitor peptide (MANS), control peptide (RNS) or vehicle control and stimulated with zymosan for 5 hours. Reactive oxygen species levels were determined by luminescence to evaluate respiratory burst. Data were analyzed by One-way ANOVA (p<0.05). RESULTS/ANTICIPATED RESULTS: We determined that normalized MARCKS protein expression is significantly increased in BAL cell lysates from horses with mild/moderate or severe EAS, compared to horses with normal BAL cytology. Preliminary findings also suggest that MANS treatment of zymosan-stimulated equine BAL cells ex vivo attenuates levels respiratory burst. DISCUSSION/SIGNIFICANCE OF IMPACT: These findings point to a possible role for MARCKS protein in the pathophysiology of EAS and support MARCKS inhibition as a potential therapeutic strategy.OBJECTIVES/GOALS: Asthma is a significant health concern that affects people of all ages worldwide. EAS demonstrates many of the pathophysiological characteristics of nonatopic human asthma, which has led EAS to be used as naturally occurring model. Previous work from our lab determined that MARCKS (Myristoylated Alanine Rich C Kinase Substrate) protein is an essential regulator of cellular inflammatory functions. In the current study, we hypothesized that MARCKS levels would be increased in BAL cell lysates from horses with EAS, and that inhibition of MARCKS in zymosan-stimulated BAL cells ("}
+{"text": "We demonstrate a 31% reduction in the RMS error for the predicted 17O Cq values relative to standard plane-wave methods using a carefully constructed test set comprised of 22 oxygen-containing molecular crystals. We show comparable improvements in accuracy using five different hybrid density functionals and find predicted Cq values to be relatively insensitive to the choice of basis set used in the single molecule calculation. Finally, the utility of high-accuracy 17O Cq predictions is demonstrated by examining the disordered 4-Nitrobenzaldehyde crystal structure.Modern approaches for calculating electric field gradient (EFF) tensors in molecular solids rely upon plane-wave calculations employing periodic boundary conditions (PBC). In practice, models employing PBCs are limited to generalized gradient approximation (GGA) density functionals. Hybrid density functionals applied in the context of gauge-including atomic orbital (GIAO) calculations have been shown to substantially improve the accuracy of predicted NMR parameters. Here we propose an efficient method that effectively combines the benefits of both periodic calculations and single-molecule techniques for predicting electric field gradient tensors in molecular solids. Periodic calculations using plane-wave basis sets were used to model the crystalline environment. We then introduce a molecular correction to the periodic result obtained from a single-molecule calculation performed with a hybrid density functional. Single-molecule calculations performed using hybrid density functionals were found to significantly improve the agreement of predicted  Solid-state nuclear magnetic resonance (SSNMR) spectroscopy has proven highly effective at characterizing molecular crystals. Advances in NMR hardware and the development of novel pulse sequences continue to improve the accuracy and availability of experimental data. However, mapping relationships between NMR observables and structural features remains a formidable challenge. SSNMR investigations are often coupled with X-ray diffraction and first-principals calculations to form the interdisciplinary field of NMR crystallography. The success of NMR crystallography has been greatly facilitated by the availability of accurate computational methods for predicting NMR parameters which typically employ density functional theory (DFT) .There are two broad classifications for DFT-based methods commonly applied to molecular crystals. First, the gauge-including projected augmented wave (GIPAW) method  employs 1H, 13C, 15N and 51V nuclei have shown fragment methods with hybrid density functionals improve the accuracy of predicted isotropic chemical shifts . Numerous studies have shown that using hybrid density functionals improves the accuracy of predicted NMR parameters . Previoul shifts . Fragmenl shifts  and pred for 14N .Recently, a novel approach involving GIPAW with a molecular correction (GIPAW + MC) was put forward for modeling the chemical shift tensor . This sc17O nucleus  to CS tensors has proven particularly effective in modeling NMR parameters for the quadrupolar  nucleus . Specifito GIPAW . Improvito GIPAW .17O environments. We demonstrate a 31% improvement in the accuracy of predicted Cq values relative to traditional plane-wave methods with a negligible increase in computational cost. These findings are particularly promising for NMR crystallography applications given the crucial role EFG tensor predictions have come to play in crystal structure refinement  series of basis sets. The performance of six commonly used density functionals are compared to demonstrate uniform improvement in accuracy through the application of a range of hybrid density functionals in the molecular calculation. We examine the relative improvement in EFG and CS tensor GIPAW calculations through the application of a molecular correction. Finally, GIPAW + MC EFG calculations are shown to accurately predict Cq values for the disordered oxygen atoms in the 4-Nitrobenzaldehyde crystal structure.In the following, benchmark data are employed to examine basis set convergence and the accuracy of the predicted V resulting from the charge distribution surrounding the nucleus.The EFG tensor is obtained from the second spatial derivative of the electrostatic potential V33|\u2265|V22|\u2265|V11|. The principal components of the EFG tensor are used to derive two NMR observables. First, the nuclear quadrupolar coupling constant Cq is obtained from V33 according to,e is the elementary charge, Q = \u221225.58\u00a0mb  is constructed from three separate calculations as follows,Minor structural changes can have a pronounced impact on both ly local , and theFirst, the EFG tensor is computed using a full plane-wave GIPAW calculation at the lower level of theory  to obtain Vmol terms rely on isolated gas-phase molecule calculations. Finally, the corrected EFG tensor is then subject to diagonalization to obtain the principal components which are used along with According to Cq values  chemical shielding calculations were performed using the optimized geometries. Calculations were performed using CASTEP  with ther nuclei . Full sp\u03c9B97XD (n (n = 1\u20134) basis sets were used to determine if the accuracy of predicted Cq values could be improved using basis sets optimized for predicting NMR parameters. The Dunning-type and pcs-n basis sets where obtained from the basis set exchange   .17O EFG tensor parameters with those obtained experimentally from NMR and NQR spectroscopy. We have selected the quadrupolar 17O nucleus for two reasons. First, 17O has tremendous biological and pharmaceutical importance. Second, previous GIPAW + MC studies involving the CS tensor showed the largest magnitude improvement in predicted isotropic shieldings for 17O relative to other second-row nuclei  and those obtained from the GIPAW + MC calculations. In most cases, the sign of Cq cannot be determined from the NMR experiment therefore we provide the magnitudes of the predicted Cq values and report the absolute error (in MHz) relative to experiment.We have selected 22 crystal structures with 46 unique Cq values obtained from GIPAW + MC calculations relative to traditional GIPAW. Specifically, introducing a molecular correction carried out at the PBE0/cc-pCVTZ level reduces the RMS error by 31% and reduced the maximum absolute error by 26%. The choice of density functional and basis set used in the preliminary analysis was motivated by previous studies . To ensure convergence extends to all principal components we examine the deviation in all three principal components obtained from PBE0/pcs-n EFG tensor predictions for n = 1\u20133 relative to pcs-4. V33| (red), |V22| (blue), and |V11| (green) relative to pcs-4 calculations applied to the benchmark set. The largest RMS deviations were observed for the largest EFG tensor component, V33, followed by V22, and V11 yields the smallest deviation. Together, \u03b6 basis sets. These findings are in agreement with previous work involving Dunning-type basis sets  uniformly improve the accuracy of predicted dictions . Extendidictions  yields tto TPSSh . Minor dto TPSSh .17O NMR parameters are highly sensitive to crystalline lattice effects  level and standard linear regression methods were used to map the predicted absolute shieldings to experiment. The details of the 17O regression models along with the experimental and calculated CS tensor data are provided in the supporting information.Based on the success in predicting 17O Cq values, isotropic shieldings (\u03c3iso) and the CSA tensor elements (\u03c3ii). The RMS error for the 17O isotropic chemical shift predictions is 11.53 and 9.35\u00a0ppm for GIPAW and GIPAW + MC, respectively. This corresponds to a 19% relative improvement for GIPAW + MC which is in agreement with previous work (17O CSA tensor elements by 4% (19.88\u00a0ppm for GIPAW compared to 18.99\u00a0ppm for GIPAW + MC). These results are influenced by the larger variation in experimental uncertainties for isotropic shifts and CSA tensor elements . However, the GIPAW Cq predictions in Cq predictions which bracket the experimental value. This results in a weighted average of the GIPAW + MC predicted Cq values which more closely matches experiment relative to either structure examined in isolation.The predicted Cq values, we have shown the molecular correction improves the accuracy of predicted 17O CSA tensor elements. Comparing the relative improvement obtained through introducing a molecular correction to both EFG and CS tensor predictions we find a larger improvement in the accuracy of predicted EFG tensors. Finally, we apply GIPAW + MC EFG tensor calculations to the disordered crystal structure of 4-Nitrobenzaldehyde and show the molecular correction improves resolution between the different crystal geometries present in the disordered crystal (In summary, the present work establishes the GIPAW + MC method as a simple yet powerful approach for improving the accuracy of traditional plane-wave EFG tensor calculations. Introducing a correction based on the EFG tensor computed on an isolated monomer using a hybrid density functional substantially improves the accuracy of GIPAW calculations. The molecular correction is relatively insensitive to the choice of basis set, ensuring the cost of the molecular correction is a small fraction of the corresponding GIPAW calculation. In addition to improving the accuracy of predicted  crystal ."}
+{"text": "Left ventricular (LV) thrombus is a complication of acute myocardial infarction and is associated with systemic thromboembolism. We describe a trans-aortic endoscopic approach to the removal of an LV thrombus in a patient undergoing concurrent coronary artery bypass grafting and aortic valve replacement.A 47\u00a0year old male presented following an embolic middle cerebral artery stroke and underwent transthoracic echocardiography demonstrating a mobile LV thrombus. Additional investigation revealed a moderately stenosed bicispid aortic valve, two vessel coronary artery disease and ischemic cardiomyopathy. The patient underwent early surgery to reduce the risk of further embolic episodes. A trans-aortic approach was utilized with videoscopy and single shafted instrumentation to aide in removal of the thrombus. The patient then underwent aortic valve replacement and coronary artery bypass grafting.We report an alternative technique for the removal of a left ventricular thrombus in a patient undergoing concurrent coronary and aortic valve surgery. The transaortic video-assisted approach provided excellent visualisation of the apex and near complete removal of the thrombus without damaging the surrounding trabeculae. The main benefit of this technique is sparing of LV tissue, thereby preserving left ventricular function. Left ventricular (LV) thrombus is a complication of acute myocardial infarction (MI) and is associated with systemic thromboembolism , 2. It oWe describe a patient with severe two vessel disease, ischemic cardiomyopathy and moderate bicuspid aortic stenosis diagnosed after an admission with a left middle cerebral artery (MCA) stroke. Transthoracic echocardiography demonstrated a mobile thrombus. Given the high risk of further embolic sequalae, the patient underwent surgical removal at the time of aortic valve replacement and coronary artery bypass grafting to reduce the patients risk of further stroke.A 47-year-old male presented following acute onset right upper limb weakness and expressive dysphasia. The past medical history included well controlled epilepsy and hypertension. There was no history of diabetes mellitus, hypertension or previous smoking. Urgent CT angiography of the head and neck demonstrated a distal left MCA embolic stroke. Transthoracic echocardiography demonstrated left ventricular dilatation with severe systolic dysfunction (left ventricular ejection fraction [LVEF] 25%). Mobile thrombus was noted at the apex of the left ventricle, measuring 14\u2009\u00d7\u200912\u00a0mm , demonstrated the frontal lobe infarct with no evidence of further haemorrhagic transformation. Apixaban was discontinued and the patient commenced on intravenous heparin in preparation for surgery.The patient underwent surgery via median sternotomy and the left internal mammary artery (LIMA) was harvested as an in-situ pedicle graft. The left radial was harvested as a free graft. Systemic heparinisation commenced and cardiopulmonary bypass was instituted with bi-caval and distal ascending aortic cannulation. The left ventricle was vented via the right superior pulmonary vein. The aorta was cross clamped and the heart arrested via anterograde and retrograde cold blood cardioplegia. This was repeated at regular intervals to provide myocardial protection.Intra operative transesophageal echocardiography confirmed a bicuspid aortic valve with moderate aortic stenosis, severe left ventricular dysfunction and apical left ventricular thrombus with a mobile component Fig.\u00a0. The aorOn review six weeks following surgery there was no evidence of left ventricular thrombus. The aortic valve appeared well seated and there was mild paravalvular aortic regurgitation. There was no residual sequelae from his previous stroke.Left ventricular thrombus is a recognised complication following acute MI, and can occur as frequently as in 25% of patients following an anterior MI . TransthRemoval of these thrombi via a left ventriculotomy is feasible, however cases of this approach have been reserved for patients with a concurrent ventricular aneurysm requiring repair . The conCase studies report the use of videoscopy to visualise intra-cardiac structures and to assist in excision of left ventricular lesions as a viable alternative to a ventriculotomy. A systematic review by Soylu et al. summarises a total of 34 studies incorporating 54 patients where left ventricular cardiac tumours were removed with the use of videoscopic devices . The majWe report an alternative technique for the removal of a left ventricular thrombus in a patient undergoing concurrent coronary and aortic valve surgery. The transaortic video-assisted approach provided excellent visualisation of the apex and near complete removal of the thrombus without damaging the surrounding trabeculae. The main benefit of this technique is sparing of LV tissue, thereby preserving left ventricular function."}
+{"text": "A 54-year-old man presented with severe acute respiratory syndrome coronavirus-2 (SARS-COV-2) positivity after experiencing flu-like symptoms. His condition progressed to acute respiratory failure, and he was placed on mechanical ventilation. Chest computed tomography (CT) showed bilateral ground-glass opacities with mild reticulation A. The pa-Diffuse pulmonary ossification is a rare chronic process characterized by the formation of small mature bone fragments in the pulmonary parenchyma. It is classified as nodular or dendriform, with the former usually occurring in the context of chronic congestion. DPO is an interstitial process that occurs in the setting of fibrosing interstitial lung disease. It may evolve with osseous metaplasia, which is seen as nodular and branching calcifications in imaging studies. This pattern has been observed mainly in areas of reticulation rather than in honeycombingAnother condition recently related to DPO is cicatricial organizing pneumonia. This distinctive form of organizing pneumonia may manifest as persistent linear opacities that mimic fibrosing interstitial pneumonia. It may also be displayed as ossification foci in imaging and pathology studies"}
+{"text": "During aging, alterations of hematopoietic stem cells are associated with functional decline of the blood system. Caloric restriction (CR) interventions have been reported to improve adult stem cells in other tissue types during aging so we sought to evaluate the effects of CR on the aged HSC compartment. We find significant epigenetic alterations in HSCs isolated from aged mice after life-long CR compared to ad libitum fed aged mice. We further evaluated the epigenetic landscapes and functional potential of aged HSCs shortly after allowing life-long CR mice access to ad libitum food. We uncover epigenetic modification associated with functional alterations of the HSCs, defining potential mechanisms by which restrictions in food consumption affect the aging hematopoietic compartment."}
+{"text": "A 49-year-old woman presented to our dermatology department with a 1-year-long history of asymptomatic nail discoloration affecting the thumb of her right hand. She referred that she was treated with oral fluconazole by her general practitioner with no clinical improvement.Dermatological examination showed dark green discoloration of the nail plate . DermoscGreen nail syndrome is caused by the accumulation of pyocyanin that is produced by Pseudomonas aeruginosa bacterium . Althoug"}
+{"text": "It was declared a global pandemic by the World Health Organisation (WHO) on 11A Quality Management System (QMS) can be defined as a coordinated set of activities to direct and control an organisation regarding quality. A laboratory QMS is cardinal for achieving desirable laboratory performance and assurance of good laboratory results . ClinicaLaboratory mentorship has been known to be a pivotal factor to the successful implementation of laboratory QMS. In Zambia, this model has mainly been supported by external cooperating partners . HoweverMany countries depend on international trade for goods and services. The COVID-19 pandemic and the resulting global restrictions in air travel has negatively impacted the global supply chain . MedicalThe COVID-19 pandemic has greatly impacted health-care workers . Staff iThe COVID-19 pandemic has resulted in a global recession with a severe impact on the economy of Zambia including funding challenges to the health sector . Most la1) Increase local mentorship capabilities by training mentors drawn from accredited laboratories. Remote (offsite) mentorship using video conferencing tools such as Zoom, Microsoft Teams and similar applications should be explored. 2) Strengthen in-country training and certification of biomedical engineers to handle equipment maintenance and calibration needs of clinical laboratories. Traceability can be provided through training certification and externally calibrated reference equipment. 3) Laboratories should ensure the strict monitoring of reagent and consumable consumption data in order to have enough stock to sustain testing during unforeseen circumstances while procurement arrangements are being made. 4) In-country interlaboratory comparison should be encouraged through peer-to-peer assessments following the evaluation of possible referral laboratories. 5) Integrate COVID-19 testing in the QMS of laboratories to ensure quality. When changes in response to COVID-19 are planned and implemented, laboratories should ensure that the integrity of their QMS is maintained and that all applicable accreditation requirements are met. 6) Employment of medical laboratory personnel should be prioritised to meet the increased demand in testing. 7) There should be enough local funding for laboratory operations to cushion the impact of changing priorities by donors.The COVID-19 pandemic may affect QMS and ultimately healthcare in Zambia. There is need for targeted mitigation measures to ensure continual implementation of QMS and laboratory improvement."}
+{"text": "Anastomotic stenosis following esophagojejunostomy reconstruction by the overlap method with absorbable barbed sutures occurs only rarely in patients who have undergone laparoscopic surgery. We report anastomotic stenosis by the overlap method that we attributed to the lack of tactile sensation during robot-assisted surgery.An 83-year-old man underwent robot-assisted laparoscopic proximal gastrectomy and lymph node dissection at our hospital for treatment of gastric cancer. Double tract reconstruction followed with side-to-side esophagojejunostomy (overlap method) performed with an endoscopic linear stapler. On completion of the anastomosis, the enterotomy was closed under robotic assistance with absorbable barbed suture. Once solid foods were introduced, the patient had difficulty swallowing and felt as though his digestive tract was stopped up. When upper gastrointestinal endoscopy was performed, we found the anastomotic lumen to be coated with food residue. After rinsing off the residue with water, we could see barbed suture protruding into the anastomotic lumen that had become entangled upon itself, which explained how the food residue had accumulated. We cut the entangled suture under endoscopic visualization using a loop cutter.This case highlights a stricture caused by insufficiently tensioning barbed suture, which subsequently protruded into the anastomotic lumen and became entangled upon itself. We believe this occurrence was associated with the lack of tactile sensation in robot-assisted surgery. Esophagojejunostomy reconstruction by the overlap method is commonly performed in laparoscopic proximal or total gastrectomy, and enterotomy closure is often performed using absorbable barbed suture. Reported cases of stenosis are extremely rare \u20135. AbsorAn 83-year-old man underwent radical gastrectomy at our hospital for treatment of gastric cancer. Because the tumor was located just below the gastric cardia and clinical staged as cT2N0M0 and stage I according to the American Joint Committee on Cancer 8th edition, robot-assisted laparoscopic proximal gastrectomy and lymph node dissection were performed. Double-tract reconstruction followed, with side-to-side esophagojejunostomy (overlap method) performed with an endoscopic linear stapler . On compUnder endoscopic visualization, we cut the entangled suture using a loop cutter Fig.\u00a0. Over thAnastomotic stenosis following overlap reconstruction occurs only rarely in patients who have undergone laparoscopic surgery \u20135. The sRobot-assisted surgery has not only restored the surgeon\u2019s natural 3-dimensional vision but has also improved the surgeon\u2019s skills by allowing fluid movements while eliminating the inevitable tremors and shaking of the surgeon\u2019s hand and permitting increased reproducibility of movements , 8. AddiWe believe that this case should cause surgeons to realize the importance of overcoming the lack of tactile sensation, which is the present situation in robot-assisted surgery."}
+{"text": "A 60-year-old man with a background of resected clear cell renal cancer and resected colorectal adenocarcinoma presented with a pulmonary mass lesion in the left upper lobe which was avid on 18-F FDG PET/CT. Needle biopsy confirmed metastatic renal cell cancer, which was surgically excised with wedge resection. Follow-up imaging 6 months later demonstrated a second slowly enlarging subcentimeter nodule in the contralateral lung with increasing FDG avidity, suspicious of further small volume oligometastatic disease. Following surgical resection of the second pulmonary lesion, histopathological examination demonstrated nodular pulmonary amyloidosis and no evidence of malignancy. Amyloidosis encapsulates a group of diseases which involve the deposition of misfolded, insoluble, polymeric protein fibrils which ultimately result in damage to the surrounding tissue or organ. Solitary pulmonary amyloidomas are great mimickers of malignancy and should be considered in a patient with a pulmonary nodule even in the setting of metastatic disease. We present a case of a solitary pulmonary amyloidoma mimicking metastases in a patient with previous proven pulmonary metastatic disease from renal cell cancer.A 60-year-old man with history of left nephrectomy for clear cell renal cancer (stage I) and resected colorectal adenocarcinoma (stage II) presented with a pulmonary mass lesion in the left upper lobe on surveillance imaging. Transaxial CT B revealeHistopathology of CT-guided core needle biopsy showed tumour cells with relatively uniform nuclear and clear cell cytoplasm with positive staining for PAX8 and renal cell antigen, consistent with metastatic renal cell carcinoma. The patient underwent wedge resection of the left upper lobe metastasis with clear excisional margins.6 months later, follow-up imaging with 18-F FDG PET/CT and diagnostic CT was performed. Transaxial CT B demonstHistopathology of the second pulmonary nodule demonstrated no evidence of malignancy. Instead, there was amorphous hyaline acellular amyloid-like material associated with a rim of multinucleated inflammatory cells . The chrAmyloidosis encapsulates a group of diseases which involve the deposition of misfolded, rigid, polymeric protein fibrils which ultimately result in damage to the surrounding tissue or organ Although misfolded amyloid proteins are not metabolically active, plasma cells producing amyloid proteins and the resultant inflammatory response are metabolically active. This results in variable FDG avidity within the pulmonary nodule, acting as a mimicker of primary pulmonary malignancy Delineation between malignancy and amyloidosis with evaluation of morphological appearance and metabolic activity on imaging is often difficult. Dual phase FDG PET/CT has been described as a technique to delineate between malignancy and amyloidosis This case study demonstrates that localised nodular amyloidosis is uncommon but may act as a great mimicker of malignancy. Amyloidosis should be a consideration in patients with enlarging FDG avid pulmonary nodules even in the setting of previous pulmonary metastatic disease."}
+{"text": "Successful health outcomes in older patients are linked to the quality of the patient-provider relationship. Our study objective was to further understand the role of this relationship specific to pain management through perspectives from older adults and healthcare providers. Semi-structured interviews and focus groups were conducted with 9 older adults and 11 multidisciplinary healthcare providers. Transcripts were analyzed using a thematic analysis. Three main concepts emerged: (1) defining pain management goals \u2014 differences in providers and patients\u2019 goals for pain and function, with sub-themes of realistic goal setting and a shift in pain treatment to minimize opioids as a first-line medication; (2) communication \u2014 perceived gap in providers communicating and coordinating across disciplines and with patients, with sub-themes of improving positive communication and inconsistent messaging among providers; and (3) therapeutic alliance \u2014 all parties feel that developing a relationship is built on consistent trust and open dialogue. Although providers and older adults often expressed similar perspectives, there were several areas of misalignment identified within each concept, representing areas of disconnect within the patient-provider pain management relationship. Our findings indicate providers could benefit from education on improving communication around realistic goals and patient-centered outcomes and incorporation of more holistic pain management approaches when working with older adult patients. Further study should focus on developing educational interventions to address the identified shortcomings."}
+{"text": "We performed mesoscopic whole brain calcium imaging on awake animal to assess the MENs effects. Furthermore, we investigated the temporal profile of MENs in the vasculatures post-treatment and its toxicities to CNS. RESULTS/ANTICIPATED RESULTS: MENs were successfully localized to target cortical regions within 30 minutes of magnetic application. After wirelessly applying ~450 G magnetic field between 10-20 Hz, we observed a dramatic increase of calcium signals  both in vitro cultured neurons and in vivo treated animals. Whole brain imaging of awake mice showed a focal increase in calcium signals at the area where MENs localized and the signals spread to regions further away. We also found MENs stimulatory effects lasted up to 24 hours post treatment. MEN stimulation increases c-Fos expression but resulted in no inflammatory changes, up to one week, by assessing microglial or astrocytes activations. DISCUSSION/SIGNIFICANCE OF IMPACT: Our study shows, through controlling the applied magnetic field, MENs can be focally delivered to specific cortical regions with high efficacy and wirelessly activated neurons with high spatial and temporal resolution. This method shows promising potential to be a new non-invasive brain modulation approach disease studies and treatments.OBJECTIVES/GOALS: Our goal is to develop a non-invasive stimulation technique using magneto-electric nanoparticles (MENs) for inducing and enhancing neuronal activity with high spatial and temporal resolutions and minimal toxicity, which can potentially be used as a more effective approach to brain stimulation. METHODS/STUDY POPULATION: MENs compose of core-shell structures that are attracted to strong external magnetic field (~5000 Gauss) but produces electric currents with weaker magnetic field (~450 Gauss). MENs were IV treated into mice and drawn to the brain cortex with a strong magnetic field. We then stimulate MENs with a weaker magnetic field via electro magnet. With two photon calcium imaging, we investigated both the temporal and spatial effects of MENs on neuronal activity both"}
+{"text": "Married and cohabiting couples have important influences on one another\u2019s stress and well-being. Pandemic-related stress may influence the extent to which couples' stress levels are coregulated. This study examined the experience of nonspecific stress and pandemic-related stress and the moderating role of closeness among couples aged 50 and over in which at least one member had hypertension. A total of 30 couples reported their feelings of closeness to one another in a baseline interview and their feelings of nonspecific stress and pandemic-related stress every three hours for 5 days. There was no difference in closeness and nonspecific stress between husbands and wives. Wives reported greater pandemic-related stress than husbands. Actor-partner interdependence models revealed that wives\u2019 nonspecific stress predicted husbands\u2019 nonspecific stress  and that husbands\u2019 nonspecific stress predicted wives\u2019 nonspecific stress in each three hour period  and these associations were not moderated by closeness. Coregulation in pandemic-related stress among husbands and wives was moderated by wives\u2019 feelings of closeness such that when wives\u2019 feelings of closeness were lower, greater husband pandemic-related stress predicted lower pandemic-related stress for wives  whereas when wives\u2019 feelings of closeness were higher, greater husband pandemic-related stress predicted greater pandemic-related stress for wives . These findings indicate that closeness may have detrimental effects especially when considering emotional coregulation in couples regarding the pandemic."}
+{"text": "Older adults diagnosed with mild dementia can identify their wishes, values and goals of care with a high degree of accuracy and reliability. However, there is a paucity of research to guide best practices on how to incorporate Advance Care Planning (ACP) in the care of older adults living with mild dementia. Thus, only a minority of them participate in any ACP discussions. We developed an intervention called Voice Your Values (VYV) that healthcare professionals can implement to identify and document values of older adults. This single group pretest and posttest design aimed to determine the feasibility, acceptability and preliminary efficacy of the intervention. A convenience sample of 20 dyads of older adults and their trusted individuals were recruited from 4 geriatric clinics. Tailored VYV intervention was delivered to dyads on a one-on-one basis over two sessions using videoconferencing. Feasibility was determined through recruitment and retention rates, and intervention fidelity. Acceptability was assessed using modified Treatment Evaluation Inventory. Primary outcome was the Surrogate Decision-Making Confidence Scale. Secondary outcomes included an ACP engagement survey to assess older adults\u2019 engagement in ACP; Dementia Knowledge Assessment Tool for trusted individuals; and the Kessler Psychological Distress Scale for all participants. The recruitment rate was 45%, retention rate was 100% and 92% participants rated VYV as highly acceptable. Trusted individuals showed statistically significant improvement in decision-making confidence (p=.02) and psychological distress (p=.02); but no improvement in dementia knowledge (p=.47). Older adults demonstrated statistically significant improvement in ACP engagement (p=<.01). Initial feasibility of VYV was demonstrated."}
+{"text": "A challenging situation in proximal hypospadias is the presentation of patients with successful urethroplasty but with persistent or recurrent ventral curvature (VC) after multiple hypospadias repair.We present a 13 year-old boy with 7 previous surgeries  to treat hypospadias presenting with 60 degrees of VC, in spite of a well-accepted coronally neomeatus. We degloved the penis and artificial erection clearly appointed corporal disproportion causing curvature. We disconnected urethra from corpora. After excision of remnant fibrotic tissue, there was a residual curvature so a lenghtening corporoplasty with dermal graft from groin was performed. We have adjusted the urethral meatus position into a proximal penile shaft. We used a buccal mucosa graft placed in an inverted U-shape position planning a second stage urethroplasty (The aspect after corporoplasty proved satisfactory curvature correction. Patient had an excellent outcome and is scheduled for a second-stage after 6 months.Snodgrass and Bush  reportedSevere curvature associated with hypospadias should undergo a major procedure at early stage to avoid decompensation after dorsal plicature in adolescence. We had a very satisfactory result, the patient awaits the second stage procedure ."}
+{"text": "We report the case of a 73-year-old male who underwent abdominal multidetector computed tomography with vascular reconstruction that highlighted a congenital variant of iliac arteries. Iliac artery anatomical variants are exceedingly rare and only a few cases have been reported in the literature. We present a case of a 73-year-old male who presented to our emergency department for abdominal trauma due to a car incident. He underwent abdominal multidetector computed tomography that excluded abdominal traumatic pathologies. Vascular coronal volume rendering reconstruction highlighted an asymptomatic congenital anatomical variant, with cranial origin of internal iliac arteries . This pCongenital variants of the iliac arteries are exceedingly rare, and only a few cases have been reported in the literature.With an increase in noninvasive diagnostic vascular imaging, thoracoabdominal vascular anomalies are seen with greater frequency,"}
+{"text": "Breast-conserving surgery\u00a0(BCS) is a standard surgical treatment for early-stage breast cancer. The primary goal of BCS is to obtain complete tumor excision because positive resection margins are found to be associated with an increased risk of local recurrence.Using multivariable analysis, this study found that selective use of preoperative MRI was associated with a lower risk of positive resection margins (involved margins > 4 mm) after BCS for patients with screen-detected invasive breast cancer .The study results suggest that selective use of preoperative MRI for women with screen-detected invasive breast cancer promises to minimize the risk of positive resection margins after BCS. Future studies should focus on the prognostic impact of the study findings and investigate the cost-effectiveness of preoperative breast MRI for surgical planning."}
+{"text": "A best evidence topic has been constructed using a described protocol. The three-part question addressed was: In patients with anal fissure, which technique has a lower of incidence anal incontinence: Botox injection or lateral sphincterotomy? The best evidence showed that Botox injection has lower incidence of incontinence. \u2022In patients with anal fissure.\u2022Which technique has a lower of incidence anal incontinence:\u2022Botox injection or lateral sphincterotomy?\u2022Botox injection has lower incidence of incontinence. This fo2A general surgical trainee is consenting a 25 year old female with recurrent anal fissure for examination under anaesthesia plus either Botox injection or lateral sphincterotomy, the patient is wondering which technique provides a lower incidence of incontinence.3[In patient with anal fissure] [Which techniques has lower incidence of incontinence] [Botox injection or lateral sphincterotomy]?4A.Medline \u00ae 1946 to May 2021 and Embase 1974 to May 2021 using OVID interface:B.Medline \u00ae using PubMed interface:[Anal fissure OR fissure-in-ano] AND [incontinence OR anal incontinence] AND [botulinum toxin OR botulinum toxin injection OR BOTOX] AND [sphincterotomy OR lateral sphincterotomy OR lateral internal sphincterotomy].[Anal fissure OR fissure-in-ano] AND [incontinence OR anal incontinence] AND [botulinum toxin OR botulinum toxin injection OR BOTOX] AND [sphincterotomy OR lateral sphincterotomy OR lateral internal Sphincterotomy].Exclusion criteria:Unpublished studies, case reports, letter to the editors, studies in children less than 16 years studies not in English.5A total of 67 articles were identified after the removal of duplicates. Of these 51articles were excluded on the basis of title and abstract. After full-text assessment of the remaining 16 articles another 11 articles were excluded because they did not include the information needed to answer the question. A total of 5 articles  were identified to provide the best evidence to answer the question.6see the 7Lateral internal sphincterotomy (LIS) is usually performed by creating a vertical incision in the intersphincteric groove on one side of the anus, the internal sphincter fibers are then divided up to the level of the proximal extent of the anal fissure . LIS hasThe aim from this review is to assess the best studies which compare the incidence of anal incontinence among those patients undergoing Botox injection vs LIS for anal fissure.Two studies in our review showed no statistically significant difference in the incidence of anal incontinence between LIS and Botox injection these studies were conducted by De Robles et al.  and \u00c7ak\u01318According to the above articles, the best evidence showed a statistically significant lower incidence of anal incontinence among Botox injection group of patients in comparison to the LIS group.91.Small sample size in most articles2.Short period of follow in most articles.3.Lack of multicentric trialsNon.Not applicable.Not applicable.RI: conducted the literature search and wrote the paper. AAR: assisted in the literature search and SA: assisted in writing of paper.AA: assisted in the literature search.AM: design the table and help in editing of writing.Not applicable.Rashid Ibrahim.Non."}
+{"text": "Lung malignancies have become increasingly prevalent. Occasionally, an unusual tumour is diagnosed, or a common tumour type presentsunusually. This case report reviews 3 cases of thoracic neoplasm, including two cases of uncommon cancers  and an atypical presentation of malignant mesothelioma. Her chestradiograph and computed tomography (CT) scan revealed aninhomogeneous mass occupying nearly the whole right hemithorax,with an associated small pleural effusion Mr MG is a 65-year-old man who presented with left-sided chestpain. He was a non-smoker, and also reported profound weightloss. His chest radiograph showed a white-out of the left hemithoraxwith mediastinal shift. A CT scan revealed the presence of a leftmain bronchus mass with associated left lung atelactasis andcomplex collections extending to the chest wall consistent with aleft empyema neccesitans. A pigtail catheter was placed to drain thefluid. The purulent fluid aspirated did not yield any organisms onculture. A bronchoscopy was performed which revealed a left upperlobe bronchus that was partially occluded by the tumour. The biopsyconfirmed an adenoid cystic carcinoma (ACC) Mrs AM is a 53-year-old woman from the Democratic Republic ofCongo who presented with a 3-month history of generalised bodypain. On examination, she had many subcutaneous soft tissue masses. Her chest radiograph and CT chest showed a large roundedmass in the right hemithorax as well as a rounded lesion in the lefthemithorax. An ultrasound guided biopsy established a diagnosis ofa desmoplastic small round-cell high-grade sarcoma 6] The common presentationincludes marked chest wall pain and pleural effusions often with associated pleural thickening and volume loss. The patient presenteduncharacteristically, with pulmonary mass lesions with no identifiablerisk factors. The mortality is unfortunately still unacceptably higheven with chemotherapy, radiation and surgeryMMs are aggressive neoplasms arising from mesothelial surfacesof the pleura, peritoneal surfaces and tunica vaginalis. Eightypercent will arise from pleural surfaces where 70% of patients willreport exposure to asbestos. Other risk factors include radiation,carbon nanotube exposure and genetic factors such as mutations inBRCA1 associated protein 1(BAP1).[7] They are considered slowgrowing tumours, usually arising from the proximal tracheobronchialtree. The solid histological pattern has been associated with a moreaggressive clinical course and early distant metastases, in contrastto the cribriform type which shows a more benign behaviour.[8] The mainstay of therapy is surgery. Our patient probably had postobstructive pneumonia and an empyema as a result of the tumour inthe left upper lobe.Primary adenoid cystic lung cancers are rare salivary gland neoplasmsmaking up 0.04 - 0.2% of all lung cancers.[9] They are characterised histologicallyby nests of small tumour cells surrounded by cellular and vascularcollagenous stroma.11] Mostly arising in the abdominal and pelviccavity, these tumours can also originate in other sites, such as thelung and pleura.[12] DSRCTs are rare and aggressive malignanciescommonly affecting young males with only a few hundred cases reported in the literature. The prognosis is poor and therapy is stillnot well defined.Desmoplastic small round cell tumours (DSRCTs) are mesenchymaltumours arising from cells with multi-lineage potential. Firstdescribed in 1989 by Gerald and Rosai, these tumours have distinctmolecular and immunohistochemical characteristics. The molecularhallmark of DSRCT is the Erwing sarcoma and Wilms tumour gene(EWS-WT1) fusion protein.Unfortunately, all 3 patients presented with advanced disease andwere referred for oncological assessment and palliative care. This series serves as a reminder of the wide spectrum of presentations ofthoracic neoplasms."}
+{"text": "To report two cases with idiopathic unilateral diffuse opacification of the posterior hyaloid membrane (PHM) completely separated from the retina, the mechanism of which is possibly due to glial cell proliferation and migration.Two Japanese women at age 75 and 84 with no systemic or ocular history developed diffuse opacification in one eye resembling a ground glass sheet almost all over the surface of the PHM, but not within the vitreous gel or fluid. The retinas were funduscopically normal; however, optical coherence tomography demonstrated hyperreflective icicle-like anterior protrusions from the surface of the fovea. The patients received pars plana vitrectomy, resulting in visual improvement. Cell block preparations of the vitreous in one case revealed a cluster of cells immunoreactive for glial fibrillary acidic protein in consistence with gliosis, while denying vitreoretinal lymphoma from lack of atypical cells and vitreous amyloidosis due to no staining for Congo red or direct fast scarlet. The lesions did not recur during follow-up with no new funduscopic abnormalities.To our knowledge, this is the first to demonstrate such peculiar cases of vitreous opacity with idiopathic and unilateral onset. Histological assessments revealed the possible pathogenesis of gliotic opaque PHM separation to cause its ground-glass-sheet appearance.The online version contains supplementary material available at 10.1186/s12886-021-02072-5. Vitreous opacity is one of the frequent vision-threatening abnormalities. The causative diseases of vitreous opacity include intraocular inflammation, vitreoretinal lymphoma, and vitreous amyloidosis, each of which develops distinct opaque features resembling snowball in sarcoid uveitis , glass wA 75-year-old female presented with blurred vision of both her eyes gradually worsening for 12 months. The patient had no remarkable personal or family medical history except for Basedow disease in her twenties.Her decimal best-corrected visual acuity (BCVA) was 0.07 OD and 0.2 OS with mild hyperopia. The cornea and anterior chamber were clear OU. Funduscopic examination revealed no obvious abnormal findings via impaired visibility due to severe cataract OU. The patient received cataract surgery with no complication OU, and her BCVA improved to 0.9 OD and 0.6 OS with her complaint of persistent blurred vision OS. Three months postoperatively, the BCVA was almost unchanged, leading to thorough workup to find the cause of persistent blurred vision OS. Funduscopic examination showed no abnormal retinal findings with clear vitreous media OD  seen in idiopathic epiretinal membrane  and prolThe etiology of the present cases remains largely unknown because no explainable backgrounds, whether systemic or ophthalmic, could be identified so far. The two patients inflicted no occupational exposure to toxic metals or organic solvents, and shared neither genetic relationship nor any particular living environment. It would be interesting to note, however, that there were two common ocular findings in the affected eyes of both patients: subclinical vascular leakage barely detected with fluorescein angiography and icicle-like anterior protrusions clearly presented with OCT. Although these two abnormalities may have coexisted coincidentally, a possible mechanistic link is likely to be inflammation-driven migration of some undetermined retinal cells or resultant deposition of cellular debris. From lack of further evidence clinically collected, it is too speculative at present to state that such minimal vasculitis causes glial cell migration out of the retina onto the entire PHM, given that the affected eyes exhibited no signs of active or convalescent uveitis. We did not check any inflammatory cytokines such as chemotactic factors. Nevertheless, the two retinal findings associated with gliotic opaque PHM separation would definitely be worth considerable attention in terms of mechanistic insight. These limitations in the present study warrant future and further investigations into other similar cases.In conclusion, to the best of our knowledge, this is the first to report such peculiar cases of ground-glass-sheet opacity confined diffusely to the PHM surface completely separated from the retina. Immunopositivity for GFAP suggested, at least in one case, gliotic modification to the pathogenesis of this undocumented vision-threatening disorder, leading us to propose its nomenclature \u201cgliotic opaque PHM separation\u201d as a new clinical entity.Supplemental Figure S1\u00a0Ophthalmological findings in Case 1.\u00a0Top left Fundus photograph showing normal appearance OD. Top right Late-phase fluorescein angiography showing no abnormal findings OD. Bottom left Goldmann perimetry showing normal appearance except for slight enlargement of a blind spot OS. Bottom right Dark-adapted 20\u00a0J single-flash electroretinography showing normal amplitudes OU.\u00a0Supplemental Figure S2.\u00a0Ophthalmological findings in Case 2.\u00a0Top left Fundus photograph showing normal appearance OD. Top right Late-phase fluorescein angiography showing no abnormal findings OD. Middle OCT showing no abnormal findings at the macular region OD. Bottom left Humphry perimetry showing normal appearance OS. Bottom right Dark-adapted 20\u00a0J single-flash electroretinography showing normal amplitudes OU."}
+{"text": "ABSTRACT IMPACT: This work will standardize necessary image pre-processing for diagnostic and prognostic clinical workflows dependent on quantitative analysis of conventional magnetic resonance imaging. OBJECTIVES/GOALS: Conventional magnetic resonance imaging (MRI) poses challenges for quantitative analysis due to a lack of uniform inter-scanner voxel intensity values. Head and neck cancer (HNC) applications in particular have not been well investigated. This project aims to systematically evaluate voxel intensity standardization (VIS) methods for HNC MRI. METHODS/STUDY POPULATION: We utilize two separate cohorts of HNC patients, where T2-weighted (T2-w) MRI sequences were acquired before beginning radiotherapy for five patients in each cohort. The first cohort corresponds to patients with images taken at various institutions with a variety of non-uniform acquisition scanners and parameters. The second cohort corresponds to patients from a prospective clinical trial with uniformity in both scanner and acquisition parameters. Regions of interest from a variety of healthy tissues assumed to have minimal interpatient variation were manually contoured for each image and used to compare differences between a variety of VIS methods for each cohort. Towards this end, we implement a new metric for cohort intensity distributional overlap to compare region of interest similarity in a given cohort. RESULTS/ANTICIPATED RESULTS: Using a simple and interpretable metric, we have systematically investigated the effects of various commonly implementable VIS methods on T2-w sequences for two independent cohorts of HNC patients based on region of interest intensity similarity. We demonstrate VIS has a substantial effect on T2-w images where non-uniform acquisition parameters and scanners are utilized. Oppositely, it has a modest to minimal impact on T2-w images generated from the same scanner with the same acquisition parameters. Moreover, with a few notable exceptions, there does not seem to be a clear advantage or disadvantage to using one VIS method over another for T2-w images with non-uniform acquisition parameters. DISCUSSION/SIGNIFICANCE OF FINDINGS: Our results inform which VIS methods should be favored in HNC MRI and may indicate VIS is not a critical factor to consider in circumstances where similar acquisition parameters can be utilized. Moreover, our results can help guide downstream quantitative imaging tasks that may one day be implemented in clinical workflows."}
+{"text": "Mild traumatic brain injury is characterized by a Glasgow coma scale GCS between 13 and 15. It is a frequent pathology in our country because of the increasing number of circulation accidents. Trauma-induced superior oblique palsy usually results from contusion or avulsion of the trochlear nerve. Severe craniocerebral trauma is often associated with the former mechanism, whereas more minor closed-head injuries can decompensate a congenital phoria. We report a patient who developed an isolated trochlear nerve palsy following minor head trauma. Our 53 years-old patient without significant past medical history was victim of a traffic accident. He presented with a complaint of diplopia following head trauma the week prior. He lost consciousness for less than 1 minute. He noticed diplopia immediately upon awakening, but had no other neurologic symptoms. He presented to our emergency department for evaluation. Computed brain tomography (CT) performed did not show any orbital fractures. Ocular exam revealed mild to moderate infraduction deficit and supraduction excess in adduction of the left eye. Left head tilt test was negative. We finally concluded that our patient had a trochlear nerve palsy following the brain trauma. Further Magnetic Resonance Imaging (MRI) revealed an unsuspected tentorial vascular malformation that was compressing the trochlear nerve in its subarachnoid course. In the absence of other features that support decompensation of a congenital trochlear nerve palsy, compressive lesions should be sought in case of fourth cranial nerve palsy following head trauma."}
+{"text": "Urachal cancer arises from an embryologic remnant of the urogenital sinus and allantois and accounts for approximately 1% of bladder malignancies. The most encountered histologic subtype is adenocarcinoma. We present a 76-year-old man suspected to have an advanced sigmoid cancer infiltrating nearby organs. A supplemental 18F-FDG PET/CT showed high tracer uptake in a tumorous process coherent with the dome of the bladder wall involving the sigmoid colon. Cystoscopy revealed a normal bladder wall, except for a small edematous area in the anterior bladder. Biopsies from the sigmoid colon and transurethral resection from the bladder confirmed a urothelial carcinoma originating from the urachus. Urachal cancer is a rare entity which accounts for 0.5\u20132% of bladder cancer  and mostDue to the infiltrating tumorous growth involving the sigmoid colon, small intestines and lymph node metastases no primary tumor resection was performed. The patient was offered palliating oncologic treatment."}
+{"text": "ABSTRACT IMPACT: Reversing tumor microenvironment (TME) immunosuppression will help to increase the overall efficacy of treatment of chemo-resistant triple negative breast cancer (TNBC) and mitigate racial disparities in treatment response. OBJECTIVES/GOALS: We have developed an ex-vivo whole tissue culture model to test the feasibility of reversing local immunosuppression in TME by chemokine modulatory (CKM) regimen. Our current objective is to analyze the molecular changes in CKM-treated chemoresistant TNBC from White and Black women and identify factors determining response to CKM. METHODS/STUDY POPULATION: Freshly resected residual TNBC from 20 White and 20 Black women \u226518 yrs old treated with neoadjuvant chemotherapy (NAC) will be procured. Tumor explants will be prepared & cultured in the absence and presence of CKM . Chemokines implicated in cytotoxic T-lymphocyte (CTL)- & MDSC/ Treg attraction will be analyzed using Taqman & ELISA. We will have 80% power to detect a 0.7 standard deviation difference in chemokines between untreated & treated samples within and between cohorts using ANCOVA. Bulk RNA sequencing will be performed on both untreated & treated samples from CKM responding (highest aggregate increase in CTL- and highest decrease in Treg/MDSC-favoring chemokines in the top quartile) and non-responding (bottom quartile) tissues. RESULTS/ANTICIPATED RESULTS: Our preliminary data show that Black patients (pts) with breast cancer (BC) have an immunosuppressive TME associated with poor outcomes. This is similar to other existing literature showing that Black pts with BC have less favorable and more unfavorable chemokines in the TME. We anticipate the chemokine changes with CKM treatment will be larger in the Black cohort given their ability to elicit a robust inflammatory response. Therefore, we expect that CKM treatment will result in favorable TME in both groups and improve outcomes in TNBC, which has the worst prognosis of all subtypes, eliminating a key area of disparity in BC. The proposed transcriptome analysis will help identify key gene networks involved in response to CKM treatment and guide modulating the targets for non-responsiveness to improve efficacy of CKM. DISCUSSION/SIGNIFICANCE OF FINDINGS: Pts with residual disease (RD) after NAC have a 3-yr overall survival 68% vs. 94% for pts with complete response. Blacks have a higher incidence of TNBC with more likelihood of RD & mortality. We anticipate that the existing TME differences can be abrogated by our current CKM regimen or via developing an alternative CKM regimen optimized for Black pts."}
+{"text": "Older adults living in subsidized housing are often at high risk for having multiple chronic conditions and nursing home placement. Previous studies in this population have not examined the relationship between social isolation and healthcare utilization. We examine this using Lubben Social Network Scale-6 and self-reported healthcare utilization. Utilizing data from a multi-state non-profit subsidized housing provider, we performed descriptive and multivariate analyses on a sample of older adults . Overall, 95 % reported having a checkup within the last 12 months and an average of less than one emergency room visits (mean= 0.58) or hospitalizations (mean= 0.34). In adjusted models, Socially isolated older adults had lower levels of routine checkup  and higher levels of hospitalizations  compared to older adults who were not socially isolated. Efforts to address healthcare utilization should identify social isolation and explore strategies to promote social connectedness to improve health."}
+{"text": "Afferent limb syndrome is obstruction of a biliary-enteric limb following pancreaticoduodenectomy. In the past, treatment was limited to surgery or insertion of a percutaneous transhepatic biliary drainage tube. A more recent approach to treatment is Endoscopic Ultrasound (EUS)-guided gastrojejunostomy using a lumen apposing metal stent (LAMS). It was first described in two single case reports in 2015 and has been growing in its application. We present a case series of 2 patients where afferent limb syndrome was successfully managed with EUS guided gastrojejunostomy using LAMS.1-To demonstrate a novel technique for diagnosis and management of afferent limb syndrome.Case # 1- 79 year old female post Whipple\u2019s surgery for ampullary carcinoma, presented two years after surgery with significant nausea and vomiting. CT scan showed obstruction of the afferent loop suspicious for local tumor recurrence. Patient underwent EUS-guided gastrojejunostomy with successful insertion of 20 x 10 mm  stent.Case # 2-. A 51 year old male with pancreatic CA status post Whipple surgery presented with worsening abdominal pain and nausea. CT scan confirmed afferent limb syndrome. He underwent EUS- guided gastrojejunostomy with successful placement of 10 x 10 mm .Case #1: Patient improved dramatically within days and resumed oral diet. Fourteen days later, an upper endoscopy was performed in order to assess the stricture via an anterograde approach. The adult Olympus HQ gastroscope was advanced through the AXIOS stent into the afferent limb to the level of the stenosis where a tight stricture was seen. Multiple biopsies taken and were negative for malignancy. Four weeks later, she continued to tolerate oral diet well with no abdominal pain or discomfort.Case # 2: Patient continued to do well clinically 12 weeks post operation. Follow-up upper endoscopy was performed to determine the etiology of the obstruction but due to a sharp angulation, the gastroscope could not be advanced through the AXIOS stent. As such, we advanced an adult Olympus 1T gastroscope down to the site of the AXIOS stent and then utilized the Spyglass DS system to advanced deep into the afferent limb to the level of the stricture and took multiple biopsies for diagnostic purposes.Interventional endoscopic management of afferent limb syndrome has been evolving in the past few years with EUS guided LAMS gastrojejunostomy becoming a well stablished modality. We have demonstrated this technique with subsequent endoscopic anterograde assessment. In one of these cases, this anterograde assessment was performed using the cholangioscope in conjunction with the gastroscope to overcome unfavorable angulated anatomy which to our knowledge has not been described in the literature previously.None"}
+{"text": "Most algorithms for steering, obstacle avoidance, and moving object detection rely on accurate self-motion estimation, a problem animals solve in real time as they navigate through diverse environments. One biological solution leverages optic flow, the changing pattern of motion experienced on the eye during self-motion. Here I present ARTFLOW, a biologically inspired neural network that learns patterns in optic flow to encode the observer\u2019s self-motion. The network combines the fuzzy ART unsupervised learning algorithm with a hierarchical architecture based on the primate visual system. This design affords fast, local feature learning across parallel modules in each network layer. Simulations show that the network is capable of learning stable patterns from optic flow simulating self-motion through environments of varying complexity with only one epoch of training. ARTFLOW trains substantially faster and yields self-motion estimates that are far more accurate than a comparable network that relies on Hebbian learning. I show how ARTFLOW serves as a generative model to predict the optic flow that corresponds to neural activations distributed across the network. When it comes to navigation through diverse, complex environments, animals demonstrate capabilities that far outpace those of machines. Principles derived from biological systems have the potential to catalyze efficient solutions that enhance autonomy in unmanned aerial vehicles (UAVs) and other mobile robotic systems ,2,3,4. NR) and factor it out from the raw optic flow pattern .Lifelong learning: the learning process need not occur in discrete training and prediction phases\u2014learning may continue during operation.Here I present a fast, biologically inspired neural network that learns optic flow templates that can be used to estimate self-motion through arbitrary environments. The approach builds on the fuzzy adaptive resonance theory (fuzzy ART) family of biologically inspired unsupervised learning algorithms ,32. FuzzBuilding on these strengths, I made contributions in two key areas to make the fuzzy ART neural network suitable for learning optic flow and other sensory patterns.First, neurons are fully connected in typical fuzzy ART neural networks. Analogous to multi-layer perceptrons (MLPs), such dense connections do not scale well to the large numbers of features encountered when processing sensory data. Additionally, spatial relationships among features are not preserved. This is problematic for processing optic flow wherein the configuration of the motion vectors in the global pattern is important. I addressed this challenge in ARTFLOW by introducing parallel fuzzy ART modules that tile space on a discrete grid . Each moSecond, fuzzy ART consists of strictly two network layers, which does not afford learning of hierarchical relationships among features at multiple scales. In ARTFLOW, the outputs of topographically close, spatially offset fuzzy ART modules converge in the next network layer . SimilarI evaluated the ARTFLOW network using video datasets of simulated self-motion through dot-defined environments and visually realistic neighborhood and warehouse scenes rendered using the Unreal video game engine. The dot-defined scenes serve as controlled environments with which to test learning on large numbers of optic flow patterns that arise during specific types of self-motion. I decoded activations from the top \u201cMSTd\u201d layer of ARTFLOW to assess how well the learned optic flow templates support accurate heading estimation. I compared performance to an identically structured hierarchical network that replaces fuzzy ART modules with those that rely on the simpler Hebbian learning law.The neighborhood and warehouse datasets were generated using Microsoft AirSim , a simulModel MT neurons exhibit sensitivity to the speed and direction of optic flow signals over time. I based parameter values on known neurophysiology where possible.I positioned 5000 sMT integrates the optic flow signal over time:The net input of each model MT neuron is the average product of the direction and speed inputs within the RF:In Equation , AMT=0.1Equation  with a tm):n value on the 3D dot cloud (T) dataset.I applied the following sigmoid activation function to compute each MT output signal ))NMTx1) oM. The weights between the input and coding layers of the fuzzy ART network are initialized as a 2 C is initially zero.Here I summarize key stages of the fuzzy ART algorithm ,40 implej; and The activation function ,42:(7)Tji index the coding cell currently checked in the ART search cycle. The following function determines the degree of match between the input sample and weight vector i:The ART search cycle determines whether the weights of a previously committed coding cell will be updated based on the current input or a new coding cell will be committed during training. The search cycle checks how close the current input pattern  is applode mode  to enhanThe vigilance threshold The output of each module is a function of the committed coding cell activations (The activation of the committed coding cells across the 64 (8 \u00d7 8) modules are concatenated to form the input vector to the single module in the second fuzzy ART layer (henceforth \u201cMSTd layer\u201d). Because the number of committed cells is determined during training, I trained fuzzy ART layers sequentially: I trained the fuzzy ART layer 1 first, froze its weights, then trained the MSTd layer.I trained two decoders (one linear and one nonlinear) using gradient descent to estimate self-motion parameters from the MSTd layer activations. Both decoders were implemented as backpropagation neural networks that use the Adam optimizer with default parameters to minimize mean-squared error (MSE) loss. I standardized both the features and labels. A single-layer MLP served as the nonlinear decoder, which had 250 hidden units and the rectified-linear (ReLU) activation function. Each decoder network had two output units when estimating heading (azimuth and elevation angles) and five output units when estimating rotation . I used early stopping (patience of 5) to halt training when the validation set loss stopped decreasing.I trained ARTFLOW on the training set of each dataset  for 1 epI trained the decoders on the ARTFLOW MSTd layer activations produced to each sample in the training set after learning completed. The reported accuracy reflects decoder estimates of heading and rotation parameters from MSTd layer activations obtained to the test set samples.C optic flow templates, I implemented Sanger\u2019s network in each module, which adapts Hebb\u2019s Rule for learning the top C PCs [I compared ARTFLOW to an identically structured hierarchical network that implements Hebbian learning rather than fuzzy ART in each module. Because the weights of a single Hebbian neuron converge to the first principal component (PC) of its input and fuzzy ART networks learn op C PCs . To facix from Sanger modules during prediction, I applied a logistic activation function:I trained each Sanger\u2019s network with a learning rate of 0.01. Training ceased when differences between weight matrices on successive epochs dropped below a Frobenius norm of 0.01. To prevent negativity in each neural output https://github.com/owlayton/ARTFLOW (accessed on 1 October 2021).I implemented the model and performed simulations using MATLAB R2021b on an Apple MacBook Pro equipped with the six-core 2.9 Ghz Intel Core i9-8950HK processor and 16 GB of memory. Fuzzy ART layers were implemented such that training and prediction computations across modules ran in parallel on the CPU. The code is available on GitHub: I begin by highlighting key properties of the optic flow templates learned by ARTFLOW. Subsequent sections focus on the accuracy of self-motion estimates derived from the network.The ARTFLOW network learned diverse motion patterns that capture distinct characteristics of the optic flow encountered during simulated self-motion through each visual environment (first rows in Many of the learned templates from the 3D dot cloud (T) scene appear qualitatively similar to those from the neighborhood C and groIt is noteworthy that the number of optic flow templates differs across datasets without changes to the hyperparameters. This occurs because the vigilance hyperparameter  and rotational  self-motion parameters from MSTd layer activations after one epoch of training. I evaluated the accuracy on novel optic flow sequences not encountered during training  using linear and nonlinear (MLP-based) decoders. The performance of the ARTFLOW templates was compared with that of a principal component analysis (PCA)-based representation. This was achieved by simulating an identically structured hierarchical network that implemented Hebbian learning (Sanger\u2019s network) in each module instead of fuzzy ART.Estimating heading in the presence of rotation (3D dot cloud (T+R) dataset) represents a much more challenging problem . Accordi display . The conEstimates of pitch and yaw rotation derived from the networks B demonstFuzzy ART layers in ARTFLOW required substantially less time to train than layers in the Hebbian network C. FigureI performed a sensitivity analysis to better understand the robustness of decoded self-motion estimates A,B to che values B. The coe values C. ARTFLOe values B,C. Howee values E,F. The e values D\u2013F.In addition to encoding self-motion, the learned optic flow templates represent a generative model of optic flow. That is, ARTFLOW is capable of predicting the optic flow pattern that corresponds to a set of template activations. This is achieved by propagating the template activations backward layer-by-layer . This contrasts with deep learning networks that require larger amounts of data and many training epochs ,47,48 anA single hyperparameter, vigilance, controls the degree of distinction among the templates. This allows the network to self-regulate the number of templates that are needed to learn optic flow patterns with the desired granularity. Simulations revealed that the accuracy of heading estimation was robust to a wide range of vigilance values in the 3D cloud (T) and warehouse datasets . SensitiARTFLOW not only encodes self-motion parameters more effectively than a comparable network that uses Hebbian learning A but it Several neural networks have been developed that adaptively learn the self-motion templates using Hebbian or Instar biological learning laws ,50,51. HARTFLOW complements work others have done to develop fuzzy ART into a multi-layer network. ARTree ,53 is a Algorithms inspired by the design of the brain have the potential to bridge the gap between machines and animals when it comes to agile, resilient, adaptive navigation. Toward that end, I have presented ARTFLOW, a fast, unsupervised biologically inspired neural network that learns optic flow patterns that support accurate self-motion estimation in diverse environments. The network demonstrates effective encoding of self-motion parameters with one-shot learning and representations that remain stable over continued training."}
+{"text": "OBJECTIVES/GOALS: We conducted a review of CTSA websites to understand the current landscape for CRP institutional professional development and training revealed in the CTSA hub websites. METHODS/STUDY POPULATION: We accessed and reviewed 59 currently funded CTSA hub websites for evidence of CRP training opportunities. Parameters reviewed included: 1) opportunities were specified for CRPs versus K and T trainees; 2) mandated training; 3) leveling; 4) delivery methods/resources; 5) public accessibility; 6) unique features. The website reviews informed a REDCap survey sent to the CTSA Administrators (n = 149) and the Coordinator Taskforce (n = 105) listservs to gain additional knowledge of CRP training available at the institution. A subsequent repeat review of the CTSA hub websites will be conducted to determine evolving trends. RESULTS/ANTICIPATED RESULTS: A total of 40 responded to the survey from 59 CTSA hubs. Survey results are being analyzed. Website review data are being tabulated and the subsequent review of websites will be collected in February. Those findings are pending and will include a comparison of prior findings. 42% of CRP hubs list CRP training within the CTSA hub website. Required onboarding training (beyond CITI certificates) is revealed for some hubs (15%). DISCUSSION/SIGNIFICANCE OF IMPACT: On our initial website review less than half of the CTSA hub websites list specific CRP training on their website. Many were hidden behind firewalls and could not be reviewed for content. The REDCap Survey will provide more granular descriptions of programs. Data from a second website review will be collected for comparison. Based on a preliminary re-review of sites, there is a suggestion of increasing CRP workforce development information. CTSAs are well-positioned to be a central hub for promoting educational excellence of the institutional workforce, for medical centers and in other venues where clinical research is performed."}
+{"text": "Emerging evidence shows that understanding characteristic patterns between study partners (SP) and subjects can inform initiatives to diversify representation of sociocultural groups in ADRD research. This study examined same-sex spousal dyads with the goal of identifying bellwethers of opportunities to build diversity in ADRD research. Descriptive analysis of The Aging, Demographics and Memory Study (ADAMS), which enrolled a subset of subjects from the Health and Retirement Study and a SP for each subject. Eight same-sex spousal couples were among 718 SP-subject dyads (1.1%). Gay men were 3 times as likely to be spousal SPs (n=6) than lesbians (n=2), even though women far outnumber men overall. Patterns in caregiving and other characteristics also differed. Same-sex couples are underrepresented in ADRD research. Patterns among those enrolled suggest masculine and feminine norms may drive research engagement. This is discussed in the context of increasing sociocultural diversity in ADRD research across key social groups."}
+{"text": "Optimal nurse-patient-family interaction is required to provide effective family-centered care for hospitalized older adults and their families. This qualitative descriptive study explored nurses\u2019 interactions with older adult patients and their family members during acute hospitalization. We used semi-structured interviews to collect data from a convenience sample of nine dyads of older adults (aged 62-85) and family members (7 children and 2 spouses) who accompanied them during an acute hospitalization in medical or surgical units. Interviews were performed via Zoom beginning in December 2020 until August 2021, 1-12 months after the hospitalization. Thematic analysis was used to inductively capture key patterns in data. Both patients and family members revealed three factors contributing to the way nurses interact with patients and families: (1) nurses\u2019 recognition and understanding of patients\u2019 needs for family members\u2019 presence and participation in care; (2) nurses recognition that family members expect dedication of attention, beyond nurses\u2019 focus on patient\u2019s care (3) patient and family members\u2019 recognition of the extreme workload of nursing staff. Participants described a range of informal approaches used by both nurses and families to address each other\u2019s needs. Both patients and families emphasize the benefits and costs of nurses engaging in \u201cexceptional\u201d interactions with patients and families considering structural characteristics such as establishing a personal relationship or accepting family visits beyond the rules. The findings provide direction for further exploration of hospitalization structures and processes needed to support optimal nurses\u2019 interactions with families accompanying older adults and family-centered approach training in acute care context."}
+{"text": "Surgical treatment of rotator cuff tears commonly entails reattachment of the ruptured tendon to its bony insertion using suture anchors. Suture anchor design has evolved from solid metal anchors to vented biocomposite anchors with potentially biologic consequences. Few studies have investigated the differences between different modern anchor design and materials, making it difficult to justify their use or cost.To compare the rate of bony ingrowth and implant resorption between a coil-type open-architecture biocomposite suture anchor and a vented screw-type biocomposite suture anchor, used for arthroscopic double-row rotator cuff repair.In this retrospective comparative study, a consecutive series of patients who undergo a double row rotator cuff repair using a coil-type open architecture biocomposite suture anchor in the medial row and a vented screw-type biocomposite suture anchor in the lateral row will be included. A sample size calculation demonstrated that 16 participants are required in each group. Primary outcome measures will be bony ingrowth and reabsorption of the suture anchor as measured on computed tomography (CT). Secondary outcomes will include patient reported outcome measures (The American Shoulder and Elbow Surgeons score and The Western Ontario Rotator Cuff questionnaire), range of motion, postoperative tendon integrity, and cyst formation.Open-architecture suture anchors facilitate the release of marrow constituents.The rate of bony ingrowth for coil- and screw-type anchors will be assessed.The difference in functional outcome between the two anchors will be assessed. Suture anchors constitute the primary source of fixation during arthroscopic rotator cuff repair and have undergone several iterations as part of their development. Implant design and composition have evolved with corresponding advances in bioengineering. The primary goal of any such device is to produce a biomechanically stable construct that does not compromise healing of the tendon-bone interface and secondarily to minimize the short and long-term impact on the native anatomy. To achieve this various anchor design and biomaterials have been developed.First-generation bioabsorbable suture anchors were commonly manufactured from polyglycolyic acid (PGA) leading to rapid absorption and an inflammatory reaction in the surrounding bone. As a result of this, tunnel widening and the collection of peri-implant fluid were reported . To mitiin vivo behaviour of these suture anchors is crucial, but few studies have investigated the differences between suture anchors designs [Material properties aside, suture anchors have additionally advanced from conventional solid screw designs to more \u2018vented\u2019 suture anchors. Vented suture anchors have additional holes in the otherwise solid anchor body which presumably allows bone in-growth through the implant and access of marrow elements to the bone-tendon healing interface. These vented suture anchor design have now evolved into coil-type open-architecture platforms, which theoretically allow even further bone ingrowth and marrow access despite a lower material load . Despite designs 4.To compare the rate of bony ingrowth and implant resorption between a coil-type open-architecture biocomposite suture anchor and a vented screw-type biocomposite suture anchor, used for arthroscopic double-row rotator cuff repair. We hypothesise that the coil-type biocomposite open-architecture design will lead to greater bone formation and enhanced anchor resorption.The study has been approved by the Conjoint Health Research Ethics Board (CHREB) at the University of Calgary.Retrospective observational study.This retrospective study will be carried out in a tertiary referral centre for complex shoulder arthroscopy and involves patients that had surgery by the senior author (IKL) between April 2015 and February 2019.A consecutive series of patients will be identified from their billing codes and their charts evaluated for implicit consent to take part in research. General eligibility will initially be confirmed by implicit written consent present in the medical records detailing the patient\u2019s willingness to be contacted for involvement in a future study. For those patients, a member of the research team will contact them in order to gain formal consent for this particular study. An appointment for an in-person consultation will be issued so that the relevant outcome measures can be assessed.Inclusion criteria for the study include:A reparable partial/full-thickness supraspinatus/infraspinatus tear.Surgery undertaken with a compression double-row technique exclusively using 4.75 or 5.5 mm Healicoil Regenesorb coil-type open-architecture suture anchors  composed of PLGA/B-TCP/Calcium suphate for the medial low, and 4.75 mm SwiveLock BioComposite vented suture anchors composed of PLLA/B-TCP  for the lateral row.One year minimum follow-up. Patient will be grouped according to length of follow-up to approximately 1 year follow-up and 2 years follow-up.Exclusion criteria comprise the following:A history of shoulder instability.Any previous ipsilateral shoulder surgery.Single row rotator cuff repair.Partial reconstruction of the rotator cuff.A sample size calculation assuming a type I error rate of 0.05, power of 80%, and standard deviation of 50 demonstrated that 16 participants will be required in each group.Preoperative rotator cuff tears will be diagnosed by ultrasonography or magnetic resonance imaging (MRI). The indication for surgery will be ongoing symptoms despite at least six months of non-operative treatment encompassing physiotherapy and analgesia. All operations will be performed by a single surgeon in the following manner:\u2013 Patient will be operated under general anaesthesia with regional nerve block as per anaesthesia.\u2013 The patient will be placed in the lateral decubitus position.\u2013 A standard posterior viewing portal will be utilised for diagnostic arthroscopy with further portals being made according to the desired angle of approach required to reach the rotator cuff.\u2013 Subacromial bursectomy will be carried out to aid visualisation and may involve an acromioplasty if an antero-lateral spur is identified.\u2013 The rotator cuff tear will be debrided and repaired back to its footprint using a double row repair technique characterised by a 4.75 or 5.5 mm Healicoil Regenesorb anchor  for the medial row, and a 4.75 mm SwiveLock BioComposite anchor  for the lateral row. In general one or two anchors are used medially and one or two anchors are used laterally.A standardised postoperative rehabilitation protocol will be used. In brief, this entails a sling for six weeks, passive range of motion by six weeks, and active range of motion by eight weeks.Outcome measures will be assessed by a blinded musculoskeletal trained radiologist and will include the following:\u2013 Primary \u2013 Bony ingrowth and reabsorption of the suture anchor.\u2013 Secondary \u2013 Functional outcome, postoperative tendon integrity, cyst formation, and range of motion.All radiographic measurements will be taken using a computer tomography (CT) scanner  with 1.0 mm continuous slices through the shoulder. Inter-observer reliability will be determined by Cohen\u2019s kappa coefficient.A sterile suture anchor of each type being studied will be scanned by CT to obtain baseline data that will subsequently be used to determine whether the device has been completely reabsorbed and identify the nature of the material found in the location it previously occupied. A board-certified radiologist independent to the study and blinded to the intervention will use a semi-quantitative scoring system modified from that proposed by Haneveld et al to assess this at 12 months and 2-years postoperatively :\u2013 Grade 1 \u2013 Clearly visible structure.\u2013 Grade 2 \u2013 Visible structure.\u2013 Grade 3 \u2013 Partial visible structure.\u2013 Grade 4 \u2013 Structure not visible.Bony ingrowth into the anchor will be measured at 12 months and 2-years postoperatively. Oblique sagittal and coronal multiplanar reconstruction images will be reconstructed with short- and long-axis views oriented at the anchors along with axial images. Two orthopaedic surgeons blinded to the intervention will assess bony ingrowth using the ossification scale devised by Kim et al, and record the highest value from all image cuts taken  :\u2013 Stage 1 \u2013 Little or no ossification.\u2013 Stage 2 \u2013 Some ossification but discontinuous or with a wide lucent rim.\u2013 Stage 3 \u2013 Ossification with a thin lucent rim.\u2013 Stage 4 \u2013 Good ossification and vague tract border.Peri-implant cyst formation will be assessed on CT and defined as a gap where the hypodensity between the anchor and the bone exceed 1 mm in at least one image . UltrasoThe Western Ontario Rotator Cuff questionnaire (WORC) and the American Shoulder and Elbow Society (ASES) scores will be used for functional outcome assessment at 12 months and 2-years following surgery . The infTables 1 and 2).Data will be collected from all adult patients, over the age of 16-years, undergoing double row arthroscopic rotator cuff repair by the principal investigator (IKL) using the technique described in section 2.4. The data fields will be based on existing information recorded for each patient as part of the local policy governing medical record keeping for patients undergoing surgery. Specific details that will be collected concern preoperative function of the shoulder being operated upon, operative data, and outcome data . A Student t test will be used to determine differences between pre- and post-operative clinical outcome scores and range of motion. The Chi-squared test will be used to compare the rates of bony ingrowth, suture anchor reabsorption, cyst formation, and postoperative tendon integrity. The statistical significant level will be set at p < 0.05.IKL receives research support and royalties from, and performs consulting, for Smith & Nephew. The remaining authors (TT and ST) do not declare any conflicts of interests.Failure rates following rotator cuff repair have been reported to be as high as 46% . This ha8Coil-type open-architecture suture anchors represent an exciting development because they are able to effectively liberate the bone marrow constituents integral to tissue healing . Few stu2The University of Calgary\u2019s Research Ethics Committee has granted the principal investigator ethical approval for any retrospective clinical study that is conducted at the study institution. The study strictly complies with the regulations set out in that agreement and so no further approval will be required.Results from the study will be presented at international scientific conferences focussed on arthroscopic surgery and published in peer-reviewed journals. The findings will additionally be disseminated to other surgeons across North America to guide policy."}
+{"text": "Objective: High-density electromyography (EMG) is useful for studying changes in myoelectric activity within a muscle during human movement, but it is prone to motion artifacts during locomotion. We compared canonical correlation analysis and principal component analysis methods for signal decomposition and component filtering with a traditional EMG high-pass filtering approach to quantify their relative performance at removing motion artifacts from high-density EMG of the gastrocnemius and tibialis anterior muscles during human walking and running. Results: Canonical correlation analysis filtering provided a greater reduction in signal content at frequency bands associated with motion artifacts than either traditional high-pass filtering or principal component analysis filtering. Canonical correlation analysis filtering also minimized signal reduction at frequency bands expected to consist of true myoelectric signal. Conclusions: Canonical correlation analysis filtering appears to outperform a standard high-pass filter and principal component analysis filter in cleaning high-density EMG collected during fast walking or running. I.Bipolar surface electromyography (EMG) has long been the gold standard for recording electrical activity from muscles during locomotion In contrast, high-density EMG is an emerging technology that uses an array of electrodes to measure both the spatial and temporal properties of a muscle et al. measured high-density EMG from the vastus medialis during stationary cycling and found that the muscle fiber conduction velocity was relatively constant during fatiguing exercise et al. recorded high-density EMG activity at a self-selected walking speed and showed that lateral gastrocnemius activity varied spatially in healthy adults et al. measured hamstring muscle activity with a linear array of electrodes at near-maximal running speeds and found large individual differences in spatial activity patterns Recently, studies have shown the potential of high-density EMG in more dynamic settings. Schmitz As running speed increases, so too does the frequency of motion artifacts that contaminate the EMG signal et al. showed that canonical correlation analysis can improve the signal-to-noise ratio of high-density EMG recordings during seated isometric tasks High-density EMG provides an opportunity to leverage statistical processing techniques that are typically unavailable with bipolar EMG recordings. Principal component analysis is often used to extract only the important information from a large set of variables and express it in reduced dimensions Principal component analysis and canonical correlation analysis have also been effective at removing motion artifacts from high-density electroencephalography (EEG) recordings during walking. Both EEG and EMG recordings are susceptible to motion artifacts from movement at the electrode-skin interface, cable sway, and movement of system components The purpose of this study was to compare the results of different signal processing techniques on high-density EMG data during locomotion. We recorded data from two lower limb muscles in healthy individuals walking and running on a treadmill at a range of speeds. We processed their data using three different methods: (1) Standard high-pass filtering of the data with a 20 Hz cutoff frequency; (2) Monopolar and differential EMG channel cleaning using principal component analysis and component filtering; and (3) Monopolar and differential channel EMG cleaning using canonical correlation analysis and component filtering. Based on its effectiveness at removing motion artifacts from high-density EEG recordings, we hypothesized that canonical correlation analysis filtering would result in the greatest reduction in motion artifacts. To our knowledge, this is the first study to investigate the effectiveness of different data processing methods on high-density EMG recorded during walking and running.II.The average number of channels that were rejected from the high-density EMG recordings of each muscle decreased when using component decomposition filtering methods to clean the channel data prior to high-pass filtering . Both prThe greatest EMG activity in the medial gastrocnemius during stance was in the distal portion of the muscle, regardless of the speed and processing method applied to the data . During Compared to the medial gastrocnemius muscle, the spatial distribution of the tibialis anterior EMG activity during swing was more evenly distributed across the measured surface of the muscle . At slowThe frequency content of each differential channel varied based on the processing method that was applied . There wCompared to raw, unprocessed data, each processing method reduced the average overall low frequency spectral amplitude, which is predominantly associated with pure motion artifacts, during running at 5.0 m/s , 0\u201320 HzIII.Both principal component analysis and canonical correlation analysis component cleaning methods reduced motion artifact content from dynamic high-density EMG recordings more effectively than traditional high-pass filtering of channel data. Canonical correlation analysis reduced the average spectral amplitude more than the other two methods in frequency ranges typically associated with motion artifacts . Principet al. found a similar pattern in the lateral gastrocnemius during the stance phase of walking Contrasting spatial EMG activity patterns were observed in the two muscles we measured. In the medial gastrocnemius, we found the highest electrical muscle activity amplitude in the distal portion of the muscle during stance phase at all walking and running speeds. Cronin Although the spatial activation plots for each muscle appeared relatively similar after applying contrasting processing methods  and 3, tPrincipal component analysis and canonical correlation analysis are analogous, but contrasting, methods that have each been used for isolating and removing noise sources from multivariate time series channel data The physical structure of a high-density EMG system likely contributes to the amount and type of motion artifacts during dynamic conditions. Most high-density EMG systems are typically designed for use in stationary environments. Each electrode array required an attached small adapter unit that was connected to the main EMG amplifier via a 3-meter ribbon cable. Although we taped and wrapped the adapter units and corresponding cabling to the subjects\u2019 legs in an attempt to minimize movement artifacts induced by equipment and cable motions, cable sway and electrode mass are known contributors to motion artifacts in high-density biopotential recording systems There were limitations with this study. To simplify our analyses, we focused on the primary phases of the gait cycle in which each muscle is active . Because muscle activity amplitude and timing vary with gait speed IV.Our results demonstrated that high-density EMG canonical correlation analysis channel decomposition and component cleaning is likely the preferred method for processing high-density EMG during fast walking or running. It provided the greatest reduction in signal content within frequency bands expected to include motion artifacts while minimizing signal reduction within frequency bands expected to contain true myoelectric signal. Electrical phantoms using ground-truth EMG sources could help determine if this signal reduction correctly targeted pure motion artifacts. Future studies that examine a wider range of muscles and different high-density EMG systems would also help validate our conclusions.V.A.16 healthy volunteers  with no history of major lower limb injuries or neurological conditions completed this study. All subjects provided written informed consent before participating, and all procedures were in accordance with the Declaration of Helsinki and approved by the University of Florida Institutional Review Board.B.Subjects walked at two different speeds (1.2 and 1.6 m/s) and ran at four different speeds  on an instrumented treadmill. We randomized the order of the speeds for each subject and recorded data for twenty strides per leg. For safety purposes, all subjects wore a lightweight upper-body harness that did not impede or alter their running mechanics.et al.We attached high-density EMG arrays  to the medial gastrocnemius and tibialis anterior muscles of each subject's right leg . The eleth order Butterworth filter, zero lag) to extract gait event timings.We sampled the high-density EMG monopolar data at 2048 Hz with a bandpass filter of 10-500 Hz. We excluded trials that were corrupted by equipment malfunctions. We recorded ground reaction forces from an instrumented split-belt treadmill . All subjects ran on only one belt of the treadmill across all speeds. We low- pass filtered the ground reaction force data at 40 Hz  on the average number of rejected channels at each speed and the root mean square (RMS) values at each differential channel location. The latter allowed us to produce spatial statistical significance plots (p < 0.05) to reveal the influence of processing methods on high-density EMG spatial activity. To account for possible Type I error, we adjusted our results using a false discovery rate correction"}
+{"text": "Cornulin (CRNN) is linked with tumour progression. Therefore, it is of interest to document data on the molecular modeling of cornulin (CRNN) for docking with phytocompounds  from Justicia adhatoda L. Thus, wedocument the optimal binding features of these compounds with the cornulin model for further consideration. Cornulin (CRNN) is linked with tumour progression -7. ThereThe full amino acid (495aa) sequence of CRNN is downloaded from the Uniprot Knowledgebase database in FASTA format with accession number Q9UBG3. The NCBI Simple Local Alignment Search Tool (Psi-BLAST)  was usedProCheck  was usedThe Cavity Plus server  was usedThe structure data for 12 compounds from Justicia adhatoda L was downloaded from PubChem database. All the compounds were downloaded in SDF format and converted to the PDB format using Pymol.Molecular docking and visualization were done using a standard procedure using PyRx, AutoDock 4 and Pymol -13.The SWISS-MODEL homology \\cornulin was created  using a We document the optimal binding features of phytocompounds  from Justicia adhatoda L with Cornulin in the context of cancer for further consideration."}
+{"text": "Scientific Reportshttps://doi.org/10.1038/s41598-020-69342-y, published online 23 July 2020Correction to: The original version of this Article incorrectly stated that coronaviruses have the largest of all reported RNA genomes. This statement has now been corrected for accuracy. In the Introduction,\"Coronaviruses have the largest RNA genomes among all viruses.\"now reads\"Coronaviruses have some of the largest RNA genomes among all viruses.\"The original Article has been corrected."}
+{"text": "Sensory function has been linked to cognitive impairment and dementia, but the link between multiple sensory impairments and early cognitive impairment (ECI) is unclear. Sensory function  was measured in 390 BLSA participants  from 2012 to 2018 over a mean 3.6 years. ECI was defined based on 1 standard deviation below age-and race-specific means in Card Rotations or California Verbal Learning Test immediate recall. Cox proportional hazard models examined the risk of ECI for each sensory impairment and across categories of impairments. Vision impairment (vs. no vision impairment) was associated with a 70% greater risk of ECI . Participants with 1 or \u22652 sensory impairments had triple the risk of ECI  compared to those without impairment. Future studies are needed to examine whether treatment for sensory impairments can modify these risks."}
+{"text": "Background: Atrial fibrillation (AF) is the most common cardiac arrhythmia encountered in clinical practice. Catheter ablation has become an important treatment option for many AF patients. Catheter ablation has been hypothesized to reduce the need for continued medical therapy for patients with AF, but there are few empirical data which demonstrate this.Objective: The objective of this study was to estimate the impact of catheter ablation on antiarrhythmic drug (AAD) utilization and total drug expenditures among AF patients.Methods: A retrospective analysis using the Truven Health Analytics MarketScan\u00ae Research Database was performed. Patients with AF and a catheter ablation procedure who had continuous enrollment in the database 6 months prior to their first ablation and a minimum of 1-year follow-up post first ablation were compared to AF patients who were treated with AADs and not ablation. Propensity matching was used to account for baseline differences between groups, and multivariable regression models adjusted for patient characteristics and baseline healthcare resource utilization. Sub-analyses were performed for patients age \u226565.Results: AF patients treated with catheter ablation had significantly lower AAD utilization and total prescription drug costs than those treated with AADs only. These results persisted for the subset of patients age \u226565. The effects were strongest in the matched sample, where approximately 30% of ablation patients discontinued use of rhythm medication after receiving catheter ablation. Per-patient total medication expenditures were reduced by $800 to $1,200 per year in the matched sample.Conclusion: Catheter ablation for AF reduced AAD utilization and total prescription drug expenditures in a sustainable fashion up to 3 years post ablation. This reduction was consistent and significant in both the non-Medicare and Medicare populations."}
+{"text": "Burn shock is one of the most serious and complex complications suffered by patients following thermal injury. Endothelial dysfunction may play a role in the pathogenesis of burn shock. However, the mechanisms underlying the contribution to pathophysiology are still largely unknown. Previous studies have shown a connection between the rearrangement of cytoskeletal elements leading to increased vascular permeability. The aim of this study was to examine the differential expression of genes involved in cytoskeletal arrangement in endothelial cell monolayers treated with plasma from burn patients.Human umbilical vein endothelial cells (HUVECs) were seeded into transwell plates to form confluent monolayers. Plasma was collected from burn patients 4 hours post-admission. HUVEC cells were exposed to 10% multi-donor pooled healthy human plasma (HHP) or burn patient plasma. Monolayers were subsequently incubated with FIT-C Dextran  for 2 hours. Monolayer permeability was measured with indices calculated by normalizing values to blank wells (transwell inserts) and HHP-treated monolayer FIT-C diffusion. RNA was isolated from these same cells that had increased monolayer permeability and PCR analysis was carried out using an 84 gene array of human cytoskeletal regulators (Qiagen). A Ct value of 35 was used to indicate expression and a fold change of 1.5 to indicate differential expression in the control vs. injured groups.Four burn patient plasma samples were utilized to create injuries. Patients were mostly male (75%) with a mean age of 50\u00b120 years and mean %TBSA burn of 37\u00b134%. Differential gene expression in burn vs. HHP was compared. Ten genes showed significant upregulation . Four genes showed significant downregulation in . Monolayer permeability indices showed statistically significant increases when compared to controls ranging from 3-13.33% (p < .05).The interplay of burn shock and endothelial dysfunction remains a complex process of which much is unknown. However, RNA analyses of burn patient plasma reveals involvement of multiple cytoskeletal regulators. Furthermore, all these samples show a concurrent increase in permeability indices when compared to controls, further strengthening the association between cytoskeletal rearrangement and endotheliopathy. Future research to better understand the specifics of these pathways could help aid in the development of more targeted treatments of endotheliopathy and burn shock. Cytoskeletal rearrangement may be an interesting target for future work to understand this mechanistic interplay."}
+{"text": "Fall risk increases as older adults lose the functional resources necessary to maintain balance while completing everyday activities. As functional resources often decline gradually with age, momentary deficits may not be apparent until after a fall occurs. Mobile fall prevention technologies could support older adults in self-monitoring their ability to safely navigate their environments. In this paper we present perspectives on self-monitoring and feedback in a sample of older adults  who had self-assessed their balance via a smartphone for 30 consecutive days. Thematic analysis of semi-structured interviews showed that fall history differentiated a) participants\u2019 awareness of day-to-day variation in functional ability; b) trust in the accuracy of self-monitoring; and c) imaginations of what types of feedback a mobile fall prevention technology should provide. Insight on older adults\u2019 internal self-monitoring processes and guidelines for feedback design are discussed."}
+{"text": "ABSTRACT IMPACT: Our improved understanding of the changes in chromatin accessibility that occur in persistent pain states may identify regulatory genomic elements that play essential roles in modulating gene expression in the DRG. OBJECTIVES/GOALS: Efforts to understand genetic variability involved in an individual\u2019s susceptibility to persistent pain support a role for upstream regulation by epigenetic mechanisms. Our objective was to examine the transcriptomic and epigenetic basis of persistent pain following nerve injury. METHODS/STUDY POPULATION: We used a multiomic approach to identify novel molecular pathways associated with nerve injury-induced pain hypersensitivity. Adult Sprague Dawley rats were randomized to Chronic Constriction Injury (CCI) to the sciatic nerve or no treatment (naive). The ipsilateral L4-L6 dorsal root ganglia (DRG)s were removed on Day 14 and used for ChIP-seq for H3K4me1, ATAC-seq, and RNA-seq. We assessed for differential chromatin accessibility, transcription factor motifs, and enrichment for biological processes in chromatin accessible regions associated with cis-regulatory regions identified by ATAC-seq and H3K4me1 enrichment. Luciferase assays determined the functional significance of these sequences. RESULTS/ANTICIPATED RESULTS: We identified 58,446 genomic regions where H3K4me1 enrichment overlapped with chromatin accessibility. Differential analysis identified 2145 of these 58,446 regions that had changes in accessibility after CCI. The majority of these regions were located in introns or intergenic regions. Functional annotation of the differentially accessible regions identified disparate molecular functions enriched following nerve injury which suggests that altered chromatin structure plays a role in the development of mechanical hypersensitivity. Motif analysis identified specific transcription factor families whose binding sequences were enriched in regions of increased or decreased accessibility. Luciferase assays showed significant enhancement or repression of gene transcription. DISCUSSION/SIGNIFICANCE OF FINDINGS: Our data provides a comprehensive map of chromatin accessibility changes in the DRG after CCI and emphasizes the importance of chromatin structure in the development and maintenance of chronic pain."}
+{"text": "Some theories suggest that uneven distribution of collagen fibers in the mitral annulus leaves the posterior mitral annulus without a well-formed fibrous structure, which may predispose it to recurrent mechanical injury that leads to PVL. The reported incidence of PVL is 2.2%.2 Risk factors associated with PVL include the presence of mitral annular calcification, infective endocarditis, active steroid use, and continuous surgical suturing, which poses a greater risk than an interrupted surgical approach.3 Risk of PVL varies by prosthesis type, with mechanical prostheses carrying a higher risk of PVL than bioprosthetic valves.Despite improvements and advancements in surgical technique, paravalvular leaks (PVL) continue to present a challenge when caring for patients with prosthetic valve disease.Figure 1 illustrate a significant posterior PVL with dehiscence of the prosthetic valve from the mitral annulus. The patient underwent closure of the paravalvular leak with two 18-mm Amplatzer ventricular septal defect occluders (Abbott) with excellent results and trace residual mitral regurgitation post closure .Below are images of a 70-year-old male with severe mitral stenosis and pulmonary hypertension who had previously undergone mitral valve commissurotomy and subsequent mitral valve replacement with a bioprosthetic mitral valve. He presented to the hospital with pulmonary edema. Initial transthoracic echocardiogram showed depressed biventricular function with a dehiscence of the bioprosthetic mitral valve and a large eccentric posterior PVL, severe tricuspid regurgitation, and severe pulmonary hypertension. Transesophageal images in"}
+{"text": "An audit to assess the impact of an Integrated Psychological Medicine Service (IPMS) on healthcare utilization pre & post intervention. We hypothesized that an IPMS approach would reduce healthcare utilization.The IPMS focusses on integrating biopsychosocial assessments into physical healthcare pathways. It has developed in stages as opportunities presented in different specialities leading to a heterogeneous non-standardised service. The key aim is involvement of mental health practitioners, psychologists & psychiatrists in complex patients with comorbidity or functional presentations in combination with the specialty MDT. This audit is the first attempt to gather data across all involved specialities and complete a randomised deep dive into cases.Referrals into IMPS from July 2019 to June 2020 pulled 129 referrals, of which a 10% randomised sample of 13 patients was selected to analyse. 5 patients had one year of data either side of the duration of the IPMS intervention (excluding 8 patients with incomplete data sets).We analysed; the duration & nature of the IPMS intervention, the number, duration & speciality of inpatient admissions & short stays, outpatient attendances, non-attendances & patient cancellations. Psychosocial information was also gathered. One non-randomised patient was analysed as a comparative case illustration.Randomised patients; patient 78's utilisation remained static, patient 71 post-referral engaged with health psychology & reduced healthcare utilisation. Patient 7 increased healthcare utilisation post-referral secondary to health complications. Patient 54 did not attend & increased healthcare utilisation post-referral. Patient 106 had increased healthcare utilisation post-referral from a new health condition. The randomised sample identified limitations of using healthcare utilisation as an outcome measure when contrasted to the non-randomised case .Correlation only can be inferred from the data due to sample size, limitations & confounding factors e.g. psycho-social life events, acquired illness. Alternative outcome measurements documented (e.g PHQ9/GAD7) were not reliably recorded across pathways.The results evidenced that single cases can demonstrate highly desirable effects of a biopsychosocial approach but they can also skew data sets if results are pooled due to the small sample size & heterogeneous interventions. With some patients an increase in healthcare utilisation was appropriate for an improved clinical outcome. This audit identified that utilising healthcare utilisation as an outcome measure is a crude tool with significant limitations & the need to agree tailored outcome measures based on the type of intervention to assess the impact of IPMS."}
+{"text": "Older adults are viewed as being vulnerable to COVID-19. Previous research revealed that individuals would internalize or dissociate with attitudes toward aging when they aged. In this study, data collected before the COVID-19 pandemic were compared with those collected during the pandemic to assess whether the pandemic might make older adults internalize or dissociate with attitudes toward aging to a greater extent.123 Hong Kong participants  were recruited in a two-wave survey (wave 1 in 2018 and wave 2 in 2020) on attitudes toward aging and future self-views. After comparing the correlations between attitudes toward aging and future self-views in the two waves, we found stronger positive correlations between these 2 variables in wave 2 than in wave 1 in the personality and finance domains, but not in the family, independence, or health domains. These findings suggest that internalization of attitudes toward aging might be domain-specific. The pandemic might make older adults more likely to internalize positive personality attitudes toward aging and negative finance attitudes toward aging into their future self-views. Professionals may consider utilizing the internalization process to promote a positive attitude toward aging during the pandemic."}
+{"text": "Hepatitis B virus-related hepatocellular carcinoma recurrence after liver transplantation (LT) is notoriously difficult to manage and fatal. As a therapeutic option, adoptive cell therapy with HBV-specific TCR-redirected T cells could be employed to target and control relapses in these patients. However, indispensable immunosuppressive medications post-transplantation can significantly hinder the optimum efficacy of such therapy in the clinic. Here we report a new class of Armored TCR T cells which are able to attack recurrent cancer cells in liver transplanted recipients, while temporarily evading immunosuppressant drugs. We believe this strategy could open up new opportunities for treating pathologies under immunosuppressant treatment. Hepatocellular carcinoma (HCC), is the most common type of adult liver malignancy and a leading cause of cancer-related mortality globally. Different etiological factors are involved in HCC development, among which chronic Hepatitis B virus (HBV) infection accounts for approximately 50% of HCC cases globally . Among aOver the past decade, special attention was given to immune based therapy regimens such as immune check point inhibitor (ICI) and adoptive cell therapy as a promising treatment choice for HCC patients. ICIs are a type of immunotherapy drug which aims to rejuvenate and/or induce anti-tumor T cell responses. Clinical trials using ICIs have shown promising outcome in treating primary HCC . HoweverDespite the encouraging outcome of utilizing T cell immunotherapy in the initial trials, various factors present in the patient sera might adversely affect the optimum efficacy of such treatment. One of the main obstacles for implementing immunotherapy in organ transplanted subjects is the post-transplantation immunosuppression (IS) regimens which might hinder the efficacy of T cell therapy in these patients . In case"}
+{"text": "Knee osteoarthritis (KOA) is one of the most prominent causes of chronic pain, functional impairment, and disability in older adults. The current standards of care for KOA are aimed toward reducing pain and are largely comprised of analgesic medications, but existing pharmacologic approaches often produce significant adverse effects. Moreover, recent evidence suggests that KOA pain is characterized by alterations in pain-related brain mechanisms. Cranial electrical stimulation (CES), which delivers a low-amplitude alternating electric current to the brain, can facilitate the reversal of maladaptive brain function. Portable CES devices can be used at home with real-time monitoring through a secure videoconferencing platform to facilitate high adherence. Thus, the purpose of this pilot clinical study was to examine the preliminary efficacy of remotely supervised CES on clinical pain severity in older adults with KOA. Thirty participants with KOA were randomly assigned to receive 10 daily sessions of remotely supervised CES with 0.1 mA at a frequency of 0.5 Hz for 60 minutes (n=15) or sham CES (n=15). We measured clinical pain severity using the numeric rating scale . Participants  had a mean age of 59 years. Active CES significantly reduced scores on the NRS . Participants tolerated CES well without any adverse events. Our findings demonstrate the promising clinical efficacy of remotely supervised CES for older adults with KOA. Future studies with larger-scale randomized controlled trials with follow-up assessments are needed to validate and extend our findings."}
+{"text": "A best evidence topic has been constructed using a described protocol. The three-part question addressed was: In patients with Infrarenal abdominal aortic aneurysm (AAA), Does endovascular abdominal aortic repair (EVAR), AS compared to open surgical repair (OSR), has lower re-intervention rates? The outcomes assessed were the re-interventional rates in both techniques. The best evidence showed that the OSR has lower statistically significant difference rates in re-intervention rates than the EVAR. \u2022Endovascular abdominal aortic aneurysm repair is inferior to the open surgical repair regarding the re-intervention rates.\u2022Long term outcomes of the open surgical repair are better than the Endovascular repair.\u2022Secondary procedures are more in endovascular repair than the open surgical repair of abdominal aortic aneurysm. This fo1.1While consenting a 50-year-old man with AAA for EVAR repair, one of the junior doctors asked; which modality of AAA repair has lower re-intervention rates; EVAR or Open repair?\u2022\u2022[Which modality of treatment has lower re-intervention rates];\u2022[EVAR or OSR]?Three Parts Question:1.21.Embase 1974 to June 2021 using the OVID interface:[AAA OR Abdominal Aortic Aneurysm]AND [Open repair OR open surgical repair OR OSR] AND [EVAR OR Endovascular Repair] AND [re-intervention]2.Medline using the PubMed interface:[AAA OR Abdominal Aortic Aneurysm]AND [Open repair OR open surgical repair OR OSR] AND [EVAR OR Endovascular Repair] AND [re-intervention]\u2022Inclusion criteria: all original articles that review the re-intervention rate among patients with AAA who underwent open surgical repair vs. Endovascular Repair.\u2022Exclusion criteria: case reports, systematic reviews, letters to the editor, conference abstracts.The results were limited to English articles and human studies.1.3A total of 261 papers were found using both search engines. We excluded Two hundred twenty-three essays because they were irrelevant based on the titles and or the abstracts. Thirty-eight full-text articles were screened and assessed for eligibility. From these, we identified six papers to provide the best evidence to answer the question.23Treatment of AAA has changed remarkably in the last decade. EVAR is now increasingly used to treat AAA, especially in high-risk and elderly patients . This isThe re-intervention rates are also called secondary procedures and are defined as any endovascular or surgical procedure done after the first intervention. This procedure may be directly or indirectly related to the First aneurysm repair .In this article, we have reviewed the best studies that compared the two AAA repair modalities to evaluate which techniques have lower re-intervention rates.Only one study in our review showed no statistically significant difference between EVAR and OSR in re-intervention rates; this study was conducted by Majid et al. . This stIn contrast, there are another five trials; three of them were Randomized controlled trials which were conducted by Lederle FA et al. , Van SchAccording to the above articles, the best evidence shows a statistically significant lower re-intervention rate among patients with open surgical repair of abdominal aortic aneurysm in comparison to endovascular repair.Not requiredNoneAA: Conducted the literature search and wrote the paper. RI: Assisted in the literature search and Writing of paper. LY: Editing of writing. WSC: Assisted in writing of paper. MI: Assisted in the literature search and writing of paper."}
+{"text": "Spinal epidural lipomatosis (SEL) is a rare pathologic growth of histologically normal nonencapsulated adipose tissue in the epidural space. It can cause myelopathy or radiculopathy. Etiologies include chronic exposure to endogenous or exogenous steroids and obesity. Idiopathic forms are much infrequent. We present a case of lumbar SEL compressing the thecal sac in a 50-year-old female patient. A 50-year-old female patient presented to our radiology department complaining of lumbar and right lower extremity pain and weakness. Magnetic resonance imaging (MRI) of the lumbo-sacral spine demonstrated severe circumferential compression of the dural sac (from L5 to S1) caused by significant epidural fat hypertrophy Fig. , a findiSEL is a rare condition characterized by nonencapsulated adipose tissue accumulation in the thoracic or lumbar spinal canal\u2019s epidural space which can cause spinal cord or nerve root compression , 2. It c"}
+{"text": "Scientific Reports 10.1038/s41598-021-98503-w, published online 23 September 2021Correction to: The Funding section in the original version of this Article was incomplete:\u201cOpen Access funding enabled and organized by Projekt DEAL.\u201dnow reads:\u201cOpen Access funding enabled and organized by Projekt DEAL. The synchrotron xrd research leading to this result has been supported by the project CALIPSO plus under Grant Agreement 730872 from the EU Framework Programme for Research and Innovation HORIZON 2020.\"The original Article has been corrected."}
+{"text": "Taenia solium eggs and represents the parasitic disease with the greatest tropism for the human central nervous system,,,A 53-year-old man presented to the emergency department with headache and seizures. Axial fluid-attenuated inversion recovery (FLAIR) magnetic resonance imaging (MRI) revealed a nodular focus in the right temporal lobe with a halo of T2 hyperintensity . Compute"}
+{"text": "Epidemiological evidence indicates that 3-4% of community-dwelling adults over age 65 years old have functionally limiting deficits in both vision and cognition. The comorbidity prevalence is higher in older age strata and in long-term care. Seniors with co-occurrence of vision impairment and dementia have six times higher odds of disability and higher average annual Medicare fee for service costs  or neither condition . This talk will review evidence that people with early dementia and vision problems can experience improved function through appropriately tailored vision rehabilitation interventions. The talk will provide recommendations for unbiased cognitive assessment in visually impaired people. The session will outline research opportunities regarding the question of whether preventing or treating vision impairment may improve cognitive trajectories and neuropsychiatric symptoms in people with dementia."}
+{"text": "Agility in educational delivery has been catalyzed in response to national restrictions mandated by the recent COVID-19 pandemic. Increased use of assistive technologies further aligns with the General Medical Council's aims that medical educators provide an 'accessible training experience'. The study examined medical students' receptiveness to different types of interactive teaching. Two undergraduate cohorts received teaching on the Mental State Examination, either socially-distanced delivered by traditional powerpoint or remotely by mind-mapping software on a tablet hand-held digital device. We required an effective program which would retain the popular interactive elements of Psychiatry teaching and promote inclusivity across students' diverse learning styles.Two cohorts of Year 2 students from the Universities of Dundee and St Andrew's Scottish Graduate-Entry Medicine (scotGEM) course took part in an Introduction to Psychiatry seminar which involved a presentation of the Mental State Examination. One was conducted in a face-to-face setting via traditional PowerPoint. The second was conducted via remote-conferencing with mindmaps of key concepts drawn and screen-shared live to students as teaching progressed.This was a qualitative study, with online links to questionnaires for 24 student participants across 5 domains.  Response options included: strongly disagree, disagree, neutral, agree, strongly agree. A section was also included with open-ended questions pooled for thematic analysis.Response rate reached >60% with >80% respondents answering strongly agree across all domains. Thematic results demonstrated positive responses across both teaching sessions, with the interactive elements valued by students. Comments included: \u201cgreat job was done with the delivery of the session considering it was online rather than in person\u201d; \u201cdrawing element was fantastic\u201d; \u201cGood: interactivity of the session drawing and creativity element\u201d.The Mental State Examination (MSE) via live-drawn mind-maps allows salient clinical information to be conceptualised in non-linear diagramatic format. This paediological approach can offer further access points across wide range of learning styles. This pilot study demonstrated such interactive components of Psychiatry teaching continue to be well received and can be effectively delivered remotely. Such sessions also serve to promote inclusivity, linking those who are geographically distant in addition to the visual learner and the neurodiverse. We aim to incorporate these dynamic teaching sessions into our online induction programs and disseminate Intelligent Tutorials to our remote and rural learners throughout Scotland."}
+{"text": "High levels of transcription and alternative splicing are recognized hallmarks of gene expression in the testis and largely driven by cells in meiosis. Because of this, the male meiosis stage of the cell cycle is often viewed as having a relatively permissive environment for gene expression. In this review, we highlight recent findings that identify the RNA binding protein RBMXL2 as essential for male meiosis. RBMXL2 functions as a \u201cguardian of the transcriptome\u201d that protects against the use of aberrant (or \u201ccryptic\u201d) splice sites that would disrupt gene expression. This newly discovered protective role during meiosis links with a wider field investigating mechanisms of cryptic splicing control that protect neurons from amyotrophic lateral sclerosis and Alzheimer\u2019s disease. We discuss how the mechanism repressing cryptic splicing patterns during meiosis evolved, and why it may be essential for sperm production and male fertility. Pre-mRNA RNA splicing is a crucial mechanism in eukaryotes and is required to enable expression of protein-coding RNAs (mRNAs) from most mammalian genes. Splicing joins together exons within nascent RNA transcripts, thus creating open reading frames from split genes. Splicing is carried out by a molecular machine called the spliceosome . For accThe testis is considered a relatively permissive site for gene expression patterns. Most human genes produce multiple different mRNAs by using alternative splice sites or by using different combinations of exons. Such alternative splicing permits single genes to produce multiple mRNA isoforms to help amplify the information embedded in the genome. Particularly high levels of alternative splicing have been detected in the testis and in the brain compared to other tissues . Alternavia two sequential divisions. The first meiotic division is preceded by a long prophase that lasts around 2\u00a0weeks in mice, referred to as meiotic prophase I. This is divided up into five sequential sub-stages called leptotene, zygotene, pachytene, diplotene and diakinesis \u2013 all characterized by distinct chromosomal behaviors. During meiotic prophase I chromosomes condense, and non-sister chromatids form crossovers and undergo genetic recombination. Subsequently, cells separate sister chromatids through a second cell division called meiosis II. This produces haploid spermatids that after meiosis differentiate into spermatozoa  and Meioc  [Meioc genetic knockout spermatocytes have an unusually short meiotic prophase and do not reach pachytene or diplotene \u2013 the developmental window in which RBMXL2 protein is expressed . The loss of splicing factors can cause normally intronic regions to be included within incorrectly spliced mRNAs (rather than being removed by splicing). R-loops form as a result of transcription involving local melting of DNA close to the elongating RNA polymerase, and intronic regions remaining within the pre-mRNA being able to base pair with the melted DNA duplex (forming R loops), leading to DNA damage [Genes encoding mRNAs that are incorrectly spliced in the absence of RBMXL2 are enriched in functions associated with meiosis, chromosome segregation and spermatogenesis (Sara Luzzi unpublished). The inappropriate selection of cryptic splice sites in spermatocytes in the absence of RBMXL2 protein might therefore cause spermatocyte cell death by preventing proper expression of key genes needed for meiosis. RBMXL2 regulates splicing patterns of over a hundred genes during meiotic prophase. Important genes that contain cryptic splice sites that are repressed by RBMXL2 protein include rophase) . Exactlyxpressed . Similar meiosis . The effA damage . In prinA damage , it woulRBMXL2 gene originated via retro-transposition of an mRNA encoded by the X-linked gene RBMX approximately 65 million years ago. As a result of this, the RBMXL2 gene does not contain introns [RBMX gene) become transcriptionally silent during pachytene, within a heterochromatic structure called sex body (or XY body)  . This prRBMXL2 may functionally replace RBMX function during meiotic prophase, either as a direct \u201clike for like\u201d replacement or as a more specialized replacement that has evolved to control specific gene expression pathways needed for meiosis [MDM4 exon 6 [RBMXL2 is only expressed during and immediately after meiosis, so how are the genes controlled by RBMXL2 in the testis normally spliced in other tissues that do not express RBMXL2? A possible answer is that the splice events that are controlled by RBMXL2 during meiosis might be controlled instead by RBMX in other cell types within the body. In this scenario  meiosis . However meiosis . RBMX is4 exon 6 .bona fide splice sites. Cryptic splice site inclusion into mRNAs often disrupts protein-coding reading frames by introducing premature termination codons (PTCs). In cells that are not dividing by meiosis, PTC-containing mRNAs are degraded by an RNA stability pathway called Nonsense Mediated Decay (NMD) that prevents translation into truncated proteins that could be harmful to the cell. However, uniquely in the testes PTC-containing transcripts can become stabilized. This stabilization occurs during meiosis, thus increasing the likelihood of mRNAs originating from cryptic splicing being translated into potentially toxic proteins. The reason for this stabilization is because of meiotic-associated changes in the NMD pathway. One of the core protein components of the NMD pathway is a protein called UPF3B that is encoded by a gene on the X chromosome that is turned off during meiosis by MCSI. As a consequence its autosomal paralogue gene UPF3A becomes active when germ cells enter pachytene [UPF3A induces meiotic defects in a mouse model showing UPF3A expression is critical for meiosis [Why is it important to repress cryptic splice sites during meiosis? Conventional splice sites have evolved to enable exons to be precisely joined together and maintain protein-coding open reading frames. Since cryptic splice sites are usually not used they are not under the same selective pressure as achytene . Genetic meiosis . However meiosis . Hence mPtbp2 causes male germ cells to be prematurely sloughed off into the lumen of seminiferous tubules and defects to accumulate in the Sertoli cells cytoskeleton, suggesting impaired interactions between somatic and germ cells without PTBP2 protein [Other RNA binding proteins are also essential for splicing control during meiosis and have been recently reviewed . However protein . This te protein .Rbmxl2 knockout mouse model [How does cryptic splicing repression by RBMXL2 integrate with other recently discovered aspects of splicing control during meiosis? High-throughput RNA sequencing analysis of purified meiotic spermatocytes and spermatids show that 10% of the alternative splicing events during meiosis occur via intron retention ,24,60. Tse model . HoweverCBX5 gene within leukemia cells [A key question for the future is why do spermatocytes die without RBMXL2 protein, and to what extent does this resemble neuronal cell death in cells depleted for TDP43 activity? Is cell death caused by the loss of specific important proteins as a result of cryptic splicing events in protein coding mRNAs or does cell death result from genotoxic damage caused by accumulation of R-loops from incorrectly spliced mRNAs ? What isia cells ,66. Furt"}
+{"text": "Thrombus formation in the pulmonary vein (PV) stump after lung resection can cause rare cases of cerebral infarction. These infarctions can result in embolism and ischemia in the relatively large intracranial vessels, severely impacting the quality of life (QOL) of these patients. We performed endovascular thrombectomy successfully for this rare complication after lung lobectomy. A 73-year-old woman with paroxysmal atrial fibrillation (AF) suffered from sudden left complete hemiplegia 19 days after undergoing a left upper lung lobectomy (LUL). Magnetic resonance imaging\u00a0(MRI) showed middle cerebral artery occlusion. Her left hemiplegia improved after the endovascular thrombectomy. Cardiogenic embolism was first suspected, but contrast-enhanced computed tomography (CECT) showed thrombus formation in the PV stump. We continued anticoagulant therapy, and the thrombus resolved completely two months after the stroke. Our patient had a relatively good outcome due to the immediate reperfusion of the affected area. This embolic source may be overlooked because AF frequently occurs after thoracic surgeries. Care should be taken during the postoperative phase to avoid overlooking these emboli. All thoracic surgeons should be informed about mechanical thrombectomy as an effective treatment for postoperative cerebral infarction. Atrial fibrillation (AF) is a common complication that occurs after lung resection and sometimes causes systemic embolism , 2. HoweThe patient was a 73-year-old woman with hypertension and paroxysmal AF\u00a0(CHADS2 score: 1). She was not prescribed any anticoagulants but was controlled by antiarrhythmic medications and had not reported tachycardia for a few years. She underwent LUL via video-assisted thoracic surgery for lung adenocarcinoma . The postoperative course was uneventful except for paroxysmal AF, which continued for three days. The patient was then transferred to another hospital.The patient was transferred to our hospital for sudden left complete hemiplegia 19 days after the surgery. National Institutes of Health Stroke Scale 17 and electrocardiography showed AF. Magnetic resonance imaging (MRI) taken 160 minutes after the onset showed acute infarction in the right MCA region and the right M1 occlusion  showed thrombus formation in the left superior PV stump six days after the thrombectomy Figure  - A & B.Thrombus formation in the PV stump is a rare embolic source of cerebral infarction , 4 and hSome reports detected spontaneous echo contrast in the left superior PV stump using intraoperative ultrasonography or transesophageal echocardiogram , 13. TheAF is a common complication that occurs during the early period following lung resection and sometimes causes cardiogenic embolism , 2. AF oThere is no consensus whether perioperative anticoagulated therapy is indispensable after lung resection to prevent the thrombus formation in the PV stump -6, 8-9. In previous reports, infarction following lung lobectomy tends to occur in the relatively large intracranial vessels , 4, 15 aOur patient had a comparatively good outcome due to the immediate treatment. It is critical to consider the possibility of endovascular treatment when neurological deteriorations appear in patients following lung resection. Stroke physicians and thoracic surgeons should be aware that lung resection can be a source of emboli formation."}
+{"text": "Hair follicles (HFs) are unique, multi-compartment, mini-organs that cycle through phases of active hair growth and pigmentation (anagen), apoptosis-driven regression (catagen) and relative quiescence (telogen). Anagen HFs have high demands for energy and biosynthesis precursors mainly fulfilled by aerobic glycolysis. Histochemistry reports the outer root sheath (ORS) contains high levels of glycogen. To investigate a functional role for glycogen in the HF we quantified glycogen by Periodic-Acid Schiff (PAS) histomorphometry and colorimetric quantitative assay showing ORS of anagen VI HFs contained high levels of glycogen that decreased in catagen. qPCR and immunofluorescence microscopy showed the ORS expressed all enzymes for glycogen synthesis and metabolism. Using human ORS keratinocytes (ORS-KC) and ex vivo human HF organ culture we showed active glycogen metabolism by nutrient starvation and use of a specific glycogen phosphorylase (PYGL) inhibitor. Glycogen in ORS-KC was significantly increased by incubation with lactate demonstrating a functional Cori cycle. Inhibition of PYGL significantly stimulated the ex vivo growth of HFs and delayed onset of catagen. This study defines translationally relevant and therapeutically targetable new features of HF metabolism showing that human scalp HFs operate an internal Cori cycle, synthesize glycogen in the presence of lactate and modulate their growth via PYGL activity. Although HF epithelial cells contain abundant functional mitochondria3 they preferentially engage in aerobic glycolysis metabolizing 90% of glucose to lactate despite the presence of oxygen5.Anagen hair follicles (HFs) have one of highest rates of cell division seen in any mammalian tissue with correlating high levels of protein synthesis due to ongoing formation of the keratinized hair fibre7, cell metabolic needs extend beyond ATP production. Catabolism of glucose to lactate generate a high flux of metabolic precursors for biosynthesis, providing biomass accumulation9. HFs require energy and metabolite expenditure to maintain high proliferation rates, hair fibre production and hair cycle-associated HF remodelling. The importance of aerobic glycolysis to HF function has been demonstrated in mouse by the crucial role played by the enzyme lactate dehydrogenase and metabolism of glucose to lactate in the activation of epithelial HF stem cells (HFSC)10. Moreover, interplay between HF aerobic glycolysis OXPHOS and glutamine metabolism (glutaminolysis) functions as an important reversible switch between ORS lineage progression and their reversion back to HFSC11.Although aerobic glycolysis is considered energetically inefficient compared to mitochondrial oxidative ATP synthesis (OXPHOS)12. In the classical description of the Cori cycle, lactate from peripheral tissues such as the muscle is transported to the liver where it is converted via gluconeogenesis to glucose  and protect tissues from hyperlactatemia17.In a clinical context, excessive pathological production of lactate at the tissue level or impaired metabolism may cause lactic acidosisose Fig.\u00a0b13\u201315 wh19 , producing NADPH and biosynthesis precursors21. The ORS (outer root sheath) of HFs is reportedly rich in glycogen24. A role for glycogen in HF physiology has long been proposed both with regards keratinization23 and hair cycle regulation in mice25 and humans24.Glycogen permits osmotically neutral storage of energy and carbon19 Fig.\u00a0a. Glucos26, generated lactate may be utilized by the ORS and metabolized to glycogen via an internal HF/ORS Cori cycle, explaining the high levels of glycogen reported in the ORS22. We also asked whether ORS glycogen was available for HF metabolism and whether it played a role in HF function.We hypothesize that as HFs engage in aerobic glycolysis5 maintaining in vivo rates of keratinocyte proliferation, differentiation and hair fibre synthesis27 responding physiologically to a wide range of growth regulatory factors and hormones29. We now demonstrate functional glycogen synthesis and catabolism as well as the presence of an operative human HF Cori cycle. Further we show that inhibition of glycogen phosphorylase (PYGL) prolongs anagen maintenance and hair growth. Together these data show that HFs can utilize lactate from aerobic glycolysis to generate glycogen and that metabolism of glycogen plays an important role in human hair cycle regulation.To investigate this we have made use of isolated human HFs, a unique mini-organ model that can be cultured ex vivo where it continues to engage in aerobic glycolysis and glutaminolysis31 was detected in the suprabasal cells of the bulbar ORS  staining for glycogen25. Glycogen also markedly decreased in ex vivo human anagen VI HFs undergoing spontaneous catagen33 . Telogen  the major glucose transporter in human cells39 was strongly expressed in the ORS of anagen HF  downregulated  crucial in the conversion of glucose into glycogen  co-localizes within the same region of the ORS in anagen HFs as glycogen  is involved both in glycogen synthesis and degradation42. In anagen HF strongest PGM1 IF signal was detected in the cuticle  downregulated in catagen HFs . HFs maintained with GPI showed a statistically significant increase in overall hair follicle elongation over controls  and showed trends towards decreased glycogen levels compared to anagen control HFs although the effects of GPI on glycogen were mixed with 2 patients follicles showing strong response to GPI inhibition of glycogen metabolism but follicles from the third patient appearing to be unaffected  and distinct from the established bulge or stem cells region of human HFs5. The activity of lactate dehydrogenase and lactate production has been shown to drive the activation and maintenance of bulge HFSCs in mice, suggesting that metabolism acts as a stimulus in the switch between dormancy and proliferation10. Lactate generated by glycolysis in muscles is transported to the liver and where through gluconeogenesis lactate can be converted to glucose and replenish glycogen15. We showed that under conditions of nutrient starvation ORS-KC rapidly metabolized glycogen catalyzed by glycogen phosphorylase (PYGL). This demonstrated that glycogen can be utilized by the ORS and may be used as an energy store by the HF.The human HF is known to engage in aerobic glycolysis and to metabolize most of its glucose to lactate43 and the ORS contains all of the enzymes for glucose and glycogen synthesis, we asked whether HFs had an internal Cori cycle and could use lactate to generate glycogen. ORS-KC incubated with lactate significantly up-regulated glycogen levels and gluconeogenic enzymes suggesting that ORS-KC engage in gluconeogenesis and can synthesize glucose and glycogen from lactate and therefore operate an internal Cori cycle. This would allow HF to take up locally produced lactate for the synthesis of glycogen. We observed that the increase in glycogen in response to lactate was transient indicative of the glycogen shunt in which glucose is incorporated into glycogen and upon metabolic demand, enters\u00a0glycolysis\u00a0via phosphorylase rather than directly entering glycolysis, coupling glycogen synthesis and breakdown to glycolysis46.Since HF metabolize the majority of their glucose to lactate52. In memory CD8+\u2009T cells, G6P is channelled to glycolysis and to PPP to generate NADPH53. We also observed upregulation of G6PD, a key enzyme of PPP upon the treatment with lactate, suggesting similar mechanism occurring in the ORS.The glycogen shunt is frequently associated with tissues and cells that engage in aerobic glycolysis and allows cells to store glucose as glycogen for future use while maintaining homeostasis of glycolytic intermediates and ATP28 with a glycogen phosphorylase inhibitor (GPI). We used GPI to inhibit PYGL activity rather than siRNA knockdown on mRNA as we found in catagen HF that despite significant decrease in mRNA enzyme (protein) expression remained stable; possibly reflecting the long half-life of metabolic enzymes; moreover, the concentration of siRNA required to knockdown PYGL was toxic to the HF (not shown). GPI significantly stimulated HF growth which correlated with hair fibre production and significantly reduced the number of HFs entering catagen.Although the ORS contains high levels of glycogen it is not known whether this serves any function role-possibly as a HF energy store. To investigate this with regards human HF growth we cultured isolated human HF ex vivo54. our data showing that inhibition of by GPI significantly reduced the number of HF entering catagen suggest that PYGL activity is important for catagen. As the only known action of PYGL is glycogen breakdown this data suggest that glycogen metabolism is essential for catagen possible supplying the energy required for apoptosis. However, while measurement of HF glycogen showed an overall trend towards increased glycogen in GPI treated follicles  in the cuticle and the pre-cortex, together with the transient glucose accumulation suggest that they be may be regions of enzyme activity directed towards rapid keratinization and adapted to quick metabolic changes. Finally, the ORS could probably act as a stable glycogen storage site used both for anagen maintenance and remodelling and regression in catagen. This later role is suggested by our data showing that inhibition of PYGL by GPI significantly reduced the number of HF entering catagen suggesting that glycogen breakdown is essential for catagen but also despite significant decrease in mRNA expression in catagen, protein levels for the enzymes did not change significantly.Finally; glycogen has been proposed to play a role in keratinizationIn conclusion, we have shown that the HF ORS is a major site of glycogen synthesis and functional glycogen storage and is capable of gluconeogenesis. That inhibiting glycogen catabolism ex vivo promotes hair growth and delays catagen, prolonging anagen. This constitutes a promising target for future research with regards HF nutrition and nutrient sensing.27. ORS-KC were isolated as previously described56 with a modification-freshly isolated ORS-KC were seeded in collagen I  coated flasks and cultured in Keratinocyte Serum Free Medium . Starvation was performed by incubation in SILAC RPMI 1640 Flex Medium . PYGL inhibitor  and 2-NBDG  were diluted from stock DMSO solution in culture medium. Lactate  was diluted in culture media.HF units from occipital region were obtained from hair transplant patients and whole scalp skin samples from face lift patients following ethical approval granted by East London and The City Research Ethics Committee 1 (REC Alpha 09/H0704/40) and written informed patient consent, adhering to the Declaration of Helsinki Principles. All samples, slides and biological material were tracked and stored according to the \u2018Human Tissue Act\u2019 guidelines. Anagen VI HFs were microdissected and cultured as previously describedTotal RNA was extracted from ORS-KC and HFs using the Qiagen RNeasy Microkit  following the manufacturer\u2019s instructions. cDNA was synthesized using SuperScript VILO cDNA Synthesis Kit . qPCR was performed using Rotor-Gene SYBR Green PCR Kit . Relative expression was determined against B2M-Beta-2-microglobulin.Formalin-fixed paraffin-embedded (FFPE) sections were stained using Periodic Acid Schiff (PAS) Kit , according to manufacturer\u2019s protocol. Negative control sections were digested using porcine \u03b1-amylase . Sections were imaged using Nanozoomer slide scanner . PAS quantification was performed using ImageJ software, intensity of staining was calculated in the ORS of HFs and normalized to cell number.Antigen retrieval was performed on 5\u00a0\u00b5m FFPE tissue sections using Citrate buffer, primary antibodies  were incubated overnight at 4\u00a0\u00b0C followed by appropriate Alexa Fluor secondary antibodies  and DAPI for nuclear staining. Analysis of immunostaining were performed using DM5000B (Leica) and LSM880 (Zeiss) microscopes.Glycogen was quantified using a coupled enzyme colorimetric Glycogen Assay Kit  according to manufacturer\u2019s protocol, normalized to protein concentration [Pierce BCA Protein Assay Kit ].ORS-KCs and HFs homogenized in RIPA buffer containing protease and phosphorylase inhibitors  were separated using NuPAGE minigels  according to the manufacturer\u2019s instructions then transferred to a Trans-Blot Turbo PVDF membrane  and incubated overnight at 4\u00a0\u00b0C with primary antibodies  and thereafter with appropriate secondary horseradish peroxidase-conjugated antibodies . Membranes were imaged using Clarity ECL chemiluminescence solution  and visualized using ChemiDoc XRS .P value\u2009<\u20090.05.Biological replicates and number of HFs used are indicated in the respective figure legend. Statistical was carried out using either two-tailed paired t-test, one-way ANOVA or two-way ANOVA with multiple comparisons. Data was expressed as mean\u2009\u00b1 SEM and considered statistically significant at a Supplementary Information 1.Supplementary Information 2."}
+{"text": "A five-year-old boy presented to our emergency department with severe posterior neck pain that was exacerbated upon neck movement. Cervical spine radiography revealed calcification in the cervical intervertebral disk 3\u20134.Pediatric idiopathic intervertebral disk calcification is a benign, rare condition that might be complicated by associated severe neurological symptoms. In this case, the symptoms gradually subsided with conservative management alone. A five-year-old male with a history of asthma presented with complaints of neck pain that had persisted for one month. The pain exacerbated on bowing or exercising. Physical examination revealed that pain was elicited on performing neck movements, especially flexion-extension; neurological symptoms were not noted. Cervical spine radiograph was obtained .Pediatric idiopathic intervertebral disk calcification (PIIVDC) is a rare cause of neck pain in children, especially boys, 5\u201312 years of age, and is attributed to calcification of the intervertebral disks.2Neurological complications develop when the calcification herniates and compresses the nerve root or spinal cord.What do we already know about this clinical entity?Pediatric idiopathic intervertebral disk calcification (PIIVDC) is a benign, rare condition with unclear etiology.What is the major impact of the image(s)?PIIVDC is easily diagnosed with a plain radiograph. We should consider cervical spine radiograph as the initial test for children with neck pain.How might this improve emergency medicine practice?Emergency physicians should consider PIIVDC in their differential diagnosis of children with neck pain."}
+{"text": "Pseudoaneurysm formation is known to complicate arteriovenous haemodialysis access. Ultrasound guided thrombin injection is a recognised treatment option, but is not possible in pseudoaneurysms with no measurable neck. Balloon assisted techniques have been described in such cases, which transiently obstruct flow out of the pseudoaneurysm and thereby prevent non-target embolization during ultrasound guided percutaneous thrombin injection. We describe a balloon assisted technique for the treatment of a radial artery pseudoaneurysm, via retrograde access from the draining cephalic vein of an arteriovenous fistula.A 61-year-old male with a radio-cephalic fistula was found on duplex ultrasound to have a large radial artery pseudoaneurysm with no measurable neck, as well as a juxta-anastomotic cephalic vein stenosis. Endovascular treatment was selected over open surgery. Retrograde cephalic venous access was established, which allowed for concurrent treatment of both the venous stenosis and the arterial pseudoaneurysm. After balloon dilation of the juxta-anastomotic stenosis, a percutaneous transluminal angioplasty balloon catheter was advanced across the arteriovenous anastomosis and inflated across the neck of the radial artery pseudoaneurysm, to transiently obstruct blood flow. This allowed for safe injection of thrombin into the pseudoaneurysm by direct ultrasound guided sac puncture; thereby achieving thrombosis.Balloon assisted ultrasound guided thrombin injection is an endovascular treatment option that can obviate the need for open surgery in cases involving pseudoaneurysms with no measurable neck. The technique described allowed both concurrent treatment of a juxta-anastomotic venous stenosis and treatment of an arterial pseudoaneurysm from a single venous puncture. This technique avoided arterial access and its inherent complications. Pseudoaneurysm formation is a recognised complication affecting arteriovenous haemodialysis access. Cases that are not suitable for open surgical repair are often treated with minimally invasive techniques including ultrasound guided thrombin injection (UGTI) , using balloon-assisted UGTI with retrograde access from the cephalic vein draining the AVF. The procedure was undertaken on an outpatient basis, concurrently with venoplasty to treat a juxta-anastomotic cephalic vein stenosis.A 61-year-old male with a left radio-cephalic fistula presented with a low haemodialysis flow rate of 270ml/min; measured using a Transonic\u00ae flow-QC device . Duplex ultrasound (DUS) demonstrated a 24mm diameter pseudoaneurysm arising directly from the radial artery. Whilst the neck of the pseudoaneurysm was narrow, there was no measurable neck length, increasing the risk of non-target embolization with standard thrombin injection techniques , with good angiographic result.A 7\u2009\u00d7\u200940mm Sterling Balloon (Boston Scientific) was then advanced over the wire and positioned across the neck of the pseudoaneurysm under ultrasound guidance. The balloon was sized to match the diameter of the radial artery, which measured 7mm on DUS. The pseudoaneurysm was punctured with a 21-guage needle under ultrasound guidance. The 7\u2009\u00d7\u200940mm Balloon was then inflated, covering the pseudoaneurysm neck. 2mls of Thrombin was injected under ultrasound guidance, filling the pseudoaneurysm. The balloon was then deflated.After balloon deflation, DUS demonstrated a small amount of residual perfusion within the largely thrombosed pseudoaneurysm sac. This appeared to have resolved following ultrasound guided manual compression of the pseudoaneurysm. Follow up DUS 72\u00a0h later demonstrated a persistent 8mm area of perfusion within the pseudoaneurysm. A repeat procedure was therefore undertaken, employing the same technique as the initial procedure, requiring a further 1mls of thrombin to achieve complete thrombosis.No complications occurred during or immediately after either procedure. Both procedures were undertaken as day cases. A follow up ultrasound scan 72\u00a0h after the second procedure demonstrated complete thrombosis of the pseudoaneurysm with volume flow of 1400mls/min recorded in the brachial artery Fig.\u00a0. SuccessWe present a case of a radial artery pseudoaneurysm treated with balloon assisted UGTI with retrograde venous access via an ipsilateral radio-cephalic AVF. Whilst balloon assisted techniques for pseudoaneurysm embolization have been described previously (Mary et al. Our patient presented due to low haemodialysis flow and it is likely that resultant venepuncture difficulties caused the pseudoaneurysm, which lay immediately deep to the venous needling site. The position of the pseudoaneurysm also left it susceptible to further injury from inadvertent puncture during subsequent AVF cannulation.The location of the pseudoaneurysm in the mid/upper forearm made open surgery a technically difficult, higher risk treatment option. The radial artery lies deep to pronator teres at this position and the draining cephalic vein directly overlying the pseudoaneurysm would have needed to be mobilised. The patient also wished to avoid an overnight admission due to social circumstances.Treatment with a covered stent was considered and would have been attempted had balloon-assisted thrombin injection failed. The endovascular approach via the draining vein of the AVF also allowed concomitant treatment of the juxta-anastomotic stenosis; improving flow within the fistula.Arterial pseudoaneurysms in patients with radio-cephalic AVFs have previously been treated with balloon assisted techniques via a retrograde puncture of the distal radial artery (Aytekin et al. Residual filling of the pseudoaneurysm was identified by DUS following the first attempt at Thrombin injection and a second procedure was required to achieve sustained thrombosis. DUS follow up post procedure is essential to ensure thrombosis with no re-perfusion. At the time of writing the patient continues to dialyse successfully with no further complications. Clinical surveillance continues with physical examination of the AVF and regular measurement of volume flow on dialysis.This case demonstrates the feasibility of treating AVF related arterial pseudoaneurysms with no measurable neck with balloon assisted UGTI. Venous access in these cases may be preferable as it allows for concurrent treatment of AVF stenoses and carries a low risk of puncture site complications. The technique is adaptable for different anatomy and type of AVF and offers a minimally invasive treatment option as an alternative to open surgery."}
+{"text": "Gluten sensitivity can manifest with a spectrum of neurological dysfunction including ataxia, encephalopathy and neuropathy with or without associated coeliac disease (CD). Gluten sensitivity can also present with central nervous system (CNS) hyperexcitability and cortical myoclonus which is often accompanied with refractory CD. CNS hyperexcitability can also be associated with Glutamic Acid Decarboxylase (GAD) antibodies or much less commonly with Glycine Receptor Antibodies (GlyR-Abs) but the direct pathogenic roles of these antibodies remain debatable. We have previously reported a link between gluten sensitivity and anti-GAD associated ataxia which improves with the adoption of gluten-free diet. It is unclear if a similar link exists between gluten driven CNS hyperexcitability and the presence of GlyR-Abs. We report two cases of CD presenting with CNS hyperexcitability and associated GlyR-Abs. Apart from ataxia and cortical myoclonus, one patient had refractory CD and died from enteropathy-associated T-cell lymphoma. The other patient not only improved with strict gluten-free diet but also showed serological elimination of circulating GlyR-Abs. We conclude that there is an interaction between gluten sensitivity and GlyR-Abs-associated CNS hyperexcitability and in such patients gluten-free diet is an important therapeutic intervention. The elimination of GlyR-Abs by the adoption of gluten free diet suggests that these antibodies may represent an epiphenomenon rather than being directly implicated in the pathogenesis. Gluten sensitivity represents a spectrum of disorders triggered by the ingestion of gluten . The diaVarious neurological manifestations have been described in the context of gluten sensitivity the commonest of which are ataxia, neuropathy and encephalopathy . Other lStiff person Syndrome (SPS) is a rare autoimmune neurological disorder characterised by axial muscle stiffness and spasms, often accompanied by neuropsychiatric symptoms. SPS is usually associated with glutamic acid decarboxylase (GAD) antibodies found in 70% of cases . VariantWe have previously reported a significant overlap between gluten sensitivity and anti-GAD associated diseases. In our cohort of gluten sensitive patients we found anti-GAD antibodies to be present in a high proportion of patients who also displayed features of stiff person syndrome or ataxia , 11. FurBrain hyperexcitability is also seen in patients with gluten sensitivity with and without CD although patients with persistent cortical myoclonus tend to have refractory CD . It is uThis was a 72-year-old man with a past medical history of hypertension and immune mediated hypothyroidism. He first presented to secondary care with a history of weight loss. His biochemistry profile revealed iron deficiency anaemia, low vitamin D, low folate and normal vitamin B12. CD was suspected and serological testing showed positive tissue transglutaminase antibodies (TTG), gliadin antibodies and endomysium antibodies (EMA). Gastroscopy and duodenal biopsy confirmed villous atrophy, crypt hyperplasia and increased intra-epithelial lymphocytes consistent with CD. He commenced gluten-free diet. Six months later, he presented with worsening mobility and further weight loss and at that point he was noted to have marked ataxia and right facial myoclonus that was speech sensitive. He admitted that he was not adhering to a strict gluten-free diet.Neurophysiological assessment was undertaken with a Natus Quantum amplifier  at a sampling rate of 2048\u2009Hz. The recording included a multichannel electroencephalography (EEG) and surface EMG polygraphy . Data were exported for quantitative EEG/EMG analysis in Spike 2 (version 8.12) software . Somatosensory evoked potential (SEP) recordings were also performed and the possibility of C-reflexes  was assessed with surface EMG electrodes from arms and legs based on previously published methods . The recFurther serological testing revealed positive GlyR-Abs (using a cell based assay) and negative GAD antibodies. Paraneoplastic antibodies were also negative. MRI spectroscopy was markedly abnormal with N-Acetyl-Aspartate to Creatinine (NAA/Cr) ratio of 0.67 from the superior vermis and 0.61 from the cerebellar hemisphere . Reduced NAA/Cr is indicative of cerebellar neuronal dysfunction. PET-CT imaging revealed no malignancy. His neurological symptoms continued to worsen. Further immunohistochemistry on the original duodenal biopsy showed clonal changes supporting a diagnosis of refractory CD type 2 but without any evidence of enteropathy associated lymphoma. The patient was started on budesonide and mycophenolate. Levetiracetam was tried for the myoclonus. He continued to deteriorate clinically primarily due to worsening ataxia and eventually required PEG feeding as well as becoming bed bound. A repeat duodenal biopsy showed enteropathy-associated T-cell lymphoma (EATL). At that point he was deemed unfit for chemotherapy and passed away in hospital shortly after from pneumonia. This was 1 year after his initial presentation.This was a 20-year old man who presented with 8-year history of progressive painful leg spasms and extreme fatigue. He experienced difficulty with running which he used to enjoy. He felt that his muscles were becoming increasingly stiff every time he went for a run. His family also noted cognitive slowing which interfered with his academic performance. Initial investigations by his General Practitioner showed him to be iron deficient. As a result, screening for CD revealed an extremely high level of TTG antibodies, EMA and gliadin antibodies. Duodenal biopsy confirmed CD and he started a gluten-free diet. He was referred to the Gluten sensitivity/neurology clinic in Sheffield UK. Examination revealed ataxic gait, increased tone and stiffness in both lower limbs with hyper-reflexia. He had exaggerated startle response. Imaging of the neural axis did not show any abnormality apart from reduced NAA/Cr ratio of 0.81 from the vermis. The ratio from the right cerebellar hemisphere was 0.9 .EEG/EMG polygraphy undertaken as described in the previous patient did not show evidence of cortically driven myoclonus from the right thigh on cross correlation analysis. There was no abnormality in the SEP study. Exaggerated startle response was noted following presentation of an unanticipated auditory stimuli. Blink reflex excitability studies (implemented as a semiquantitative assessment of brainstem excitability) while using a short inter-stimulus interval between a conditioning and a test stimulus after 160\u2009ms were performed. Single square pulse electrical stimulation of the supraorbital nerve was delivered at 20\u201325\u2009mA and a 0.2\u2009s pulse width. The blink reflex study was noted to be abnormal with persistence of a well formed R2 component recorded following the test stimulus. This electrophysiological assessment is used as a semiquiantitative assessment of brainstem excitability .GlyR-Abs were positive and anti-GAD negative. After adopting a strict gluten-free diet he noticed gradual improvement in his symptoms. He was now able to run again and resume his academic career. After 2\u2009years on strict gluten-free diet and normalisation of the gluten sensitivity-related antibodies his glycine receptor antibodies became negative. Repeat electrophysiology showed normalisation of the blink reflex study. Repeat brain image showed improvement of the NAA/Cr ratio from the vermis (from 0.81 to 0.88).We have previously identified a link between gluten sensitivity and anti-GAD associated SPS as well as anti-GAD ataxia , 11. HerEvidence of pathogenicity for these antibodies does exist. In vitro and in vivo studies have demonstrated that binding of GAD by anti-GAD antibodies suppresses GABA release with an epitope dependence, leading to the development of cerebellar ataxia, thus suggesting that GAD antibodies may be implicated in the pathophysiology of anti-GAD ataxia . SimilarA clinical spectrum of neurological disease associated with GlyR-Abs has been described . Indeed Brain hyperexcitability can be a prominent feature in some patients with CD and neurological dysfunction . This usWe conclude that a small number of patients with neurological manifestations of CD and in particular those with hyperexcitable brain syndromes may have GlyR-Abs. Gluten-free diet may be an effective therapeutic intervention in such patents. Such diet seems to also result in serological elimination of GlyR-Abs at least in one case reported here. Confirmation of this observation in a larger series would be desirable."}
+{"text": "We report the case of a 78-year-old female patient who had a PASCAL device implanted for severe degenerative mitral regurgitation. Intraprocedural echocardiography revealed persistent severe mitral regurgitation due to device dislocation. Implanting another device was not possible. After 8\u2009days, the device was explanted, and the valve was replaced with a biological prosthesis. The PASCAL device and resected mitral valve leaflets were sent for histopathological workup. Transcatheter mitral valve repair is an alternative to surgery in symptomatic patients with secondary mitral valve regurgitation (MR) who are at high risk or deemed inoperable. Transcatheter mitral valve repair is an alternative to surgery in symptomatic patients with secondary mitral valve regurgitation (MR) who are at high risk or deemed inoperable. Percutaneous treatment in degenerative MR is still debated . We presA 78-year-old female patient was diagnosed with severe symptomatic  degenerative MR with posterior prolapse and a flail leaflet in the P2 segment due to chordal rupture. Transthoracic echocardiography showed a calcified mitral annulus, a preserved left ventricular ejection fraction (62%) and no concomitant tricuspid regurgitation. The heart team recommended mitral valve surgery, but the patient refused the operation even though she had no comorbidities (EuroSCORE II 1.86%). She was offered transcatheter intervention with the PASCAL device. Implanting the device was technically uneventful; however, persistent severe MR was observed intraoperatively due to device-leaflet detachment  and Cytosorbents Corp. The other authors have nothing to disclose. Interactive CardioVascular and Thoracic Surgery thanks Lenard Conradi and the other, anonymous reviewer(s) for their contribution to the peer review process of this article."}
+{"text": "A 25-year-old woman presented to the emergency department with two weeks of crampy right-flank pain, and urinary urgency and frequency. She was found to have a staghorn calculus filling her entire right renal pelvis on computed tomography imaging.In contrast to ureteral calculi, staghorn calculi are more commonly observed in female patients and typically present with an indolent clinical course. A low threshold for imaging should be maintained, as prompt referral to urology for stone removal or treatment is necessary. Staghorn calculi have a high likelihood of leading to renal failure or urosepsis without treatment. A 25-year-old Hispanic female presented to the emergency department (ED) with two weeks of waxing and waning right-sided flank pain. She described the pain as a cramping discomfort that worsened over the two weeks and was only mildly relieved by acetaminophen. She also reported urinary frequency and urgency without dysuria or hematuria. Physical examination was notable for right upper quadrant and mild right costovertebral angle tenderness. Urinalysis showed nitrite negative, leukocyte esterase positive urine with 685 white blood cells per high power field, 53 red blood cells per high power field, and appreciable bacteria. A computed tomography (CT) from the ED revealed a right staghorn calculus with hydronephrosis along with left nephrolithiasis , 2.Staghorn calculi are the only type of renal stones more commonly observed in female patients as a result of their association with urinary tract infections.What do we already know about this clinical entity?Struvite calculi are composed of magnesium ammonium phosphate (struvite) and calcium carbonate-apatite and are caused by urinary tract pathogens.What is the major impact of the image(s)?This image depicts struvite calculi within the renal pelvis and calyces giving the characteristic \u201cstaghorn\u201d formation for which these stones are also named.How might this improve emergency medicine practice?As these stones are notably more insidious in presentation, earlier recognition and urgent referral will hopefully result in better outcomes for patients."}
+{"text": "This study examines spouses who are in a caregiving situation to discern how they influence each other\u2019s health. Previous studies reported health concordance and cross-domain effects among caregiver and care-recipient dyads. However, it is less understood of the health dyadic relationships among spouses who are in a caregiving situation. No studies have specifically looked into the relationship between self-rated health (SRH) and cognitive functioning among spousal caregiving dyads over time. In this study we analyzed the longitudinal reciprocal relationships between SRH and cognitive functioning measured by the Telephone Interview for Cognitive Status among older adults and their spousal caregivers, and whether the relationship differed by whether husband or wife was the caregiver. Longitudinal data from the Health and Retirement Study (2010-2016) on 540 dyads were pooled and analyzed using structural equation modeling under an actor-partner interdependence model. Results revealed cognitive concordance among older spouses in which caregivers\u2019 cognition is associated with care-recipients\u2019 cognition subsequently . SRH concordance was not significant. Cross-domain results showed only one significant direction, that is, care-recipients\u2019 cognition in the subsequent time was significantly correlated with caregivers\u2019 SRH, regardless of whether husband  or wife  was the caregiver. Our study found that married couples in a spousal caregiving situation displayed cognitive but not overall health concordance, and cross-domain effects of caregiver\u2019s SRH on spousal care recipient\u2019s cognition subsequently. The reciprocal associations suggest that addressing and improving either partner\u2019s physical health and cognition may benefit both dyad members."}
+{"text": "With improved systemic therapy that has limited impact on the intracranial compartment, the incidence of brain metastasis (BM) from solid cancers is rising and negatively impacting patient\u2019s overall survival (OS). Treatment varies based on presentation, however, for patients with <4 symptomatic BMs current clinical practice involves surgical resection followed by stereotactic radiosurgery (SRS) to the resection cavity. Post-operative SRS is associated with increased risk of leptomeningeal disease (LMD) and local recurrence in the follow-up period. We hypothesize that pre-operative SRS will decrease the incidence of LMD as well as local recurrence and increase patient\u2019s OS by delivering a lethal dose of radiation to tumor cells before they are disturbed by surgical resection. In a Phase II clinical trial (NCT03398694) we are treating patients with 1\u20134 symptomatic BMs with pre-operative SRS while collecting DNA and RNA sequencing data from core and peripheral edges of the resected tumor to examine the genomic effects of SRS on tumor.Post-SRS resected tumor specimens were divided into two groups: \u2018center\u2019 and \u2018periphery\u2019 with respect to the center of SRS treatment with periphery within 50% isodose line. Previously resected untreated BMs were used as control. DNA and RNA were isolated from all samples for sequencing.Our initial analyses show that pre-treatment with SRS, results in significant genomic changes at DNA and RNA levels throughout the tumor, in both center as well as periphery. Furthermore, significant transcriptomic differences were noted among matched samples between the central and peripheral SRS locations implicating differential effect of SRS dosing within a tumor. Initial gene ontological analysis on non-small cell lung cancer samples demonstrated an overexpression of WNT and BMP signaling pathways . These pathways are typically involved in neuronal development, hinting that adaptation to the brain microenvironment was occurring post SRS treatment."}
+{"text": "Pilonidal sinus is an acquired condition caused by irritation to the hair follicles at the natal cleft, presenting with an abscess or chronic infection. It is prevalent in young adults affecting their productive lifestyle with morbidities. There are varieties of treatment options; however, there is no consensus yet for the ideal procedure. Less invasive procedures have evolved to replace the traditional surgical techniques, which cannot significantly reduce the risks of recurrence and wound complications despite extensive surgeries. We aimed to assess the effect of fibrin glue as a primary treatment after cleaning the sinus in pilonidal sinus disease. We searched for articles from PubMed\u00ae, Ovid MEDLINE\u00ae, Ovid EMBASE\u00ae, and Cochrane CENTRAL. Six studies that included 336 patients in total were analyzed. Fibrin glue treatment in these studies reported a quicker return to normal activities postoperatively, a low rate of infection, and an acceptable rate of recurrence. Thus, fibrin glue seems beneficial in the management of pilonidal disease. However, further high-quality studies are essential to support and confirm this evidence. Future research should also evaluate its cost and implications in the ambulatory service. Although there is no precise etiopathogenesis for this disease, the hypothesis is related to the recurrent erosion of hair follicles at the natal cleft  OR (\"fibrin\"[MeSH Terms] OR \"fibrin\"[All Fields] OR \"fibrins\"[All Fields] OR \"fibrine\"[All Fields]) OR (\"fibrinogen\"[MeSH Terms] OR \"fibrinogen\"[All Fields] OR \"fibrinogens\"[All Fields] OR \"fibrinogen s\"[All Fields] OR \"fibrinogene\"[All Fields]) OR (\"Fibrin Tissue Adhesive\"[MeSH Terms] OR (\"fibrin\"[All Fields] AND \"tissue\"[All Fields] AND \"adhesive\"[All Fields]) OR \"Fibrin Tissue Adhesive\"[All Fields] OR \"tissucol\"[All Fields]) OR  OR \"calcium chloride\"[All Fields] OR \"Fibrin Tissue Adhesive\"[MeSH Terms] OR (\"fibrin\"[All Fields] AND \"tissue\"[All Fields] AND \"adhesive\"[All Fields]) OR \"Fibrin Tissue Adhesive\"[All Fields] OR \"tisseel\"[All Fields] OR \"fibrinogen\"[MeSH Terms] OR \"fibrinogen\"[All Fields] OR \"fibrinogens\"[All Fields] OR \"fibrinogen s\"[All Fields] OR \"fibrinogene\"[All Fields] OR \"fibrinolysis inhibitor\"[All Fields] OR \"thrombin human\"[All Fields] OR \"thrombin\"[MeSH Terms] OR \"thrombin\"[All Fields] OR \"thrombin s\"[All Fields] OR \"thrombine\"[All Fields] OR \"thrombins\"[All Fields]) OR (\"Fibrin Tissue Adhesive\"[MeSH Terms] OR (\"fibrin\"[All Fields] AND \"tissue\"[All Fields] AND \"adhesive\"[All Fields]) OR \"Fibrin Tissue Adhesive\"[All Fields] OR \"tissel\"[All Fields]) OR (\"Fibrin Tissue Adhesive\"[MeSH Terms] OR (\"fibrin\"[All Fields] AND \"tissue\"[All Fields] AND \"adhesive\"[All Fields]) OR \"Fibrin Tissue Adhesive\"[All Fields] OR \"beriplast\"[All Fields]) OR (\"Fibrin Tissue Adhesive\"[MeSH Terms] OR (\"fibrin\"[All Fields] AND \"tissue\"[All Fields] AND \"adhesive\"[All Fields]) OR \"Fibrin Tissue Adhesive\"[All Fields] OR \"crosseal\"[All Fields]) OR (\"Fibrin Tissue Adhesive\"[MeSH Terms] OR (\"fibrin\"[All Fields] AND \"tissue\"[All Fields] AND \"adhesive\"[All Fields]) OR \"Fibrin Tissue Adhesive\"[All Fields] OR \"transglutine\"[All Fields])) AND ) OR  OR \"Pilonidal Sinus\"[All Fields] OR  OR \"pilonidal cyst\"[All Fields]) OR )). Table Eligibility CriteriaBoth new and recurrent pilonidal sinus disease were considered in this study. We included articles that reported the outcome of\u00a0fibrin glue as the primary treatment with the cleaning of the sinus.\u00a0There was no limitation to the age of patients. Any brand of fibrin sealant, including fibrinogen or a mixture of fibrinogen and thrombin, was studied. The inclusion criteria were articles published within the last ten years (2011-2021), studies related to humans only, and those published in English. We excluded review articles, those published earlier than 2011, and non-English papers.\u00a0Study Selection ProcessTwo authors independently identified records via databases, followed by the removal of duplicates. Titles and abstracts of studies were then screened. We excluded non-relevant documents. Reports of relevant themes were retrieved to assess their eligibility. We applied the eligibility criteria mentioned above to include great studies in our review. The opinion from the third author was sought when the agreement was not achieved between the two authors throughout the selection process. We also designed a data extraction form to collect the data from the included studies.Risk of Bias and Quality AssessmentWe\u00a0included six observational studies\u00a0assessed for bias using the Newcastle-Ottawa Scale (NOS). Two reviewers\u00a0independently judged the risk of bias in each article. In addition, a discussion with the third author was performed for any variability in the risk of inclination between the two reviewers.\u00a0ResultsOne hundred and twenty-six articles were retrieved from the searching of databases. Ninety-two duplicates were removed, leaving 34 papers. Six themes were non-relevant after screening the abstracts and titles; therefore, they were excluded from the review. Out of 28 reports, one report could not be recovered. We were able to retrieve 27 articles to be assessed for eligibility.\u00a0With the careful consideration of inclusion and exclusion criteria, two authors independently assessed the remaining articles and selected six articles finally. This process can be seen in the PRISMA flow diagram, Figure We extracted the data from selected six articles. The demographics such as the author's name, year of publication, location of study, sample size, age, and the number of male patients are presented in Table Table DiscussionThe management of the pilonidal disease can be divided into operative and non-operative management .\u00a0DespitePost-Procedural InfectionAlmost all of our included studies reported the rate of infection developed after the intervention.\u00a0Smith et al. reported that the group treated with pit excision and fibrin glue (PEF) had a comparable infection rate managed by lateralizing flap procedure (LFP). The infection rate was seven percent in the group treated with LFP, whereas eight percent in the PEF group. Forty-one children with a mean age of 15 were included in this study. The sealant they injected was TISSEEL\u00a0 [The comparative study by Saedon et al. evaluated the outcome of those who had cleaning the sinus tract obliterated by fibrin sealant with the other group who had excision of the sinus tract and primary closure. The sample size was 34, with an equal division between the two groups. Those managed with fibrin sealant revealed an infection rate of six percent, while those allocated to have excision and subsequent closure resulted in a 47% postoperative infection rate. There was an outstanding contrast in the infection rate among the groups with a p-value of 0.045. But this evidence was uncertain since the antibiotic was given before the procedure in some patients with infection .Hardy et al. also reported a low rate of infection, which was 11.1%. It was a retrospective study of new and recurrent pilonidal sinus disease in those aged 15-17. It investigated the effect of fibrin glue, TISSEEL, applied in the cleaned sinus tract without giving any prophylactic antibiotic .\u00a0These studies described non-identical surgical procedures and the application of fibrin glue with diverse brands and volumes. Some of them comprised of small sample size, and none of them was a randomized controlled trial. Two studies focused on only pediatric participants. There was no uniformity in the judgment of the use of pre-operative antibiotics. Due to this variableness among studies,\u00a0the overall impact of fibrin glue on the rate of infection is inconclusive. This finding is consistent with the previous systematic review conducted by Lund et al. .\u00a0Recurrence of Pilonidal SinusReturn of the disease\u00a0is one of the most critical outcomes of interest for both clinicians and patients. The condition is esteemed to have a recurrence if the clinical features reappear and at least one firm or two soft-recurrence criteria are met after the wound has fully healed without any injury to the natal cleft postoperatively . VariousEvery surgical treatment for the pilonidal disease has its recurrence rate, which varies depending on the type of surgical technique and the duration of the follow-up. For example, a low recurrence rate of 0.6% was reported in Limberg & Dufourmentel operations whereas 0.2% in Karydakis & Bascom procedures at 12-month follow-up period. However, primary midline closure was associated with a recurrence rate up to 67.9% 20 years after surgery . FurtherIsik et al., one of these retrospective studies, assessed patients who had a new presentation of a single sinus without previous infection or treatment. They looked into 40 cases. Fibrin glue was used to obliterate the dead space left after the sinus tract was curetted. It reported a recurrence rate of 10% . Sian etThe different range of follow-up and the nature of the pilonidal sinus in participants could be the possible causes of this variability among the studies. The follow-up ranged from four months to 32 months. Generally, the recurrence after fibrin glue therapy does not indicate concern according to the results of included studies.\u00a0Return to Normal ActivitiesSince the pilonidal disease manifests mainly in the productive age group, the time taken to restart work and school is a significant concern from the socio-economic point of view. Therefore, this factor becomes one of the outcomes of interest. Hardy et al. found that the median time for daily tasks was only three days . Elsey ePatient SatisfactionElsey et al. was the only study that discussed patients' satisfaction rate after having the fibrin glue procedure. This cross-sectional study evaluated the responses of 57 patients who had undergone cleaning of the sinus tract with a surgical scoop followed by fibrin glue injection. Cases were carefully selected, excluding those with acute abscesses and multiple recurrences. 79% of patients were pleased with the outcome due to rapid recovery, less surgical stress, and less pain after receiving this management . The abiWhy Our Study I/s ImportantVarious therapeutic techniques with multiple studies are available to treat the pilonidal disease, which means the ideal one is not recognized yet. According to previously published review articles, the quality of evidence is not strong enough to confirm the impact of fibrin glue on managing pilonidal disease , 23. HowLimitations of Our StudyOur systematic review analyzed six publications, including the recent studies. However, some limitations exist, such as excluding unpublished studies and having no randomized controlled trial to review. Moreover, we had only studies between 2011 and 2021 to focus on the updated information. As a result, the review might not be comprehensive.Our review is to evaluate the therapeutic effect of fibrin glue on pilonidal disease. Although our studies report relatively better outcomes regarding the recurrence rate, infection, and the time to return to normal activities, more extensive studies with proper randomization and longer duration of follow-up are still essential to confirm this weak promising result of fibrin glue. Moreover, none of these studies discussed its cost related to its primary and recurrent therapy. Therefore, the success rate compared to its price is debatable. Since other cost-effective procedures with comparable results are available, future studies should look into them meticulously. It will help discover the most feasible and ideal therapeutic option for pilonidal disease. Further research should also provide more robust evidence for using fibrin glue to fill the sinus tract under local anesthesia in the ambulatory service or general practice among selected patients."}
+{"text": "Frostbite (FB) is a severe form of cold injury that may result in significant morbidity. Freezing causes formation of ice crystals and protein denaturation leading to cellular damage and tissue necrosis. Although commonly affecting populations who live and work or become stranded in cold environments, the true prevalence is unknown due to lack of standardized reporting. Dry ice is a solid form of carbon dioxide commonly found in the food industry, that can reach temperatures as cold as -110 degrees Fahrenheit and can be purchased at local department stores. Exposure to dry ice is an unusual cause of FB injury that could occur anywhere, especially in warmer climates. Healthcare professionals practicing in warmer climates may be unprepared to assess and treat patients with such injuries.We describe a case of self-inflicted FB injury to the bilateral lower extremities (BLE) following intentional submersion in dry ice who presented to a Southern U.S. Burn Unit.A 20-year-old man with self-diagnosed Body Integrity Identity Disorder (BIID) sustained a 12% TBSA FB injury to his BLE following intentional submersion in dry ice for an estimated 4 hours . He presented to the Burn Center from an outside facility approximately 12 hours post injury with initial rewarming having already occurred. He immediately underwent catheter directed intra-arterial thrombolysis with tissue plasminogen activator (TPA) for leg length preservation. TPA infusion was initiated at 16 hours post-injury for a total infusion time of 24 hours. Wound care consisted of gentle twice daily cleansing with silver sulfadiazine and mafenide acetate creams. The patient ultimately required bilateral below the knee amputations which successfully healed with minimal autografting to the distal limbs. He was formally diagnosed with schizophrenia by our behavioral health team and initiated on risperidone. He underwent aggressive physical therapy and was discharged home with his parents after 21 days. He underwent weekly mental health follow up appointments and has been seen regularly in our burn and rehabilitation clinic.This unusual case is one of few to describe Grade 4 FB after exposure to dry ice and highlights that severe FB may occur in any climate and can cause severe morbidity. Severe cold injury management is important for burn care professionals to maximize tissue and limb preservation."}
+{"text": "We report a case of a 64-year-old man with a fusiform right extracranialvertebral artery aneurysm, spanning over half the extra-cranial V2 segment, presenting with recurrent multi-focal posterior circulation embolicischaemic stroke. The patient was treated with endovascular embolisation of theright vertebral artery to prevent further thrombo-embolic events. Distal andproximal occlusion of the aneurysmal vertebral artery was performed with amicro-vascular plug with partial aneurysm sack embolisation to aid thrombosisand reduce the risk of recanalisation. Two months post procedure MR angiographyconfirmed successful aneurysm occlusion with no post-procedural complication.The patient returned to his normal independent life. Endovascular treatment withvessel sacrifice is an effective treatment with low morbidity and we believe theMVP device to be a efficacious option in the vertebral artery. Primary (non acute traumatic) aneurysms are even rarer and arise due toconnective tissue diseases; predominantly Ehlers-Danlos syndrome, Marfan syndromeand Neurofibromatosis, and much less commonly secondary to arteriosclerosis.Extracranial vertebral artery aneurysms are uncommon and the vast majority of reportsare associated with trauma representing pseudo-aneurysm formation and acute.Reported causes have included such obscure cases as being gored by an ox,68 mass effect causing dysphagia, neck pain1015 and radiculopathy.,, Presentation also includes posterior circulation ischemia and infarction withclinical features of dizziness, diplopia, nausea, dysarthria, dysphagia, ataxia,unilateral limb weakness and visual field defects. In general posterior circulationstrokes account for 20\u201325% of all ischaemic stroke.Extracranial vertebral artery aneurysms can present following rupture and symptomsrelated to acute haemorrhage,We report an unusual case of a growing chronic long length fusiform vertebral arteryaneurysm extending over half the length of the extra-cranial segment presenting withrecurrent multi-focal embolic posterior circulation acute infarction which wassubsequently treated with endovascular embolisation. In addition we have reviewedthe literature on treatment of chronic and perceived primary extracranial vertebralartery aneurysms and excluded acute trauma cases.A 64-year-old man presented with acute onset of dizziness and a left sided fielddefect. The patient complained of \u2018dazzling bright lights\u2019 in the left lower fieldof vision. He had no headache or neck pain and there was no recent trauma. Pastmedical history included cholecystectomy and migraine with aura, but no regularmedications. Subsequently in the patient\u2019s admission further questioning by theinterventional neuroradiologist revealed the patient had fallen down subway stairstwenty years previously with significant trauma but did not receive any treatment.On examination there was a left lower homonymous quadrantinopia. National Instituteof Health Stroke Scale of 1 was attributed to the partial visual field defect.Routine biochemical and hematological investigations were all within normal limitsexcept a mildly elevated cholesterol at 5.1\u2009mmol/L and non-HDL 3.5\u2009mmol/L. ECGdemonstrated sinus rhythm. Blood pressure recorded 181/92\u2009mmHg with the remainingobservations within normal parameters. The patient was a semi-retired publican, anon-smoker and consumed 20units of alcohol per week. Previous soft tissue neckimaging from 2015 for an intramuscular lipoma identified a right vertebral arteryaneurysm with cervical spine remodeling, the patient was asymptomatic and no followup imaging was arranged. Although dedicated vascular imaging was not undertaken atthat time maximal axial aneurysm dimension measured approximately 13\u2009mmmaximally.Initial CT identified hypoattenuation in the right occipital lobe consistent withinfarction subsequently confirmed on MR but with multiple further foci of infarctionin the posterior circulation involving the right occipital lobe, left thalamus andcerebellum in keeping with acute embolic infarction . The T2 CT angiography demonstrated a grossly dilated right vertebral artery measuring up to35\u2009mm in diameter isolated to the V2 . Areas of stenosis wererelated to the constraint of the aneurysmal vertebral artery in the transverseforamina, which would predispose to turbulent flow and hence aneurysm progressionand thrombus formation. The aneurysm had a thick thrombus lining the lumen withareas of fissuring and crenulation , the aneThis case was urgently discussed in a dedicated neurovascular multi-disciplinary teammeeting, composing of interventional neuro-radiologists, neuro-surgeons andneurologists. Careful discussion was undertaken with the patient regarding the riskbenefit of best medical therapy, endovascular or open surgical treatment. Given theevidence of historic \u2018silent\u2019 thrombo-embolic events, based on establishednon-restricting multifocal elevated T2 foci on MRI, and the theoretical risk offuture catastrophic major vessel thromboembolism in the posterior circulation thepatients preference was for interventional treatment. Urgent endovascular evaluationand treatment of the aneurysmal right vertebral artery to prevent further embolicischaemic strokes or rupture of the aneurysm was undertaken. Digital subtractionangiography (DSA) confirmed a chronic fusiform aneurysmal right vertebral arterywith areas of saccular dilatation. The origin, V1 segment , V3segment  and V4 segment  and basilarartery were normal .The patient underwent general anaesthesia prior to endovascular intervention(American Society of Anaesthesiologists (ASA) grade 1). Procedure was performed in abiplane neuro-interventional suite .Under ultrasound guidance the right common femoral artery was punctured and a 6\u2009Frsheath inserted. 5000units of intra-arterial heparin was administered. Initialangiogram in the left vertebral artery confirmed excellent calibre and supply to thebasilar and posterior circulation. An unfolded aortic arch was encountered butcatheterisation with a 5\u2009Fr vertebral curve catheter of the right subclavian arterywas relatively uncomplicated. An exchange manoeuvre was performed to gain stableaccess with a 80\u2009cm 8\u2009Fr Neuronmax  long sheath. A 5\u2009FrSofia  with an Excelsior XT-27 microcatheter  and Synchro microwire  was navigated through to the V3segment. Embolisation was performed with a proximal 5\u2009mm micro-vascular plugs (MVP-3Microvascular Plug) and distal 3\u2009mm plug and five platinumcoils (Microplex)  . Post-em atorvastatin 40\u2009mg and amlodipine 5\u2009mg once daily. Two months post proceduretime of flight MR angiography confirmed no flow in the aneurysmal segment andstandard imaging did not demonstrate any post-procedural infarction. The patientreturned to his normal pre-procedural state leading an independent life with no newneurological deficit.The patient was transferred to the neuro-intensive care unit and recovery wasunremarkable, subsequently he was discharged on dual anti-platelet therapy (aspirinand clopidogrel) for 21\u2009days, then clopidogrel 75\u2009mg once daily lifelong, as percurrent secondary prevention guidelines,,,915,,2029 twelve of which were notassociated with a connective tissue disorder  which may have mandated either surgery or complex stent assisted treatment topreserve the vessel.Although direct comparison between surgery and endovascular treatment of extracranialvertebral artery aneurysm has not been performed or likely to be feasible, given thelow incidence, treatment of intracranial vertebral artery dissection aneurysms hasbeen subject to meta-analysis from which one might glean some information. Bothsurgical trapping and stent-assisted coiling demonstrated high rates of goodlong-term neurologic outcomes and low recurrence and mortality rates in intracranialdissecting vertebral artery aneurysms, but one should consider these in the contextof acute dissection and the pre-existing morbid state.In the literature there were twenty-one patients with follow up which reportedperi-operative complications in four patients and symptomatic improvement wasreported in fourteen patients (66%), one patient had recurrent radiculopathy, onehad new radiculopathy and one endovascular patient developed a delayedarterio-venous fistula. Therefore treatment of vertebral artery aneurysms can bedeemed relatively safe and lead to improvement in local symptoms. The risk profileis similar to any endovascular vessel occlusion procedure. Technical factors would also preclude the use of flow diverting stent as thelargest available measure 5\u2009mm in maximal diameter, although the stent could besized to the \u2018normal\u2019 proximal and distal vessel there would still be long length ofstent with no apposition. The authors felt immediate vessel sacrifice with themicrovascular plug device was the quickest option with the lowest risk profile. Itwas felt preservation of the distal extracranial vertebral artery (V3 segment) wasnot required as the main aim was to preserve the right PICA, which was clearlyachieved by retrograde flow in the right V4 segment. Vessel sacrifice has long beenknown to be a definitive procedure to manage any aneurysm with low morbidity ifadequate intracranial anastomosis and perfusion is confirmed. The microvascular plug(MVP) device has been primarily used in peripheral vascular procedures, such as inrenal artery occlusion. The benefit of the MVP was ease of deployment and relative low cost comparedto specific neurovascular devices, perhaps historical detachable balloon devicewould also have been a consideration, but have since been removed from the market. Complete aneurysm sacembolization was not undertaken as this was felt to be excessive as proximal anddistal control was achieved and also this would allow some regression in the localmass effect given the distortion of the pharynx, in addition this would haverequired many coils with significant cost. Of note previous report of proximalligation resulted in continued aneurysm filling from muscular anastomosis and a case treated with proximal endovascular embolisation resulted inpersistent filling and even developed aberrant outflow to become fistulous. Therefore it is essential to obtain distal and proximal occlusion. In thiscase partial embolisation of the aneurysm sack was also performed to aid thrombosisand reduce the risk of recanalisation.Flow diverting stent placement was not favored in this case for several reasons.Primarily wall apposition plays an important role in speed of and likelihood ofendothelialization of the flow diverting stent, this in turn is critically importantfor aneurysm occlusion., however death from rupture into the thoracic cavity despite emergentendovascular balloon placement to control haemorrhage has been reported. The risk of lifetime rupture is unknown given the rarity of these lesions andthe incidence is likely higher than reported as many cases remain asymptomatic. Mostreports are associated with an underlying connective tissue disorder and growth ofthe aneurysm can be asymptomatic, aneurysms have been reported to measure up to 5\u2009cmdiameter, over ten times the normal calibre. Continued aneurysm growth must be taken into consideration, in a paediatricpatient with Neurofibromatosis type-1 followed up from age one to seven showedprogressive enlargement of a vertebral aneurysm with associated upper limb symptoms,as well as massive aneurysmal dilatation of the thoracic aorta. This highlights the importance of appropriately counselling the patient ontreatment and possible future growth if untreated.Rupture of an extracranial vertebral artery aneurysm can result in simple haematomaand neck painExtracranial vertebral artery aneurysms are a rare entity and can present withposterior circulation ischaemic strokes. They are most often associated with anunderlying connective tissue disorder; however, primary aneurysm formation orprevious trauma are possibilities to consider. Endovascular treatment with vesselsacrifice is an effective treatment with low morbidity and we believe the MVP deviceto be a efficacious option in the vertebral artery."}
+{"text": "In conclusion, neurological recovery was an independent factor having a significant positive association with post-operative neck pain attenuation in patients with cervical myelopathy caused by OPLL who underwent cervical spine surgery.Although favourable surgical outcomes for myelopathy caused by cervical ossification of the posterior longitudinal ligament (OPLL) have been reported, factors significantly associated with post-operative neck pain attenuation still remain unclear. The primary aim of the present study was to determine factors significantly associated with post-operative neck pain attenuation in patients with cervical OPLL using a prospective multi-centre registry of surgically treated cervical OPLL. Significant postoperative neck pain reduction (50% reduction of neck pain) was achieved in 31.3% of patients. There was no significant difference in neck pain attenuation between surgical procedures. Statistical analyses with univariate analyses followed by stepwise logistic regression revealed neurological recovery as a factor having a significant positive association with post-operative neck pain attenuation ( Computed tomography screening has revealed an unexpectedly high prevalence of OPLL in the cervical spine, which affects about 7\u201310% of the general population in Japan3. Increase of thickness of ossification foci can cause compression of nerve roots and the spinal cord, possibly resulting in neurological deficits4. Favourable surgical outcomes for cervical OPLL have been reported. Nerve root and spinal cord symptoms including numbness, palsy, and vesico-rectal disturbance can be attenuated after surgery for cervical OPLL5.Ossification of the posterior longitudinal ligament (OPLL) is a disease with heterotopic ossification in the spinal posterior longitudinal ligament6. Previous reports revealed neck pain attenuation by cervical spine decompression/fusion surgeries for cervical OPLL10. However, the precise aetiology of neck pain, postoperative change of neck pain, and factors significantly associated with post-operative neck pain attenuation in patients with cervical OPLL still remain unclear.In addition to neurological symptoms including radiculopathy and myelopathy, cervical OPLL can cause local symptoms such as neck pain and stiffness, which can be main complaints for patientsThe primary aim of the present study was to elucidate the post-operative change of neck pain and to determine factors significantly associated with post-operative neck pain attenuation in patients with cervical OPLL using a prospective multi-centre registry of surgically treated cervical OPLL.Patient demographics are shown in Table There was no significant difference in pre-operative VAS neck pain score between surgical procedures. Post-operative VAS neck pain scores, neck pain reduction score, and proportion of neck pain reduction showed no significant difference between surgical procedures Table .Table 3Cp\u2009=\u20090.04, odds ratio 5.68 , Table Age, diabetes mellitus, disease duration and Japanese Orthopedic Association score for evaluating cervical myelopathy (JOA score) recovery rate were identified as possible candidates for factors having significant association with postoperative neck pain attenuation by initial uni-variate analyses Table . LogistiThe present results demonstrated that neurological recovery was an independent factor having a significant positive association with post-operative neck pain attenuation.There are many previous reports showing the possible aetiologies of neck pain.11. Various kinds of muscle preserving posterior approaches have been reported to attenuate post-operative axial neck pain14. The anterior approach does not invade the posterior musculo-ligamentous complex; therefore, post-operative muscle-related neck pain can be decreased compared with that in the posterior approach15. However, the present results showed that there is no significant difference in post-operative neck pain attenuation between surgical approaches (anterior and posterior) or surgical procedures , suggesting that surgical damage of the cervical musculature has no significant association with post-operative neck pain in the present patient series. Possible explanations for this discrepancy in muscle damage-related neck pain between previous reports and the present data might be as follows: the posterior approach-related muscle damage decreased according to the recent popularization of muscle-preserving posterior approaches and the impact of posterior approach-related muscle damage might be limited to the early post-operative phase and not the chronic phase.Axial pain, as first reported by Hosono, which is defined as post-operative neck pain related to posterior approach-induced muscle damage, is regarded as a major cause of post-operative neck pain18. Fusion surgery can be indicated for discogenic/facet genic neck pain because this category of pain can theoretically be attenuated by fusion of the pain-generating segment19. However, the present results unexpectedly showed that there was no significant difference in post-operative neck pain attenuation between segmental motion-preserving laminoplasty and fusion surgeries (anterior and posterior). Therefore, discogenic/facet genic neck pain was not likely to be a major aetiology of neck pain in the present series.Discogenic and/or facet genic neck pain, which is caused by degenerated intervertebral disks and facet joints accompanied with segmental instability, can be another possible source of neck pain19. Segmental spinal cord sign caused by compressive myelopathy may, like girdle pain, be another origin of neck pain20. Segmental spinal cord compression can cause local impairment of the spinothalamic tract at its chiasma at the central grey matter of the spinal cord21. Irrespective of the precise cause, a large-scale cohort study revealed that cervical myelopathy can cause neck pain22.The present results revealed post-operative neurological recovery as an independent factor having a significant association with post-operative neck pain attenuation. These lines of evidence suggest that neurogenic pain is one of the major causes of neck pain in patients with cervical OPLL. There might be several possible origins of myelopathy-related neck pain. Spinal cord compression can stimulate the posterior ramus of the spinal nerve, possibly resulting in neck painIn addition, there is a possibility that the natural course of the disease is attributed to postoperative neck pain attenuation. Theoretically, progression of ossification foci can lead to spontaneous fusion of intervertebral segments, potentially resulting in neck pain attenuation. However, we could not find articles describing the natural history of neck pain in OPLL patients. Therefore, we had no proper answer for this question at present. Our multicenter study group is now constructing another prospective registry for OPLL patients receiving non-operative treatment with long term follow-up. Precise natural course of OPLL might be elucidated in future.23. Therefore, the outcome might be changed significantly if cervical sagittal alignment data were added. To solve this problem, future collection of data regarding cervical sagittal alignment is needed. Another major limitation of the present study is that the present registry lacks information about the precise location and characteristics of neck pain and evaluation of neuropathic pain. Those data are important to elucidate the origin of neck pain. As a result, we can only speculate on the origin of neck pain using indirect evidence including post-operative change of neck pain, pre-operative patient factors, surgical factors, radiological changes, and neurological status. Future data collection of the precise characteristics of neck pain and neuropathic pain evaluation are warranted.The present study includes several major limitations. The present registry lacks data regarding cervical sagittal alignment. Recently, the concept of sagittal alignment has been introduced to the cervical spine, similar to the thoracolumbar spine. Cervical sagittal alignment is important to evaluate neck pain because it has been reported to correlate with neck painIn conclusion, neurological recovery was an independent factor having a significant positive association with post-operative neck pain attenuation in a prospective study of a cohort of patients with cervical myelopathy caused by OPLL who underwent cervical spine surgery.We used a prospective cohort design for the present study.We assembled as investigator\u2019s meeting before the initiation of the present study and twice a year during the study period for training to standardize the data collection and imaging analyses. All the clinical and imaging data were collected by physicians except for surgeons who performed surgery in each institute. Cleaning of collected data was performed by the committee member of the present study group. Missing data was mainly caused by patients\u2019 drop out from follow-up.24. We also excluded patients received anterior\u2013posterior combined surgery because the number of those patients was very small (n\u2009=\u20097) to obtain statistical significance.The registry included data from 478 patients who underwent cervical spine surgery for myelopathy caused by cervical OPLL. Amongst these patients, we excluded data from those who lacked pre-operative neck pain evaluation (40 cases), who showed a pre-operative neck pain score\u2009<\u200930\u00a0mm on a visual analogue scale  to avoid possible ceiling effects in evaluation for pain attenuation and several previous pain trials set similar exclusion criteriaTherefore, we included data from 265 patients with cervical OPLL and a pre-operative neck pain severity score\u2009\u2265\u200930\u00a0mm on a VAS. Patient demographics are shown in Table 24. In addition, another reason why we adopted 50% pain reduction as the outcome measure is that the impact of absolute value of pain evaluation could differ between patients having different preoperative neck pain.Neck pain was evaluated using the VAS score pre- and post-operatively. The proportion of VAS score reduction was calculated as (pre-operative VAS neck pain\u2014post-operative VAS neck pain) / pre-operative VAS neck pain\u2009\u00d7\u2009100 (%). Post-operative neck pain deterioration was expressed as the negative proportion of VAS score reduction. We employed \u201c50% pain reduction\u201d as classification for sufficient postoperative neck pain attenuation because we think it is comprehensive at a glance and it is one of the popular outcomes in pain research fieldPossible explanatory factors having significant association with postoperative neck pain attenuation were as followings.Patient factors Patients factors included age at surgery, sex, body mass index, disease duration, and diabetes mellitus.Neurological status Pre- and post-operative neurological status were analysed using the Japanese Orthopedic Association score for evaluating cervical myelopathy . The recovery rate of JOA score was calculated using the following method: (post-operative JOA score\u2014pre-operative JOA score) / (17 (full mark)\u2014pre-operative JOA score)\u2009\u00d7\u2009100 (%)26. Post-operative neurological deterioration was expressed as the negative value JOA score recovery rate.Imaging factors Imaging factors including types of OPLL  in lateral radiogram of cervical spine  curves to determine their cut-off values. All the statistical analyses were conducted with statistical analytics software JMP  under the supervision by the biostatistician in our department (one of the co-author KF). Those statistical analyses were performed on data obtained 1 and 2\u00a0years after surgery.Factors showing a"}
+{"text": "Immigrant family caregivers for persons living with dementia (PWD) have constant stress due to the 24/7 responsibility. These family caregivers of PWD often have high morbidity and mortality. We provided a cultural and language specific home-visit intervention for these vulnerable family caregivers. There is a lack of an objective measure of stress for caregivers. We assessed caregivers\u2019 stress by measuring heart rate variability (HRV), a physiological measure of stress, using a smartwatch for a one-month intervention. Weekly home visits for a month were provided to dementia family caregivers by trained community health workers with stress reduction techniques: mindful breathing and compassionate listening. Linear mixed-effect models were used to analyze the trends for the daily stress levels as measured by HRV from the smartwatch. We had 22 participants who completed the 4-week intervention . The models showed a significant decrease in the stress level of all participants for 3 weeks . At 28 days (4 weeks) all three groups showed a decrease in stress: Korean group , Vietnamese group , Latino group  and all caregivers . The findings demonstrated a reduction of immigrant family caregiver stress with a home-visit weekly intervention for one month using mindful breathing and compassionate listening by culturally/linguistically appropriate community health workers. Large-scale studies to determine long-term outcomes of family dementia caregivers are necessary and should be carried out."}
+{"text": "Parachute mitral valve with reticular chordae tendineae is an extremely rare anomaly.We present a case of parachute mitral valve associated with distinctive reticular chordae tendineae in an adult. It was diagnosed from the echocardiogram. The patient was referred for surgery. Valve analysis showed thickened mitral valve leaflets and commissures. The chordae tendinae were lengthy and thick. All the chordae tendinae merged into a solitary papillary muscle. A distinctive reticular fibrous tissue was found on mitral valve apparatus as the chordae tendinae intermixed each other. The only functional communication between the left atrium and the left ventricle was through the reticular spaces. This anomaly was considered to be unrepairable and was replaced with a mechanical valve.An extremely rare and unique case of parachute mitral valve associated with reticular chordae tendineae was reported. Mitral valve replacement is a reasonable choice in patients with parachute mitral valve with reticular chordae tendineae.The online version contains supplementary material available at 10.1186/s13019-021-01448-4. Parachute mitral valve (PMV) is characterized by a unifocal attachment of the mitral chordae tendinae to a single papillary muscle , 2. VeryA 36-year old man developed exertional dyspnea and fatigue of 2\u2009months duration. There was no history of orthopnea or paroxysmal nocturnal dyspnea. Physical examination revealed a well-built man with supine right upper arm blood pressure of 135/76\u2009mmHg, regular pulse rate of 88 beats/min, and no evidence of heart failure. Precordial examination showed normal heart sounds, a 3/6 diastolic rumble murmur. No opening snap or third sound was audible. An electrocardiogram revealed sinus rhythm with a heart rate of 86beats/min, left atrial overload and normal atrio-ventricular conduction. The chest skiagram showed mild left atrial prominence. Routine Laboratory tests showed no anaemia, liver dysfunction or renal dysfunction. He underwent detailed transthoracic echocardiographic examination.2 with a trans-mitral peak and mean gradient of 9 and 5\u2009mmHg respectively. Abnormal chordae tendineae with reticular structures attached to a solitary papillary muscle originating from the posteromedial wall was detected (Fig. Echocardiogram revealed dilated left atrium, normal left ventricle and normal left ventricular function. Mitral valve area by planimetry and the pressure half-time method was 1.02\u2009cmThe patient was referred for surgery. The operation was performed through a minimally invasive right thoracotomy with the use of cardiopulmonary bypass. Through an interatrial approach, the mitral annulus, leaflets, chordae tendinae, and papillary muscles were exposed. Valve analysis showed two thickened mitral valve leaflets and commissures, but all the chordae tendinae merged into a solitary papillary muscle. It presented as a funnel-type structure. The chordae tendinae were lengthy and thick. A distinctive reticular fibrous diaphragm with scattered holes obstructing the valvular orifice was found on mitral valve apparatus as the chordae tendinae intermixed each other Fig.\u00a0. An addiThe postoperative recovery was uneventful. The patient was discharged 7\u2009days after surgery. At the 5-year follow-up examination, the patient was in good health.Parachute mitral valve is a very rare congenital mitral valve anomaly which may remain asymptomatic in life-time or may present with mitral valve stenosis or regurgitation or both. It is characterized by unifocal attachment of the chordae tendineae of both leaflets to a single papillary muscle. It is highly associated with other congenital heart anomalies. Isolated PMV in an adult is very rare, while the presence of a reticular chordae tendineae--as in the present case--is extremely exceptional.In the developmental process of mitral valve, PMV occurs due to disturbed delamination of the anterior and posterior parts of the trabecular ridge . These pAlthough adult patients with isolated PMV usually present with dyspnea, PMV may be incidentally diagnosed during echocardiography. Such patients generally require no medical or surgical treatment. Mitral valve surgery when feasible needs to be performed only in those patients with hemodynamically significant stenosis or regurgitation . It is wWe reported an extremely rare and unique case of parachute mitral valve associated with reticular chordae tendineae in an adult. Mitral valve replacement is a reasonable choice in patients with this anomaly when the leaflets are thickened and severely stenotic.Additional file 1:. Abnormal chordae tendineae which was attached to a solitary papillary muscle originating from the posteromedial wall was detected. A small muscular ridge or trabecula was present at the location of anterolateral papillary muscle without any chordal attachment.Additional file 2:. 3D transesophageal echocardiography showed reticular chordae tendineae with scattered holes among them.Additional file 3:. Valve analysis showed all the chordae tendinae merged into only 1 major papillary muscle. The chordae tendinae were lengthy and thick. A distinctive reticular fibrous diaphragm with scattered holes obstructing the valvular orifice was found on mitral valve apparatus as the chordae tendinae intermixed each other. The only functional communication between the left atrium and the left ventricular was through the reticular spaces."}
+{"text": "To describe the spontaneous closure of a degenerative lamellar macular hole with epiretinal proliferation (LHEP) as documented with tracked spectral domain optical coherence tomography (SD-OCT).A 54-years-old diabetic female patient presented with progressive vision loss in the left eye. SD-OCT illustrated LHEP associated with cystic fluid in the outer nuclear layer. Sequentially tracked SD-OCT showed progressive closure of the degenerative lamellar macular hole and resolution of the CME over almost 4\u00a0years, in the absence of any surgical intervention.LHEP may represent a specialized form of degenerative epiretinal membrane associated with Muller cell activation. Spontaneous degenerative LMH closure may rarely occur with these lesion types, in the absence of surgical intervention, possibly due to Muller cell proliferation preceded by PVD. Lamellar macular hole (LMH) with epiretinal proliferation or LHEP is a unique form of degeneration associated with secondary Muller Cell proliferation . These EIn this report, an interesting case of LHEP is presented in which the lamellar macular hole spontaneously closed without surgical intervention. We present the sequential tracked OCT findings of this outcome and discuss the mechanism of closure which may relate to Muller cell activation preceded by posterior vitreous detachment (PVD).A 54-year-old female type 2 diabetic patient presented with a history of progressive vision loss of the left eye (OS). The right eye was legally blind due to end stage proliferative diabetic retinopathy (PDR).On examination, best corrected visual acuity (VA) was hand motions in the right eye and 20/200 in the left eye. Ophthalmoscopic retinal examination OD was not possible due to a prepupillary fibrotic membrane. Retinal examination OS showed panretinal photocoagulation scars and evidence of regressed fibrotic PDR.Spectral domain \u2013 optical coherence tomography (SD-OCT) OS illustrated a lamellar macular hole with epiretinal proliferation associated with cystic degeneration predominantly located in the outer nuclear layer Fig.\u00a0A. A gradSD-OCT 1\u00a0year later illustrated persistent LHEP, improvement of the CME and a partial grade 3 PVD  or lamellar macular holes (LMH) with epiretinal proliferation (LHEP) represent a distinct subset of ERM easily differentiated from tractional ERMs . AlthougMuller cell activation and proliferation may lead to non-surgical closure of the LMH that was documented in this case report with sequentially tracked SD-OCT over 2\u00a0years . BringmaSurgical management may be deferred in these cases due to the degenerative Muller cell component and the stable natural history.LHEP may represent a specialized form of degenerative lamellar macular hole associated with Muller cell proliferation. Non surgical closure may rarely occur with these lesion types possibly due to Muller cell activation preceded by PVD."}
+{"text": "In vivo modeling combined with CRISPR/Cas9-mediated somatic genome editing has contributed to elucidating the functional importance of specific genetic alterations in human tumors. Our recent work uncovered tumor suppressor pathways that affect EGFR-driven lung tumor growth and sensitivity to tyrosine kinase inhibitors and reflect the mutational landscape and treatment outcomes in the human disease. Sequencing data of human tumors show that EGFR alterations co-occur with alterations in many putative tumor suppressor genes.2 Whether these alterations have biological implications and whether their relative alteration frequency reflects their functional importance remains largely unknown. Understanding the extent to which tumor suppressor gene alterations contribute to TKI sensitivity and resistance could improve treatment approaches (EGFR mutant tumors.2Tyrosine kinase inhibitors (TKIs) are the standard of care treatment for oncogenic epidermal growth factor receptor (EGFR)-driven lung adenocarcinomas.proaches . Moreovein vivo studies on the function of tumor suppressor genes in oncogenic EGFR-driven lung cancer. This was at least partially due to the absence of suitable autochthonous EGFR-driven lung cancer models with which to investigate the biological consequences of gene inactivation.3 In our recent work, we leveraged tumor barcoding with high-throughput barcode sequencing (Tuba-seq)5 and applied it to a novel model of EGFR mutant and Transformation related protein 53 -deficient lung adenocarcinoma to study the functional importance of tumor suppressor genes that are frequently altered in human lung tumors.3 \u20136 Our findings revealed tumor suppressor genes that when inactivated promoted tumor growth, most notably RNA binding motif protein 10 (Rbm10), Retinoblastoma 1 (Rb1), and Adenomatous polyposis coli (Apc).3 Importantly, these tumor suppressor genes were also some of the most frequently altered genes in EGFR/P53 mutant human lung tumors, supporting the importance of these tumor suppressor pathways in driving EGFR mutant lung tumors.3AT-rich interaction domain 1A (Arid1a) and Cyclin-dependent kinase inhibitor 2A (Cdkn2a) inactivation appeared to increase tumor growth only later during tumor progression, suggesting that specific tumor suppressor genes can have different effects at different stages of tumor development. Inactivation of other putative tumor suppressor genes that we investigated did not promote tumor growth, indicating that the function of some tumor suppressor genes may be highly context-dependent  may play a role in determining genetic epistasis, suggesting that experimental approaches are particularly important for understanding why this is observed.7 Oncogenic EGFR alterations (mainly affecting EGFR exons 18 through 21) and oncogenic Kirsten rat sarcoma viral oncogene homologue (KRAS) missense mutations  represent major drivers of lung adenocarcinoma.2 Given that both these oncogenes are components of the same pathway, we anticipated that tumor suppressor genes would have similar impacts on in vivo growth of EGFR and KRAS mutant lung tumors. Although inactivation of Rbm10, Rb1, or Apc did have similar effects on EGFR and KRAS mutant tumor growth, Serine/threonine kinase 11  and SET domain containing 2, histone lysine methyltransferase (Setd2) inactivation had opposite effects in the two oncogenic settings. Lkb1 and Setd2 inactivation are two of the strongest drivers of KRAS mutant tumor growth; however, their inactivation reduced EGFR mutant tumor growth.8 These results correlate with the relative frequency of LKB1 and SETD2 alterations in human EGFR and KRAS mutant lung tumors, suggesting the existence of a synthetic lethal relationship between Lkb1/Setd2 inactivation and oncogenic EGFR. These findings underscore the importance of quantitative modeling of genetic alterations in vivo. More broadly, the observation that inactivation of certain genes can have different effects depending on the specific oncogenic alteration present  revealed surprising context specificity of the role of these genes in cancer  inactivation reduced sensitivity to this therapy.3 Our in vivo data mirror clinical data suggesting that KEAP1 pathway alterations predict poor clinical responses to TKIs.3 Thus, we established a causal link between this tumor suppressor pathway and TKI sensitivity in EGFR mutant lung adenocarcinoma.Osimertinib, a third generation TKI that leads to better overall survival compared to other TKIs, has been approved as first-line therapy for patients with metastatic EGFR-driven lung cancer.in vivo CRISPR/Cas9 screening approach that we used allows us to interrogate multiple genes simultaneously and assess their contributions to tumor phenotypes.11 Thus, it provides quantitative cause-and-effect information and avoids confounding factors that are inevitable in human tumors . However, our model systems do not yet recreate the extent of genomic complexity and intratumoral heterogeneity found in human lung tumors. Future studies will also be required to uncover the molecular mechanisms by which these tumor suppressors normally constrain tumor growth and by which their inactivation sensitizes tumors to therapy. Our study represents an initial step in defining the role of tumor suppressor genes in oncogenic EGFR-driven lung tumors. We anticipate that assessing broader panels of putative tumor suppressors will further elucidate the functional genomic landscape of this disease and allow genotypes to be related to diverse cancer phenotypes, including their response to different therapies. Despite the efficacy of single agent osimertinib, quantifying the impact of rational combination therapies on defined genotypes of lung tumors will drive further gains in the treatment of specific subsets of tumors. We envision that these types of multiplexed in vivo studies will ultimately contribute to the development of tailored treatments for patients with EGFR mutant lung cancer.The multiplexed"}
+{"text": "These friendship features (W1) were investigated as potential mediators of the prospective association between teacher-rated ADHD symptoms (W1) and self-rated depressive symptoms (W2) seven months later. Parent\u2013child relationship quality (W1) was tested as a moderator of any indirect effects of ADHD on depression via friendship. ADHD symptoms were inversely associated with friendship presence, friendship quality and positive characteristics of classroom friendship groups. Depressive symptoms were inversely associated with presence and quality of friendships. Friendship quality had indirect effects in the association between ADHD and subsequent depressive symptoms. There was some evidence of moderated mediation, whereby indirect effects via friendship quality attenuated slightly as children reported warmer parent\u2013child relationships. This highlights the importance of considering the quality of friendships and parent\u2013child relationships in children with ADHD symptoms. Fostering good quality relationships may help disrupt the link between ADHD symptomology and subsequent depression risk.Attention deficit/hyperactivity disorder (ADHD) is associated with friendship difficulties. This may partly account for the increasingly recognised association between ADHD and subsequent depression. Little is known about the types of friendship difficulties that could contribute to the association between ADHD and depressive symptoms and whether other relationships, such as parent\u2013child relationships, can mitigate against potential adverse effects of friendship difficulties. In a representative UK school sample (The online version contains supplementary material available at 10.1007/s10802-021-00798-w. Attention Deficit/Hyperactivity Disorder (ADHD) is a DSM-5  are important in increasing vulnerability to depressive symptoms in those with elevated ADHD symptoms. A secondary aim of this study was to investigate whether any indirect effects via elements of friendship were moderated by mother\u2013child or father-child relationship quality. A follow-up exploratory research question was whether indirect effects differed according to sex. The study included children in the first year of secondary school followed over a seven-month timespan.n\u2009=\u20091372). For 1020 of these 1372 children (74.3%), teachers completed the section rating the children\u2019s baseline ADHD symptoms. Of the 1020 children, self-rated depressive symptom data at follow-up were available for 901. Of these, there were 752  for whom data were additionally available on friendship and sociodemographic variables. To address bias that might be caused by missingness, predictors of missingness were investigated  in the last month completed a measure assessing their perception of each parent\u2019s warmth and hostility towards them using the Iowa family interaction rating scale . All analyses presented are adjusted for confounders by including these variables in the models as covariates.ADHD symptoms were standardised meaning a point increase in SDQ hyperactivity score was equivalent to a standard deviation unit increase. Linear regression was used to test the association between ADHD symptoms and depressive symptoms 7\u00a0months later. Separate linear and logistic regressions were used as appropriate to test associations between ADHD symptoms and indicators of three friendship elements , and to test associations of these friendship indicators (standardised if continuous) with depressive symptoms. Regressions included the school class as a random effect to account for potential hierarchical data structure or clustering.To test whether the different features of friendship contributed to the association of ADHD and depressive symptoms, indirect effects were tested separately using the [sureg] STATA command. Sureg conducts Seemingly Unrelated Regressions Zellner, , from whZ-tests) of the difference between the observed indirect effect at the mean level of the moderator compared to the mean level of the moderator -1SD (for hostility) or\u2009+1SD (for warmth) were conducted. To investigate which path(s) in the indirect effects were being moderated, we additionally tested models with an interaction effect on the path between ADHD symptoms and friendship or the path between friendship and depression symptoms only.Moderated mediation was tested using [sureg] to investigate whether any indirect effects via friendship varied according to the warmth or hostility of parent\u2013child relationships. The model used tested combined moderation of the pathway from ADHD symptoms to friendship and the pathway from friendship to depression symptoms  p\u2009=\u20090.002).ADHD symptoms at baseline were associated with naming fewer friends and lower friendship quality at baseline, both of which were associated with increased depressive symptoms at follow-up. ADHD symptoms were also associated with being part of a classroom friendship group that had higher total difficulties and was rated as less cooperative and more disruptive at baseline. Stability of the best friendship from baseline to follow-up was inversely associated with depressive symptoms Table . ADHD syADHD and depressive symptoms were associated directly and indirectly via friendship quality, both for best friend and top three friends, when tested separately Table . They shThe indirect effect of ADHD symptoms on depressive symptoms via friendship quality was larger for females than males (Supplement p\u2009=\u20090.040) as mother\u2013child relationship warmth increased   children reported that they had been in contact with their mother in the last month and 92.5% with their father. Indirect effects via top three friendships quality attenuated  Fig.\u00a0.Fig. 1PlAll results were very similar before and after imputation Below is the link to the electronic supplementary material."}
+{"text": "Glioblastoma (GBM) is the most common primary malignant brain tumor. Sex has been shown to be an important prognostic factor for GBM. The purpose of this study was to develop and independently validate sex-specific nomograms for estimation of individualized GBM survival probabilities using data from 2 independent NRG Oncology clinical trials.This analysis included information on 752 (NRG/RTOG 0525) and 599 (NRG/RTOG 0825) patients with newly diagnosed GBM. The Cox proportional hazard models by sex were developed using NRG/RTOG 0525 and significant variables were identified using a backward selection procedure. The final selected models by sex were then independently validated using NRG/RTOG 0825.Final nomograms were built by sex. Age at diagnosis, KPS, MGMT promoter methylation and location of tumor were common significant predictors of survival for both sexes. For both sexes, tumors in the frontal lobes had significantly better survival than tumors of multiple sites. Extent of resection, and use of corticosteroids were significant predictors of survival for males.https://npatilshinyappcalculator.shinyapps.io/SexDifferencesInGBM/.A sex specific nomogram that assesses individualized survival probabilities  for patients with GBM could be more useful than estimation of overall survival as there are factors that differ between males and females. A user friendly online application can be found here\u2014The online version contains supplementary material available at 10.1007/s11060-021-03886-5. Glioblastoma (GBM) represents 48.3% of all malignant primary brain tumors . Despite) promoter methylation status and presence of an IDH1 or IDH2 mutation are well-validated prognostic factors, [While extent of resection, age at diagnosis, Karnofsky performance status (KPS), O-6-Methylguanine-DNA Methyltransferase  wildtype GBM patients specifically . These nExempt approval was obtained from the University Hospitals Institutional Review Board (IRB) for all analyses presented. De-identified data were provided by NRG Oncology for the clinical trials NRG/RTOG 0525 and NRG/RTOG 0825 for which a written informed consent was obtained for each study subject under IRB approved protocols for each participating NRG study site , 15. NRGDescriptive statistics were used to assess any differences in patient characteristics and prognostic factors by sex using t-tests for continuous variables and chi-square tests for categorical variables. Non-parametric equivalents were used as appropriate. The analyses were performed using NRG/RTOG 0525 as the training dataset and NRG/RTOG 0825 as the validation dataset. Both overall survival (OS) and progression-free survival (PFS) were examined for the trial dataset using the Kaplan\u2013Meier method and were compared by sex using the log-rank test. Upon examination of the Shoenfeld residuals by sex, the proportional hazards assumption for all analyses by sex was not violated.In the initial phase of nomogram development to select prognostic factors, we fit a multivariable Cox proportional hazards model by sex for both OS and PFS to the training set (0525). Cox models were found to be superior for survival prediction on these datasets in a previous publication , and a mhttps://npatilshinyappcalculator.shinyapps.io/SexDifferencesInGBM/. All analysis were performed using R v3.6.0 (http://www.r-project.org/) and the online application was developed using R Shiny application.Calibration of the final models by sex for both OS and PFS for both training and validation dataset was visually evaluated by assigning all patients into quintiles of the nomogram-predicted survival probabilities and plotting the mean nomogram predicted survival probability against the Kaplan\u2013Meier estimated survival for each quintile. A user-friendly online application to obtain individualized predicted survival probabilities by sex was developed and can be found here\u2014In both trials, treatment either did not affect primary outcomes (OS and PFS) or the outcomes did not reach the prespecified improvement target; therefore, the data from both of the studies were used in this analysis . The comparison of patient characteristics between the trials is shown in Supplemental Table Kaplan\u2013Meier curves were generated for OS and PFS for both NRG/RTOG 0525, the training dataset  and validation (NRG/RTOG 0825) datasets for predicted 6-, 12-, and 24-month overall survival by sex . This tool will be useful to health care providers in determining individualized survival probabilities by sex. Further research should be done to better characterize the exact biological mechanisms underlying sex differences in GBM.The differences in the nomograms by sex shown here indicates that the prognosis of females and males may be different and that these nomograms are useful tools for estimating patient-level survival probabilities. To facilitate clinical use of this nomogram, free software for its implementation is provided (Supplementary file1 (DOCX 296 kb)Below is the link to the electronic supplementary material."}
+{"text": "OBJECTIVES/GOALS: Clinical translational studies inform clinical practice patterns through dissemination of clinical practice guidelines (CPG). In EM practices change to rapidly for timely local EHR implementation. We test the OMG BPM+Health specification for rapid deployment of best practices relevant to EM. METHODS/STUDY POPULATION: The OMG Business Process Management for Healthcare  specification combines BPMN\u2122 with Case Management Model and Notation (CMMN\u2122) and Decision Model and Notations (DMN\u2122) to \u201cdisseminate and leverage evidence-based best-practices at the point of care.\u201d The American College of Emergency Physicians (ACEP) Board-certified Emergency Physicians modeled practice guidelines in the BPM+ modeling language during on-line meetings. Two common emergency conditions were selected for initial pilot testing: 1) evaluation and treatment of first trimester bleeding in pregnant patients, and 2) the evaluation and treatment of non-traumatic low back pain. RESULTS/ANTICIPATED RESULTS: The protocols were successfully modeled during four on-line meetings in less than 2 months. Process steps from initial evaluation to disposition were implemented using BPMN\u2122. When clinicians need to evaluate the patient to collect data for decision making the inputs and outputs were modeled in CMMN\u2122. Decision logic is represented as DMN\u2122. The software tool linked the components for easy browsing and authoring the logic. The Physicians easily followed the displayed logic. The practice recommendations from each policy were successfully modeled, using the standard BPM+ notation to support rapid implementation in EHRs. Detailed implementation specifications will be shared. DISCUSSION/SIGNIFICANCE OF IMPACT: This pilot project demonstrated the feasibility of the OMG approach to solving Clinical Practice Guideline Implementation and Dissemination Barriers. Ongoing work by involved specialty societies will be necessary to demonstrate the scalability and sustainability of this approach."}
+{"text": "Mitochondrial DNA (mtDNA) may play an important role in Alzheimer\u2019s disease (AD) and cognitive decline. A particular haplogroup of mtDNA (haplogroup J), has been observed more commonly in patients with AD than in cognitively normal controls. We used mtDNA haplogroups to predict change in cognitive performance over seven years. We hypothesized that haplogroup J would predict poorer cognitive function and steeper cognitive decline. We analyzed data from 140 cognitively normal older adults (age 65+) who participated in the University of Kansas Alzheimer\u2019s Disease Center annual registry. We used factor analysis to create three composite scores  from 11 individual cognitive tests. We performed latent growth curve modeling to describe trajectories of cognitive performance and change. We compared haplogroup H, the most common, to haplogroup J, the potential risk group. Results indicated haplogroup J carriers had significantly lower baseline performance  and slower rates of improvement  on tests of verbal memory compared to haplogroup H. For executive function, groups did not differ at baseline , but haplogroup J had slower rates of improvement . There were no differences in attention across groups in performance  or change . Our results reinforce the important role of mtDNA in changes to cognitive function with aging and imply that the effects of haplogroup J may vary across cognitive domains. Future research should investigate the mechanisms by which mtDNA might affect performance on specific cognitive domains across haplogroups."}
+{"text": "Subacute cutaneous lupus erythematosus (SCLE) is a rare\u00a0cutaneous lupus erythematosus (CLE) subtype manifesting in middle-aged Caucasians with photo-distributed papulosquamous or annular lesions. Drug-induced SCLE (DI-SCLE) forms present in a similar manner but direct oral anticoagulants are rarely implicated.\u00a0We report an unusual case of SCLE in a 37-year-old African American patient with a history of unprovoked deep vein thromboses (DVT) who presented with new-onset photoprotected polymorphic lesions two months after the initiation of apixaban anticoagulation therapy. Our case demonstrates the heterogeneous nature of SCLE presentation and highlights the possibility of apixaban as a potential causative agent of DI-SCLE in immunogenetically susceptible individuals. Moreover, we hypothesize on the etiopathogenesis of our patient\u2019s atypical presentation. Subacute cutaneous lupus erythematosus (SCLE) is a rare\u00a0cutaneous lupus erythematosus (CLE) subtype, and it usually manifests in middle-aged Caucasian individuals . SCLE prA 37-year-old African American female with a history of two unprovoked deep venous thromboses (DVT) treated with apixaban was evaluated for a pruritic rash of two weeks' duration. She had started apixaban two months prior to the rash onset; there were otherwise no changes in her medication regimen. The exam showed hyperpigmented brown scaly plaques with central atrophic patches on the conchal bowl of the ears Figure , violaceA 4-mm punch biopsy of a representative lesion from the medial knee was performed.\u00a0Histopathologic findings suggested early SCLE and consisted of basilar vacuolar degeneration with scant dermal perivascular lymphocytic infiltrate Figure . ColloidCLE comprises three subtypes for which no standardized classification criteria exist . The SCLThere is significant histologic overlap between CLE phenotypes, and their differentiation on the basis of histology alone is unreliable. Common CLE findings include interface dermatitis with mononuclear cell infiltrate at the dermoepidermal junction, basal cell degeneration, perivascular and periadnexal inflammation, dermal mucin deposition, and hyperkeratosis . A superAs SCLE is rare in African Americans , our patMoreover, it is possible that her new-onset SCLE was related to the recently initiated apixaban therapy. Drug-induced SCLE (DI-SCLE) is clinically as well as serologically indistinguishable from the idiopathic form and can occur days or years after drug initiation . Unlike A wide range of drugs have been associated with DI-SCLE; however, direct oral anticoagulants are rarely implicated. McCarthy et al. have published a case of rivaroxaban-induced SCLE, which presented with typical clinicopathologic features three weeks after the drug administration and resolved within four months of drug discontinuation and concurrent topical corticosteroid therapy . RecentlWe presented a patient with SCLE with newly diagnosed SLE. Our patient displayed features spanning the lupus erythematous spectrum, which along with atypical findings makes this case unique and equally informative. It is important to emphasize that the\u00a0hypothesized relationship between our patient\u2019s ethnicity and photoprotected SCLE distribution, as well as the possible association between apixaban and DI-SCLE, are both merely speculative and require\u00a0further investigation."}
+{"text": "A best evidence topic has been constructed using a described protocol. The three-part question addressed was: In patients with Infrarenal abdominal aortic aneurysm (AAA), Does endovascular abdominal aortic repair (EVAR), AS compared to open surgical repair (OSR), has lower secondary rupture rates? The outcomes assessed were the secondary rupture rate in both techniques. The best evidence showed that The OSR has statistically significant lower secondary rupture rates than the EVAR. \u2022Endovascular abdominal aortic aneurysm repair is inferior to the open surgical repair regarding the secondary rupture rates.\u2022Long term outcomes of the open surgical repair are better than the Endovascular repair.\u2022Secondary rupture is more common in endovascular repair than the open surgical repair of abdominal aortic aneurysm. This fo2After resuscitating a 70-year-old man who presented to the emergency department (ED) with haemorrhaogic shock due to secondary rupture after open repair of infrarenal abdominal aortic aneurysm, one of the ED registrars asked; which modality of AAA repair has lower secondary rupture rates; EVAR or Open repair?\u2022\u2022[Does EVAR has lower Secondary rupture rates];\u2022[As compared to OSR]?Three Parts Question:3A. Embase 1974 to June 2021 using the OVID interface: [AAA OR Abdominal Aortic Aneurysm]AND [Open repair OR open surgical repair OR OSR] AND [EVAR OR Endovascular Repair] AND [Secondary rupture]\u2022Inclusion criteria: all original articles that review the secondary rupture rate among patients with AAA who underwent open surgical repair vs Endovascular Repair.\u2022Exclusion criteria: case reports, systematic reviews, letters to the editor, conference abstracts.B. Medline using the PubMed interface: [AAA OR Abdominal Aortic Aneurysm]AND [Open repair OR open surgical repair OR OSR] AND [EVAR OR Endovascular Repair] AND [secondary rupture]. The results were limited to English articles and human studies. 4A total of 853 papers were found using both search engines. We excluded 812 papers because they were irrelevant based on the titles and abstracts. Forty-one full-text articles were screened and assessed for eligibility. From these, six papers were identified to provide the best evidence to answer the question.5The search results are summarized in 6Endovascular repair of abdominal aortic aneurysm repair has increased worldwide. It has become a powerful alternative to open surgical repair since Juan C. Parodi did the first successful endovascular repair in 1991 . This isIn this article, we have reviewed the best studies which compared the open repair to the endovascular repair considering only the secondary rupture after the primary repair and any pre-interventional rupture were excluded.All the five studies in our review reported statistically significant Lower secondary rupture rate difference in the OSR than the EVAR group. Three of them were Randomized controlled trials which were conducted by Lederle FA et al. , Van Sch7According to the above articles, the best evidence shows a statistically significant lower secondary rupture rate among patients with open surgical repair of abdominal aortic aneurysm in comparison to endovascular repair.Ethical approval was not required.No source of funding.Ahmed Abdel Rahim (AA): Conducted the literature search and wrote the paper.Rashid Ibrahim (RI): Assisted in the literature search and Writing of paper.Lu Yao(LY): Editing of writing.Ahmed Khalf (AK): Assisted in writing of paper.Mohammed Ismail (MI): Assisted in the literature search and writing of paper.1. Name of the registry:2. Unique Identifying number or registration ID:3. Hyperlink to your specific registration (must be publicly accessible and will be checked):Ethics committee approval was not required as the study was review of previously done studies.Ahmed Abdel Rahim.No conflicts of interest."}
+{"text": "Recent data has shown a consistent but modest association between hearing impairment and poor mobility; both are strongly associated with cognition. Cognitive function may moderate the relationship between hearing and mobility. We analyzed 601 cognitively normal older participants from the Baltimore Longitudinal Study of Aging who had concurrent data on cognition , hearing , and mobility . We performed multivariable-adjusted linear regression to test two-way interactions between each cognitive measure and PTA. There were significant PTA interactions with all cognitive measures on 400-meter time. There was a significant interaction between PTA and sensorimotor function on 6-meter gait speed. Among cognitively normal older adults, poorer hearing is more strongly associated with poor mobility in those with low cognition, especially sensorimotor function. Future studies are needed to understand how cognition may moderate the relationship of hearing impairment with mobility decline over time."}
+{"text": "Pituitary adenomas (PA) are one of the most common primary brain tumors and comprise approximately 15% of brain neoplasms. Most PA are histologically benign, but can cause significant morbidity. Previous studies utilized whole genome and exome sequencing to identify a few somatic variants, but no recurrent mutations were observed. Further studies are warranted to identify driver mutations occurring at low frequencies. We used single-cell RNA sequencing (10X Genomics) to investigate cellular heterogeneity in 12 non-functioning pituitary adenomas. Our analysis identified discrete clusters of cells associated with specific functional pathways. One of these clusters corresponded to cells expressing genes related to metabolic pathways, primarily lipid metabolism. Another cluster consistent amongst the three patients comprised cells involved in antigen presentation and processing. In addition, the copy number variation analysis highlighted distinct chromosomal alterations within our samples. Interestingly, we were able to identify clonal variations within each tumor based on chromosomal aberrations. For example, in our first patient we observed a gain of chromosome 19 and loss of chromosome 2. Our analysis showed three different clonal populations within this tumor. All three populations harbored the loss of chromosome 2, one population exhibited gain of chromosome 19, while a third population exhibited loss of chromosome 19. These early results indicate the loss of chromosome 2 as an early event in tumorigenesis and gain/loss of chromosome 19 as late events. We are currently in a process of identifying somatic variations within these tumors by variant calling. Currently we are expanding our analysis to 20 non-functional PA. Mapping the single-cell gene expression profiles with mutational phylogeny will reveal the differences in clonal evolution within the tumor subtypes. This study will help us define the molecular fingerprint of pituitary adenomas and provide insights which could be utilized in the clinic for better management of these tumors."}
+{"text": "Mi\u00f1o et al.). After receiving an extensive counseling, more women opted for an invasive prenatal testing while less women opted for the first trimester combined test and cell free DNA testing, as compared to those without extensive counseling .There has been a geometric explosion in genetic capabilities such that currently a wide variety of prenatal screening and diagnostic testing for fetal chromosomal abnormalities are available. Ideally, all woman should be counseled in each pregnancy about the benefits and limitations of available testing . In counCheng et al.). Although more non-pregnant women accepted ECS compared to pregnant women (70.7 vs. 61.2%), fewer non-pregnant women heard about ECS than pregnant women (32.3 vs. 42.4%). The majority of them showed a lack of understanding about ECS despite being given pamphlets . It is important to improve women\u2019s understanding of reproductive risk before making an informed decision, especially the issue related to false-negatives, of which the readers can refer to a recent excellent review  recommends a consistent and equitable approach for offering carrier screening to all women during pregnancy or before conception . Next-get review .While prenatal chromosomal microarray analysis (CMA) is a current standard genetic testing, prenatal whole exome sequencing and eventually whole genome sequencing are emerging technologies that will become front line tests in the future. CMA can detect major chromosomal imbalances as well as copy number variations that are too small to be detected by traditional karyotyping. Diagnostic sequencing is useful for evaluation of fetuses for whom CMA is uninformative. It may be offered concurrently according to accepted practice guidelines. CMA is less optimal than sequencing for the presenting fetal phenotype according to expert genetic opinion . The authors used an extended segregation analysis including the parents and their relatives to provide further useful information for genetic counseling.The prenatal identification of a baby with a MECP2 missense mutation and 15q11.2 microduplication in a family with a child having developmental epileptic encephalopathy associated with a Lin et al.). A compound heterozygous mutation with c.856 + 1G > T and c.857-619_1269 + 243delinsTTGCCTTGC changes were found in the first family while homozygous c.857-619_1269 + 243delinsTTGCCTTGC mutations were found in the second family. These mutations are associated with autosomal recessive renal tubular dysgenesis which is a severe disorder with an unfavorable outcome. Notably, a few earlier reports from Taiwan had pointed out that the mutant allele c.857-619_1269 + 243delinsTTGCCTTGC of the AGT gene is very likely to be a founder variant in the Chinese population, which may aid in the prompter identification of the molecular pathology in that rapid trio-WEs case .Another limitation of prenatal sequencing is long turn-around time. In the present issue, prenatal diagnosis of two families with recurrent oligohydramnios by rapid trio-whole-exome sequencing (WES) which revealed mutations in the AGT gene within 1 week was reported . GS enabled accurate identification of all breakpoints in these ten cases, revised the conventional karyotype results in nine cases, and provided additional information and changed the interpretation of the BCAs in four cases . These results show us the importance of precisely delineation of breakpoints as BCAs are associated with neurodevelopmental disorders including intellectual disability and autism spectrum disorder.Recently, whole-genome sequencing (WGS) has been used to delineate the breakpoints of balanced chromosomal abnormalities (BCA) which have no visible gain or loss of genetic material at cytogenetic resolution . The usePauta et al.). This new molecular work-up included two quantitative fluorescence PCR (QF-PCR) rounds, and a high-resolution SNP-array in those cases with normal QF-PCR results. QF-PCR and CMA can overcome the pitfalls of conventional karyotyping including culture failure and submicroscopic abnormalities. Besides, the authors also proposed transcervical chorionic villus sampling (CVS) during surgical or before medical uterine evacuation to avoid maternal contamination. They found that transcervical CVS was more effective in the retrieval of embryonic tissue for chromosome analysis than examining POC after evacuation .Chromosome analysis of both couples with recurrent pregnancy loss (RPL) and products of conception (POC) is most informative in the investigation of possible genetic causes of RPL . ParentaChuang et al.). The authors explored whether the incidence of mosaicism for individual chromosome in blastocysts is correlated with chromosome length, highlighting the complex mechanisms of causing mosaicism in blastocysts.NGS after trophectoderm (TE) biopsy have been used for preimplantation genetic testing for aneuploidies (PGT-A) because of its high sensitivity . Compare"}
+{"text": "Cells of osteogenic sarcoma line 791T were treated in vitro with a selectively cytotoxic methotrexate-human serum albumin-monoclonal antibody conjugate at concentrations which were toxic but allowed the \"escape\" of a small number of tumour cell colonies (less than 0.3% compared with controls). These colonies were propagated as clones in order to test their expression of the monoclonal antibody ( 791T /36)-defined antigen and their resistance to methotrexate (MTX) by comparison with parental cells. Most of the conjugate-treated clones were incapable of prolonged growth and died out, in contrast to untreated 791T clones which virtually always grow progressively. Only four treated clones grew at rates comparable with the parental line. Flow cytofluorometric analysis indicated that the surviving clones expressed normal or enhanced amounts of 791T /36-defined antigen and clonogenic assays demonstrated that they were sensitive to cytotoxicity by MTX. As could be predicted from these results, further exposure to the conjugate inhibited growth of the clones at doses comparable with those active against parental 791T cells. It is concluded that tumour cell clones emerging after exposure to a toxic concentration of a drug-antibody conjugate are not necessarily modified resistant clones, but may have severely impaired long-term growth potential or be susceptible to further contact with the same conjugate."}
+{"text": "Iodo(14C-)antipyrine autoradiography and imaging bioluminescence have been combined to obtain pixel-to-pixel correlations between absolute values for local blood flow and ATP concentrations at a microscopical level within designated areas in hamster melanomas. Positive pixel-to-pixel correlations were obtained in 4 of 6 tumours. Both flow and ATP values were less in mostly necrotic than in mostly viable tumour regions. The data provide evidence for the energetic state of cancer cells being strongly influenced by the efficiency of tumour microcirculation in several but not in all malignancies investigated."}
+{"text": "Production of colony-stimulating factor (CSF) was examined in three patients with lung cancer associated with neutrophilia. All three patients presented a marked increase in neutrophil count  that continued at least for 3 weeks and rapidly disappeared after surgical removal of the tumours. Culture media (CM) incubated with the excised tumour tissues stimulated the colony formation of bone marrow myeloid progenitor cells in vitro. Northern blot analysis of poly(A)+ RNA from the tumour tissues revealed a constitutive expression of granulocyte (G), macrophage (M), and granulocyte-macrophage (GM) CSF genes in all tumours. Immunoassay specific for these CSFs revealed that G- and M-CSF immunoreactivity was detected in all CM and GM-CSF protein in two out of three CM. The plasma CSF levels also increased before operation and decreased to normal or near-normal range after operation. In contrast, tumour cell CM obtained from two lung cancer patients without leucocytosis neither stimulated haematopoietic colony formation nor contained immunoreactive CSFs. These results indicated that the neutrophilia found in the three patients was probably caused by constitutive production of multiple CSFs by lung cancer cells."}
+{"text": "P-glycoprotein expression was demonstrated in two human intestinal adenocarcinoma cell-lines  by immunoprecipitation of a 170-180 kDa protein with monoclonal antibody JSB-1. Both HCT-8 and T84 formed functional epithelial cell layers of high transepithelial electrical resistance (greater than 700 omega.cm2) when grown on permeable matrices. These epithelial layers demonstrated vectorial secretion . These vectorial vinblastine secretions were sensitive to inhibition by verapamil. Passive transepithelial vinblastine permeation was limited by the presence of intercellular (tight) junctions, as demonstrated by the high transepithelial electrical resistance, and verapamil increased this passive vinblastine permeation concomitant with a reduction in the electrical resistance. Cellular vinblastine loading was significantly greater from the basal side, and this was also susceptible to inhibition by basal verapamil. The demonstration of vectorial transport of vinblastine in human intestinal colonic adenocarcinoma cell layers is direct evidence in favour of the hypothesis that the function of mdr1 in epithelial from the gastrointestinal tract is to promote detoxification by a process of epithelial secretion. This study also highlights that cellular vinblastine accumulation depends not only upon P-glycoprotein function, but also upon differential apparent membrane permeabilities and the presence of intercellular (tight) junctions that may restrict drug permeation and cellular accumulation to apical or basal membrane domains."}
+{"text": "SR 4233  is the lead compound of the benzotriazene-di-N oxides which are selectively toxic to tumour cells under hypoxic conditions. However much higher concentrations given to rats caused bone marrow toxicity and necrosis of the low oxygen Zone 3 part of the liver. In the following effects of SR 4233 on hepatocytes under hypoxic vs aerobic conditions have been compared. (1) SR 4233 did not affect hepatocyte viability (as determined by plasma membrane disruption) or glutathione levels under aerobic conditions. SR 4233 however induced cyanide-resistant respiration, an indicator of redox cycling mediated oxidative stress and became cytotoxic if hepatocyte catalase or glutathione reductase was inactivated. Glutathione oxidation occurred well before cytotoxicity ensued. Addition of ascorbate markedly enhanced SR 4233 cytotoxicity to these compromised hepatocytes. (2) In contrast, SR 4233 was highly toxic to hypoxic hepatocytes. Addition of ascorbate to enhance SR 4233 reduction also caused a marked increase in hepatocyte toxicity and an SR 4233 radical was detected with ESR spectroscopy. SR 4233 cellular reduction and toxicity was prevented with fructose or inhibitors of NADPH:cytochrome P-450 reductase. Inactivation of catalase or glutathione reductase had no effect on SR 4233 toxicity and hepatocyte GSH was not oxidised indicating oxidative stress did not occur during hypoxic SR 4233 hepatocyte toxicity. (3) The lack of SR 4233 cytotoxicity under aerobic conditions could probably be attributed to the detoxification of the SR 4233 radical by mitochondrial oxidation as SR 4233, but not its metabolite SR 4317 markedly increased state III and IV mitochondrial respiration in the presence of NADH. The increased respiration was inhibited by the respiratory inhibitors KCN and antimycin A but not by rotenone. Furthermore SR 4233 cytotoxicity under aerobic conditions was markedly increased by partially inhibiting hepatocytes respiration with cyanide but not rotenone."}
+{"text": "The prognostic value of cellular DNA content in melanoma metastases was investigated by flow cytometric analysis of fresh or paraffin-embedded tumour blocks from 95 consecutive patients referred to the Helsinki University Central Hospital Melanoma Team. Thirty-three per cent of the tumours were DNA diploid and 67% DNA aneuploid. S-phase fractions were lower in DNA diploid than in DNA aneuploid tumours (10.7% and 17.6%). Tumour ploidy and S-phase fraction were shown by multivariate Cox model analysis to be independent prognostic variables and major determinants of survival after first recurrence. Surprisingly, patients with DNA aneuploid tumours and with tumours with low SPF survived significantly longer than those with DNA diploid or high SPF tumours. This exceptional finding of favourable prognosis for DNA aneuploid tumours was more prominent among patients receiving intensive systemic therapy and among patients with stage IV disease, probably indicating a tendency for DNA aneuploid tumours to have higher sensitivity to systemic therapy."}
+{"text": "Observation of Coincident arrhythmias is not uncommon but the co-existence of idiopathic verapamil sensitive left ventricular tachycardia (ILVT) with other arrhythmias is very rare. We hereby presented a 30 year old male patient with a history of frequent episodes of palpitations and sustained narrow complex tachycardia. During electrophysiologic study two arrhythmias, one with narrow complexes which was shown to be typical atrioventricular nodal re-entrant tachycardia and the other with wide QRS complexes and right bundle branch block and left axis morphology, compatible with ILVT, were inducible. Radiofrequency catheter ablation of both arrhythmias was done at two consecutive sessions. The patient has remained asymptomatic without antiarrhythmic therapy for the past six months. Idiopathic sustained ventricular tachycardia (VT) accounts for 10-20% of patients with sustained monomorphic VT , but coeWe hereby presented a 30 year old male patient with three years history of frequent episodes of palpitation. He had no structural heart disease. His previous medical records revealed several ECGs during arrhythmia all showing regular narrow complex tachycardia with a rate of 180beat/min. There was no documented wide complex tachycardia. During initial EP study a narrow complex tachycardia was reproducibly induced  which waearliest PP recording site  were introduced via left femoral vein and positioned at RV apex (and right ventricular outflow tract), His bundle and high right atrium. A 7F steerable decapolar catheter (2-5-2 mm) was introduced via left femoral artery  and positioned in LV on interventricular septum for recording intracardiac signals during sinus rhythm and tachycardia. This catheter was used as a guide for localization of earliest purkinje potential (PP) recording site by ablation catheter. A 7F ablation catheter  was introduced via right femoral artery and positioned in LV on septum for mapping and subsequent RF ablation. The ILVT was terminated by mechanical pressure at ing site . RF enerThis case describes the coincidence of AVNRT and ILVT. Occurrence of AVNRT in combination with idiopathic VT has been previously described. In patients with RVOT tachycardia the incidence of AVNRT has been reported to be as high as 15% . Our finearliest PP during tachycardia should be targeted.Wagshal AB, et al.  also repThis case represents the co-incidence of ILVT and AVNRT and underscores the importance of searching for dual AV node physiology and AVNRT in patients with ILVT."}
+{"text": "The outcome of salvage treatment was reviewed in 55 patients relapsing during or after their primary chemotherapy for advanced malignant germ cell tumours. Fifty-two patients had been given cisplatin-based chemotherapy as their primary treatment, whereas three patients had received carboplatin-based chemotherapy. The median time to relapse was 2 months (range: 0-96 months) from discontinuation of the primary treatment. Two patients underwent radical surgery only, and one patient had radiotherapy to a brain metastasis as his only curatively intended salvage treatment. Six patients did not receive any treatment for their recurrent malignancy  except for purely palliative measures. The disease-free survival for the total group was 27% at 5 years. Complete response to primary treatment lasting for > or = 6 months was the only parameter which significantly predicted a favourable outcome ."}
+{"text": "A study involving the measurement of glutathione S-transferase activities and isoenzyme distributions in human ovarian tumours has been carried out. These tumours have been obtained either at initial debulking surgery, prior to cytotoxic chemotherapy, or at second look laparotomy following chemotherapy. The response rates of these two groups to chemotherapy differ markedly, with patients who have relapsed following initial chemotherapy showing a reduction in response rates to subsequent chemotherapy. Analysis of these data show no statistically significant differences between the glutathione S-transferase activity or isoenzyme distribution in these two groups of patients. Significant differences were observed in the glutathione-S-transferase activities (GST) between tumours and normal ovaries. GST activities in pre-chemotherapy tumours  and post-chemotherapy tumours  where significantly higher than the GST activity in normal ovaries (n = 15). One feature was the expression of the basic isoenzyme which is expressed more in normal ovaries than in tumours. No differences in these parameters were observed in normal peritoneal tissue taken from patients before or after chemotherapy. These data do not support the hypothesis that changes in glutathione S-transferase enzyme activity or isoenzyme expression are major determinants of response to chemotherapy in ovarian tumours."}
+{"text": "ECG in sinus rhythm with ventricular preexcitation and changing QRS morphology was seen that was initially interpreted  as the multiple accessory pathway from elsewhere. .The following mechanisms are potentially involved in the electrogenesis of changing QRS morphology in WPW syndrome: 1) multiple accessory pathways ; 3) ventElectrophysiologic study showed short PR (75 ms) interval with wide QRS (152 ms) and negative HV (-12 ms) interval. No change in delta wave polarity was observed during HRA and CS pacing. In full preexcitation, no breakthrough was seen in the CS. During incremental ventricular pacing, atrial breakthrough site is initially recorded on the HRA catheter and then changed to distal pole of CS catheter with progressive decrease in pacing cycle length. During ventricular pacing at cycle length of 500 ms (S1), earliest atrial activity is recorded on HRA catheter.multiple APs because only right-sided AP had bidirectional conduction and no distal CS breakthrough was seen simultaneous with changing QRS morphology. The possibility of aberrant conduction is excluded by presence of negative HV interval in the beats with differing QRS morphology. No sinus cycle length variation before and after the beats with different morphologies are against the occurrence of functional LBBB. The prematurity of ventricular electrogram in His recording catheter with variable HV (H-electrogram is recorded after V-electrogram in second beat and before V-electrogram in third beat) and fixed V-RB intervals  are compatible with ventricular fusion of preexcited sinus impulse with ectopic ventricular impulse originating from parahissian area (explaining LBBB and inferior axis morphology of the beats with changing QRS) but not from the His bundle or RBB itself  (Changing QRS could not be explained by presence of r fusion)."}
+{"text": "Objective To study the microbial etiology of tubo-ovarian abscess (TOA).                Methods We recruited 11 women in Nairobi, Kenya who failed antibiotic therapy alone and requiredsurgical drainage of a presumptive TOA. Pus from the nine abscesses and two pyosalpinges were collected andcultured for aerobic, facultative and anaerobic microorganisms.Results Eleven women suspected of having a TOA were hospitalized and treated for a median of 6 days (range3\u201314 days) prior to surgical drainage of the abscess. Nine (82%) specimens were culture positive. Aerobeswere present in all nine specimens. Seven of the nine positive cultures (78%) were polymicrobial and five ofthe polymicrobial cultures contained both anaerobes and aerobes. Anaerobic Gram-negative bacilli  and Streptococcus sp.  were themost common microorganisms isolated. Neisseria gonorrhoeae and Chlamydia trachomatis were not isolated byculture or detected by polymerase chain reaction.Conclusions In Kenya, persistent TOAs are associated with endogenous flora similar to that normally foundin the gastrointestinal tract."}
+{"text": "A 25 year old man underwent electrophysiology study for recurrent symptomatic paroxysmal palpitations. There were no documented episodes of supraventricular tachycardia on surface ECG.  Delta waves were absent on baseline ECG.A decapolar catheter was placed in the coronary sinus with the distal and proximal pair of electrodes configured as CS 1-2 and CS 9-10 respectively. Quadripolar catheters were positioned in the high right atrium, His-bundle region and right ventricular apex. During straight atrial pacing with a drive-cycle length of 340ms, the following arrhythmia was induced . The corThe surface ECG revealed a narrow complex supraventricular tachycardia with alternating R-R intervals at 310ms and 360ms . The int On close inspection of the intracardiac electrogram, two different alternating A-H intervals were observed, which presented as alternating R-R intervals on the surface ECG.The A-H intervals were 110ms and 160ms consecutively. We deduced that the antegrade limb of this macro-reentrant circuit involved both the fast and slow AV nodal pathways alternating with each other.Radiofrequency ablation of the left lateral pathway via a retrograde aortic approach was performed. The tachycardia was successfully terminated. Further electrophysiology studies confirmed the presence of dual AV nodal pathways. There were no further inducible arrhythmias even with isoproterenol infusion. The slow pathway was thus not ablated.The mechanism for this supraventricular tachycardia with alternating R-R intervals involved two alternating antegrade limbs  with different conduction times and a common retrograde concealed left sided accessory pathway. This electrophysiological mechanism had been postulated previously based on appearance of the surface ECG without intracardiac recordings ."}
+{"text": "The dentate gyrus is well known for its mossy fiber projection to the hippocampal field 3 (CA3) and its extensive associational and commissural connections. The dentate gyrus, on the other hand, has only few projections to the CA1 and the subiculum, and none have clearly been shown to extrahippocampal target regions.Using anterograde and retrograde tracer techniques in the Madagascan lesser hedgehog tenrec  it was shown in this study that the dentate hilar region gave rise to a faint, but distinct, bilateral projection to the most rostromedial portion of the olfactory tubercle, particularly its molecular layer. Unlike the CA1 and the subiculum the dentate gyrus did not project to the accumbens nucleus. A control injection into the medial septum-diagonal band complex also retrogradely labeled cells in the dentate hilus, but these neurons were found immediately adjacent to the heavily labeled CA3, while the tracer injections into the rostromedial tubercle did not reveal any labeling in CA3.The dentate hilar neurons projecting to the olfactory tubercle cannot be considered displaced cells of CA3 but represent true dentato-tubercular projection neurons. This projection supplements the subiculo-tubercular projection. Both terminal fields overlap among one another as well as with the fiber terminations arising in the anteromedial frontal cortex. The rostromedial olfactory tubercle might represent a distinct ventral striatal target area worth investigating in studies of the parallel processing of cortico-limbic information in tenrec as well as in cat and monkey. The dentate gyrus (Dt) may be known best for its input from the entorhinal cortex and its mossy fiber projection to the CA3 -3. In adEchinops telfairi, Et) will demonstrate some true dentate hilar cells projecting to a circumscribed region in the olfactory tubercle. The projection may represent an additional parallel pathway transferring cortico-limbic information to the ventral striatum [Continuing our attempts to elucidate the hippocampal and parahippocampal circuits in mammals with a poorly differentiated brain -29 the pstriatum -32.Among the experiments with tracer injections into the hippocampus Table  two caseThe latter two cases revealed the well-known hippocampo-striatal projection pattern to the nucleus accumbens (Acb) and the olfactory tubercle (Tu) . No hippIn Et01-21B the course of fibers towards Tu appeared to pass exclusively within the molecular layer of the hippocampal continuation  but getThe present data show for the first time a projection from the dentate gyrus to the rostromedial olfactory tubercle. Its cells of orgin, located in the dentate hilus, cannot be considered displaced neurons of CA3 but represent true dentato-tubercular projection neurons. The projection is assumed to be present in other mammals, too. In the tenrec the dentato-tubercular projection overlaps with the subiculo-tubercular projection and the fiber terminations arising in the anteromedial frontal cortex. The circumscribed ventral striatal target area appears worth investigating in studies of the parallel processing of cortico-limbic information in tenrec as well as in cat and monkey.Echinops telfairi, Et) is a member of the tenrecomorpha classically considered an insectivoran suborder [The lesser hedgehog tenrec . Thesuborder  built upsuborder ,81.Eleven tenrecs weighing between 80 and 140 gm were anesthetized with tribromoethanol  and injected with tracer into the hippocampus (n = 7), the ventral striatum (n = 4) and the septum (n = 1) following the German laws on protection of animals . Wheat germ agglutinin conjugated to horseradish peroxidase  and biotinylated dextran amine  were used as tracer substances. Most cases have been described previously with regard to other connections ,28,82. TThe brains were soaked overnight in a 30% phosphate-buffered sucrose solution, embedded in an albumin-gelatine mixture and cut on a freezing microtome at 40 \u03bcm in the frontal plane. The WGA-HRP staining was usually done on two out of four sections according to the standard tetramethylbenzidine technique  and a moBright-field illumination and polarized light were used for the analysis. Images were captured on an Ilford 50 negative film or a Fujichrome 64T positive film (using a Zeiss axiophot microscope), scanned (Nikon Coolscan 5000) and transported into Adobe Photoshop (v. 7.0) and Corel Draw (v. 11.0). The sharpness, contrast and brightness were adjusted to reflect the appearance of the labeling seen through the microscope. For the sake of clarity the most disturbing crystalline artefacts were removed, particularly in darkfield images. In some darkfield micrographs the light reflecting embedding medium was also removed. Furthermore to facilitate the analysis all micrographs are shown with the injection site on the left.Acb \u2013 nucleus accumbensBDA \u2013 biotinylated dextran amineCA1/3 \u2013 subfields of cornu ammoniscma \u2013 commissura anteriorDgMS \u2013 diagonal band-medial septum complexDt \u2013 dentate areaDtGr \u2013 dentate granule cell layerDtHi \u2013 dentate hilar regionDtMo \u2013 dentate molecular layerEt \u2013 Echinops telfairiHCt \u2013 hippocampal continuationSbi \u2013 subiculumTu \u2013 olfactory tubercleWGA-HRP \u2013 wheat germ agglutinin conjugated to horseradish peroxidase"}
+{"text": "A cytofluorometric assay allowing the measurement of thymidine phosphorylation in single cells had been established . This assay enables us to correlate intracellular thymidine kinase (TK) activity with the DNA content of single cells. Enzyme activity levels from neuroblastoma cells and normal fibroblasts derived from the same patient were determined. Using this cytofluorometric assay in a mixture of both cell types the neoplastic cells could be distinguished from the normal fibroblasts because of their higher TK level. A human lymphoblastoid cell line was compared with the cell line KG-1, derived from an acute myelogenous leukaemia, in the same way. The increased enzyme activity enabled us to detect KG-1 cells in a mixture with an 10,000-fold excess of Epstein Barr virus transformed lymphocytes."}
+{"text": "Vasoactive drugs have a variety of effects upon splanchnic and hepatic haemodynamics which may alter tumour blood flow and potentiate the delivery of a chemotherapeutic drug to hepatic tumour. We have investigated the effects of vasopressin infusion on hepatic tumour blood flow in an experimental model of liver tumour. Hepatic tumour was induced by the intraportal inoculation of HSN sarcoma cells. Hepatic and splanchnic blood flow was determined using a dual reference microsphere technique before and after an intravenous infusion of vasopressin at a dose of 0.1 mU kg-1 min-1 for 10 min. There was a significant increase in systemic arterial blood pressure associated with a rise in portal venous inflow  and a significant fall in hepatic arterial flow (P less than 0.05). The tumour: liver blood flow ratio was significantly increased by vasopressin infusion (P less than 0.02). Vasopressin infusion decreases hepatic arterial flow and increases tumour blood flow which may potentiate the delivery of a regionally delivered chemotherapeutic drug to hepatic tumour."}
+{"text": "The variation in survival of women with clinically similar breast cancers may lead to difficulty in clinical management so it is important to recognise factors which indicate the prognosis. Immunoperoxidase staining patterns of primary breast tumours using monoclonal antibody NCRC-11 have been shown to relate to overall survival  but the results have not been reproducible in other centres. In this study paraffin sections of 483 primary breast cancers were stained with NCRC-11 and 3E1.2 using an immunoperoxidase system. The tumour staining patterns were compared with overall survival using life tables and tested for relative prognostic significance by Cox's multivariate analysis. NCRC-11 related to survival in all 483 cases  but both antibodies achieved maximum prognostic significance in lymph node negative patients  in whom no other factor was more significant. Immunoperoxidase staining patterns produced by monoclonal antibodies NCRC-11 and 3E1.2 are important prognostic factors in breast cancer."}
+{"text": "Central airway obstruction is a common complication of lung cancer. The microdebrider is a new device available for treatment of central airway obstruction.We report a case a 59-yr-old male with T3N2M1 non-small cell lung cancer with malignant distal left mainstem obstruction treated successfully with a novel elongated rotating tip microdebrider via rigid bronchoscopy with sufficient length to reach distal bronchial lesions.The microdebrider is an excellent addition to the spectrum of interventions available for the management of central airway obstruction with advantages including accuracy and immediate removal of debris without a need for separate suctioning or limitation in oxygenation. The microdebrider is a recent addition to the armeratarium available to the interventional bronchoscopist for central airway occlusion, following the successful application of laryngeal microdebriders for over a decade -3. HowevA 53-yr-old male with T3N2M1 non-small cell left upper lobe lung cancer with bilateral brain metastases diagnosed one-month prior was referred for management of dyspnea and hemoptysis. The patient had noted a dramatic increase in dyspnea over the prior 3 days. Past medical history was unremarkable and he had a negative smoking history.Physical exam revealed reduced breath sounds in the left lower zone. Chest x-ray demonstrated a left hilar mass with loss of volume and post obstructive pneumonia in the left lower lobe Figure . Axial C\u00ae (APC) was utilized to devitalize the tissue. The devitalized tissue was then debulked using the Straightshot\u00ae microdebrider with rotating tip  declare that they have no competing interests."}
+{"text": "Sodium polyanethol sulphonate (SPS) when incorporated into rat erythrocyte lysate (REL) containing semi-solid agar medium at 1 mg ml-1. markedly enhanced colony formation by a number of anchorage-independent cell lines. REL usually needed to be included for the expression of SPS induced potentiation as in its absence SPS was generally cytotoxic. Studies suggested that SPS reduced the lag prior to colony initiation resulting in the earlier appearance of colonies and in a higher cloning efficiency. The effectiveness of SPS in potentiating colony formation by responsive cell lines was markedly influenced by the species of serum and to a lesser extent by differences between individual batches. Enhancement by SPS was greater with poorer foetal calf serum (FCS) batches than with better. This effect may have been partly due to SPS interfering with the action of a growth inhibiting serum component, possibly a lipoprotein. Studies in which delipidated FCS was substituted for normal FCS suggested that SPS was also able to compensate for the lack of a growth-promoting lipid component. Binding studies showed that initially 125I-SPS bound equally well at 4 degrees C and 37 degrees C with continued labelling occurring only at 37 degrees C. Autoradiography of cells labelled at 37 degrees C for 24 h revealed the presence of intracytoplasmic 125I-SPS."}
+{"text": "In the article \u201cNatural Variability and the Influence of Concurrent Control Values on the Detection and Interpretation of Low-Dose or Weak Endocrine Toxicities,\u201d p-dioxin (TCDD)  . Second,There are many reasons why males from different rat strains obtained from different breeding facilities using different animal feed and housing conditions might differ in DSP. We thus disagree with the interpretation by"}
+{"text": "Eighty-one patients with small cell lung cancer (SCLC) with a survival of more than 2 years after start of chemotherapy were studied. Twenty-six of the 28 patients who died of relapsed SCLC had in fact relapsed before two years and of the 55 who had not then only two (4%) relapsed subsequently. It is stressed that with such observations treatment related factors should be taken in account. Second tumours were observed in ten patients, nine proven malignant. Of the eight patients with non-small cell lung cancer three had residual disease after initial chemotherapy. In our patient group after a 2 year disease-free interval the risk of developing non-small cell lung cancer seems higher than a subsequent relapse of SCLC."}
+{"text": "Using immunohistochemistry and the monoclonal antibody C219 we have investigated P-glycoprotein expression in 26 locally advanced breast cancers. Twenty four patients had received four cycles of chemotherapy  prior to mastectomy; two received tamoxifen. Twelve tumours exhibited an objective response to the chemotherapy. A background pattern of isolated weakly positive (1+) stromal staining (myofibroblast) was observed in seven tumours, two of which had been treated by tamoxifen alone. Two of the tumours treated by induction chemotherapy showed positive staining (1+) within a very small number of isolated tumour cells (maximum of three) and macrophages. The significance of this staining is not clear although C219 may simply be cross reacting with myosin. We have failed to demonstrate a clear clinical utility for C219 in breast cancer, particularly regarding the identification of patients in whom MDR chemotherapy be avoided once metastases develop."}
+{"text": "Phospholipids from malignant, benign and noninvolved human breast tissues were extracted by chloroform-methanol (2:1) and analysed by 31P MR spectroscopy at 202.4 MHz. Thirteen phospholipids were identified as constituents of the profiles obtained among the 55 tissue specimens analysed. Observed patterns in phospholipid tissues profiles were distinct, allowing qualitative characterisation of the three tissue groups. Multivariate analysis of lysophosphatidylcholine (LPC) and an uncharacterised phospholipid were shown to be independently significant in predicting benign tissue histology as either fibrocystic disease or fibroadenoma in 92% of cases. Univariate analysis of relative mole-percentage of phosphorus concentrations of individual phospholipids using the Scheff\u00e9 comparison procedure revealed that in malignant tissues, phosphatidylethanolamine was significantly elevated compared to benign (+ 32%) and noninvolved tissues (+ 22%). Phosphatidylinositol (+ 33%) and phosphatidylcholine plasmalogen (PC plas) (+ 25%) were increased in malignant compared to benign and LPC was decreased (-44%) in malignant compared to noninvolved. LPC was significantly depressed (-39%) in benign tissue compared to normal. Phospholipid indices computed to further characterise the three tissue groups showed PC plas/PC elevated in malignant tissue compared to benign and PE plas/PE depressed in malignant tissue compared to noninvolved. These findings support previous investigations reporting that the alkyl-phospholipid analogues of phosphatidylcholine are released by malignant tissues and that levels of ethanolamine are elevated in malignant tissues. Indices describing the choline-containing phospholipids showed that these lipids are depressed significantly in malignant tissue relative to healthy tissue."}
+{"text": "Epidermal growth factor receptors were measured using a radioligand binding assay in membrane preparations from 67 cancer and 25 non-malignant tissues. The binding characteristics of EGFr were similar in tumour and normal breast membranes. The concentrations were significantly higher in non-malignant tissue than in cancer. EGFr concentrations were directly correlated with steroid receptors in non-malignant tissue, whereas in cancer an inverse correlation between EGFr and steroid receptors was found."}
+{"text": "There is paucity of literature describing complex elbow trauma in the pediatric population. We described a case of an uncommon pediatric elbow injury comprised of lateral condyle fracture associated with posterolateral dislocation of elbow.A 12-year-old boy sustained a direct elbow trauma and presented with Milch type II lateral condyle fracture associated with posterolateral dislocation of elbow. Elbow dislocation was managed by closed reduction. The elbow stability was assessed under general anaesthesia, followed by open K-wiring for the lateral condylar fracture fixation. The patient had an uneventful recovery with an excellent outcome at 39 months follow-up.Complex pediatric elbow injuries are quite unusual to encounter, the management of such fractures can be technically demanding. Concomitant elbow dislocation should be managed by closed reduction followed by open reduction and internal fixation (K-wires or cannulated screws) of the lateral condyle fracture. Traumatic elbow dislocation is a rare injury in children constituting 3\u20136% of all elbow injuries . It moreThere is limited evidence available in the literature describing complex elbow fracture dislocation in the pediatric population -7. This A 12-year-old boy presented with a grossly swollen and deformed left elbow after sustaining a fall off skateboard and directly landed on the elbow. There was no neurovascular deficit in the extremity. The anteroposterior and lateral radiographs showed posterolateral dislocation of the left elbow in association with Milch type II lateral condyle fracture  declare that they have no competing interests.Each author has equally contributed. HS collected the data and written up the manuscript, RA helped in scrutiny of the paper and obtaining illustrations. GRT had the idea and granted permission to use his patient data for preparing the manuscript.The pre-publication history for this paper can be accessed here:"}
+{"text": "Seventy-four patients previously treated in our department for germ cell tumour of the testis underwent a series of tests to determine the frequency of long-term therapeutic complications. All had received cisplatin-based chemotherapy as part of their treatment. There was a significant deterioration in renal function throughout the group. Eighteen (24%) had supine blood pressure greater than systolic 140 mmHg or diastolic 90 mmHg after treatment but hypertension did not correlate with renal impairment. Raynaud's phenomenon was common after chemotherapy (26/74) as was persistent sensory neuropathy (23/74). Although 34% had testosterone levels below the normal range, only six patients had a low free testosterone index with one testis still in situ; 18 patients have fathered children after chemotherapy. Approximately half of the patients completed a psychosexual questionnaire and some 30% of them admitted to sexual problems which they attributed to their treatment. Long-term sequelae of cisplatin-based chemotherapy for testicular malignancy are frequent and persistent, and follow-up of these patients should include prospective measurement of changes in blood pressure."}
+{"text": "However, multiple rounds of amplification are required when assaying very small amounts of starting RNA. Moreover, certain cRNA-DNA mismatches are more stable than the analogous cDNA-DNA mismatches and this might increase non-specific hybridization. We sought to determine whether a recently developed linear isothermal amplification method (ribo-SPIA) that produces single stranded cDNA would offer advantages over traditional IVT-based methods for microarray-based analyses of transcript expression.The most widely used amplification method for microarray analysis of gene expression uses T7 RNA polymerase-driven A single round of ribo-SPIA amplification produced sufficient sscDNA for hybridizations when as little as 5 ng of starting total RNA was used. Comparisons of probe set signal intensities obtained from replicate amplifications showed consistently high correlations (r = 0.99). We compared gene expression in two different human RNA samples using ribo-SPIA. Compared with one round IVT, ribo-SPIA had a larger dynamic range and correlated better with quantitative PCR results even though we used 1000-fold less starting RNA. The improved dynamic range was associated with decreases in hybridization to mismatch control probes.The use of amplified sscDNA may offer substantial advantages over IVT-based amplification methods, especially when very limited amounts of starting RNA are available. The use of sscDNA targets instead of cRNA targets appears to improve hybridization specificity. PCR on [IVT] ,14, but on [IVT] .A new single primer, isothermal linear amplification method (ribo-SPIA) has been specifically developed for amplification of very small samples for use on DNA microarrays ,17. WithWe used the ribo-SPIA method to amplify several different total RNA samples. RNA was obtained from a pool of human tissues , mouse liver (Experiment 2), a second pool of human cells , and K562 human erythroleukemia cells . The amount of starting total RNA ranged from 5\u2013100 ng and yields were in the range of ~6\u201312 \u03bcg of sscDNA . sscDNAs were fragmented in preparation for hybridization resulting in fragments of ~50\u2013200 bp. These results are similar to those previously obtained using this method ,17.Each of the experiments included replicate amplifications . We hybridized each replicate to a separate microarray and calculated intensities for each probe set. Fig. 2 [mean K562 intensity/mean sUHR intensity]) and average signal intensity . M and A values obtained using sscDNA are shown in Fig. 7-fold higher in sUHR than K562 cell RNA (M < -7), but no differences of this magnitude were identified using cRNA. The number of probe sets associated with greater than 2-fold differences in expression (|M| > 1) was 1518 for sscDNA and 1043 for cRNA. 51% of the genes with >2-fold differences in expression on sscDNA arrays were not detected as >2-fold on cRNA arrays, but only 25% of the genes that were >2-fold different on cRNAs were not detected as >2-fold different on sscDNA arrays  primers for the synthesis of first strand cDNA, so this explanation is less likely.The new observation that sscDNA gave a wider range of relative expression (M) values despite lower average intensity (A) values could be explained by improved hybridization specificity under the conditions used in this study. This is plausible because the binding energy for DNA-DNA interactions is more sensitive to base pair mismatching than the binding energy for DNA-RNA interactions ,27. To lWe wished to compare how measurements made using amplified sscDNA and microarrays compared with measurements made using other approaches. We began by comparing results obtained using sscDNA and cRNA microarray hybridizations for all 12,625 probe sets on the arrays. Since the sscDNA and cRNA methods would be expected to introduce different systematic biases, we were not surprised that direct correlations between signal intensities obtained with the two different methods showed show relatively poor agreement . The finding indicates that it will not be useful to directly compare one array hybridized with sscDNA to another one hybridized with cRNA.We next compared differential gene expression measures  determined using sscDNA with those determined using cRNA. There was a clear correlation /(sUHR copy number), that could be directly compared to M values from arrays. 37 putative duplicate probe sets from 17 genes probe sets were hand-curated to confirm that they would correspond to the predicted qPCR product. In two cases probe sets were found to be misidentified in the GeneChip annotation and were removed from the analysis. In the remaining cases of duplication, the qPCR and microarray values were averaged across the duplicates. The final set of 106 curated genes and the associated data can be found at .Next we generated another set of expression measurements that could be used as a basis for comparison for the sscDNA and cRNA array results. qPCR is typically used as \"gold standard\" to confirm putative differentially expressed genes detected with microarrays. Since we saw a subset of genes for which expression differed between sscDNA and cRNA targets, we next assessed if either method tracked more closely to qPCR. We chose qPCR primers and probe sets from a large group of >1000 sets that have been developed for various studies. From these, primers and probes for four subsets of genes were selected for qPCR. The first set included all genes with >4 fold difference in expression between K562 and sUHR samples as determined using the sscDNA method, the cRNA method, or both methods (53 primer/probe sets). The second set included all other genes in which the two methods disagreed by more than 2-fold (29 primer probe sets). The third set consisted of a group of 33 empirically-derived 'housekeeping genes.' These were all genes that were nearly equally expressed (|M| < 0.1) in K562 and sUHR samples according to both the sscDNA and cRNA methods and gave strong signals (A > 5 for both methods). The fourth set included 8 housekeeping genes that had been previously validated as controls for qPCR in other experiments. We determined the gene copy number for each qPCR primer and probe set and then calculated a measure of relative expression, M = logThere were clear correlations between qPCR M values and array M values obtained using sscDNA Fig.  or cRNA We examined the suitability of a new isothermal linear amplification method for application to Affymetrix GeneChip microarrays. We performed a series of tests using starting amounts of RNA ranging from 5 to 100 ng for amplification yield and reproducibility. The amplification reactions consistently produced sufficient sscDNA for multiple array hybridizations. Pairwise comparison of technical replicates hybridized to microarrays by regression analysis showed excellent consistency. When we used sscDNA to analyze differential gene expression between two samples, we found a larger dynamic range than that obtained with cRNA hybridizations. The improved performance appears to be related to increased sscDNA hybridization specificity. The data obtained using this new method also more closely matched the results from qRT-PCR than data obtained using standard IVT reactions, even though the amount of starting RNA used was 1000-fold less. This new amplification method is a useful alternative approach for preparing targets that is especially well-suited for experiments involving small amounts of starting material.Clontech Human Universal Reference Pool total RNA (cUHR), derived by pooling RNA from a variety of human tissues, was purchased from BD Biosciences and used in Experiment 1. Mouse total liver RNA was isolated by standard methods from C57/BL6 mice according to procedures approved by the UCSF Committee on Animal Research and used in Experiment 2. For Experiment 3, we used Stratagene Human Universal Reference Pool and K562 erythroleukemia total RNAs from the same batches used in a previous study . All samsscDNA samples were prepared using the NuGEN Technologies Ovation RNA amplification and Biotin Labeling system (Version 1.0) according to the manufacturer's directions from the indicated amount of starting RNA (5\u2013100 ng). All reactions were performed in 0.2 ml strip PCR tubes in an MJ GeneWorks PTC-100 thermocycler using recommended programs. Since the seal for PCR tubes and caps tends to deteriorate with repeated use, we replaced the caps for each tube before each resealing step in the protocol. Following amplification, sscDNA product was purified using QIAquick PCR purification kits (Qiagen). Samples were fragmented and end labeled with biotin. After stopping, each reaction was concentrated in a Microcon YM-3 column to a final volume of ~20 \u03bcl. The concentrated material was purified using a Centri-Sep 100 spin column (Princeton Separations). Negative control reactions were prepared by replacing input RNA with the appropriate volume of RNase free water.. K562 and sUHR microarray data were also analyzed using Microarray Suite 4.0 in order to calculate PM-MM values for each transcript probe set. Probe level analyses were performed using the BioConductor [All samples were placed in standard Affymetrix hybridization buffer. The sample denaturation time for the sscDNA samples was reduced from 5 to 2 minutes and hybridization time increased from 16 to 20 hours as recommended by NuGEN Technologies. cUHR gene expression was assayed using Affymetrix Human Genome U133A GeneChip arrays (Experiment 1). Mouse liver RNA was assayed using Murine Genome Mu6500A arrays (Experiment 2). K562 and sUHR RNAs were assayed using Human Genome U95Av2 arrays (Experiment 3). One template independent sample was also analyzed using a Human Genome U95Av2 array (Experiment 4). Arrays were stained with phycoerythrin-streptavidin according to the manufacturer's instructions. Metrics for all sample hybridizations including scaling factors, mean background intensities, and percent present calls have been provided  PCR was used to measure the expression of selected genes in sUHR and K562 cells. Gene-specific primers for multiplex real time RT-PCR were designed for each gene of interest using \"Primer Express\" software (Perkin-Elmer) and purchased from Biosearch Technologies. Sequence data for all oligonucleotides primers has been provided (see Additional File CSB conceived of the study, participated in the design and coordination, and wrote the manuscript. CG participated in the design of the study and both CG and KH performed the microarray experiments. GMD carried out the real time PCR studies. JYHY performed the statistical analyses. DJE participated in the study design and analysis and revised the manuscript. All authors read and approved the final manuscript.Hybridization Metrics is a .txt file suitable for opening in Microsoft Excel containing information about each individual hybridization.Click here for fileTaqman Primers provides sequence information for oligonucleotides used for qRT-PCR.Click here for file"}
+{"text": "The effects of shock waves generated by an experimental Siemens lithotripter in combination with cytostatic drugs or cytokines on several bladder cancer cell lines were examined in vitro. Proliferation after treatment was determined with the 3-4,5-dimethylthiazol-2,5 diphenyl tetrazolium bromide assay. Dose enhancement ratios were calculated for each drug and each shock wave application mode in order to characterise the sensitising effect of shock wave pretreatment. The influence of the time between shock wave and drug treatment as well as the effects of different sequences of shock wave and drug treatment or concomitant treatment were assessed for selected combinations of cell lines and drugs. It was found that shock wave treatment could render certain cell lines more susceptible to subsequent cis-platinum, mitomycin C or actinomycin D incubation. Cell lines sensitive to tumour necrosis factor alpha or interferon alpha were further sensitised to these cytokines by shock wave pretreatment. The enhanced sensitivity to cis-platinum and actinomycin D decreased rapidly during the first hours after shock wave treatment. The antiproliferative effect was most pronounced after concomitant shock wave and drug treatment. The sensitisation to interferon alpha diminishes more slowly after shock wave exposure. From the results presented in this study it is concluded that transient shock wave-induced permeabilisation of cell membrane not only enhances drug efficiency, but also causes damage to cell organelles and alterations in cellular metabolism."}
+{"text": "Thrombolysis with recombinant tissue plasminogen activator (rtPA) is an established treatment in acute stroke. To prevent rethrombosis after rtPA therapy, secondary anticoagulation with heparin is commonly performed. However, the recommended time-point and extent of heparin treatment vary and are not well investigated.We report a 61-year-old man who developed an acute global aphasia and right-sided hemiparesis. Cranial CT was normal and systemic thrombolytic therapy with tPA was started 120 minutes after symptom onset. Low-dose subcutaneous heparin treatment was initiated 24 hours later. Transthoracic echocardiography (TTE) 12 hours after admission showed slightly reduced left ventricular ejection fraction (LVEF) but was otherwise normal. 48 hours later the patient suddenly deteriorated with clinical signs of dyspnea and tachycardia. TTE revelead a large left ventricular apical thrombus as well as a reduction of LVEF to 20 %. Serial further TTE investigations demonstrated a complete resolution of the thrombus and normalisation of LVEF within two days.Our case demonstrates an intracardiac thrombus formation following rtPA treatment of acute stroke, probably caused by secondary hypercoagulability. Rethrombosis or new thrombus formation might be an underestimated complication of rtPA therapy and potentially explain cases of secondary stroke progression. Recombinant tissue plasminogen activator (rtPA) is an approved treatment option for acute ischemic stroke within three hours of symptoms onset. It is well known that reperfusion of ischaemic brain tissue, when performed in a timely manner, improves clinical outcome ,2. HowevWe present a patient with acute ischaemic stroke who developed a transient left ventricular apical thrombus after systemic thrombolysis.A 61-year-old man was admitted to the Emergency Department immediately after he experienced global aphasia and right-sided hemiparesis. The clinical diagnosis of acute cerebral ischaemia in the middle cerebral artery (MCA) territory was made by a neurologist. A cranial CT-scan showed no early signs of cerebral infarct and no intracranial bleeding. Atrial fibrillation was recognised on the initial ECG and an cerebral infarct of cardiac embolic origin was assumed. The patient had no history of stroke but suffered from coronary heart disease and sustained an anterior cardiac wall infarction in the past. Further known vascular risk factors were hypertension and smoking. Even so, the patient took no medication at the time of admission.Thrombolysis with 70 mg rt-PA (0.9 mg/kg) was started two hours after the onset of symptoms. The neurological status during and after rt-PA treatment remained unchanged. Transthoracic echocardiography (TTE) performed 12 hours after initiation of thrombolytic therapy revealed a moderately reduced left ventricular systolic function (ejection fraction: 41%), left ventricular regional dyssynergy, and no intracardiac thrombus.The D-Dimer antigen plasma concentration as a marker of coagulation activation was raised 24 hours after rt-PA treatment and showed a tendency to normalisation during the following days.Extracranial Duplexsonography revealed moderate arteriosclerotic plaque formation in the carotid bulb on both sides but no hemodynamic stenosis of the carotid and vertebral arteries. Using transcranial duplexsonography a severe stenosis was found in the proximal segment of the left middle cerebral artery. No diabetes or hyperlipidaemia were diagnosed. Cerebral MRI, twenty-four hours after lysis revealed a cortical infarct with a clinically asymptomatic haemorrhagic transformation in the left-sided MCA territory. Antithrombotic treatment with subcutaneous low-dose heparin  was initiated 24 hours after thrombolysis. The fluid balance was continuously monitored and kept net 0 ml/24 hours to avoid fluid overload.rd day after admission, the patient developed acute dyspnea, tachypnea, tachycardia, and an elevated blood pressure. Acute myocardial infarction was excluded on the basis of ECG and blood tests . A CT-scan detected no pulmonary embolism, but massive bilateral pleural effusion. TTE revealed an apical thrombus measuring 2.0 \u00d7 2.0 cm in the left ventricle (figure On the 3e figure  with lefSystemic rt-PA thrombolysis in acute stroke has been implemented into daily clinical practice during the last decade. The treatment within three hours of stroke appears to be effective in reducing the neurological deficit ,7. HowevSome authors have reported a significantly higher incidence of parenchymal haematomas if thrombolysis was immediately followed by intravenous or subcutaneous heparin administration . Howeverrt-PA has a short biological half-life of 8\u201312 minutes but alters the physiological balance between coagulation and anticoagulation for a longer time period . After dOtherwise, clinical studies of fibrinolytic therapy in myocardial infarction show, that early heparin treatment starting immediately after thrombolysis significantly decreases the risk of cardiac vessel reocclusion . The capIn our patient, treated with low dose heparin, an apical thrombus developed within 72 hours after thrombolytic therapy, strongly suggesting a causal relationship of secondary hypercoagulability and thrombus formation. The patient's history and risk profile suggests an increased risk for cardiac events . We postCoronary angiography was not performed, considering the cerebral state of the patient and the observation that repeated ECGs were normal and cardiac enzymes not elevated. The clinical status stabilised spontaneously and the cardiac thrombus resolved within two days without initiation of a specific therapy, further supporting the hypothesis of a temporary status of hypercoagulation after thrombolysis.rd day and not directy after stroke which makes the diagnosis of neurogenic stunned myocardium further unlikely [Another hypothesis for the temporary cardiac detoriation in our patient could be an acute neurogenic stunned myocardium. This phenomenon is described as sudden, reversible left ventricular dysfunction with abnormal left ventricular wall motion and reduced ejection fraction. Levels of creatine kinase MB and troponin may be elevated and ECG alterations as depression or elevation of the ST segment or T wave inversion can be observed. However, acute neurogenic myocardial stunning has so far only been reported after subarachnoid hemorrhage -20 and iunlikely ,20,21.In summary, our case demonstrates an intracardiac thrombus formation following rtPA treatment of acute stroke, probably caused by secondary hypercoagulability. Rethrombosis or new thrombus formation might be an underestimated complication of rtPA therapy and potentially explain cases of secondary stroke progression. Early systemic anticoagulation with heparin might reduce the risk of rethrombosis but also increase the risk of a bleeding complication. Systematic studies concerning the incidence of thrombus formation after rtPA therapy and the effects of different post-thrombolysis anticoagulation strategies are required to assess the clinical relevance of the discussed secondary hypercoagulability. Closed echocardiographic monitoring in stroke patients treated with systemic thrombolysis might be useful for early detection of the described potential cardiac complications especially because repeated measurement of ECG and cardiac enzymes alone might fail."}
+{"text": "Moisture content in commercially available milk powder was investigated using near infrared (NIR) diffuse reflectance spectroscopy with an Indian low-cost dispersive NIR spectrophotometer. Different packets of milk powder of the same batch were procured from the market. Forty-five samples with moisture range 4\u201310% were prepared in the laboratory. Spectra of the samples were collected in the wavelength region 800\u20132500 nm. Moisture values of all the samples were simultaneously determined by Karl Fischer (KF) titration. These KF values were used as reference for developing calibration model using partial least squares regression (PLSR) method. The calibration and validation statistics are"}
+{"text": "The mechanism of tumour necrosis photosensitised by liposome-delivered Zn(II) phthalocyanine (Zn-Pc) has been studied in mice bearing a transplanted MS-2 fibrosarcoma. Ultrastructural analyses of tumour specimens obtained at different times after red light-irradiation  indicate an early (3 h) photodamage of malignant cells especially at the level of the mitochondria and rough endoplasmic reticulum. The cellular damage becomes more evident between 6 h and 15 h after photodynamic therapy. On the other hand, the capillaries supplying the tumour tissue are modified at a much slower rate and appear to be severely damaged only after 15 h from irradiation, when the whole tissue becomes necrotic. Occasionally, mildly damaged capillaries are observed even at 72 h after irradiation. These findings support the hypothesis that low density lipoproteins (LDL) play a major role in the delivery of Zn-Pc to the tumour tissue; the photosensitiser is released specifically to malignant cells as a consequence of a receptor-mediated endocytosis of LDL."}
+{"text": "Mediastinal pancreatic pseudocyst is a rare complication of acute or chronic pancreatitis.This case report describes the management of a difficult case of pancreatic pseudocyst with a mediastinal extension in a patient having chronic pancreatitis. Different management strategies were used until complete resolution of this complex pseudocyst occurred using open surgical cystogastrostomy.Despite the availablity of different minimally invasive techniques to treat pancreatic pseudocysts, management of complex mediastinal pseudocyst may still require open surgical drainage procedures. Mediastinal pancreatic pseudocyst is a rare complication of acute or chronic pancreatitis. Since its first description in 1951, approximately 50 cases have been reported in the world literature. We report a case of mediastinal pseudocyst associated with alcoholic pancreatitis successfully treated with cystogastrostomy.A 22-year-old female patient with a known history of chronic alcohol abuse was referred to hepato-biliary unit with recurrent upper abdominal related to chronic pancreatitis. Prior to this she has had multiple hospital admissions in previous one year with similar symptoms. In the past, ultrasonography had excluded gallstones and a CT scan 12 months ago had shown normal-looking pancreas. Her most notable symptomatic episode was 4 months ago when she was admitted with left lateral chest pain and dyspnoea. A CT-scan although excluded a pulmonary embolism but incidentally revealed a left gastric artery pseudoaneurysm  declare that they have no competing interests.All the authors have been involved in literature search, writing and final reviewing of this manuscript."}
+{"text": "The renal function was evaluated with 131I-Hippuran clearance in 171 patients with malignant germ cell tumours. Assessments were performed before treatment and at three fixed times afterwards within 5 years. The patients were treated with surgery only (20 patients), infra-diaphragmatic radiotherapy only (median midplane dose 36 Gy) (48 patients), cisplatin-based chemotherapy  plus surgery (64 patients), cisplatin-based chemotherapy  with or without surgery (23 patients) or cisplatin-based chemotherapy  plus infra-diaphragmatic radiotherapy (16 patients). No renal impairment was observed for patients treated with surgery only. In patients who received radiotherapy no change of the renal function occurred during the first year post-treatment. Three to five years after treatment discontinuation a statistically significant reduction within the normal range was observed in patients who were greater than 40 years at the time of irradiation. Cisplatin-based chemotherapy led to a statistically significant irreversible renal impairment for all the three groups. The greatest reduction was seen in patients who received the highest total cisplatin dose or who were treated with irradiation in addition to chemotherapy. The clinical significance of the observed nephrotoxicity is still unknown."}
+{"text": "The successful treatment of paroxysmal supraventricular tachycardia with adenosine 5` triphosphate (ATP) was initially reported by Somlo  in 1955.Non-invasive diagnosis of dual AV node physiology (DAVNP) in patients with AV nodal reentrant tachycardia by administration of ATP or adenosine has been reported by different authors ,5. ThougIn patients with palpitations of unclear etiology, ATP test identifies those who are likely to have AVNRT or AVRT  with a high positive predictive value . ATP/ade"}
+{"text": "Left ventricular free wall rupture after myocardial infarction has a high mortality. Suturing techniques of repair may be technically difficult and require cardiopulmonary bypass. We report a case of left ventricular rupture in a 47 year old man managed off pump employing a sutureless technique with Gelatine-Resorcin-Formalin glue and bovine pericardial patches. Left ventricular free wall rupture post myocardial infarction has a high mortality and therefore, rarely presents to the cardiac surgeon. Conventional approaches to this condition include ventricular repair with teflon buttressed sutures using cardiopulmonary bypass (CPB). Coronary artery bypass grafting may be performed concomitantly. Some authors have suggested sutureless techniques with or without cardiopulmonary bypass for this condition. We report a case of off-pump repair with bovine pericardial patches using Gelatine-Resorcin-Formalin (GRF) glue.A 47 year old man presented to the Emergency department with central chest pain. Lateral myocardial infarction (MI) was confirmed by typical changes in leads I, AVL and V6 and raised troponin T levels. The patient was not thombolysed. He was haemodynamically stable initially and a coronary angiogram was contemplated. However, before this could be performed, he developed further chest pain and became haemodynamically unstable with tachycardia, hypotension and collapse (at 48 hours). An urgent trans- thoracic echocardiogram (TTE) showed a pericardial effusion. Left ventricular (LV) free wall rupture was suspected. Contrast-enhanced computed tomography (CT) of the chest was performed which confirmed this, as well as a large pericardial effusion figure . He was Myocardial infarction complicated by left ventricular free wall rupture and pericardial tamponade occurs in 2\u20134% of cases and is associated with a high mortality . AutopsyTraditional left ventricular free wall rupture repair techniques such as a series of interrupted pledgeted sutures, reinforced linear teflon strips and circular patch repair often involve tying sutures though friable necrotic muscle . HeparinMariani et al  describeThe traditional approach is to proceed with infarctectomy and replacement with a prosthetic patch under CPB . Prior tBasically, there are two types of glue: synthetic (most commonly cyanoacrylates) and biological . Degradation of the cyanoacrylates can lead to tissue toxicity. The shorter-chain compounds (butyl) tend to have a higher degree of tissue toxicity than the longer-chain derivatives (octyl). These adhesives work by polmerising after which the adhesive may become brittle and is subject to fracturing. This is especially true in areas of high tension. These limitations of synthetic glues lead to the development of biological glues. The GRF glue should be used as a tissue reinforcer, the two-component fibrin sealer is preferable when haemostatic action must be accompanied with mechanical barrier and the cryoprecipitate glue can be used when haemostatic action is the only requirement.It is not known whether the benefit of CABG is worth the inherent risk involved in delaying definitive surgical therapy by performing coronary angiogram. In a review of literature, only 9 of the 87 long term survivors of free wall rupture repair had CABG as part of their surgical intervention [On the basis of our case report and the current literature we can say that left ventricular free wall rupture after myocardial infarction can potentially be repaired without the use of extra-corporeal circulation using the sutureless technique with glue and pericardial patch. Gluing is an alternative to suturing in such a desperate situation."}
+{"text": "Fifty-two patients with epithelial ovarian cancer were treated with yttrium-90-labelled monoclonal antibody HMFG1 administered intraperitoneally following conventional surgery and chemotherapy as part of an extended phase I-II trial. The treatment was well tolerated and the only significant toxicity observed was reversible myelosuppression as previously described. Following conventional surgery and chemotherapy, 21 out of the 52 patients had no evidence of residual disease and were regarded as receiving treatment in an adjuvant setting. To date, two of these patients have died of their disease . This extended phase I-II study suggests that patients with advanced ovarian cancer who achieve a complete remission following conventional therapy may benefit from further treatment with intraperitoneal radioactive monoclonal antibody."}
+{"text": "Recent studies have demonstrated a consistent inverse relationship between oestrogen receptor (ER) and epidermal growth factor receptor (EGFR) levels in female human breast cancer. Serial cross-section studies have suggested that separate populations of ER+/EGFR- and ER-/EGFR+ cancer cells exist in tumours deemed by immunocytochemical assay (ICA) to be positive for both. We have developed a dual ICA that is able to stain for both ER and EGFR on a single 5 microns frozen section sample of breast tissue. Twenty-two samples of female human breast cancer tissue that exhibited positivity for ER and EGFR by ER-ICA using the H222 monoclonal antibody and EGFR-ICA using the EGFR1 monoclonal antibody underwent the dual ICA. There was a significant correlation in receptor positivity between the single and dual assays for both ER  and EGFR . Individual cancer cells exhibited one of three staining patterns: nuclear staining only (ER+/EGFR-), membrane-associated and cytoplasmic staining only (ER-/EGFR+) or no staining (ER-/EGFR-). No cancer cells exhibited both nuclear and membrane/cytoplasmic staining. This is the first description of a simultaneous dual immunocytochemical assay system for ER and EGFR in clinical breast cancer specimens. The results suggest that ER and EGFR expression are mutually exclusive within an individual breast cancer cell in vivo with separate populations of ER+/EGFR- cells, ER-/EGFR+ cells and ER-/EGFR- cells coexisting."}
+{"text": "Incisional sustained tachycardias are frequent in patients who have undergone a surgical repair of interatrial defect. A 43-year-old woman with drug refractory, highly symptomatic, persistent atrial tachycardia in the last year, was referred to our unit for catheter ablation. The patient had undergone a cardiac operation for repairing interatrial secundum ostium type defect with a patch five years before. A previous radiofrequency ablation procedure had been performed for common atrial flutter. We describe a case of incisional  atrial tachycardia ablation guided by the new EnSite NavX system equipped with a new electroanatomic mapping system. Incisional sustained tachycardias are frequent in patients who have undergone surgical repair of  an interatrial defects ,2. The mA 43-year-old woman with drug refractory, highly symptomatic, persistent atrial tachycardia in the last year, was referred to our unit for catheter ablation. Five years ago the patient was undergone  a cardiac operation for repairing an interatrial secundum ostium type defect. ECG showed an atrial tachycardia whose features resembled a common atrial flutter. Echocardiography images showed no  significant atrial dilation, no residual interatrial shunt and a normal ventricular systolic function.A quadripolar Josephson diagnostic catheter was inserted into the coronary sinus via left subclavian vein as a reference. A bipolar Cournard diagnostic catheter was inserted into the right ventricular apex. A  20-pole steerable catheter was placed around the tricuspid annulus. An 8 mm tip catheter (Boston Scientific EP Technologies) was used for mapping and ablation. The electrophysiological findings showed a stable atrial tachycardia of 230 ms cycle length which was firstly misunderstood as a common atrial flutter (counter clockwise) showing a caudocranial septal activation and craniocaudal activation along the right lateral atrial wall. The ablation catheter was therefore positioned on the cavo-tricuspid (CT) isthmus, considering this region crucial for the macroreentry circuit. But overdrive pacing at 210 ms cycle length from CT isthmus did not show any concealed entrainment. So we were inclined to believe that it was an incisional tachycardia and therefore we performed a reconstruction of the three-dimensional geometry of the right atrium  using the EnSite NavX system.An activation-voltage map was obtained moving the ablation catheter point by point inside the right atrium while the patient was still in stable atrial tachycardia. The voltage map showed a large no-signal area  on interatrial septum corresponding to a large patch used for repairing an interatrial defect . A largeRF application  in continuous way (70 Watts 55 \u00b0C) was then attempted along this isthmus drawing back the ablation catheter from the scar area to the tricuspid valve annulus, trying to connect the two areas of anatomic obstacles. We moved the ablation catheter along this line obtaining local electrogram disappearance or  voltage reduction more than 70%. EnSite NavX mapping system allowed us to move ablation catheter in  the right atrium without using fluoroscopy  during the procedure.After four RF applications along the isthmus between the patch on the atrial septum and the tricuspid valve annulus, atrial tachycardia was not yet interrupted though no significant local electrogram was still detectable along the ablation line we had performed. In order to verify ablation line continuity we performed an electroanatomic and activation remapping of the isthmus region which showed a gap on the ablation line  near theThe patient was followed up monthly after the procedure. Each month history, 12-lead ECG and 24 hour ECG Holter were analyzed. Ten months after the procedure though the patient had not taken any anti-arrhythmic drugs, there was no recurrence of palpitation or documented atrial tachycardia.The case shows that EnSite NavX system provides an excellent electroanatomic and activation map of any cardiac chamber and reliable monitoring of the ablation catheter. This system let us quickly made a diagnosis of incisional tachycardia with an anatomic circuit of macroreentry different from that of a common atrial flutter allowing us to identify a slow conduction isthmus in a place that was not the CT isthmus, though the electrocardiography feature of the atrial tachycardia was similar to a common atrial flutter. The Ensite NavX system rapidly identified a gap in the linear lesion we had performed, and allowed us to terminate the atrial tachycardia. NavX significantly reduces fluoroscopy time during ablation procedures and also allows to successfully perform difficult procedures with complex substrates. NavX supports detection of anatomic isthmus variations, particularly deep pouches or recesses ,14."}
+{"text": "Echocardiography plays an integral role in the diagnosis of congestive heart failure including measurement of left heart pressure as well as mechanical dyssynchrony.In this report we describe novel therapeutic uses of echo pulsed wave Doppler in atrioventricular pacemaker optimization in patients who had either not derived significant symptomatic benefit post biventricular pacemaker implantation or deteriorated after deriving initial benefit. In these patients atrioventricular optimization showed novel findings and improved cardiac output and symptoms.In 3 patients with Cheyne Stokes pattern of respiration echo Doppler showed worsening of mitral regurgitation during hyperpneac phase in one patient, marked E and A fusion in another patient and exaggerated ventricular interdependence in a third patient thus highlighting mechanisms of adverse effects of Cheyne Stokes respiration in patients with heart failure. All 3 patients required a very short atrioventricular delay programming for best cardiac output. In one patient with recurrent congestive heart failure post cardiac resynchronization, mitral inflow pulse wave Doppler showed no A wave until a sensed atrioventricular delay of 190 ms was reached and showed progressive improvement in mitral inflow pattern until an atrioventricular delay of 290 ms. In 2 patients atrioventricular delay as short as 50 ms was required to allow E and A separation and prevent diastolic mitral regurgitation. All patients developed marked improvement in congestive heart failure symptoms post echo-guided biv pacemaker optimization.These findings highlight the value of echo-guided pacemaker optimization in symptomatic patients post cardiac resynchronization treatment. Echocardiography has become the gold standard for non invasive assessment of diastolic function . BesidesA 51 year old African American obese male with a history of non-ischemic dilated cardiomyopathy improved CHF symptoms from NYHA class III to class II after biv pacemaker implantation. Patient developed recurrent CHF with NYHA class III symptoms and an LVEF of 20% 8 months post CRT. On interrogation there was normal sinus rhythm and pacemaker was programmed in the DDD mode, AV delay of 160 ms and a VV delay of 0 ms. Mitral inflow PW Doppler and respirogram revealed cyclic variation of heart rate from 56 to 94 beats per minute during Cheyne Stokes respiratory cycle. Post apneac hyperpnea was associated with tachycardia Figure  and hypoA 76 year old Caucasian female developed increasing shortness of breath and NYHA class III symptoms for 8 weeks. Patient had a history of RV pacemaker implantation for a complete heart block followed by development of CHF class II-III. RV pacemaker was upgraded to a biv pacemaker that led to improvement in symptoms for about 7 months. A-pacing at 60 bpm and paced and sensed AVD of 170 and 150 ms respectively and LV pre-excitation of 20 ms were programmed. Moderate to severe mitral regurgitation (MR) with onset in diastole was seen at these settings Figure  and 3B. A 72 year old African American female with ischemic cardiomyopthy and prior left cerebrovascular accident and right hemiparesis presented with CHF and NYHA class III symptoms 1 year after biV pacing. LVEF was 25%, there was mild MR and peak pulmonary artery systolic pressure was 50 mm Hg. Cheyne Stokes respiratory pattern was seen on respirogram. Hyperpnea was associated with decreased RV-RA gradient during each inspiration Figure  and 6B. A 73 Caucasian male was referred for bi-V pacemaker optimization 7 months post CRT for ischemic cardiomyopathy. Symptoms of CHF improved initially, however worsening shortness of breath and fatigue occurred 5 months later to NYHA class III symptoms. BNP was 1040 pg/ml. The device was programmed in the DDD mode, with sensed AV delay of 150 ms and paced AV delay of 160 ms. PW Doppler showed absent mitral inflow A waves at baseline pacemaker settings despite presence of sinus rhythm Figure . AV delaAn 83-year-old Caucasian male with a history of ischemic cardiomyopathy, CHF and NYHA class II symptoms underwent biv pacemaker implantation. Sensed AVD was 100 ms and RV-LV offset was 20 ms. Routine pre-discharge optimization revealed late diastolic MR Figure  at an AVA 67 year old Caucasian female underwent biv pacemaker implantation for non ischemic dilated cardiomyopathy, severe mechanical dyssynchrony, left bundle branch block, NYHA class III and LVEF of 35%. She was referred for persistent shortness of breath upon exertion post CRT. Programmed AVD of 130 ms showed marked E and A fusion Figure  and diasOur findings describe the utility of AV pacemaker optimization using PW echocardiography in optimizing diastolic mitral inflow in patients who remain symptomatic post CRT. Our report also highlights the mechanisms of adverse effects of Cheyne Stokes pattern of respiration on cardiac performance.Other investigators have reported the incremental improvement in cardiac function and functional class by echocardiographic guided pacemaker optimization in patients who undergo CRT -3. StudiShortening of AV delay has been shown to reduce diastolic MR in patients with right sided pacemaker , and cauCentral sleep apnea is common among patients with CHF, being present in 30\u201340% of patients . It contOurs is not a consecutive series of patients, rather a collection of patients in whom echo Doppler during AV optimization allowed novel observations that provide insight into the mechanism of failure of CRT and adverse effects of Cheyne Stokes respiration. A systemic study is needed to prospectively evaluate prevalence of Cheyne Stokes respiration in symptomatic patients post CRT and effect of AVD optimization in this group.We report 3 separate mechanisms whereby Cheyne Stokes respiration can contribute to worsening of heart failure symptoms in patients with CHF post CRT. These include compromised diastolic filling during hyperpneac phase of respiration, increase in diastolic mitral regurgitation during hyperpneac phase and development of a constrictive physiology with enhanced ventricular interdependence. A short AVD helped improve diastolic filling, reduce diastolic MR and reduce ventricular interdependence in all 3 patients. We also report the use of short AVD in abolishing diastolic MR in patients without Cheyne Stokes respiration as well as improvement in diastolic filling by an extraordinarily long AVD in a patient with heart failure post CRT. Our findings extend the use of echo Doppler in evaluation of patients who remain symptomatic post CRT as well as in determining optimal AVD.AVD = Atrioventricular DelayCHF = Congestive Heart FailureCRT = Cardiac Resynchronization TreatmentCPAP = Continuous Positive Airway PressureLVEF = Left Ventricular Ejection FractionLV = Left Ventricle (Ventricular)MR = Mitral RegurgitationNYHA = New York Heart AssociationPW = Pulsed waveRA = Right AtriumRV = Right Ventricle (Ventricular)VTI = Velocity Times IntegralThe author(s) declare that they have no competing interests.TZN conceptualized the design of the study, imaging methodology and interpreted data during acquisition. AMR analyzed echocardiographic data and helped to draft the manuscript. All authors read and approved the final manuscript."}
+{"text": "Twenty seven patients with malignant lymphoma of lymphocytic type/B-chronic lymphocytic leukaemia  diagnosed from lymph node and splenectomy specimens were studied histologically and immunologically. Lymph node biopsies showed a diffuse effacement of normal architecture by small round lymphocytes usually with scattered proliferation centres (PC). A1 spleens showed white pulp with or without red pulp involvement, sometimes with tumour nodules present. PC-like cells or PC were only found in the white pulp or tumour nodules. Studies of 13 specimens using the ABC immunoperoxidase technique on frozen sections with a large panel of monoclonal antibodies showed that although a part of the monoclonal B cell neoplasm, the proliferation centres or splenic white pulp have a different phenotype from the surrounding cells. Some of these phenotypic changes are similar to those reported with in vitro induction of \"maturation\" of ML, L/B-CLL cells. The implications for normal B-cell development are discussed. In contrast to reported peripheral blood findings, T cells, predominantly of T helper phenotype in lymph nodes, were present but usually not numerous."}
+{"text": "Natural and lymphokine activated killer cells (NK and LAK) are believed to play an important role in the control of tumour progression and metastasis. Their specific receptors on tumours cells are still unknown. Several studies suggest that these cells recognise and eliminate abnormal cells with deleted or reduced expression of MHC class I molecules. Previous reports suggest that interferons (IFN), by increasing MHC class I expression on target cells, induce resistance to killing by NK cells. We investigated the role of MHC molecule expression by two human breast cancer cell lines T47D and ZR75-1 in their susceptibility to NK and LAK cells. These two cell lines spontaneously express low levels of HLA class I antigens but no HLA class II molecules. After IFN-gamma treatment they both overexpressed MHC class I and de novo expressed class II molecules as detected by flow cytometry, quantified by a radioimmunoassay and analysed by two-dimensional gel electrophoresis. Opposed to untreated cells these IFN-gamma treated cells were resistant to NK and LAK lysis. Furthermore, preincubation of IFN-gamma treated breast cancer cells with F(ab')2 fragments of monoclonal antibodies to HLA class I and HLA class II molecules was unable to restore lysis. In contrast, several complete monoclonal antibodies including anti-HLA class I and HLA class II induced the lysis of target cells whether or not they had been treated by IFN-gamma. The therapeutic use of monoclonal antibodies directed against antigens expressed on tumour cells (ADCC) in conjunction with interferon therapy should be discussed in lymphokine-based strategies for treatment of cancer patients."}
+{"text": "A genetically reshaped human IgG1 monoclonal antibody (Hu2PLAP) with anti-tumour specificity, was radiolabelled with Indium-111 by chelation with a new macrocyclic compound (DOTA) which allows the production of stable radioimmunoconjugates for in vivo application. This was used to image seven patients with malignant disease, of whom two had been previously exposed to mouse monoclonal antibodies and had developed human anti-mouse antibodies (HAMA). Successful tumour localisation was seen in the four patients with active disease and antigen positive tumours. No patient showed any antibody responses against Hu2PLAP, but three out of six patients tested showed an immune response against the macrocycle DOTA. Reshaped human monoclonal antibodies with anti-tumour specificity may facilitate repeated administrations of radioactive antibodies, thus allowing new possibilities, both in the diagnosis and treatment of cancer."}
+{"text": "Conditioned media from 14 short term fibroblast cell lines were mitogenic for human breast cancer cells with different steroid receptor profiles in serum-free culture. Fibroblast-conditioned medium stimulated tritiated thymidine incorporation in short term culture and growth in a longer proliferation study as measured by the MTT colorimetric assay. Conditioned media from benign and malignant epithelial cells were non-stimulatory for breast cancer cells but that derived from endothelial cells showed similar stimulation to fibroblasts. Partial purification of fibroblast-conditioned medium identified a peptide with a molecular weight of approximately 8 kDa that showed no affinity for heparin and was mitogenic for MCF-7 breast cancer cells."}
+{"text": "Cells with \"hand mirror\" morphology have not, to the best of our knowledge, been described in a primary effusion sample. This paper describes a case of T-cell lymphoma with eosinophilia in a patient with suspected peritoneal carcinomatosis. Rarely, a T-cell lymphoproliferative process may mimic primary peritoneal carcinomatosis, clinically suggested by a presentation in CT imaging of omental caking with bilateral massive loculated effusions in a patient without lymphadenopathy or splenomegaly.A 60 year old caucasian male presented with vague abdominal discomfort and increasing abdominal girth. Computed tomography showed a two centimeter thick omental cake and a small loculated effusion. The clinical presentation and imaging findings were most consistent with peritoneal carcinomatosis. Cytologic evaluation of the effusion was undertaken for diagnostic study.Rapid intraprocedural interpretation of the effusion sample showed a monomorphic population of cells with \"hand-mirror\" cell morphology exhibiting cytoplasmic extensions (uropodia) with 3\u20135 course dark cytoplasmic granules and a rim of vacuolated cytoplasm capping the opposing \"mirror head\" side. These cells were seen within a background of mature eosinophils. Flow cytometric evaluation of the ascites fluid demonstrated an atypical T-cell population with the following immunophenotype: CD2-, CD3+, CD4-, CD5-, CD7-, CD8+, CD56+. T-cell receptor (TCR) gene rearrangement was positive for clonal TCR-gamma gene rearrangement, supporting the diagnosis of a T-lymphoprolifereative disorder.A T-cell lymphoproliferative process may present with \"hand mirror\" morphology in an effusion sample. These cells may show polar cytoplasmic vacuolization and 3\u20135 course granules within the \"handle\" of these unique cells. Cytoplasm shows peripheral constriction around the nucleus. Cells with \"hand mirror\" morphology have not, to the best of our knowledge, been described in a primary effusion fluids . The celWhen a suspected lymphoproliferative process is evaluated during an immediate FNA interpretation specimen adequacy evaluation is critical. This can facilitate optimal sample handling for immunohistochemistry, flow cytometry, molecular analysis or chemical/enzymatic evaluation .The present case describes a loculated eosinophilic peritoneal effusion with hand-mirror cells (HMC) in association with peritoneal caking. Clinical suspicion based on CT imaging included peritoneal carcinomatosis. This ascites fluid also showed an increased relative proportion of unremarkable eosinophils. Eosinophilic effusions (defined as exceeding 5% eosinophils) have been associated with many etiologies including trauma, infection, peritoneal dialysis and malignancy . Both thThis 60 year old Caucasian male presented to his primary care physician with a chief complaint of vague abdominal pain and increasing abdominal girth of 3 months duration. His past medical history was essentially unremarkable.Peripheral blood showed mildly elevated WBC and platelet counts with mild relative lymphocytopenia and normal eosinophil counts. Carcinoembryonic antigen, Alpha-feto protein, CA15-3 and CA125 were all within normal ranges. Calcium was consistently mildly decreased during the course of hospital stay with slightly elevated prothrombin times.Initial imaging of abdomen by computed tomography (CT) demonstrated large volume ascites, fatty changes of liver, and omental-peritoneal \"caking\" measuring up to 2.0 cm in thickness Figure: . There wUltrasound guided aspiration of ascites fluid was obtained for routine cytology using a 22 gauge needle. Following the initial ultrasound guided paracentesis a CT guided Fine needle aspirate samples of omental cake was performed using an 18 gauge core biopsy. Initial aspirate samples were evaluated onsite for specimen adequacy by the cytopathologist. Additional samples were retained for ThinPrep, cell block, core Bx and microbiologic culture. The patient tolerated the procedure without difficulty. Rapid interpretation documented a sample adequate for cytomorphologic evaluation, special studies and microbiologic culture.Cytologic interpretation of the FNA for both the left flank omental mass and ascites specimen showed an atypical lymphoid population with prominent hand-mirror cell morphology and frequent eosinophils. This was felt to be strongly suspicious for a lymphoproliferative process, possibly T-Cell derived Figure: . The nucFlow cytometric and Immunohistochemistry revealed an atypical CD56+ T-Cell population suggestive of a T-Cell lymphoproliferative process. PCR analysis for TCR gamma gene rearrangement revealed two monoclonal peaks with TCR gamma primers, corresponding to V-gamma 11 gene rearrangement and V-gamma [This was a case of a 60 year old man with loculated peritoneal eosinophilic effusion and omental caking who was diagnosed with T-cell lymphoma by FNA. Cytologically distinct hand-mirror forms comprised the majority of the cells in the effusion. The finding of hand mirror cells in a peritoneal effusion has not, to the best of our knowledge, been described in the current literature. The patient declined treatments, entered hospice care and died within three months of the diagnosis.The term hand-mirror cell differentiation is descriptive. The cell is characterized by an asymmetrical cytoplasmic elongation extending out from one pole of the nucleus (uropod). Both the nucleus and the elongated cytoplasmic \"handle\" together give the appearance of a hand-mirror. The hand-mirror cell morphology had in the past been classified as a distinct morphologic variant of acute lymphoblastic leukemia ; howeverHand-mirror cells have also been reported with many diagnostic entities including cutaneous natural killer cell lymphomas , AnaplasThe distinct morphology most likely represents an aspect of immune responsivity or challenge involving the incorporation of immune complexes. AlthougThe CT findings in this case were associated with peritoneal involvement by lymphomatosis however the CT observation of omental \"caking\" has been identified as an unreliable means to distinguish peritoneal carcinomatosis or tuberculous peritonitis from lymphomatosis. Ascites without loculation or septation and diffuse distribution of enlarged lymph nodes may however help to differentiate peritoneal lymphomatosis from other eitiologies .This case also illustrates advantages of on-site specimen adequacy evaluation which proved essential in obtaining samples for appropriate special studies.Immunophenotypic, flow cytometric and molecular studies in this case documented a T-Cell lymphoma. It also provided an opportunity to offer a rapid interpretation which in this case did not support the provisional diagnosis of peritoneal carcinomatosis which had been based on CT observation of omental caking. The preponderance of hand mirror cells and the presence of an eosionophilia in the effusion were consistent with the final diagnosis."}
+{"text": "Serial frozen sections from eleven patients with malignant breast tumours and five patients with benign disease were studied by indirect immunoperoxidase using a panel of mouse monoclonal antibodies to human leucocyte antigens. More infiltrating leucocytes were seen in tumour sections than those of benign conditions. A considerable proportion of the infiltrating cells were T cells, and more of these were of the suppressor/cytotoxic subset than the helper/inducer subset. The T cells were apparently not all activated as indicated by lower levels of staining with anti HLA-DR than anti-leucocyte antibody. Diffuse staining was sometimes seen with HLA-DR and T cell subset antibodies. Tumour cells did not stain or were only very weakly positive with anti HLA-A, B, C."}
+{"text": "Objective: To survey the evolution over the past decade of attitudes and practices of obstetricians in maternal\u2013fetal medicine fellowship programs regarding the management of human immunodeficiency virus (HIV)-infectedpregnant women.Methods: Directors of all 65 approved maternal\u2013fetal medicine training programs were sent questionnaires,responses to which were to reflect the consensus among members of their faculties. Programs were stratifiedbased upon the number of HIV-infected pregnant patients cared for in the previous year.Results: Responses reflect experience with over 1000 infected pregnantwomen per year, nearly one-quarter withadvanced disease. Combination antiretroviral therapy was prescribed by all respondents, universally in the 2nd and3rd trimesters. A three-drug regimen (often containing a protease inhibitor) was used more often by those whotreated at least 20 HIV-infected pregnant patients per year than by those programs seeing a lower number ofpatients (80 vs 59%).Despite the known and unknown risks of the use of antiretrovirals during pregnancy, only halfof all responding programs report adverse events to the Antiretroviral Pregnancy Registry; reporting was morecommon among the institutions seeing a higher number of patients (61 vs 45%). Seventy-eight percent of highervolume programs enroll their patients in clinical studies, usually multicenter, versus 35% of lower volumeprograms.Conclusions: Care for HIV\u00b2 pregnant women has dramatically changed over the past decade. Antiretroviraltherapy is now universally prescribed by physicians involved in maternal\u2013fetal medicine training programs.Given limited experience with these agents in the setting of pregnancy, it is essential for maternal\u2013fetal medicinepractitioners to actively report on adverse events and participate in clinical trials."}
+{"text": "Intrahepatic tumour is associated with alterations in splanchnic haemodynamics. To investigate the hypothesis that these are the result of a circulating vasoactive agent, rat small bowel segments were cross-perfused with arterial blood from groups (n = 12) of paired tumour-bearing (intrahepatic HSN sarcoma) and control rats. The vascular resistance of the segment was significantly greater during perfusion by tumour-bearing animals , suggesting that intrahepatic tumour may be associated with a circulating vasoactive agent. A similar mechanism may underlie changes in the hepatic perfusion index in patients with liver metastases."}
+{"text": "Medicago truncatula roots, and quantified YFP fluorescence and mRNA levels. YFP fluorescence was normal in pOpOff2 transformed roots without dexamethasone but was reduced with dexamethasone treatment. Interestingly, dexamethasone removal did not reverse YFP inhibition. YFP expression in roots transformed with pER8 was low even in the absence of inducer. We used the dexamethasone system to silence acetyl-CoA carboxylase gene and observed prolific root growth when this construct was transformed into Medicago until dexamethasone was applied. Our study shows that dexamethasone inducibility can be useful to silence vital genes in transgenic roots.Understanding the functions encoded by plant genes can be facilitated by reducing transcript levels by hairpin RNA (hpRNA) mediated silencing. A bottleneck to this technology occurs when a gene encodes a phenotype that is necessary for cell viability and silencing the gene inhibits transformation. Here we compared the use of two chemically inducible plant promoter systems to drive hpRNA mediated gene silencing in transgenic, hairy roots. We cloned the gene encoding the Yellow Fluorescence Protein (YFP) into the dexamethasone inducible vector pOpOff2 and into the estradiol induced vector pER8. We then cloned a hpRNA targeting YFP under the regulation of the inducible promoters, transformed  Arabidopsis thaliana, could be transformed into an RPS2 plant by cloning the gene behind a chemically inducible promoterConditionally inducible vectors are useful for activating the expression of genes whose constitutive expression would have deleterious effects on the plant. For example the avrRPT2 gene, which in the presence of the RPS2 disease-resistance gene causes cell-death in The most common chemically inducible expression systems are comprised of two components; a chimeric transcription factor that is activated by the inducer and a promoter that is recognized by the chimeric transcription factor6810The estrogen inducible system employs a chimeric transcription factor XVE comprised of the DNA binding domain of the bacterial repressor lexA, the transcription activating domain of VP16 and the human estrogen receptor ERSteroid inducible promoters have been used to drive the expression of short interfering (si) RNA molecules produced by dicer like cleavage of double stranded RNAs (dsRNA). The siRNAs direct Argonaute nucleases to cleave endogenous transcripts with sequence homology to the dsRNAs, leading to the silencing of the endogenous transcripts. The pHELLSGATE transformation vectors were developed to allow hpRNA constructs to be generated using the Gateway recombination systemAgrobacterium rhizogenes transformation is an effective tool for investigating the functions of genes encoding phenotypes in plant rootsA. rhizogenes to introduce hpRNA constructs targeting candidate genes into roots16Agrobacterium rhizogenes mediated root transformation and monitored the kinetics and reversibility of YFP inhibition. We then showed that the dexamethasone system can be used to transform a hpRNA construction that targets a critical gene into Medicago roots and that chemical induction of this construct leads to a lethal phenotype. This study characterized the functionality of each modified system and tested their inducible silencing of a target gene, thereby providing a tool to investigate gene functions for root biology and fundamental RNAi process in plants.Petunia hybrida chalcone synthase A gene (CHS-A) intron behind the inducible promoter in each vector (M. truncatula roots by A. rhizogenes transformationWe modified the pOpOff2 and pER8 vectors to contain a Yellow Fluorescence Protein (YFP) gene transcriptionally regulated by the mas promoter to use as a visual markerh vector . These pTransgenic Medicago roots containing either pPopY, pPopY-hpYFP, pER8Y or pER8Y-hpYFP were treated with various concentrations of dexamethasone (Dex) or estradiol respectively, photographed YFP fluorescence daily, and fluorescence quantified using ImageJ. In the absence of Dex, the roots transformed with either pPopY or pPopY-hpYFP had similar YFP fluorescence levels , suggestWhen 1, 3 and 40\u2009uM Dex was applied to pPopY-hpYFP roots, four days after induction fluorescence was reduced ~35%, 70% and 90% respectively relative to the absence of inducer , showingWe evaluated the changes in YFP mRNA levels by quantitative RT-PCR after treatment with the chemical inducers. Six days after the treatments with increasing concentrations of Dex, YFP mRNA levels were reduced up to 97% comparing with non-induced basal levels . To furtAs predicted from the fluorescence, there was a significant reduction in YFP mRNA in pER8Y-hpYFP roots even without chemical induction. However, the levels of YFP mRNA was further reduced in roots four days after the treatments with 1 and 10\u2009uM estradiol .As indicated in To examine the reversibility of silencing after induction of the pPopY-hpYFP vector, we moved the roots to new media without inducer after 6 days\u2019 treatment. YFP fluorescence did not recover up to 16 days after removal of Dex , althougTo evaluate YFP mRNA levels after Dex is removed, we isolated mRNA from induced roots at different time points after inducer removal and performed RT-PCR. For at least 16 days after removal of Dex, YFP mRNA levels remained at similar levels as before Dex removal, except for the slight elevation in message levels at day 16 . It is lWe are characterizing these vectors in roots with the goal of generating transgenic plants with RNAi constructs targeting genes that are critical for root survival. As a proof of concept, we inserted a RNA hairpin structure targeting cytosolic acetyl-CoA carboxylase (AccASE) into pPopY-hpYFP and transformed it into Medicago roots. AccASE catalyzes the ATP-dependent formation of malonyl-CoA from acetyl-CoA and bicarbonate and is a key enzyme for de novo fatty acid synthesisWe examined root growth rates in Medicago transformed with pPopY-hpACC or pPopY-hpYFP before and after Dex induction. Transformed Medicago roots were grown in non inducing media for seven days; then pPopY-hpACC transgenic roots and controls, i.e. pPopY-hpYFP, were moved onto media with or without 50\u2009uM Dex for continuing growth and photographing roots daily. Notably, although most pPopY-hpACC transgenic roots are YFP positive (marked as pPopY-hpACC YFP+) and they did grow out few YFP negative roots (marked as pPopY-hpACC YFP\u2212), indicating the growth of the sporadic non-transformed root cells. After moving to the new plates, the initial growth of all the genotype plants slowed in presence or absence of Dex. From 4\u20136 days, all the plants increased the growth rates. Markedly, along the monitored growth at different time points, Dex treated pPopY-hpACC YFP+ roots consistently revealed greatly reduced the growth rates compared to the treated pPopY-hpACC YFP\u2212 roots, the untreated pPopY-hpACC roots and to the treated pPopY-hpYFP controls , suggestTo validate the silencing of AccASE gene, we examined transcript levels of YFP and AccASE after the treatment of 50\u2009uM Dex for 24\u2009hours. Comparing with non-treated roots, Dex induced ~60% reduction in AccASE mRNA and ~85% reduction in YFP mRNA in pPopY-hpACC roots after 24\u2009hours , suggestZuo and Chua (2000) summarized important traits for a chemical inducible systemIn the absence of Dex, Medicago roots transgenic for pPopY-hpYFP had similar levels of YFP fluorescence and mRNA as transgenic roots without the hairpin. In contrast, pER8Y-hpYFP transformed roots had reduced fluorescence and reduced basal mRNA levels compared to empty vector controls. Other researchers have reported on the leakiness of pER8 in the absence of inducer2223310Ideally chemical inducible promoters are sensitive to low concentrations of inducer and dosage dependent across a wide dynamic range. Previous studies showed GUS expression driven from pOp6 inducible promoter reached maximal levels 10 hrs after Dex treatment10In transgenic roots the pPopY-hpYFP vector was induced by Dex at concentrations ranging from 1\u2009uM to 100\u2009uM in a dose-dependent manner; no additional silencing was observed at higher concentrations . Our pPo10et al., 2005, i.e. unlike endogenous PDS gene, the silencing of LUC transgene was not reversed after removing Dex. Although the authors did not give reasonsA previous report of the Dex inducible pOp6 promoter showed reversal of the silenced PDS gene mRNA, but not silenced LUC transgene mRNA, within 10 days after Dex removalThe vector has a bidirectional pOp6 promoter that can drive transcriptions of two genes at once1010When roots were exposed to 3\u2009uM or more Dex, YFP mRNA was depleted within 24\u2009hours while no significant changes of YFP fluorescence was observed during the same period of time. These data suggested that the YFP protein half-life in Medicago roots is around 2.5 days. Using a similar approach, the half-life of GFP in C. elegans was estimated around 1.5 daysAlthough the application of dexamethasone system has been reported in leavesMedicago truncatula accession Jemalong A17 was obtained from Dr. Doug Cook . Agrobacterium rhizogenes strain MSU440 was used for root transformation.Seeds of the AflII site of pOpOff2 and the PvuII site of pER8. A hairpin cassette consisting of 373\u2009bp of YFP sequences (base pairs 339\u2013711) cloned as an inverted repeat flanking a CSHA intron was then cloned behind the inducible promoter in each plasmid. The GUS gene in the original pOpOff2 vector was deleted and replaced with a unique SfaA1 restriction enzyme site. The modified vectors were renamed pPopY-hpYFP and pER8Y-hpYFP respectively (The vectors pOpOff2ectively .Root transformations were performed as previously described using the A. rhizogenes strain MSU440http://rsb.info.nih.gov/ij).Transgenic roots were photographed under the dissecting fluorescent microscope with a Canon EOS 70D camera  and the intensity values (arbitrary units) of YFP fluorescence quantified by Image J software  adjacent to the YFP root ROI. Similar ROI calculations were done at different time points to quantitate YFP changes over time. The temporal changes in YFP fluorescent intensities were expressed relative to the basal YFP intensity prior to treatment.Transformed roots from pPopY-hpYFP or pER8Y-hpYFP system were induced by indicated concentrations of Dex or estradiol respectively and photographed for YFP fluorescence daily. Reversibility of induction was investigated by transferring pPopY-hpYFP roots onto media without Dex or with 50\u2009uM Dex and photographed an additional 16 days.Medicago roots using the TRIzol reagent , treated with DNase1, and further purified using RNeasy Mini Spin columns . RNA (1ug) from each sample was converted to cDNA using High Capacity cDNA Reverse Transcription kit . 4\u2009ng of reverse-transcription reactions was used for each RTPCR with primers (shown in Medicago Gene Index TC108192) and a ubiquitin carrier protein (Medicago Gene Index TC176441) as reference genes29\u2212\u0394\u0394Ct method, was employed. Similar results were obtained for both reference genes  assay, total RNA was isolated from shown in  using ance genes , so the Root growth was monitored by marking the plate at the position of the root tips and then measuring growth every 24\u2009hours using Image J (NIH). For each genotype, 20\u201340 independent root replicas were measured. The root growth rate was defined by root length growth divided by the time.t-test. Differences were considered significant at P\u2009<\u20090.05 and highly significant at P\u2009<\u20090.01.All the experiments were arranged in a complete randomized design with indicated independent replicates. Data are expressed as means +/\u2212 SEM for the roots from minimal three independent plants or as indicated. The data obtained were compared between either two different experimental conditions or two genotypes using a two-tailed Student\u2019s How to cite this article: Liu, S. and Yoder, J. I. Chemical induction of hairpin RNAi molecules to silence vital genes in plant roots. Sci. Rep.6, 37711; doi: 10.1038/srep37711 (2016).Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations."}
+{"text": "According to clinical and pathological factors the prognosis of a patient with non-muscle invasive bladder tumors can be assessed. The prognosis is determined by the likelihood of recurrence(30-70%) and/or progression to muscle invasive bladder cancer(1-15%).Trans urethral resection of bladder tumors remains the initial therapy but adjuvant intravesical instillations are necessary.All patients benefit from a single immediate post operative instillation with a chemotherapeutic agent and for low risk tumors this is the optimal therapy.Patients with intermediate and high risk tumors need more intravesical chemo-or immunotherapy. Chemotherapy reduces recurrences but not progression. Intravesical immunotherapy(BCG) prevents or delays progression. Patients at high risk for progression may need upfront cystectomy."}
+{"text": "A 61-year-old man with type II diabetes mellitus was referred with breathlessness onexertion. On auscultation, there was a continuous ejection systolic murmur on the leftupper sternal border. Transthoracic echocardiography showed a dilated vessel in aorticwall in the parasternal long axis view and a spPrimary coronary artery fistulas (CAF) are rare congenital communications between one ormore coronary arteries and a cardiac chamber or a great vessel. The RCA represents themost frequent site of origin of CAF in 60% of cases followed by the left coronary arteryin 35% while two CAF are uncommon (< 5%).The current case demonstrates the utility of CTCA in elucidating otherwise unusualtransthoracic echocardiographic appearances."}
+{"text": "Polycyclic aromatic hydrocarbons (PAH) and their alkylated derivatives are generally mutagenic or carcinogenic compounds and are common trace components of environmental samples. Besides classical analytical methodologies such as capillary gas chromatography and liquid chromatography, high resolution spectrofluorometry (HRS) at low temperature in n-alkane matrices (Shpol\u2019skii effect) is seeing an increasing interest \u20133.Since the first observation in the early fifties , this meT \u226a 77 K). The low temperature luminescence spectra exhibit a 0-0 transition with several sharp peaks (\u201cquasi-lines\u201d) having FWHM about 0.1 nm called multiplet structure and related to different substitution sites of the aromatic molecules in the n-alkane lattice [Fluorescence and phosphorescence spectra of aromatic compounds usually present broad bands at room temperature, having full widths at half-maximum (FWHM) of about 3 nanometers. A sharpening of the luminescence spectra is observed when PAH are incorporated into an appropriate n-alkane matrix frozen at low temperature  and the host  molecules seems to exist . When th\u22126 M and less), the formation of aggregates is minimized and the reproducibility of fluorescence intensity is not altered [A preliminary fast freezing of solution at 77 K in liquid nitrogen is also necessary to avoid aggregate formation . Another altered ,12.The American Environmental Protection Agency (EPA) has retained about 16 PAH as priority pollutants . They haMost of the EPA PAH could easily be identified and quantified by this technique. Low molecular weight aromatic compounds  were difficult to detect due to their low fluorescence quantum yield. To evaluate the accuracy of this method, we have analyzed several organic extracts  used for intercalibration exercises organized by the National Bureau of Standards . The results (imprecision less than 15%) obtained by Shpol\u2019skii spectroscopy have been compared with values obtained by other analytical methodologies . As presented in Partial results presented here show the analytical capability of high resolution spectrofluorometry in Shpol\u2019skii matrices for the determination of different priority pollutant aromatic compounds in the total organic extract of natural samples."}
+{"text": "Myocardial salvage is currently being used as endpoint in several clinical trials and is determined by relating final infarct size to myocardium at risk (MaR). T2-weighted imaging (T2-STIR) cardiac magnetic resonance (CMR) has previously been shown to enable assessment of MaR up to one week after acute myocardial infarction. Recent experimental data indicate that the extent of MaR by T2-STIR varies over the first week which would have implications on how to design clinical cardioprotection trials using myocardial salvage as endpoint and in the clinical diagnosis of patients with myocardial infarction and normal coronary arteries.To investigate whether MaR as assessed by T2-STIR differs depending on scan day during the first week after the acute event in patients with reperfused first-time myocardial infarction.196 STEMI-patients from the MITOCARE and CHILL-MI trials undergoing acute percutaneous coronary intervention were included in the study. Eight additional patients with CMR on day 1 were also included. T2-STIR MR imaging was performed 1-7 days after the acute event and was used to evaluate MaR. Diagnostic quality on a scale from 0-3 and ability to correctly assign culprit vessel compared to angiography.There was no significant difference in MaR over the first week (p = 0.44, Figure Myocardium at risk by T2-STIR CMR imaging do not change in humans over the first week after acute reperfused myocardial infarction suggesting that MaR is a stable measure during this period of time."}
+{"text": "Freeman-Sheldon syndrome (FSS) or \u201cwhistling face\u201d syndrome is a rare congenital disorder complicated by characteristic facial deformities and muscular contractures. We report on a 64-year-old male patient presenting for surgical replacement of his aortic valve and review the available literature on anesthetic considerations and perioperative management principles. FSS frequently poses a significant challenge to airway management and gaining vascular access. Moreover, these patients are reportedly at risk for developing malignant hyperthermia (MH) or neuroleptic malignant syndrome.  Freeman-Sheldon syndrome (FSS) was first described in 1938  and is dWritten consent was provided for publication and photographs of this case.2) in combination with a severely decreased left ventricular function (left ventricular ejection fraction (LVEF); 25%). He had a known long-standing history of coronary artery disease and acute coronary syndromes and had undergone coronary stenting procedures repeatedly in recent years. Twice he suffered ST-segment elevation myocardial infarctions (STEMI). Admission chest X-rays showed cardiac congestion with bilateral pulmonary infiltrates. His blood work showed signs of systemic infection including elevated markers of inflammation and leukocytosis. After initiation of antibiotic and heart failure therapy his symptoms improved and he was scheduled for aortic valve replacement. A calculated EuroSCORE II of 2.08% lead to our center's interdisciplinary heart team decision for surgical aortic valve replacement (SAVR).Our patient was referred from another hospital with newly diagnosed critical aortic valve stenosis ; 0.7\u2009cmHis past medical history was otherwise significant for type 2 diabetes, colonic diverticulosis, and COPD. During childhood and adolescence he had undergone numerous surgical procedures to correct skeletal deformities. Despite significant physical disabilities the patient had remained ambulatory and able to sufficiently perform activities of daily living (ADL) without assistance .\u03bcg) for additional analgesia and light sedation during intubation. Endotracheal intubation was successful without distress or hypoxemic events. After induction of general anesthesia (GA), direct laryngoscopy confirmed a Cormack Lehane 4 view. As alternate plan of securing the airway in case of failed AFOI or difficulties with ventilation, the attending surgeon remained in standby during induction to perform an awake tracheotomy in the spontaneously breathing patient.The patient did not report problems with previous anesthetics on preoperative evaluation. Written records of previous anesthetics could not be obtained. Given his orofacial anatomy including microstomia, retrognathia, and limited mobility of his neck, his airway was secured via awake nasal fiberoptic intubation (AFOI) . After l\u03bcg/h) infusions titrated to bispectral indices between 40 and 60. A trigger-free anesthetic was chosen to mitigate the risk for malignant hyperthermia (MH) or anesthesia-induced rhabdomyolysis.Prior to skin incision, cisatracurium (10\u2009mg) was administered once. GA was maintained by propofol (4-5\u2009mg/kg/h) and sufentanil  the patient was transferred to our intensive care unit sedated and intubated.Sedation was stopped on postoperative day (POD) 1. The patient initially presented disoriented with weak muscular tone and only minimal movement. During a spontaneous breathing trial at that time his respiratory mechanics appeared insufficient and labored and he was lacking sufficient cough and appropriate swallowing reflexes. Subsequently, light sedation with propofol was continued (Richmond Agitation Sedation Score- (RASS-) 1). Six hours later, the patient's sensorium and muscular tone had recovered enough to allow for safe extubation.During his postoperative course, creatine kinase levels were repeatedly measured and remained in low-normal range. Also, the patient never developed fever or acidemia.The patient was discharged from the ICU on POD 4 and left the hospital to rehabilitation on POD 7.To our knowledge this is the first report on the anesthetic management of an adult FSS patient undergoing cardiac surgery.While FSS remains a rare condition, the likelihood of perioperatively caring for adult patients with congenital pathologies will increase in the future. With an increasing life expectancy, ailments like cardiovascular disease become more prevalent and might require  interventions.Managing orphan diseases and congenital syndromes remain challenging. Most available literature to guide decision-making stems from pediatric patients. The fundamental topics for perioperative clinicians caring for FSS patients are the management of a difficult airway and vascular access . MoreoveEven though difficult airway anatomy is frequently encountered in patients undergoing thoracic surgery, patients with FSS almost invariably present with a challenging anatomy. Their small mouth opening and receding chin make oral intubation difficult and the limited nasopharyngeal space might render nasal placement of an adequately sized endotracheal tube impossible. A laryngeal mask airway can be a viable alternative in some patients without significant reflux disease or impaired gastrointestinal motility. AFOI is deemed best practice to secure these patients' airway. However, AFOI in FSS frequently can present a significant challenge, even for experienced practitioners .Establishing venous and arterial access can also be difficult in patients with contractures. The widespread utilization of ultrasound to visualize vessels has significantly improved success rates of vascular cannulation  Figures and 2.While regional and local anesthesia are considered ideal in these patients and recommended where possible  they areThe choice of sedative and anesthetic drugs is still debated notwithstanding that detrimental side effects seem to be rare. Benzodiazepines have been safely used as premedication although their intrinsic potential for muscle relaxation must be taken into account , 8. Keta\u03bc-receptor agonist, based on the visualized analogue pain scale.Several cases of hyperthermia possibly related to the use of anesthetics have been reported in FSS, and an inherent risk of MH cannot be safely confirmed or ruled out to date , 10. TheMetoclopramide has been linked to neuroleptic malignant hyperthermia in one patient with FSS, which was terminated by dantrolene . Given sAdult FSS patients undergoing cardiac surgery can be safely managed. Advance interdisciplinary planning and assignment of appropriate resources to the management of a potentially challenging airway and vascular access anatomy as well as planning for a prolonged ICU stay enable safe patient outcomes. A well-balanced, trigger-free anesthetic with short-acting opioids, limited use of muscle relaxants, and postoperative sedatives as well as neuroleptic drugs seem prudent in FSS."}
+{"text": "The aim of the present study was to investigate various risk factors of suicidal behaviors, including mixed feature specifier, in Korean patients with bipolar disorder.We retrospectively reviewed medical charts from 2005 to 2014. A total of 334 patients diagnosed with bipolar disorder using DSM-IV TR were enrolled. The subjects were categorized into two groups according to history of suicidal behaviors and compared regarding demographic and clinical characteristics including mixed feature specifier. We re-evaluated the index episode using the DSM-5 criteria and classified into index episode with and without mixed feature. Logistic regression was performed to evaluate significant risk factors associated with suicidal behavior.Suicidal behavior had independent relationship with mixed feature at index episode using DSM-5 criteria and number of previous depressive episodes in Korean bipolar patients. The mixed feature specifier was the strongest risk factor in the present study.Suicidal behavior had independent relationship with mixed feature at index episode using DSM-5 criteria and number of previous depressive episodes in Korean bipolar patients. The mixed feature specifier was the strongest risk factor in the present study."}
+{"text": "A 70-year-old male presented with direct trauma to his loin with gross hematuria, as an isolated case of blunt renal trauma (BRT) due to a traffic accident. A pre-existing renal lesion (PERL) was strongly suspected by his past history of gross macroscopic hematuria and monotrauma to the kidney without other associated injuries. Spiral CT scan with contrast and a retrograde pyelogram (RGP) confirmed an occult complex renal cyst. The gold standard of CT diagnosis in this situation is stressed. Computed tomography is particularly useful in evaluating traumatic injuries to kidneys with pre-existing abnormalities. The decision on the initial course of conservative management, ureteral retrograde stenting to drain extravasation, and its final outcome are discussed. Radical nephroureterectomy was carried out by a transperitoneal approach with an early vascular control of the renal pedicle. A brief review of recent literature has been undertaken."}
+{"text": "CRISPR\u2013Cas systems have provided revolutionary tools for genome editing. The discovery of Cas proteins with alternative activities has now enabled sensitive and robust tools for detecting nucleic acids. Recent reports harnessing these new CRISPR\u2013Cas technologies display their potential for providing low-cost and practical diagnostic tools for pathogen and disease detection. Prokaryotic CRISPR\u2013Cas  immune systems have offered a treasure trove of biotechnological tools over the past 5\u00a0years . Most ofThe origins of CRISPR\u2013Cas systems as bacterial and archaeal defense mechanisms have led to an enormous diversity of Cas proteins owing to co-evolution between host cells and their invaders . The majcis with the target or in trans . TheTarget-activated nonspecific nucleases provide a robust mechanism for host defense, because Cas endonucleases can first sense invasive nucleic acid through specific target recognition and then amplify the signal through promiscuous collateral cleavage activity . SimilarIn early work aimed at developing a Cas13a-based RNA detection tool, East-Seletsky et al.  demonstrCas13a-based RNA detection opens the possibility of diagnostic applications through the sensing of nucleic acids associated with pathogens or diseases. However, useful diagnostic tools must be sensitive enough to detect very small amounts of nucleic acids, down to the attomolar range. To overcome the limited sensitivity of initial RNA detection tools, Gootenberg et al.  developeEGFR and BRAF genes.By coupling isothermal amplification to Cas13a target-activated reporter cleavage, SHERLOCK enabled detection of viral and bacterial nucleic acids with attomolar sensitivity . ImportaTrans Reporter), which couples isothermal amplification with Cas12a-based DNA reporter cleavage  molecules that are produced upon target-recognition by the class 1 Csm complex draws clear parallels to target-activated collateral cleavage by Cas12a and Cas13 , 10. GooThe early successes of CRISPR\u2013Cas diagnostic tools present an exciting outlook for the future of this technology. The simplicity with which these tools can be reprogrammed makes them readily configurable for a huge variety of applications. Successful deployment of SHERLOCK in a paper-based lateral-flow format also demonstrates its capacity for easy application without the need for technical expertise or expensive equipment, similar to home pregnancy tests. However, it remains to be seen how effective these tools will be in clinical situations, especially in field conditions that could vary wildly from the laboratory settings in which the tools were developed. The use of RNA reporters for Cas13-based detection could present a potential limitation, because RNA is relatively unstable and susceptible to cleavage by cellular RNases. This could result in false positive results when using samples prepared in non-laboratory settings. It is possible that Cas12a-based diagnostics such as DETECTR [The discovery of new CRISPR\u2013Cas systems has provided exciting opportunities for innovation over the past few years. Continued investigation of newly discovered systems will undoubtedly uncover more useful enzymes that may be implemented for improved sensitivity or stability of the current diagnostic tools. Nevertheless, the tools may already be mature enough for implementation and clinical testing. The potential to use these types of tests for rapid diagnostics could have an enormous impact in point-of-care settings, including early detection of viral outbreaks to ensure timely public health response. As with genome editing, these new CRISPR\u2013Cas diagnostic tools are poised to revolutionize the accessibility of rapid, sensitive and accurate diagnosis of infectious and genetic diseases for people around the world."}
+{"text": "Adult extracorporeal carbon dioxide removal (ECCO2R) systems and pediatric ECMO share the common objectives of having a low blood flow rate and low priming volume while safely maintaining sufficient respiratory support. The Hemolung is a highly simplified adult ECCO2R system intended for partial respiratory support in adult patients with acute hypercapnic respiratory failure. The objective of this work was to conduct pre-clinical feasibility studies to determine if a highly efficient, active-mixing, adult ECCO2R system can safely be translated to the pediatric population.14 healthy nonsedated juvenile sheep were used for acute  and 7-day chronic  in-vivo studies to evaluate treatment safety independently of respiratory related injuries. In all evaluations, we hypothesized that gas exchange capabilities of the Hemolung RAS in this model would be equivalent to the adult configuration performance at similar blood flows - minimum CO2 removal of 50 mL/min at a venous partial pressure of CO2 equal to 45 mmHg. Target blood flow rates were set to a minimum of 280 mL/min. Swan Ganz catheters were used under general anesthesia in the two acute subjects to evaluate blood gas status in the pulmonary artery.The Hemolung RAS was found to have adequate gas exchange and pumping capabilities for full respiratory support for subjects weighing 3 \u2013 25 kg. The Hemolung device was estimated to provide a partial respiratory support for subjects weighing 27 \u2013 34 kg. The seven-day studies in juvenile sheep demonstrated that veno-venous extracorporeal support could be provided safely at low flows with no significant adverse reactions related to device operation.The study outcomes suggest the potential use of the Hemolung RAS in a veno-venous pediatric configuration to safely provide respiratory support utilizing a significantly less complex system than traditional pediatric ECMO."}
+{"text": "Cognitive impairments including deficits in working memory are commonly observed in schizophrenia. A bottom-up attentional bias has been suggested for encoding visually salient yet irrelevant information. To date it is not known if this bias persists when additional top-down information in the form of a predictive cue is provided. We were motivated to clarify this issue.40 patients with schizophrenia were measured and matched with 40 healthy control participants. During a change detection task four Gabor patches (two flickering and two non-flickering) with varying orientations were shown and participants had to memorize the orientations of the Gabor patches. A colored fixation cross was displayed before the stimuli either cueing two (predictive cue) or all four (non-predictive cue) Gabor patch locations resulting in a 2 x 2 design of four conditions with the factors salience (flickering vs. non-flickering) and cue (predictive cue vs. non-predictive cue). During retrieval a single Gabor patch was displayed, and participants reported if the orientation was the same or had changed in that location. At the beginning of each block participants were instructed to either encode the flickering or non-flickering patches (targets) whose location could either be cued or uncued. In 80 % of trials, a target was probed during retrieval.Patients encoded less information than healthy controls in all four conditions. Both healthy controls and patients encoded more visually salient information than non-salient information, and performance was near chance level during non-target trials. Patients encoded significantly more information when a predictive cue was provided before encoding visually non-salient information.Patients were able to overcome their bottom-up attentional bias of encoding visually salient irrelevant information when provided with top-down information. These findings are in line with previous reports of a bottom-up attentional bias during working memory encoding in schizophrenia. We propose that this bias can be overcome by providing additional top-down information."}
+{"text": "A 45-year-old man presented with a thunderclap headache. Brain computed tomography (CT) scan without contrast showed massive subarachnoid hemorrhage (SAH). We transferred him to the angiography unit where he was diagnosed with a left (Lt) distal internal carotid artery (ICA) aneurysm. We secured the aneurysm using 8 coils. He was stable the following days. 1He was monitored via daily transcranial sonography (TCS) for the potential development of vasospasm. In TCS, the coiled distal ICA aneurysm was visualized as a round hyperechoic mass anterior to the midbrain. There was no aneurysm refilling on consequent evaluations. Unenhanced TCS is proposed as a screening tool for coiled aneurysm refilling."}
+{"text": "Jdpd is an open Java simulation kernel for Molecular Fragment Dissipative Particle Dynamics with parallelizable force calculation, efficient caching options and fast property calculations. It is characterized by an interface and factory-pattern driven design for simple code changes and may help to avoid problems of polyglot programming. Detailed input/output communication, parallelization and process control as well as internal logging capabilities for debugging purposes are supported. The new kernel may be utilized in different simulation environments ranging from flexible scripting solutions up to fully integrated \u201call-in-one\u201d simulation systems. Mesoscopic simulation aims at describing supramolecular phenomena at the nanometer (length) and microsecond (time) scale for large interacting physical ensembles (representing millions of atoms) within comparatively short computational time frames (hours) by \u201ccoarse grained\u201d neglect of uninteresting degrees of freedom. Dissipative Particle Dynamics (DPD) is a mesoscopic simulation technique for isothermal complex fluids and soft matter systems that combines features from Molecular Dynamics (MD), Langevin Dynamics and Lattice-Gas Automata \u20135. It saWhereas DPD particles in general may be arbitrarily defined \u201cfluid packets\u201d  the MoleA simulation kernel software comprises the fundamental data structures and numerical calculation algorithms that are necessary to approximate the temporal evolution of a defined particle ensemble. DPD (as well as similar MD) code consists basically of a main loop over  successive simulation steps in which  particle pair force evaluations are the most time-consuming part , 14. ThuThe new Jdpd library enriches the small set of existing commercial , 16, opeDPD particle trajectories are guided by Newton\u2019s equation of motion , 5:\\docuDissipative  and random forces oppose each other and act as a thermostat conserving the total momentum and introducing Brownian motion into the system. The conservative forces comprise soft DPD particle repulsions (with a common cut-off length of 1 DPD unit), harmonic springs between bonded particles and electrostatic interactions between charged particles (the implemented model for the latter is an ad-hoc approach to take electrostatic long-range interactions between \u201ca few\u201d charged particles in the simulation box into account\u2014details are outlined in  where anDissipative forceRandom forceapplied) . \\documeharmonicBonds, dpdCutoff1 and electrostatics. An additional gravitational acceleration that acts on particle masses may be defined for every direction. All calculation classes for DPD and electrostatics forces and potentials extend abstract class ParticlePairInteractionCalculator of package interactions which itself implements a cut-off length based simulation box cell partitioning [getParallelisationSafeCellChunks of class CellBox in package utilities): These chunks guarantee a separated non-overlapping access of internal force array elements from parallelized calculation threads so that fast lock-free array manipulations become possible . An analogue lock-free parallelization feature with separated parallelizable bond chunks is realized within the bond related calculation classes (see package harmonicBonds).The sketched forces and corresponding potentials are implemented in calculation classes of the packages itioning : The resParticlePairDistanceParameters in package utilities). This caching avoids the time-consuming recalculation of particle pair distances (see relative performance factors of the different implemented integration schemata below): The saved number of expensively safe-guarded particle pair distance calculations may be  evaluated to be about 7 times the total number of particles in simulation for a common DPD particle density of 3. An upper bound for this empirical number may be deduced from the average number of all neighbor-cell particle pairs which is 40 times the number of particles in the simulation (which overestimates the number of relevant particle pair distances since\u2014incorrectly\u2014particle pairs with a distance above the cut-off length of 1 DPD unit are included):Another significant performance improvement is achieved by efficiently caching the already evaluated interacting particle pairs for reuse throughout different force calculations within a single simulation step (see use of caching class integrationType) that cover different integration techniques: (1) The original Groot-Warren scheme (GWMVV) [Since (unlike MD) dissipative DPD forces depend on relative particle velocities the common Velocity-Verlet (VV) integration of the equations of motion , 14 has  (GWMVV) , 28, 29  (GWMVV)  with an  (GWMVV) , 32 and  (GWMVV)  that reqDpdSimulationTask  that may be submitted to an appropriate thread executor service to be invoked. The DpdSimulationTask constructor requires six configuration objects: (1) An  RestartInfo instance that contains information about a possible simulation job restart , (2) an input instance that implements the IInput interface with all simulation settings , (3) an output instance implementing the IOutput interface for all output data, (4) a progress monitor instance implementing the IProgressMonitor interface for real-time simulation progress information, (5) an ILogger instance for log-level dependent accumulation of detailed internal calculation progress information and (6) a ParallelizationInfo instance that describes internal settings for parallelized calculations. All interfaces are located in package interfaces and possess concrete sample implementations like classes FileInput and FileOutput of package samples that implement file-based I/O methods. The RestartInfo and ParallelizationInfo classes are found in package parameters.A single simulation task is performed by instantiating a IInput object contains a Factory instance (located in package utilities) that implements enumerated type definitions for random number generation, DPD and electrostatics calculations, harmonic bonds or integration schemata. The factory pattern allows a simple extension or replacement of computational algorithms used throughout the whole simulation kernel, e.g. the implemented random numbers generators [Factory class. An IInput object also provides detailed molecular information (see class MoleculeDescription in package utilities): These molecular descriptions differentiate between topological bonds of a molecules\u2019 particles for an adequate description of covalent connectivity and bonds between backbone particles that maintain a defined spatial 3D structure, e.g. ring systems or secondary and tertiary structures of proteins. As a matter of course both bond types are treated equally throughout calculations.An nerators \u201336 may bFileLogger and MemoryLogger in package logger) with different (extensible) log-levels to obtain detailed information about the simulation progress.For software programs with extensive parallelized numerical calculations the debugging facilities of current integrated development environments are often not sufficient to tackle subtle errors. Thus Jdpd comprises (extensible) loggers  but does not explicitly exploit specific hardware environments or devices like graphics processing units : AsJdpd is a new open DPD simulation kernel completely written in Java that complements the small available set of general purpose DPD kernels. It especially supports molecular fragment structures and offers parallelizable force calculation plus efficient caching options with an interface and factory-pattern driven design for comfortable and low expenditure code extensions, customizations or replacements. Detailed input/output communication, parallelization and process control as well as internal logging capabilities for debugging purposes are supported. The new kernel may be utilized in different simulation environments ranging from flexible scripting solutions up to fully integrated \u201call-in-one\u201d simulation systems described in  where itThe Jdpd library uses the Apache Commons RNG libraries  and is p"}
+{"text": "After spinal cord injury (SCI), sensory feedback circuits critically contribute to leg motor execution. Compelled by the importance to engage these circuits during gait rehabilitation, assistive robotics and training protocols have primarily focused on guiding leg movements to reinforce sensory feedback. Despite the importance of trunk postural dynamics on gait and balance, trunk assistance has comparatively received little attention. Typically, trunk movements are either constrained within bodyweight support systems, or manually adjusted by therapists. Here, we show that real-time control of trunk posture re-established dynamic balance amongst bilateral proprioceptive feedback circuits, and thereby restored left-right symmetry, loading and stepping consistency in rats with severe SCI. We developed a robotic system that adjusts mediolateral trunk posture during locomotion. This system uncovered robust relationships between trunk orientation and the modulation of bilateral leg kinematics and muscle activity. Computer simulations suggested that these modulations emerged from corrections in the balance between flexor- and extensor-related proprioceptive feedback. We leveraged this knowledge to engineer control policies that regulate trunk orientation and postural sway in real-time. This dynamical postural interface immediately improved stepping quality in all rats regardless of broad differences in deficits. These results emphasize the importance of trunk regulation to optimize performance during rehabilitation. In healthy conditions, descending supraspinal commands continuously tune the dynamics of these circuits to ensure that movement-related afferent inputs adequately adjust gait patterns6. After spinal cord injury (SCI), the descending sources of modulation are severely disrupted. Consequently, sensory feedback signals become the primary source of control to produce and regulate leg movements after SCI10.Leg sensory feedback circuits play an important role in the generation and regulation of leg movements14. Repeated activation of sensory feedback circuits during standing and walking promotes activity-dependent reorganization of neural connections that ameliorates locomotor performance16. In particular, various studies showed that proprioceptive feedback circuits play a pivotal role in guiding motor execution and circuit reorganization after SCI. For example, epidural electrical stimulation of the lumbar spinal cord specifically modulates proprioceptive feedback circuits associated with extension and flexion of the legs, which enabled refined control of leg motor patterns during gait19. Moreover, we found that mice lacking muscle spindle feedback circuits fail to display the activity-dependent reorganization of neural pathways that support recovery after SCI20. These findings stress the importance of targeting proprioceptive feedback circuits in the design of rehabilitative strategies.The objective of gait rehabilitation therapies is to steer the functional reorganization of spared sensory pathways and residual descending projections through task-specific physical training in order to improve recovery24. In these scenarios, the trunk is typically constrained within bodyweight support systems providing vertically restricted forces, or exoskeletons that constrain pelvis movements. However, natural locomotion involves precisely-timed trunk movements in multiple directions25, which directly determine leg biomechanics, and consequently leg sensory feedback during locomotion29. Indeed, therapists commonly seek to adjust pelvis movements manually during rehabilitation. When possible, they also provide cues to the trunk in order to reinforce the interplay between trunk posture and leg biomechanics. However, the lack of technologies to assist these movements limits the spectrum of possibilities offered to therapists during rehabilitation. The development of rehabilitation protocols and robotic systems that actively regulate trunk posture during training relies on a deeper understanding of the interactions between trunk posture, proprioceptive feedback circuit modulations and leg motor pattern production during locomotion.The critical role of movement-related sensory information to steer recovery has motivated the design of training protocols, robotic interfaces and neuroprosthetic systems that predominantly focus on reinforcing reproducible leg movements during rehabilitationHere, we aimed to address these combined aspects in a well-controlled SCI rodent model of bipedal locomotion. First, we designed and fabricated a robotic postural interface that allows real-time control of mediolateral trunk orientation during locomotion in rats with severe spinal cord injury. This robotic system uncovered robust relationships between mediolateral trunk orientation and the bilateral modulation of leg motor patterns during locomotion. We next used a neurobiomechanical computational model of muscle spindle feedback circuits to study some of the mechanisms underlying these modulations. We found that mediolateral trunk orientation modulates the flow of information in muscle spindle feedback circuits. In turn, optimal locomotor performance emerged when mediolateral trunk orientation helped preserve the balance between muscle spindle feedback circuits associated with extensor and flexor muscles for both limbs. This knowledge guided the design of control algorithms that regulated mediolateral trunk orientation in real-time based on subject-specific deficits. Compared to static trunk orientation, this targeted strategy improved locomotor performance across a broad spectrum of gait asymmetries and motor deficits. These results provide an important proof of concept that stresses the need to develop similar dynamic trunk assistance during gait rehabilitation in humans.We developed a closed-loop robotic postural interface that supports the control of trunk orientation and postural sway in the mediolateral direction during bipedal locomotion in rats Fig.\u00a0. To enab15  received a severe lesion of the spinal cord contusion that led to leg paralysis. To enable locomotion, we delivered an electrochemical neuromodulation therapy to the lumbar spinal cord according to methods described previously15 Fig.\u00a0. Detaile15 Fig.\u00a0.We then used this robotic postural interface to characterize the impact of trunk orientation on gait patterns. We mapped the relationships between trunk orientations  and the resulting changes in bilateral leg kinematics, muscle activity and ground reaction forces.Prior to stepping, we calibrated the attachment of each rat to the backplate ensuring that both feet touched the treadmill belt symmetrically. This posture was defined as the baseline trunk orientation.During stepping, rats exhibited variable gait asymmetries that emerged from well-known differences in the performance of the left and right legs after severe spinal cord injury. For example, Fig.\u00a0Comparisons across rats (n\u2009=\u20095) with different lesion severities confirmed these results Fig.\u00a0. RegardlWe next sought to study the neural mechanisms that were likely to underlie the corrections induced by trunk posture on gait patterns. Due to the extensive loss of supra-spinal control, sensory afferent feedback signals were the primary source of control and modulation of leg movements. In particular, muscle spindle afferent feedback circuits are known to play a critical role in the production of locomotion after SCI. These afferents directly encode the changes in limb abduction during trunk rotations. We thus investigated the impact of mediolateral trunk orientation on muscle spindle afferents firing during gait.18 to estimate the changes in afferent firing rates for multiple leg muscles. For each trunk orientation, we fed the recorded joint angle trajectories into a realistic 3D biomechanical model of the hindlimb30 and we estimated through inverse kinematic the corresponding muscle stretch and stretch velocity profiles for three pairs of antagonistic muscles acting at each joint of the leg   Fig.\u00a0. We thenComputer simulations revealed that the trunk orientation profoundly altered the stretch profiles of all the simulated leg muscles, in particular those acting at proximal joints Fig.\u00a0. At the The impact of trunk orientation on muscle spindle feedback circuits stressed the importance to optimally define trunk orientation, accounting for deficits that arise throughout movement execution. Commonly, optimal trunk orientations are set empirically by therapists at the beginning of each session, and then remain constant throughout training. We sought to regulate trunk posture automatically based on continuous monitoring of locomotor performance.We previously showed that trunk orientation monotonically modulates the abduction angles of the right and left legs, which in turn correlate with locomotor symmetry Fig.\u00a0. We thusTo evaluate the performance of this control structure, we quantified its degree of controllability and stability Fig.\u00a0. We set We then verified that the corrections of the controller converged towards optimal values for gait rehabilitation. We asked experienced trainers to fine-tune trunk posture for each rat during a training session in order to optimize locomotor performance, and compared the resulting trunk orientation with the rotation computed by the controller Fig.\u00a0. DespiteWe finally aimed to capitalize on this robotic interface to restore postural sway during stepping. In healthy subjects, locomotion involves cyclic shifts in bodyweight, which are essential to reinforce loading during stance. The resulting afferent signals reinforce muscle recruitment and contribute to increasing lateral stability. These observations suggest that optimal gait patterns would emerge when reinforcing this aspect of gait at each phase of the locomotor movements.To test this hypothesis, we implemented an open-loop control logic that accommodated alternating changes in trunk orientation into the intrinsic stepping rhythm of each rat Fig.\u00a0. SwayingCompared to static conditions, the delivery of dynamic swaying rotations in trunk orientation immediately increased the amplitude of vertical ground reaction forces and extensor muscle activity . Actuation was provided using a servomotor (Faulhaber 1028E012B) in combination with a zero-backlash gearhead (Faulhaber 12/5-161:1) which provided a theoretical output torque of 47.8 mN\u00b7m Fig.\u00a0. This frThe control of the robotic postural system was implemented as a custom-made Simulink xPC Target application  that communicated with the sensing and actuation components via a Humusoft MF624 I/O board . To enable real-time control of posture based on the animal locomotor performance, we interfaced this application with a high-speed motion capture system  that monitored leg movement in real-time Fig.\u00a0.Reflective markers (1\u2009mm) were attached to bilateral hindlimb landmark joints, i.e. iliac crest, greater trochanter (hip joint), lateral condyle (knee joint), lateral malleolus (ankle) and distal end of the fifth metatarsophalangeal (MTP) joint. Raw 3D positions for each marker were continuously recorded (200\u2009Hz) and imported into the Simulink application through an Ethernet connection (TCP/IP) using a dedicated datastream SDK library .Raw signals were filtered using adaptive filters (least mean squares), and processed online to account for missing data resulting from occlusions (interpolation from neighboring markers). Each marker was then assigned a specific label corresponding to the corresponding hindlimb joint. Custom-made rules ensured robust maker labeling along the limb. Transmission latencies through the complete loop remained within 20\u2009ms.All further control policies were implemented as Simulink blocks within the xPC target application. A dedicated graphical user interface (GUI) allowed to modify control parameters, modes and targets during the experimental session.We sought to design feedback and feedforward control policies providing automatic adjustments to trunk postural orientation on the basis of online locomotor performance.To align postural changes to the stepping rhythm of each animal, the real-time system continuously monitored bilateral hindlimb kinematics and extracted key gait events (foot-strikes and foot-off events) Fig.\u00a0. Foot-stFirst, we implemented a feedback  controller in order to correct asymmetric locomotor patterns and excessive abduction Fig.\u00a0. At everSecond, we developed an open-loop feedforward control logic to enable rhythmic swaying rotations during locomotion Fig.\u00a0. At pre-53 and validated experimentally54. We fed the computer model with crest, hip, knee, ankle, and metatarsophalangeal joint angle traces recorded experimentally in rats under different postural conditions (n\u2009>\u200910 steps) and we calculated the corresponding muscle stretch and stretch velocity profiles through inverse kinematics for 3 pairs of antagonist muscles, i.e., Tibialis Anterior (TA) and Medial Gastrocnemius (GM) for the ankle joint, Vastus Lateralis (VL) and Semi Tendinosus (ST) for the knee joint, and Gluteus Medius (GMed) and Ilipsoas (IL) for the Hip joint . Rats were housed individually on a 12-hour light-dark cycle, with access to food and water ad libitum. Animals were handled daily for at least two weeks before the surgeries. Animal care was performed twice daily throughout the post-injury period. All procedures and surgeries were approved by the Veterinarian Office of the canton of Vaud, Switzerland. All experiments and methods were performed in accordance with the relevant guidelines and regulations.17. Interventions were performed under aseptic conditions and general anesthesia (1\u20133% Isoflurane via facemask) on a heating pad to prevent hypothermia. Three animals received an incomplete lesion  and three additional animals received a complete spinal cord transection at the same level. One animal of this second group died right after surgery. A partial laminectomy was performed from T7 to T9 in which the spinous processes and the dorsal and lateral aspects of the vertebral column were removed to expose the spinal cord. The dura was opened along the mid-line. Contusions were performed using an Infinite Horizons Impactor (Precision Systems Instruments LCC) with special clamps attached to vertebrae T6 and T10. The spinal cord was impacted by a metal probe (1.3\u2009mm diameter) with a force of 370\u2009\u00b1\u200930 kDyn. For complete transections, the exposed spinal cord was cut with customized tools. The extent of contusion lesions and the completeness of spinal cord transections were verified histologically post-mortem.All surgical procedures have been previously described in detailTo record electromyographic signals, bipolar electrodes were implanted into extensor  and flexor  muscles of the ankle joint. Recording electrodes were fabricated by removing a small part (0.5-mm notch) of insulation from the implanted stainless steel wire . A common ground was created by removing about 1\u2009cm of Teflon from the distal extremity of an additional wire, inserted subcutaneously over the right shoulder. All electrode wires were connected to a percutaneous amphenol connector (Omnetics Connector Corporation) cemented to the skull of the rats. The proper location of the electrodes was verified postmortem.Stimulating electrodes were created by making a notch (~1\u2009mm) in the insulation of Teflon-coated wires (same as for EMG recordings), which were subsequently secured during surgery at the midline overlying spinal levels L2 and S1 by suturing the wires to the dura. A common ground wire  was inserted subcutaneously over the right shoulder. All electrode wires were connected to a percutaneous amphenol connector (Omnetics Connector Corporation) cemented to the skull of the rat.Analgesia  and antibiotics  were provided for 5 days post-surgery.\u22121, ~40\u201360% BWS). Hindlimb locomotion was enabled by epidural electrical stimulation applied at S1 and L2 spinal segments  and systemic administration of pharmacological neuromodulators 7. Behavioral recordings started once the animals reached a stable locomotor performance (after ~21 days of training). Characterization and control experiments were performed on subsequent days.Starting 7\u201310 days post-injury, rats were trained for bipedal locomotion for 20\u201330\u2009minutes every other day. Training took place on a bodyweight-supported treadmill , and Ranksum test or two-tailed Kruskal-Wallis test were used for nonparametric evaluations. The statistical a level P\u2009<\u20090.05 was considered significant.The datasets generated and analyzed during the current study are available from the corresponding author on reasonable request.Supp Video 1"}
+{"text": "Liquid biopsy technologies allow non-invasive tumor profiling for patients with solid tumor malignancies by sequencing circulating tumor DNA. These studies may be useful in risk-stratification, monitoring for relapse, and understanding tumor evolution. The quality of DNA obtained for these studies is improved when blood samples are collected in tubes that stabilizing white blood cells (WBC). However, ongoing germline research in pediatric oncology generally requires obtaining blood samples in EDTA tubes, which do not contain a WBC-stabilizing preservative. In this study, we explored whether blood samples collected in WBC-stabilizing tubes could be used for both liquid biopsy and germline studies simultaneously, minimizing blood collection volumes for pediatric patients.\u00ae tubes. Germline DNA was extracted from all blood samples and subjected to whole-exome sequencing and microarray profiling.Blood was simultaneously collected from three patients in both EDTA and Streck Cell-Free DNA BCTQuality control metrics of DNA quality, sequencing library preperation and whole-exome sequencing alignment were virtually identical regardless of the sample collection method. There was no discernable difference in patterns of variant calling for paired samples by either whole-exome sequencing or microarray analysis.Our study demonstrates that high-quality genomic studies may be performed from germline DNA obtained in Streck tubes. Therefore, these tubes may be used to simultaneously obtain samples for both liquid biopsy and germline studies in pediatric patients when the volume of blood available for research studies may be limited. Strategies for applying liquid biopsy assays to the treatment of pediatric solid tumors is still in the early stages of development \u20134. Studi\u00ae collection tubes from three patients.In pediatrics, the volume of blood drawn for research is sometimes restricted to ensure the safety of young children who have smaller blood volumes and may be more hemodynamically affected by sample collections. Thus, researchers must often choose between collecting samples for one research project over another. We anticipate that this may limit the usefulness of requesting that additional blood be collected in WBC-stabilizing tubes in ongoing research efforts in pediatric oncology. Therefore, we sought to determine whether samples obtained in WBC-stabilizing tubes could be used simultaneously for two purposes: 1) liquid biopsy studies and 2) germline studies. While the use of WBC-stabilizing tubes for ctDNA studies have been well-validated, to our knowledge there are no published studies describing the quality of germline DNA obtained from these tubes and their usefulness in performing germline genomic analyses. Here, we describe our experience performing whole-exome sequencing (WES) and genotyping by copy number and single nucleotide polymorphism (SNP) array analysis of germline samples obtained simultaneously in standard EDTA and Streck Cell-Free DNA BCT\u00ae tube.Blood samples were collected from patients enrolled on a Dana-Farber Cancer Institute IRB-approved banking study (DFCI protocol #11\u2013104). Written informed consent was obtained from participants or parents of minor participants prior to study inclusion. Patients were selected for participation based on an expectation that they would have normal or near-normal WBC counts based on their clinical course. We also chose children older than 11 years old for the study to ensure that drawing multiple tubes of blood simultaneously would not infringe on the hospital established blood volume limits as it would in younger patients. We chose patients who were expected to require venous access for clinical purposes so that no additional procedures were required to obtain these samples. For each patient, 5 mL of blood was drawn into a purple top EDTA tube immediately followed by the collection of 10 mL of blood into a Streck Cell-Free DNA BCTBlood samples were processed at the Boston Children\u2019s Hospital Biorepository on the same day as the specimens were acquired. For blood collected in both EDTA and Streck tubes, samples were first centrifuged at 1000 x g at 4\u00b0 Celsius for 10 minutes in the collection tube. Plasma was then removed and stored for future use. The remaining blood, a combination of red blood cells and white blood cells, were then removed from the collection tube and subjected to DNA extraction using the Gentra Puregene Blood Kit (Qiagen) according to the manufacturer\u2019s instructions. DNA was quantified for each sample using the Quant-iT PicoGreen dsDNA Assay Kit (Thermo Fisher Scientific).Control DNA for this experiment was obtained from the human B-lymphocyte cell line CEPH1408 (GM10831),  . A totalhttp://broadinstitute.github.io/picard/picard-metric-definitions.html). Reads were then aligned to the b37 edition of the human genome reference sequence (Human Genome Reference Consortium) using bwa (http://bio-bwa.sourceforge.net/bwa.shtml) utilizing the parameters \u201c-q 5 -l 32 -k 2 -o 1\u201d. Duplicate reads were identified and removed using Picard tools [https://www.broadinstitute.org/gatk/gatkdocs/org_broadinstitute_gatk_tools_walkers_indels_IndelRealigner.php). Base quality score recalibration was also performed using GATK  [Pooled sample reads were deconvoluted and sorted using Picard tools (rd tools . Alignmeon-bqsr) . Unalignhttps://trace.ncbi.nlm.nih.gov/Traces/sra/?study=SRP120033.Variant analysis for single nucleotide variants (SNV) was performed using MuTect v1.1.4 and annotated by Variant Effect Predictor (VEP). The SomaticIndelDetector tool from GATK was used for indel calling , 10. MuThttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE105032.Microarray analysis was performed on 1 ug of DNA sample. Each test sample was digested in parallel with a sex matched control  using the restriction enzymes Alu I and RSA I to obtain 200-500bp fragments. Following digestion, the test samples were labeled with Cyanine 5-dUTP and control samples were labeled with Cyanine 3-dUTP. The unincorporated dye was removed. Each test sample and correlating control were combined and hybridized to a custom 4x180K CGH plus SNP microarray . The copy-number probes on the array  have an average spacing of one probe every 35 kb throughout the genome and one probe every 10 kb in regions known to have clinical significance while the SNP probes  have an average spacing of 40 kb across the genome. Slides were scanned on a SureScan Microarray Scanner (Agilent) and data was analyzed through CytoGenomics v4.0.3.1.2 (Agilent) and Genoglyphix v3.1 (Perkin Elmer). Array data can be accessed at the NCBI Gene Expression Omnibus site Genomic DNA was obtained from blood collected in both EDTA and Streck blood collection tubes using a standard extraction kit with no modifications to the protocol for either tube. In all samples, we extracted over 100 \u03bcg of genomic DNA material using these standard procedures . In mostSequencing libraries were prepared from 100 ng of genomic DNA from each sample. All sequencing libraries were prepared and purified uniformly but with unique barcodes so that samples could be multiplexed for sequencing and then de-multiplexed during analysis. Library yields from all blood samples were remarkably similar and were comparable with the DNA library yields generated from DNA extracted from a human cell line, CEPH1408 . BioanalRecently published cancer predisposition studies have used both whole-genome sequencing and targeted sequencing approaches to identify recurrent germline variants in patients and families with a high incidence of cancer \u201315. TargThere were a similar number of total sequencing reads generated per sample . Plasma Sequence variants were identified by comparing each sample to DNA extracted from a human cell line, CEPH1408, which was sequenced simultaneously with the germline samples. A similar number of unfiltered variants were identified for each patient, regardless of whether the germline sample sequenced was collected in an EDTA or Streck tube . Since aDNA samples were also analyzed with genome-wide combined copy number/SNP mircroarrays. For each patient, regions of copy number alteration and homozygosity were identified and compared between samples obtained in EDTA tubes and Streck tubes. The quality control metrics were excellent for copy number analysis using the derivative log ratio spread (DLR) metric and SNP analysis using the call rate (CR) metric, regardless of how the sample was collected . Copy nuThe use of liquid biopsy assays that detect, quantify, and profile ctDNA are being routinely incorporated into clinical trials for adult cancers \u201324. Theshttps://clinicaltrials.gov/ct2/show/NCT02402244), the GAIN Consortium\u2019s iCAT2 study , and the NCI-MATCH study for pediatrics .Such efforts in pediatric cancers are also beginning to emerge \u20134. PubliThere are several logistical hurdles to overcome in developing liquid biopsy technologies in trials enrolling pediatric patients at multiple institutions. One major issue is that samples must be collected and shipped to a central laboratory before being processed. ctDNA is easily extracted from plasma isolated from blood collected in EDTA tubes using standard extraction kits. However, several studies have demonstrated that plasma must be isolated from blood collected in EDTA tubes within eight hours of collection to prevent the chance of lysis of WBCs that will contaminate the plasma with genomic DNA \u201335. ThisOne competing research priority in pediatrics is the collection of a blood sample for germline DNA profiling. DNA for these studies are most often extracted from WBCs obtained from blood collected in an EDTA tube. A potential solution for collecting plasma for ctDNA studies while still prioritizing the collection of germline material for genetic studies would be to utilize a single tube of blood for both germline and liquid biopsy studies. To determine the feasibility of this approach, we collected blood from three patients simultaneously in EDTA and Streck tubes and performed WES and SNP-arrays on the matched germline DNA extracted from cells from each tube. We demonstrated that the WES and SNP-array data was of very similar quality for germline studies, suggesting that both ctDNA and germline study samples can be collected from a single WBC-stabilizing tube for pediatric cancer patients. Similar results were observed when utilizing column-based extraction methods to obtain genomic DNA from EDTA and Streck tubes (data not shown). One potential limitation of this study is that we were not able to test the effects of exposing blood samples to a wider range of temperatures or processing times. However, guidelines for handling Streck tubes suggest that samples be maintained at room temperature during shipment and processed within 7\u201310 days. We would expect that conforming to those guidelines would ensure the quality of cell-free and germline DNA extracted from blood collected in Streck tubes. We believe this data will facilitate the collection of liquid biopsy studies on multi-institutional trials without compromising germline studies or increasing the blood volumes requested for ongoing research."}
+{"text": "Apis mellifera) collect and store both honey and pollen in preserved forms. Pollen storage involves the addition of honey or nectar and oral secretions to pollen granules. It is controversial whether the duration of pollen storage alters the palatability or nutritive value of the pollen storage medium. We examined how bees utilize different-aged stored pollen during an extended pollen flow. The deposition of pollen into wax cells and subsequent consumption were monitored daily on 18 brood frames from 6 colonies over an 8d observation period. Despite a greater abundance of older stored pollen cells on brood frames, bees showed a marked preference for the consumption of freshly-stored pollen. Two to four day-old pollen cell contents were significantly more likely to be consumed, while pollen cell contents more than seven days old were eaten at much lower rates. Similar experiments that controlled for cell abundance and spatial effects using cage assays yielded the same result. One day-old stored pollen was consumed approximately three times more often than 10d-old stored pollen, and two times more often than 5d-old stored pollen. These consumption preferences for freshly-stored pollen occurred despite a lack of clear developmental advantages. Young adult workers reared for 7 days on 1d-, 5d-, or 10d-old stored pollen showed no difference in body mass, stored pollen consumption, hindgut fecal material accumulation, or hypopharyngeal gland (HPG) protein titers, suggesting that different-aged pollen stores did not vary in their nutritional value to adult bees. These findings are inconsistent with the hypothesis promoting a period of microbially-mediated, \u201cbeebread maturation\u201d that results in greater palatability or nutritive value for aged pollen stores. Rather, stored pollen that is not eaten in the first few days accumulates as excess stores preserved in a less preferred, but nutritionally-similar state.Honey bees ( Apis mellifera maintains large populations across periods of food scarcity by bulk preservation and storage of food materials [As a highly eusocial insect, the honey bee aterials ,2. Used aterials ,3\u20135. Duraterials \u20138. Antheaterials . Corbicuaterials .All collected pollen is packed into storage cells before consumption by colony members. Young adult workers consume over 80% of all stored pollen to complete their adult development and redistribute pollen to other bees in the form of nutrient rich secretions and semi-processed pollen fragments \u201316. YounLargely unknown is how honey bees consume stored pollen as pollen stores accumulate and age in the colony. Numerous authors have speculated that stored pollen undergoes significant microbially-driven nutrient changes during the initial phases of storage ,6,28\u201331.In this study, we examined how bees utilize different-aged stored pollens in the colony environment. We first tested honey bee consumption preferences for different-aged stored pollen produced over 8 days of storage. We focused on feeding preferences of young adult workers because these bees are overwhelmingly the primary consumers and redistributors of pollen resources for the colony \u201316,32,33A key prediction of the beebread maturation hypothesis is that older stored pollen is nutritionally superior to freshly-stored pollen. Because dietary pollen quality impacts adult development and function, we examined worker growth on pollen stored for different durations. We also examined the development of a tissue whose growth is known to depend on pollen availability. HPG produce proteinaceous glandular secretions used to feed developing larvae and other adult bees \u201314. HPG Apis mellifera linguistica) for all experiments and collections. All colonies were established in April 2014 from 1.4 kg worker bee packages headed by Italian queens . Each colony was maintained in a 10 frame single Langstroth deep box with a top feeder, entrance reducer, and bottom board . Colonies were kept in an apiary at the eastern edge of the Red Rock Agricultural Center  from colony establishment (April 2014) through use in field experiments (mid- to late-August 2014). The RRAC apiary was located in a Lower Sonoran desert creosote bush community consisting of rangeland bisected by drainage ditches and cattle pools [Larrea divaricata), triangle bursage (Ambrosia deltoidea), mesquite (Prosopis velutina), and acacia (Acacia spp.), with the latter two predominantly located along dry washes and pools.We used honey bee colonies headed by Italian queens  and distantly along the Santa Cruz River . However, no agricultural crops or weeds were in bloom at the main research station from colony establishment through the experimental period. Frequent observations of colony foragers revealed that workers foraged almost exclusively on native plants within 240m of the apiary during the month leading up to and including the experimental period. Workers engaged in water foraging gathered untreated surface water and/or ground water from ephemeral puddles, a water tank in the apiary, and a cattle pond located 380m from the apiary. Pesticide analysis of food stores from these colonies after the experiment and from colonies at this site in subsequent years revealed an absence of agrochemicals aside from Varroa mite treatment residues from previously-used comb. No chemical treatments were applied to the colonies from the time of package establishment through the end of the experiment. Representative samples of stored pollen and stored nectar/honey were removed from the colonies and analyzed for pesticide contents by the National Science Laboratory . 3 g of each material were pooled from 120\u2013150 cells in 6 colonies. No pesticides aside from trace levels of the miticides Amitraz and Thymol were detected in these food materials in full pesticide panel screenings.Colonies were amply provided with food store frames and supplemental sugar and pollen before the experiment to support worker nutrition and limit foraging on distant agricultural fields. All colonies had excess stores of pollen and nectar present for at least three weeks prior to and through the experiment. Colonies were further supplemented with pollen patty (1:1:1 mixture (w/w) of dried corbicular pollen , MegaBee pollen supplement and sucrose ) and 2:1 sucrose:water sugar syrup from the start of the mid-summer dearth in early July 2014 up until 1 week before the experiment. By the beginning of the experimental period in mid-August 2014, each colony contained approximately 22,000 to 26,000 adult workers, 5\u20137 frames of brood, and at least 2200 cells of stored pollen. Colonies slightly increased brood production and net pollen stores through the 8d experimental period.Experiments were conducted in mid-August 2014 during the summer monsoon after four weeks of significant rains. Colony pollen collection was characterized by direct observation of foragers and monitoring of four sentinel colonies that were similar in size, food stores, and bee populations to the experimental colonies. Colony foragers collected polylectic mixtures of pollens that included at least 13 distinct plant species as determined by direct observation of foragers between the colonies and flowers . ColonieForagers were observed flying directly between the four sentinel colonies and these flowering plants. All colonies had foragers visit and manipulate the flowers of these plants. All plants were within 240m of the colonies. , 36Experiments 2 and 3 (described below) required pollen comb sections containing stored pollen of uniform age. These sections were obtained by restricting colony pollen deposition to a single frame for a limited time period (24h). Stored pollen was acquired from 6 colonies containing 20,000 to 32,000 workers and 4\u20137 frames of brood. Bees were housed in hive equipment consisting of (top to bottom) a top board, a top feeder, a Langstroth deep box , 10 fully drawn Langstroth deep frames (48.26 cm L x 23.18 cm H), an entrance reducer, and a bottom board .Pollen deposition was concentrated on comb sections by directing the access of pollen foragers to a single frame. First, an empty Langstroth deep box (\u201cpollen deposition box\u201d) was placed between the brood box and the bottom board. To keep returning foragers from entering the brood box, a rectangular wire mesh barrier with worker-excluding openings  was placed between the upper brood box and the lower pollen deposition box. A single Langstroth deep frame containing empty cell wax comb (\u201cpollen deposition frame\u201d) backed by Plasticell foundation  was placed in the pollen deposition box to provide empty cells for pollen deposition by the foragers. A second frame completely filled with nectar and capped honey stores was placed next to the pollen deposition frame to provide a sugar source for the foragers. Bee escapes were placed on the corners of the brood box to allow workers to leave to forage but prevent their return to the brood box . Returning foragers entered the colony through the entrance formed by the pollen deposition box, entrance reducer, and bottom board and deposited their corbicular pollen in cells on the pollen deposition frame. Pollen deposition occurred under these restricted conditions during a 24h period from 1000 hours to 1000 hours the following day. However, the bulk of the pollen deposition (over 96%) occurred in the early morning (0515 to 1000 hours) near the end of the 24h collection period.Once the pollen deposition period ended, the single-aged stored pollen frame was placed in a hive configuration that greatly limited further pollen deposition and oviposition. The pollen deposition box containing the single-aged stored pollen frame was moved to the top of the brood box. Further pollen deposition and oviposition on the single-aged stored pollen frame was restricted by the placement of a rectangular wire mesh barrier with queen excluding openings  between the upper pollen deposition box and the lower brood box. This barrier selectively allowed workers to tend the stored pollen but prevented the passage of queens or additional corbicular pollen into the pollen deposition box. Single-aged stored pollen frames were stored in this manner until use in bioassays.Single-aged stored pollen frames were cut into uniform-sized comb sections to provide food choices of standardized size and deposition age to bees in bioassays. Each frame was carefully cut with heavy shears into rectangular 8 cm H x 5 cm W sections before use in bioassays. Each comb section contained about 90 to 120 stored pollen cells out of the approximately 160 cells present. Honey and nectar cells on the comb were emptied by pipette and then cleaned of residues by selective exposure of cell contents to sugar-deprived workers.The deposition and emptying (consumption of cell contents) of stored pollen in storage cells was monitored by marking pollen cell changes on a transparency sheet placed over the frame face on a daily basis . During We readily recognize that this method of cell monitoring is highly conservative in that it only detects changes in pollen content at the whole cell level and underestimates small changes in individual stored pollen cells . Full st+) were at least 8d-old, but were otherwise indeterminately older. All other stored pollen cell contents were deposited during a known time interval and were referred to by their maximum possible \u201cage\u201d of pollen deposition from 1d-old to 7d-old.During the eighth and final monitoring time point (end of day 7 observation period), the total number of new stored pollen cells deposited (cells filled since the previous day\u2019s observation) and emptied were tabulated by cell age for all monitored frames. Stored pollen cells marked on the first day with a black circle (8d+-old pollen cells) during this final interval.After the last marking time point, we calculated the number of stored pollen cells created and emptied (cell contents removed) during the last 24h interval. This set of markings was the only time point for which all stored pollen age classes were fully represented. The absolute numbers of stored pollen cells present, newly-formed (freshly deposited), and emptied (cell contents consumed) were tabulated for each of the eight age groups  would likely be consumed in greater numbers than less abundant pollen types based simply on their higher abundance on the frames. To obtain an accurate understanding of consumption preferences, we needed to correct for the relative abundance of each stored pollen age class. We calculated the relative pollen cell emptying rate (RPCER) for a given pollen age-class as:This metric readily detects over-emptying or under-emptying  of stored pollen cell age classes relative to the values expected if pollen cell emptying was random with regard to stored pollen age. No value could be calculated for emptying of 0d to 1d-old stored pollen since these stored pollen cells were emptied before their deposition was detected.One problem with our field assessments of worker stored pollen age preferences is that different-aged stored pollens vary in their abundance and spatial distribution on colony frames. Bees foraging for stored pollen on colony frames encountered many more older stored pollen cells than newer stored pollen cells based on numbers alone. To address these concerns, we conducted a series of dual choice assays where caged bees were presented with two different pollen comb sections of approximately uniform stored pollen cell age, size, and abundance.Dual choice assays were conducted with 3d- to 4d-old (post-emergence) adult workers because adult pollen consumption increases sharply just before this age . Each chad libitum on the two pollen sources for 20 hours. Each comb section was weighed before and after the assay. The total pollen consumed from each source was calculated as the difference between the pre- and post-assay masses of the source. Six cage replicates were performed for each of the three choice comparisons .In the dual choice assay, bees were given a choice between two different single-aged pollen comb sections (prepared as previously described). Each 8 cm H x 5 cm W comb section was placed vertically against the side wall such that the two sections were separated by the width of the cage. Bees were allowed to feed The development of young workers reared exclusively for 7 days on a single-aged stored pollen source was compared across three single-aged stored pollen treatments . Newly-emerged adult workers were collected from caged capped brood frames over an 8h period. Approximately 60 newly-emerged workers were placed in a Plexiglas cage as previously described. Each cage was provisioned with 20 mL 1:1 sugar syrup and 20 mL deionized water bottles. Four cage replicates were established for each of the three pollen treatments. All cages were maintained in an environmental chamber in the dark at 30\u00b0C at 35% relative humidity. Sugar syrup bottles were changed daily to avoid fermentation.The bees in each cage were provided with a pre-weighed pollen comb section containing either 1d-, 5d-, or 10d-old stored pollen (previously described). Each pollen source was provided in excess (90 to 120 pollen cells) to avoid overcrowding during feeding. The pollen source of each cage was replaced daily with new, preweighed material. The amount of pollen consumed was calculated as the difference between the pre-weight and post-weight masses of each pollen source.At the end of 7 days, the bees were anaesthetized with carbon dioxide and three bees were randomly selected from each cage for analysis of adult development. To obtain a more accurate measurement of worker body mass, we removed the highly variable gut contents of the honey stomach (crop), hindgut, and rectum before weighing the remainder of the body. The contents of these gut sections consist largely of food materials (sugar solutions (honey stomach) or feces (hindgut/rectum)) that otherwise inflate whole body measurements of worker mass. The whole body mass (wet weight) was measured immediately after removal of these contents. Hindgut and rectal fecal contents then were measured separately to provide an index of the amount of pollen consumed by the bee during adult development. Hindgut and rectal fecal contents have previously been used to estimate relative consumption of solid foods since adult workers do not defecate inside their nest (i.e. the cage) but accumulate feces in their hindgut and rectum . The fecEach bee head was then dissected and chemically analyzed to assess HPG development. Gland development was quantified as the total soluble protein content of macerated HPG tissue, a metric commonly used as a proxy for HPG size and quality ,37. SoluConsumption biases towards different-aged pollen stores were detected by comparing the observed consumption rate with the rate expected under random consumption. The overall distribution of emptied and unemptied cells across pollen-age classes was compared against the numbers expected by random emptying (consumption of cell contents) alone by a chi square test of independence. Post-ho+ older stored pollen cells. In the last observation interval, older stored pollen cells comprised 68.2% of the stored pollen cells emptied of their contents . Bees displayed significantly higher emptying rates of freshly-deposited stored pollen cells when cell emptying rates were adjusted for cell abundance on the frames. 2d-, 3d-, and 4d\u2014old stored pollen cells were fully emptied at levels significantly higher than 7d-old and 8d-old stored pollen cells ). These newer stored pollen cells were fully emptied at rates 193% to 354% above predicted levels. By contrast, 7d-old and 8d+-old stored pollen cells were emptied at lower rates relative to their abundance. A critical change in cell content consumption patterns occurred between the 5d- and 6d-old stored pollen cells. Intermediate-aged 5d-old and 6d-old pollen cells were neither over-emptied nor under-emptied but appeared to represent a transitory phase in attractiveness to bees foraging for food within the colony.However, a different pattern of stored pollen consumption emerges among bees when the relative abundance of different-aged stored pollen cells is factored in. Bees emptied different-aged stored pollen cells at different rates  . Our locHow these feeding preferences contribute to mechanisms that regulate colony pollen use has yet to be explored. As individuals in a colony, honey bees must balance activities that result in pollen collection, pollen consumption, and brood rearing . Honey bWhile forager activities partially correct imbalances in pollen supply, worker feeding preferences shape the use of pollen once it is stored within the colony. However, the role of pollen consumer preferences in colony pollen utilization is less understood than foragers. Young nest workers that consume most stored pollen have different responses and olfactory sensitivities towards food materials than older workers, an attribute thought to contribute to age-related polyethism \u201375. The It remains to be demonstrated if the cues underlying these observed preferences are generalized cues or specific to this foraging system. Nonetheless, we have observed feeding preferences for fresh pollen in two locations on different types of forage at different times of the year . A key fS1 File(XLSX)Click here for additional data file."}
+{"text": "This original clinical research study id focused on description of baseline anatomy and outcomes after transcatheter aortic valve implantation (TAVI) in patients presenting with severe aortic stenosis (AS) and bicuspid aortic valve (BAV). We compared this BAV population with a population of patients with AS and tricuspid aortic valves after a propensity score matching developed by a multivariate logistic regression according to a non-parsimonious approach. Baseline anatomical characteristics were obtained by transthoracic echocardiography (TTE) and multi-sliced computed tomography (MSCT) and compared by chi-square and t-student tests. Outcomes were evaluated by correct fisher test at in hospital and 30 days follow-up. We found that BAV patients presents more complicated baseline anatomy as compared to patients with tricuspid valves. These anatomical features lead to higher procedural complications as the need for a second device implantation. However this does not translate into increase in mortality rate at 30 days follow-up but rather correlate to a lower device success rate. Specifications TableValue of the data\u2022Aortic stenosis in bicuspid aortic valve (BAV) remains a challenge for transcatheter aortic valve implantation (TAVI).\u2022BAV patients presenting severe aortic stenosis are increasing in clinical practice\u2022There is little evidence concerning TAVI in this population.\u2022Our data can be an additional evidence for the feasibility of TAVI in BAV.\u2022Indeed many questions are still open to optimize the sizing and find some dedicated devices for this population. Registries and sizing comparisons between operators could find a way to improve TAVI procedures in this subset.1\u2013This study is a comparison analysis between patients with bicuspid or tricuspid aortic valves undergoing TAVI for severe AS.\u2013Patients with AS and BAV present more complicated baseline anatomy as compared to patients with tricuspid valves.\u2013These anatomical features correlate to a lower device success rate but are not related to increase in mortality rate at 30 days follow-up.\u2013The lower device success rate reported was mainly related to a second device implantation need since nor PVL or mean gradient and mortality rate were significantly different.\u2013Pre-procedural imaging and novel device technologies will help to address proper sizing and valve choice in the future.2From January to December 2016, 460 patients with tricuspid aortic valve underwent TAVI procedure in our institution for symptomatic severe AS.From January 2015 to April 2017, 83 consecutive patients with BAV had TAVI at our institution. The majority of these patients were indeed treated in 2016 (87%). Patients undergoing TAVI due to bio-prosthesis degeneration were not included.BAV were classified following the Sievers classification as reported in T test and categorical variables with a chi-square test. A propensity-score matching was applied to account for differences in baseline characteristics of both groups.Continue variables were compared using a Student\u2019s A 1:2 propensity-score matching was performed on the basis of clinical risk factors for cardiovascular mortality and was developed by a multivariate logistic regression according to a non-parsimonious approach Baseline anatomical features and procedural characteristics were compared between the two groups as previously described. Outcomes were evaluated following the Valve Academic Research Consortium-2 definitions (VARC)-2 definitions. PPM values were classified into mild, moderate, severe and were analyzed at both in-hospital and 30 days follow-up The primary endpoint was all-cause mortality and early safety at 30 days. Secondary endpoint included device success.p Value \u2264 0.05. All results were obtained using the Statistical Package for the Social Sciences version 21.0 .Statistical significance was considered as"}
+{"text": "There are limited data on the cardiac effects of radiotherapy and chemo-radiotherapy on the heart in patients with non-small cell lung cancer (NSCLC). CART is a pilot and feasibility study designed to investigate change in myocardial function and identify changes in myocardial tissue properties in patients being treated with radical radiotherapy. Patients will undergo cardiac magnetic resonance (CMR) exam at baseline, during treatment, at 6 weeks and at 6 months after treatment completion. One component of a multi-parametric CMR protocol is contrast-enhanced first-pass perfusion assessment. Here we report our preliminary findings related to temporal changes in myocardial perfusion index (MPI).CMR was performed on a Siemens MAGNETOM Verio  3.0 Tesla scanner. First-pass myocardial perfusion was assessed by saturation recovery prepared dynamic contrast enhanced sequence during administration of 0.1 mmol/kg of gadoterate meglumine (Dotarem). Semiquantitative analysis was performed on segmented basal and mid-LV short axis slices to derive normalized upslopes of myocardial signal intensity profiles . The change in MPI over time was analysed statistically using a linear mixed effects model.13 patients currently have undergone CMR at baseline and during treatment , 8 patients have undergone CMR at 6 weeks post treatment initiation (5 patients lost to follow-up/ died), and 6 patients have undergone CMR at 6 months from baseline (n= 2 lost to follow-up/ died).Perfusion index Figure  varies sBased on our results, perfusion CMR is a feasible tool to assess changes in microvascular function in patients with NSCLC following radiotherapy/chemo-radiotherapy. We have found that the change in microvascular perfusion is most pronounced 6 weeks following the completion of treatment. This finding will be used in the design of future clinical studies, where measurement of MPI will provide a robust comparison of different existing and emerging treatment protocols for NSCLC with regard to their effects on myocardial physiology."}
+{"text": "The rate of revision for some designs of total hip replacements due to idiopathic aseptic loosening has been reported as higher for women. However, whether this is environmental or inherently sex-related is not clear.e.g. metal vs polymer)? The objective of this study was to test for material dependent inflammatory osteolysis that may be linked to sex using CoCrMo and implant grade conventional polyethylene (UHMWPE), using an in vivo murine calvaria model.Can particle induced osteolysis be sex dependent? And if so, is this dependent on the type of implant debris  or CoCrMo particles (0.9um ECD) or received sham surgery. Bone resorption was assessed by micro-computed tomography, histology and histomorphometry on day 12 post challenge.Female mice that received CoCrMo particles showed significantly more inflammatory osteolysis and bone destruction compared to the females who received UHMWPE implant debris. Moreover, females challenged with CoCrMo particles exhibited 120% more inflammatory bone loss compared to males (p<0.01) challenged with CoCrMo implant debris (but this was not the case for UHMWPE particles).We demonstrated sex-specific differences in the amount of osteolysis resulting from CoCrMo particle challenge. This suggests osteo-immune responses to metal debris are preferentially higher in female compared to male mice, and supports the contention that there may be inherent sex related susceptibility to some types of implant debris. The 1). CoCrMo particles had a median diameter of 0.88 \u00b5m diameter ECD number-based . UHMWPE particles had a median diameter of 0.95 \u00b5m diameter ECD number-based . These CoCrMo alloy an UHMWPE particulate sizes and shapes of particulate debris produced from comercially available implants have been shown to be clinically relevant and able to induce inflammatory responses in innate immune cells [The particle sizes of CoCrMo alloy particles  were produced from a commercially available total hip arthoplasty head component , using proprietary cryomilling . Particulate size was characterized by using low angle laser light scattering (LALLS) and Scanning Electron Microscopy (SEM), Fig. . To keep the samples in position during scanning, the skulls were placed in a tightly fitting rigid plastic tube filled with 10% neutral buffered formalin. To determine accurately the region of interest (ROI), a three-dimensional rendering of the whole sample was performed using the manufacturer\u00b4s software. If osteolysis or particles were visible, the ROI was defined as a cylinder with a diameter of 3.84mm and a thickness of 1.47mm beginning from the first slide that captured the bone surface in the ROI. The particle artefact was not observed and did not affect bone fraction calculations. The specific morphometric parameters bone volume (BV) and tissue volume (TV) were measured with a threshold of 350 HU (Hounsfield unit) and the BV/TV ratio was calculated.2.3\u00ae .Four-micrometer thick sections of calvaria were collected at the depth at which the presence of particles was detected within the calvarial tissue. The sections were mounted on glass slides and subsequently HE staining was performed. The HE-stained specimens were photographed digitally using a standard high-quality light microscope . The image was oriented with the midline suture in the middle of the field. The sections were coded and blinded prior to analysis. Histomorphometric measurements were performed with the image analysis software AperioThe program was calibrated using a calibration micrometer. The region of interest to be measured was defined as the area within a distance of 2 mm around midline suture. In this area the volume of the bone stock and potential osteolysis were determined and the relative ratio of osteolysis to the bone stock volume (Osteol./BV) calculated. The mean values per animal of each available section  were calculated.2.4Data is graphically shown as the mean with standard deviation. The Kolmogorov-Smirnov-Test was used to establish normality (p\u2264 0.05) for n=18 male and n=18 female mice. ANOVA was used to establish significant differences for multigroup comparison (p<0.05). Subsequent statistical comparison was conducted with Student`s t-test where p<0.05 was used to establish significance. The software SPSS 22  was used to carry out the statistical computations. Summary statistics of data are expressed as means and standard deviations.32 and 3).We observed significant differences for all histomorphometric  and micro-CT parameters (BV/TV) in all animals that received UHMWPE or CoCr particles on the calvaria in comparison to the sham control groups . Example 3D reconstruction of bone within standardized regions clearly illustrates the increase in osteolysis associated with Female vs. Male mice challenged with CoCrMo particles . Using histomorphic measures of bone loss of bone volume (BV) to total standardized cylindrical volume (TV) of  and micro-CT parameters (BV/TV) differences within groups were compared . Males demonstrated greater bone volume compared to females with sham surgery only, indicating slight but significant sex differences in calvaria bone volume for age matched controls. In comparison to these baseline sham controls, both metal (CoCrMo) and plastic (UHMWPE) particles induced inflammatory bone loss (p<0.05), where the greatest amount of bone loss was observed in female mice challenged with CoCrMo particles.Selected cylindrical control volumes of mouse calvaria encompassing the placement of particle challenge upon the exposed calvaria were analyzed for total bone volume and compared to sex matched controls for volume of bone loss. 3D reconstructions of bone volume (BV) within these standardized cylindrical regions of total volume (TV) were used for quantitative analysis of the murine calvaria bone loss . This analysis of the data revealed that females challenged with CoCrMo particles had significantly more osteolysis than did any other group with greater than 100% more bone loss than males treated with the same amount of CoCrMo particles demonstrating the severe sex effect of CoCrMo particles when compared to plastic UHMWPE particles of similar size and dose. All other challenged groups normalized to sham surgery controls  did not significantly differ. Similar results were obtained for histomorphometric  analysis of H&E stained sections , where there was over 120% increase (p<0.01) in the amount of areal calculated bone loss for female CoCrMo challenged calvaria compared to males with CoCrMo. Histomorphometric  analysis also demonstrated a similar lack of sex difference between UHMWPE treated groups, supporting a metal/sex specific immunogenic mechanism of inflammatory bone loss.On a normalized basis to sham sex matched controls , the pattern of bone loss was similar to non normalized data . An inflammatory pannus with the capability to actively resorb bone is clearly illustrated where the thickness of the inflammatory tissue was approximately 2x as thick in CoCrMo challenged calvaria when compared to the pannus induced by UHMWPE for both males and females. The particle challenge is shown isolated within the inflammatory pannus and excluded from the bone interface, yet a high degree of cell infiltrates can be observed associated with pits of active bone resorption. The composition of the cell/tissue infiltrates (pannus) co-localized with pits of bone loss generally showed vascularized soft tissue fibroblasts with an abundance of macrophage or macropahge-like cells migrating into boney areas. There was no evidence of extensive lymphocyte infiltrates or aseptic lymphocyte vasculitis associated lesions (ALVAL)histology that would be associated with an adaptive immune responses. Additionally, there was no evidence of active multinuclear osteoclasts inside the calvaria responding to inflammatory stimulus and resorbing bone from the inside out . Qualitatively there was a 2x greater foreign body response associated with female murine calvaria compared to males when challenged with either UHMWPE or CoCrMo particles .Over 15 histologic sections per treatment group were analyzed at the midline suture of the calvarial bone plates proximal to particle challenge used for histomorphometric analysis. Qualitative analysis revealed a relatively increased inflammatory pannus associated with CoCrMo 5). Instead macrophages, fibroblasts and osteoclast-like cells were observed at the sites of bone resorption and eminating from the inflammatory pannus  (Note:Bars indicate 0.1mm). Neogenic woven bone can be seen in both UHMWPE and CoCrMo challenged calvaria  indicative of the compromise time period between maximal inflammatory osteolysis and maximal neogenic bone, used in this investigation.At high magnification there was no evidence of multinucleated osteoclasts at the bone pannus interface of particle treated calvaria . Instead this evidence supports a more complex picture where toxicity  and/or adaptive immune reactivity  [Our results indicate that CoCrMo implant debris induces significantly increased osteolysis in females over that of males using a murine model of particle induced osteolysis. However, not all implant debris types induced sex based differences in osteolysis using this model. Our results indicate that UHMWPE particles do not induce significantly sex-based differences in either soft-tissue inflammation or resulting osteolysis. This is consistent with clinical observations that have reported women can suffer higher failure rates of some metal-on-metal THA designs under conditions of elevated metal release . Howeverin vitro -19, whicin vitro , as wellin vitro , 21, 22 in vitro -25, bothignaling , 26, 27.itivity) , 23-25 min vivo murine model to approximate human particle induced osteolysis affected by sex and different implant materials. The compromise time point between maximal osteolysis and maximal bone-neogenesis, was practically limited to a single point at 12 days post-op. While this time point represents a combination of osteolysis and osteogenesis in the murine model, it precludes determination of whether the observed differences were due to sex based inflammatory osteolysis or osteogenic differences or a combination of both. Additionally, a cross sectional time of 12 days may have acted to obfuscate osteolysis differences for UHMWPE that may be significantly apparent at earlier time points, i.e. 5-7 days post operatively . Thus, further investigation with earlier time points and greater number of subjects may help reveal more subtle sex differences in UHMWPE. However, the results of this study support our hypothesis to some degree, indicating that sex-based differences could be detected in response to CoCrMo particulate metal debris. This is the first report demonstrating the ability of metal CoCrMo-alloy implant debris particles to induce sex dependent osteolysis differences at time points where UHMWPE did not. Because evidence for the clinical analogue of this sex-dependence has been reported for patients with metal debris in metal-on-metal hip arthroplasty revisions [There were important limitations of using an evisions , 29, theWe found sex-based influence on inflammatory osteolysis/osteogenesis reactions to CoCrMo particles (but not UHMWPE), implying increased female osteo-immuno reactivity to metallic (CoCrMo) but not polymeric (UHMWPE) implant debris. This may explain one aspect of population dependent implant performance in the outcome of orthopedic implants that preferentially release Cobalt-alloy metal debris. Further research targeting specific mechanisms of toxicity and immune responses (innate vs adaptive) that may mediate sex dependent outcomes in joint replacement surgery is needed to support these findings."}
+{"text": "We also found that glabridin could attenuate the inhibitory effect of taurocholate on type I interferon signaling by depleting the level of cell-surface NTCP. These results demonstrate that our screening system could be a powerful tool for discovering drugs targeting HBV entry.Sodium taurocholate cotransporting polypeptide (NTCP) is a major entry receptor of hepatitis B virus (HBV) and one of the most attractive targets for anti-HBV drugs. We developed a cell-mediated drug screening method to monitor NTCP expression on the cell surface by generating a HepG2 cell line with tetracycline-inducible expression of NTCP and a monoclonal antibody that specifically detects cell-surface NTCP. Using this system, we screened a small molecule library for compounds that protected against HBV infection by targeting NTCP. We found that glabridin, a licorice-derived isoflavane, could suppress viral infection by inducing caveolar endocytosis of cell-surface NTCP with an IC Hepatitis B virus (HBV) is the causative agent of chronic hepatitis B (CHB), which can lead to liver cirrhosis and hepatocellular carcinoma. The World Health Organization reported that over 240 million people worldwide have chronic HBV . DespiteIn the HBV life cycle, the hepatitis B surface antigen (HBsAg) initially attaches to heparan sulfate proteoglycans on the host cell surface . This atin vitro and in vivo, and is currently undergoing a phase II clinical trial for chronically HBV-infected patients -taurocholic acid (TCA) in a sodium-free or sodium-containing buffer at 37\u00b0C for 15 minutes to allow TCA uptake into cells. Cells were washed and intracellular radioactivity was measured using a liquid scintillation counter.Cells were treated with [t test with Prism 6 software (GraphPad).All graphs represent means and standard deviations. The statistical significance of differences between two groups was tested using a two-tailed unpaired"}
+{"text": "We report a case of combined central retinal vein occlusion and branch retinal artery occlusion. A previously healthy 47-year-old male presented with decreased vision in the right eye after completing a half marathon. A fundus exam and retinal imaging revealed a combined central retinal vein and branch retinal artery occlusion.In the present report, we review the literature and discuss the possible mechanisms behind combined retinal vessel occlusions.To our knowledge, this is the first reported case of combined central retinal vein occlusion and branch retinal artery occlusion following intense exercise. Combined central retinal vein occlusion (CRVO) and branch retinal artery occlusion (BRAO) rarely occur together and predominantly arise in patients over 60 years of age .\u00a0FortunaA 47-year-old, previously healthy, male presented with a central scotoma in his right eye after running a half marathon.\u00a0He denied any associated symptoms, including pain, photopsias, or floaters. A review of the systems was negative except for a family history of glaucoma (grandmother) and cataracts (grandmother).\u00a0His best corrected visual acuity (BCVA) was 20/20 in both eyes and intraocular pressure was 24 mmHg in the right eye and 20 mmHg in the left eye. A fundus examination of the right eye revealed retinal whitening along the inferior arcade with scattered dot-blot hemorrhages near the macula and mid-periphery\u00a0and dilated and tortuous veins\u00a0Figure .\u00a0The funThe dilated and tortuous veins, slightly delayed arteriovenous transit on fluorescein angiogram, and a few peripheral dot-blot hemorrhages of the right eye suggest that the patient had an incipient CRVO together with an inferior BRAO. The patient underwent a full hypercoagulable workup, which was negative. A carotid Doppler ultrasound was performed, and it did not show any significant narrowing or soft dislodging plaques.\u00a0He was started on timolol bid in both eyes to decrease intraocular pressures.At the one-month follow-up, his vision remained 20/20 bilaterally. The retina whitening and hemorrhages had resolved. He continued to note a scotoma in his right eye, which had improved since the initial visit. He was continued on timolol bid in both eyes and was advised not to perform endurance exercises.Retinal vascular occlusions following intense exercise and dehydration are a rare occurrence. In the literature, there are few reports of isolated CRVO caused by intense exercise -3. Our rDifferent combinations of retinal artery and vein occlusion as a result of different etiologies have been reported in the literature . These iHowever, the mechanism behind combined retinal vein and branch retinal artery occlusion is less intuitive. Two plausible mechanisms have been proposed to explain such combined occlusions. The first mechanism suggests the occluded vessel (vein or artery) compressing the unoccluded vessel at the site of an arteriovenous crossing. Retinal arteries and veins share a common adventitial sheath at crossing sites, and a distended vein or artery secondary to an occlusion may result in the compression of the normal vessel at these points. The second mechanism suggests that the occlusion initially takes place in the venous system . Since tRed blood cells (RBCs) play a key role during exercise by transporting oxygen from the lungs to the tissues and delivering carbon dioxide to the lungs for expiration. Studies have shown that athletes tend to have a lower plasma viscosity and hematocrit (sports anemia) as well as less rigid RBCs as compared to normal individuals . The lowStudies have shown hemorheological alterations in patients who develop exercise-induced central retinal vein thrombosis . These pWe report the case of a young patient who developed combined CRVO and BRAO soon after completing a half marathon. We review the literature and discuss the possible mechanisms behind combined retinal vessel occlusions. To our knowledge, this is the first report of combined CRVO and BRAO following intense exercise."}
+{"text": "Sciatic nerve injuries following total hip arthroplasty are disabling complications. Although degrees of injury are variable from neuropraxia to neurotmesis, mechanical irritation of sciatic nerve might be occurred by protruding hardware. This case shows endoscopic decompression for protruded acetabular screw irritating sciatic nerve, the techniques described herein may permit broader arthroscopic/endoscopic applications for management of complications after reconstructive hip surgery.An 80-year-old man complained of severe pain and paresthesias following acetabular component revision surgery. Physical findings included right buttock pain with radiating pain to lower extremity. Radiographs and computed tomography imaging showed that the sharp end of protruded screw invaded greater sciatic foramen anterior to posterior and distal to proximal direction at sciatic notch level. A protruding tip of the acetabular screw at the sciatic notch was decompressed by use of techniques gained from experience performing endoscopic sciatic nerve decompression. The pre-operative pain and paresthesias resolved post-operatively after recovering from anesthesia.This case report describes the first documented endoscopic resection of the tip of the acetabular screw irritating sciatic nerve after total hip arthroplasty. If endoscopic resection of an offending acetabular screw can be performed in a safe and minimally invasive manner, one can envision a future expansion of the role of hip arthroscopic surgery in several complications management after total hip arthroplasty.The online version of this article (10.1186/s12891-018-2091-x) contains supplementary material, which is available to authorized users. Sciatic nerve irritation due to an acetabular screw following total hip arthroplasty (THA) is rare; the few reported were treated with revision procedure to remove an acetabular screw . Recent An 80-year-old man complained of severe pain and paresthesias following acetabular component revision surgery via the original posterolateral approach. The patient subsequently complained of right leg pain and paresthesias. The symptoms were exaggerated during initial hip flexion and internal rotation that limited ambulation. Physical findings included right buttock pain with radiating pain to the ipsilateral lower extremity. Radiographs and computed tomography imaging Figs.\u00a0, and 4 sEight months after the aforementioned surgery, the patient underwent supine hip arthroscopy without distraction on a fracture table . The operating table was tilted right side upward to increase accessibility of ipsilateral buttock. An anterolateral viewing portal and poster lateral working portal were developed without incident. For deep gluteal space visualization, a 70-degree high definition long arthroscope with adjustable length cannulas were utilized. The cannula was opened to maintain the fluid flow when utilizing the radiofrequency probe. Fluid pressure was set to 60\u00a0mmHg with intermittent pressure increases up 80\u00a0mmHg. After endoscopic greater trochanteric bursectomy, the repaired piriformis from previous revision surgery was well visualized Fig.\u00a0. EndoscoAfter this endoscopic surgery, immediate hip range of motion was begun with a continuous passive motion machine. The pre-operative pain and paresthesias resolved post-operatively after recovering from anesthesia. The patient advanced to household ambulation without upper extremity aids at 1 postoperative week despite recommendations for 2\u00a0weeks of ambulation using crutches. By 3\u00a0months postoperatively, he had returned to full activities. At 6\u00a0months postoperatively, he had a negative active and passive piriformis test and he remained pleased with the outcome. Postoperative imaging included radiographs and computed tomography scans with 3-dimensional reconstruction demonstrating complete resection of the offending portion of the acetabular screw.Nerve lesions following total hip arthroplasty (THA) are disabling complications occurring in 0.06 to 2.2% of arthroplasties , 6. HardAn expandable cannula facilitated safe resection of the protruding screw tip while avoiding injury to the adjacent superior gluteal nerve and sciatic nerve. Circulating endoscopy fluid might decrease thermogenesis during metal-on-metal burring of the offending screw. In addition, generated metallic debris is removed immediately through suction system attached burr and cannula to minimize bodily retention with possible adverse consequences.The decision to remove rather than try to preserve the piriformis muscle was influenced by the surgeon\u2019s experience with deep gluteal space exploration often performed for sciatic nerve decompression.Relevant suggestions and pearls are summarized in Table\u00a0For this patient, resection of offending screw tip using endoscopy was considered first, because the acetabular component implanted revision surgery had bony ingrowth without evidence of loosening. Although sciatic nerve irritation from a protruding acetabular screw is rare and its described treatment even rarer, the endoscopic techniques described herein may have broader applications. Recent interest in hip arthroscopy along with more advanced techniques gained from the endoscopic management of sciatic nerve entrapment syndrome/deep gluteal syndrome have allowed the application of minimally invasive hip surgery for conditions once thought treatable only by open sciatic nerve exploration, screw resection and/or revision hip arthroplasty. The endoscopic exploration and screw resection described herein enables less invasive surgery permitting early joint motion, accelerated rehabilitation, and potential outpatient management. Beyond iliopsoas tenotomy, endoscopic treatment may expand to other complication of THA including protruding screws causing adjacent neurovascular compromise.A protruding acetabular screw at the sciatic notch was decompressed by use of techniques gained from experience performing endoscopic sciatic nerve decompression. Expandable cannula was used to protect superior gluteal neurovascular bundle proximally and sciatic nerve distally, followed by exposure of screw using an arthroscopic shaver.Additional file 1:Endoscopic section of acetabular screw tip to decompress sciatic nerve. Via endoscopic and intermittent multiplanar fluoroscopic visualization, further dissection was performed proximally and distally to prevent inadvertent injuries to the sciatic nerve and the superior gluteal neurovascular bundle. Partial osteoplasty of the sciatic notch with a motorized burr performed under endoscopic guidance. Endoscopic resection of the offending screw tip was performed with a 5.5\u00a0mm motorized round burr. (MP4 4460 kb)"}
+{"text": "Sperm DNA fragmentation has been associated with reduced fertilization rates, embryo quality, pregnancy rates and increased miscarriage rates. Various methods exist to test sperm DNA fragmentation such as the sperm chromatin structure assay (SCSA), the sperm chromatin dispersion (SCD) test, the terminal deoxynucleotidyl transferase mediated deoxyuridine triphosphate nick end labelling (TUNEL) assay and the single cell gel electrophoresis (Comet) assay. We performed a systematic review and meta-analysis to assess the value of measuring sperm DNA fragmentation in predicting chance of ongoing pregnancy with IVF or ICSI. Out of 658 unique studies, 30 had extractable data and were thus included in the meta-analysis. Overall, the sperm DNA fragmentation tests had a reasonable to good sensitivity. A wide variety of other factors may also affect the IVF/ICSI outcome, reflected by limited to very low specificity. The constructed hierarchical summary receiver operating characteristic (HSROC) curve indicated a fair discriminatory capacity of the TUNEL assay (area under the curve (AUC) of 0.71; 95% CI 0.66 to 0.74) and Comet assay . The SCSA and the SCD test had poor predictive capacity. Importantly, for the TUNEL assay, SCD test and Comet assay, meta-regression showed no differences in predictive value between IVF and ICSI. For the SCSA meta-regression indicated the predictive values for IVF and ICSI were different. The present review suggests that current sperm DNA fragmentation tests have limited capacity to predict the chance of pregnancy in the context of MAR. Furthermore, sperm DNA fragmentation tests have little or no difference in predictive value between IVF and ICSI. At this moment, there is insufficient evidence to recommend the routine use of sperm DNA fragmentation tests in couples undergoing MAR both for the prediction of pregnancy and for the choice of treatment. Given the significant limitations of the evidence and the methodological weakness and design of the included studies, we do urge for further research on the predictive value of sperm DNA fragmentation for the chance of pregnancy after MAR, also in comparison with other predictors of pregnancy after MAR. Traditionally, the diagnosis of male subfertility is based upon the analysis of semen volume and sperm concentration, motility and morphology. Although there is a direct relationship between semen quality and pregnancy rates both in natural conception and after medically assisted reproduction (MAR), there is no definite predictive threshold for success for conventional semen parameters \u20134. ConveThe integrity of our genome is continuously challenged by endogenous metabolic by-products and exogenous factors. Depending on variables like cell type, cell cycle stage and the type of DNA damage, a cell has several ways to repair damaged DNA and inaccurate repair can have different consequences ,7. WhileRecent studies have highlighted the significance of sperm DNA integrity as an important factor that affects functional competence of the sperm. Therefore the detection of sperm DNA fragmentation could be clinically useful as part of fertility workup . For thiThe SCSA bases its results on (1) the DNA fragmentation index (DFI), which is the percentage in the sample that have measurable increased red fluorescence due to acridine orange attaching to a single strand portion of DNA at sites of DNA strand breaks and then collapsing into a crystal that produces a metachromatic shift to red fluorescence under exposure to blue light and (2) the percentage of high DNA stainability (HDS), which is due to excess histones and proteins other than protamines that prevent full condensation of the sperm chromatin \u201332.The SCD test, also known as Halo Sperm assay, estimates the level of DNA fragmentation indirectly by quantification of the amount of nuclear dispersion/halo after sperm lysis and acid denaturation to remove excess nuclear proteins ,34.The principle of TUNEL involves labelling of the 3\u2032-ends of single- and double-strand breaks with biotinylated dUTPs. The incorporated labelled nucleotides can be quantified by flow cytometry or (fluorescence) microscopy to determine the number of (apoptotic) sperm cells containing fragmented DNA . HoweverThe Comet assay quantifies the shape of the single cell nuclei after gel electrophoresis. Small fragmented DNA has a faster rate of migration towards the anode in an electrophoretic field (tail region) as compared to larger non-fragmented DNA (head region), leading to a typical comet shape ,31.Using these tests, the percentage of sperm with fragmented DNA was shown to be comparable in idiopathic subfertile men with normal sperm parameters and in subfertile men with abnormal sperm parameters, and significantly higher in both these groups in comparison to fertile controls \u201337. HoweThe electronic databases Pubmed, Embase, Cochrane and CINAHL were searched from inception (September 1967) to January 2016 for articles which described sperm DNA fragmentation tests and outcome after MAR. The Medical Subject Headings terms and/or text words that were used in our search can be found in the appendix. We also manually reviewed the bibliographies of retrieved original papers and review articles. We used the preferred reporting items for systematic review and meta-analysis checklist (PRISMA) while conducting this study .Titles and abstracts of all identified studies were screened and the full paper of the preselected articles was read by two researchers (S.M. and M.C.). Both researchers extracted the data from the article independently by using standardized data extraction forms. If 2x2 tables could be constructed the study was selected for final inclusion. In the 2x2 tables, the numbers of pregnant and non-pregnant women for different sperm DNA fragmentation cut-off values were recorded. Any disagreement between the two researchers was resolved through discussion or by consultation with a third researcher (I.S.).All studies investigating the effect of sperm DNA fragmentation detected by the SCSA, the SCD test, the TUNEL assay or the Comet assay on the outcome of IVF and/or ICSI were considered eligible for inclusion. The search was restricted to studies in humans. Studies were excluded if they had no original data available for retrieval and duplicate publications were also excluded. Studies that included cycles with donor oocytes and experiments that asses sperm DNA fragmentation in specific male factor pathologies e.g. azoospermia and co-intervention experiments e.g. antioxidant treatment were excluded from analysis.The primary study outcome was ongoing pregnancy  at the 12th week of gestation). Other study outcomes were clinical pregnancy  and live birth (defined as a live-born baby \u2265 24 weeks of gestation). All outcomes were reported per cycle.Each selected study was scored for their relevance and methodological quality by using the QUADAS 2  checklist . FurtherIn order to evaluate the overall accuracy, including the whole range of possible thresholds, we used hierarchical summary receiver operating characteristic (HSROC) plots to display the results of individual studies in a ROC space, each study being plotted as a single sensitivity-specificity point. Reported estimates for sensitivity and specificity from different studies may be based on different positivity thresholds . If there are multiple thresholds reported in one study, we chose the threshold that was most comparable to the others. Based on the binomial distributions of the true positives and true negatives we calculated a summary point, with a 95% confidence interval (CI) and predictive interval by using STATA version 14 . As recommended for meta-analysis of diagnostic accuracy studies , we usedAn area under the curve (AUC) of 1 implies perfect discrimination, whereas an AUC of 0.5 means that the test does not discriminate at all . For thiIn cases where insufficient data was available to perform HSROC analyses for clinical pregnancy, (ongoing) pregnancy or live birth independently, different pregnancy outcomes were combined when minimal differences in sensitivity and specificity were found. When minimal differences in sensitivity and specificity were found, studies with different timing of the sperm DNA fragmentation test (pre- and post-wash) were combined.2 statistic, which represents the percentage of total variability across the studies that is due to heterogeneity instead of chance. Moderate heterogeneity is defined as a value < 50%  OR (\"dna\"[All Fields] AND \"damage\"[All Fields]) OR \"dna damage\"[All Fields]) OR (\"dna\"[All Fields] AND \"fragmentation\"[All Fields] OR \"dna fragmentation\"[All Fields]) AND (\"humans\"[MeSH Terms] OR \"humans\"[All Fields] OR \"human\"[All Fields]) AND (\"comet assay\"[MeSH Terms] OR (\"comet\"[All Fields] AND \"assay\"[All Fields]) OR \"comet assay\"[All Fields] OR \"comet\"[All Fields]) OR  OR SCSA[All Fields] OR (\"chromatin\"[MeSH Terms] OR \"chromatin\"[All Fields]) OR (\" acridine orange\" [All Fields]) OR (\"in situ nick-end labeling\"[MeSH Terms] OR (\"situ\"[All Fields] AND \"nick-end\"[All Fields] AND \"labeling\"[All Fields]) OR \"in situ nick-end labeling\"[All Fields] OR \"tunel\"[All Fields]) OR (\"in situ nick end labelling\"[All Fields] OR \"in situ nick-end labeling\"[MeSH Terms] OR (\"situ\"[All Fields] AND \"nick-end\"[All Fields] AND \"labeling\"[All Fields]) OR \"in situ nick-end labeling\"[All Fields] OR (\"situ\"[All Fields] AND \"nick\"[All Fields] AND \"end\"[All Fields] AND \"labeling\"[All Fields]) OR \"in situ nick end labeling\"[All Fields]) AND (\"spermatozoa\"[MeSH Terms] OR \"spermatozoa\"[All Fields] OR \"sperm\"[All Fields]) AND (\"pregnancy\"[MeSH Terms] OR \"pregnancy\"[All Fields]).S1 Fig(DOCX)Click here for additional data file."}
+{"text": "Genomics has changed the way we diagnose and treat cancer . Our abiKDM3A  [However, there is more to a genome map than a linear DNA sequence and yet we might know less than we think. A recent study has published discoveries about an epigenetic factor named  JHDM2A) .The Jumonji family of histone demethylases regulates transcription by removing methyllysine modifications from histone tails. Therefore, direct DNA interaction may not be required for the biochemical demethylase function. Amore efficient way to accomplish gene target specificity is by cooperating with transcription factors that recognize promoter and enhancer motifs via their DNA-binding domains Figure . Since tA predominant signature of androgen-dependent signaling plays a key role in prostate cancer progression and its resistance to androgen-deprivation therapy, which is the primary treatment for metastatic or locally advanced disease . TranscrMany of the factors controlled by the epigenomic regulator KDM3A are well-known biomarkers such as the prostate-specific antigen (PSA). Why can we not create a simple test that tells us if we have good genes but an unfavorable epigenome? Our epigenome is highly dynamic. Epigenomic regulators, including Jumonji family members of histone demethylases, remove or add chemical marks allowing for transient gene read-outs while blocking it in the next minute . PersonaAn additional complication is that gene activity can respond to the environment. Epigenetic silencing can, for example, arise as diet-induced consequence of inflammation . Typical"}
+{"text": "The first of two studies showed FDG activity in the left deltoid and ipsilateral axillary lymph nodes explained by influenza vaccination the day prior. The second 18F FDG-PET/CT showed multiple FDG-avid lymph nodes on both sides of the diaphragm without tracer accumulation at the vaccination site. Three months later the CT was negative for lymphadenopathy within the chest or abdominal region. Although influenza vaccination is a potential source of false positive results in FDG PET studies, generalised lymph node activation post vaccination is a rare finding with only one prior published report in individuals infected with HIV-1. This case emphasizes the necessity of taking a history of vaccination prior to a FDG PET study, and consideration of a vaccine-related immune response even without evidence of tracer activity at the vaccination site when generalised FDG-avid lymphadenopathy is encountered.We report on a 59-year-old female patient with an infected vascular graft investigated with  Influenza vaccination is a potential source of false positive results in FDG PET studies -7 as 80%A 59 year old female patient presenting with two weeks of lower back pain, nausea, fatigue and chills was referred for investigation of an infected aorto-bifemoral graft. The CT component of the PET/CT study showed fat stranding and collections around the graft. The FDG component demonstrated diffuse metabolic activity surrounding the aortic graft and multiple FDG-avid foci indicating an infected graft with multiple abscesses. The FDG PET study also showed activity in the left deltoid and left axillary lymph nodes. (A) On questioning, the patient gave a history of having had the influenza vaccination the day prior.Intravenous antibiotics were started and 26 days later the patient was referred for a repeat FDG PET/CT study to assess treatment response. The PET/CT study showed reduced but persistent FDG activity around the aortic graft indicating an incomplete metabolic response to antibiotic therapy. In addition, the FDG PET/CT study demonstrated enlarged lymph nodes with FDG accumulation on both sides of the diaphragm involving the bilateral cervical and axillary, porta hepatis, coeliac and left femoral nodal stations. Interestingly, the previously documented FDG uptake in the left deltoid muscle related to the influenza vaccination had completely resolved (B). Three months after removal of the infected graft and femoral vein reconstruction, the patient was assessed by CT angiogram revealing resolution of the lymphadenopathy above or below diaphragm (C).Generalized lymph node activation following influenza vaccination is a rare and unexpected finding with only one prior published report in HIV-1-infected individuals  while abThe authors declare no conflict of interest."}
+{"text": "Bacillus species 062011 msu is a harmful pathogenic strain responsible for causing abscessation in sheep and goat population studied by Mariappan et al. (2012) Bacillus cereus and exhibits 99% sequence homo;logy with the genomes of B. cereus ATCC 10987 and B. cereus FRI-35. Hence, we have renamed the organism as Bacillus cereus 062011msu. The Whole Genome Shotgun (WGS) project has been deposited at DDBJ/ENA/GenBank under the accession NTMF00000000 (https://www.ncbi.nlm.nih.gov/bioproject/PRJNA404036(SAMN07629099)). Specifications TableValue of the data\u2022Bacillus cereus 062011msu is a deadly pathogenic bacterium known for causing abscess mainly in the female sheep and goat population. Hence, the genome sequence resource and their annotation details can be effectively utilized to understand the pathogenicity of the bacterium for the benefit of the farmers who rear the sheep and goat.The \u2022Bacillus cereus 062011msu provided a broad overview regarding the subsystem features, metabolic pathways, orthologous groups, virulence factors and antibiotic resistant genes associated with the genome of the species. Most of the unique genes of the species were found to be clustered in ten genetic islands. In this study we provided a detailed analysis of the genes clustered on the genetic islands.The genome annotation data of \u2022Bacillus species provided significant information regarding the identification and taxonomic classification of this new bacterial strain. Although according to the previous study using the partial 16S RNA sequences the pathogen was reported to be genetically similar to Bacillus anthracisBacillus cereus and phylogenetically related with B. cereus ATCC 10987 and B. cereus FRI-35.The data obtained from 16S rRNA analysis and genome sequence comparison with other \u2022The entire genome dataset can be utilized further for determining the genes and biochemical pathways related to the pathogenicity (abscess) of the strain and developing new antimicrobial drugs for the pathogen.1Bacillus cereus 062011msu. B. cereus 062011msu. The data describing the length and Phred quality score distribution of the raw and filtered reads are illustrated in the B. cereus 062011msu genome based on RAST genome annotation. The complete list of the RAST annotated genes is given in SBacillus cereus 062011msu based on RAST annotation are listed in Bacillus cereus 062011msu resulted from BLAST genome alignment. B. cereus 062011msu obtained from DNAPlotter.The overall data represents the genome sequencing, assembly, annotation and comparative analysis of pathogenic bacteria 22.1Bacillus cereus 062011msu was isolated from the abscess tissue of the affected female sheep and goats in Maruthamputhur village near Alangulam Region, Tirunelveli District, Tamil Nadu, India https://www.bioinformatics.babraham.ac.uk/projects/fastqc/) The 2.2Bacillus cereus 062011 msu were annotated by using the NCBI Prokaryotic Genomes Automatic Annotation Pipeline (PGAAP) http://rast.nmpdr.org/) http://www.pathogenomics.sfu.ca/islandviewer/) The draft genome contigs of Bacillus cereus 062011msu were identified by annotating the protein coding sequences against the KEGG pathway database using the BLAST2GO program Bacillus cereus 062011msu were performed by using the EggNog database  embedded within the BLAST2GO software Simultaneously the data obtained from the RAST annotation server revealed that the draft genome contains 8721 coding sequences and 472 subsystems with \u201cAmino Acids and Derivatives\u201d and \u201cCarbohydrates\u201d were the most represented subsystem features. In addition the annotated subsystem features denoted 257 genes associated with \u201cVirulence, Disease and Defense\u201d including 154 genes associated with antibiotics and toxicity resistance, 52 genes associated with the synthesis of antibacterial peptides, Bacteriocins, 50 genes associated with invasion and intracellular resistance and one gene associated with adhesion. The KEGG (Kyoto Encyclopedia of Genes and Genomes) biological pathways associated with the genome of Bacillus cereus 062011msu were further screened by annotating the coding sequences against the Virulence Factor Database (VFDB) B. cereus 062011msu, indicating that the flagellar proteins might play regulatory role in the pathogenicity of the bacterium. The previous in vitro experiments by Mariappan et al., 2012 reported that the pathogen was sensitive to tetracycline (TET) and ciprofloxacin (CPFX) Bacillus cereus 062011msu were screened by using the curated database, Antibiotic Resistance Genes Database (ARDB) (http://ardb.cbcb.umd.edu/) Emphasizing the pathogenic nature of the strain, the virulence factors and toxic genes residing in the genome of 2.3Bacillus cereus 062011msu based on the genome sequence comparison using RAST server were identified as Bacillus cereus AND1407 (score 544), Bacillus cereus MSX-D12 (score 406) and Bacillus cereus BAG3O-2 (score 387). Based on the local similarity of the aligned nucleotide sequences using the rapid sequence comparison tool BLAST Bacillus cereus 062011msu exhibited 99% sequence homology with the genomes of Bacillus cereus ATCC 10987, Bacillus cereus strain M3, Bacillus cereus FRI-35, Bacillus thuringiensis serovar finitimus YBT-020, Bacillus cereus strain CC-1, Bacillus cereus NC7401, Bacillus cereus AH187 respectively. In microbial genomics research the comparison of 16S rRNA gene sequence has emerged as a reliable technique to identify new bacterial strains associated with pathogenicity and infections Bacillus cereus 062011msu genome was aligned to its nearby homologs using the Clustal W multiple sequence alignment and the phylogenetic analysis was performed through the maximum likelihood method with 100 bootstrap replicates using the MEGA7 software (www.megasoftware.net/) Bacillus cereus and exhibits close evolutionary relationship with B. cereus ATCC 10987 and B. cereus FRI-35 as they were clustered together as a monophyletic clade. Simultaneously we have also performed the phylogenetic analysis based on 23S rRNA gene sequence comparison using the MEGA7 software. The 16S rRNA gene derived phylogenetic tree was found to be concordant with the 23S rRNA gene tree as it also identified B. cereus ATCC 10987 as the closest evolutionary homolog of the pathogen. The complete genomic map of Bacillus cereus 062011msu representing the GC content, GC skew graphs, coordinates and coding sequence features on both forward and reverse strands obtained from RAST annotation was generated by DNAPlotter (http://www.sanger.ac.uk/science/tools/dnaplotter) The closest neighboring strains for"}
+{"text": "We present a new and simple laser-based process to porosify thin film silicon using a pulsed laser. During deposition, we incorporate gas atoms or molecules into the Si thin film. Pulsed laser radiation of wavelength  The research on porous silicon (Si) is of current interest due to its various applications . Sensors2O2 by a less than 10 nanometers thin metal layer on the surface. Depending on the metal and the doping of Si, different porosities using different etching rates are produced due to local redox reactions [3 or CrO3) to produce porous films on top of the Si wafer. The thickness of the porous films produced by stain etching is limited to 100 nm in thickness [Porous Si is usually produced by wet chemical etching of crystalline Si wafers. The most common method and well established process is anodic etching ,6. A Si eactions . The stahickness . Bao et hickness , which CThe present contribution presents a new method using pulsed laser radiation to porosify Si thin films. Successful porosification requires incorporated gas atoms within the Si film. We show that hydrogen in plasma enhanced chemical vapor deposited (PECVD) Si and Argon (Ar) in sputtered Si fulfill this requirement and allow the porosification with pulsed laser radiation. The gas atoms serve as a source for explosively expanding gas bubbles to create porous thin film Si.a = \u03c3 is the standard deviation. Amorphous Si deposited on stainless steel substrate is fixed to an x with a constant velocity x. A laser pulse repetition frequency The rolled stainless steel (X5CrNi18-10) foil substrates of thickness As a reference, we use evaporated Si for thin film Si containing no gas atoms. Evacuation of the recipient to base pressure Winters and Kay showed the relation between sputter pressure and argon (Ar) concentration in sputtered nickel films . They mep of the sputter recipient is in the range of We deposit sputtered Si layers with a Leybold Z 550 radio-frequency (RF) sputtering system operating at a frequency + ions dissociate SiH4 molecules, resulting in thin film Si growth. Knights showed the relation of decreasing hydrogen content with increasing substrate temperature during deposition [Plasma enhanced chemical vapor deposited thin film Si contains chemically bonded hydrogen, which is usually used to saturate dangling bonds in amorphous Si to improve electrical properties of the thin film. During deposition, the plasma containing Arposition . SubstraThe Raman spectra of the thin films for different fluence Renishaw plc. Evaporation of silicon in vacuum with a base pressure e formed . The founcreases . TherefoAnnealing of the effusion . A compaent heat . ExplosiIn contrast to annealed PECVD samples, tempering of sputtered Si for The comparison of the porosity of PECVD Si with sputtered Si shows a difference in the surface structure. Only sputtered Si shows pellet formation before pore formation occurs. Apparently the type of gas and its reactivity influence the porosification process. Nevertheless, both kinds of Si contain gas atoms and show an increase in pore diameter with increasing fluence. Evaporated Si containing no gas as reference shows no pore formation after laser irradiation and both PECVD Si and sputtered Si\u2014which contain gas atoms\u2014show pore formation, which supports our theory for the mechanism of pore formation.We present a new method to produce porous Si thin films with pulsed laser radiation of wavelength"}
+{"text": "Aortic rupture is a rare but possible complication during spine surgery. It may manifest as severe intraoperative hemorrhage or present in a delayed manner after the formation of an aneurysm or an arteriovenous fistula. Though it is commonly encountered during anterior surgeries involving the surgical field close to the thoracic or abdominal aorta, it can also occur during a posterior surgery. Aortic injury could be associated with surgeries ranging from the commonly performed pedicle screw instrumentation to a complex three-column osteotomy. It can also occur, as in the reported case,\u00a0while performing complex procedures in the presence of a pre-existing aneurysm or aortic adhesions due to coexisting infectious or inflammatory pathologies. The treatment options for such aortic ruptures range from open repair to endovascular stenting techniques. We discuss a case of an aortic rupture that occurred during a posterior vertebral column resection (PVCR) procedure performed on a 58-year-old female with spastic paraparesis secondary to tuberculous spondylodiscitis and the lessons learnt. Aortic rupture during a spine surgery is a known yet disastrous complication. It can be fatal and lead\u00a0to the death of a patient on the operative table. It can occur due to pre-existing aortic aneurysms or aortic adhesions due to coexisting infectious or inflammatory pathologies, during anterior surgery while working around big vessels and rarely during posterior spinal surgery. The incidence depends on the anatomical region, surgical approach, primary pathology, implant-related issues, and the surgical expertise . Injury HistoryA 58-year-old female presented with a gradually progressive, painful kyphotic deformity of the mid back of five months duration associated with progressive spastic paraparesis, with onset two weeks before presenting to our clinic. On examination there was a tender gibbus deformity in the thoracolumbar junction with spastic paraparesis and exaggerated deep tendon reflexes. Her hematological parameters showed leukocytosis  with an elevated erythrocytic sedimentation rate (70 mm/hr). X-rays showed a focal kyphotic deformity at the thoracolumbar junction. Magnetic resonance imaging (MRI) was suggestive of spondylodiscitis at T12-L1 with epidural soft tissue components  due to massive blood transfusion.\u00a0Spinal infections have been reported to be associated with spontaneous aortic rupture with or without associated aneurysmal formation . Cage miAortic rupture while performing a PVCR for spondylodiscitis has not been described before. Doing PVCR in spondylodiscitis can be a problem since long standing infection can be associated with the adherence of great vessels to the vertebral body. Our case highlights the significance of carefully evaluating the surrounding structures on the MRI preoperatively to look for adherent fragments to the aorta and leaving such fragments in situ during surgical resection to prevent surgical catastrophes."}
+{"text": "Suspected for a while to shape the phenotype of monocytes and peripheral macrophages, HCK activity indeed regulates the evolutionarily conserved contributions of these cells to host defence, wound healing and tissue repair [According to populist dictionaries, \u201cHick\u201d describes a poorly educated person of provincial existence. As much as one can draw parallels between individual characters of e repair . Recent e repair ,3.HCK ablation impaired phagocytic activity of macrophages in vitro and LPS-induced endotoxemia in vivo and reduced host-defence against Listeria parasites [de novo oncogenic HCK fusion protein in hematopoietic cells can result in acute myeloid and other leukemias, while excessive HCK activity in the \u201cright cells at the right time\u201d promotes macrophage and neutrophil migration, rather than causing cellular transformation [HCK gene expression or catalytic activity correlates with poorer survival for colon cancer patients.HCK is a myeloid and B-cell specific member of the SRC family of tyrosine kinases (SFKs) where the prototypical member c-SRC confers neoplastic transformation when constitutively activated. The latter not only occurred following the Rous sarcoma virus' hijacking of a carboxyl terminally truncated version of c-SRC or of viral proteins corrupting the functions of SFKs, but also as a consequence of SFKs acquiring carboxyl terminal non-sense mutations. Meanwhile, the cellular homologues of SFKs play important roles in signal transduction from growth factor and immune cell receptors, as well as of various immune-cell integrins. Accordingly, genetic arasites . In contormation . Howeverormation . AlthougMyeloid HCK activity promotes solid cancer growth by regulating polarization of macrophages and most likely neutrophils: the more HCK activity the stronger the expression of genes associated with alternative activation characterized by an anti-inflammatory M2 endotype . Indeed,While adoptive transfer experiments show that HCK affects bone marrow-derived macrophages and possibly their monocytic Ly6G precursors, it remains unclear whether HCK also regulates polarization of tissue-resident macrophages derived from a MYB-positive yolk sac precursor. However our unpublished observations suggest that HCK activity also hinders elimination of (transplanted) cancer cells by the immune system. This is likely to involve the adaptive immune system as suppression of HCK appears to augment the anti-tumor immune response conferred by immune checkpoint inhibitors on immunogenic cancer cells as well.There remains the question as to where HCK fits in to the signalling cascades that may sense a need for polarization, mediate it and ultimately execute the effect on neoplastic epithelium. HCK is physically associated with the receptors for CSF-1, the IL6-family and other cytokines implicated in regulating macrophage endotypes. Whether the physical association of HCK with leukocyte adhesion receptors may prime or reinforce macrophages for polarization by cytokines remains unknown. Strikingly, excessive HCK activity still endows an M2 endotype in the absence of STAT6 and therefore limits responsiveness to IL4/13 as the classical inducers of alternative macrophage activation [To return to the \u201cHick\u201d analogy, macrophages remain highly susceptible to the poor education signals provided by adjacent cancer cells and designed to support tumor progression through enhanced nutrient supply and establishing an immune tolerant shield. As a regulator of macrophage polarization, HCK may stand up as an alternative to PI3K\u03b3 and CSF-1R, which are pursued as clinical targets for re-educating tumorigenic M2 macrophages to adopt a tumoricidal M1 endotype. Whether medicinal chemistry can overcome the challenges of identifying small molecules inhibitors with sufficient specificity to overcome the extensive molecular similarity within the 10 members of the SFK remains to be seen."}
+{"text": "This dataset presents the mitochondrial genome variants associated with oncocytic tumors. These data were obtained by Sanger sequencing of the whole mitochondrial genomes of oncocytic tumors and the adjacent normal tissues from 32 patients. The mtDNA variants are identified after compared with the revised Cambridge sequence, excluding those defining haplogroups of our patients. The pathogenic prediction for the novel missense variants found in this study was performed with the Mitimpact 2 program. Specifications tableValue of the data\u2022The data identified inherited mtDNA variants associated with patients with oncocytic tumors.\u2022The data showed some identified mtDNA variants could have functional consequences.\u2022The data might help to detect new genetic predisposition markers for oncocytomas.1The data were presented as tables, where positions, detail changes , and the2NC_012920). The heteroplasmy were defined if a double peaks of two residues were verified at the same position in the electro-chromatograms. Pathogenic prediction were analyzed using PolyPhen2 (http://genetics.bwh.harvard.edu/pph2/) We collected 32 cases of the parafin-bedded tissues with oncocytic tumor and matched adjacent normal tissues, mtDNA were amplified by PCR using 24 previously reported pairs of mtDNA primers to cover the whole mtDNA genome as our previous work"}
+{"text": "To study if difference between the tricuspid and mitral valve opening time evaluated using cardiac magnetic resonance imaging (CMR) correlates with echocardiographic measurements of left atrial pressure (LAP).The ratio of the transmitral early inflow velocity (E wave) and the tissue Doppler mitral annular velocity (e' wave) can be used to measure left atrial pressure on the echocardiographic examination. An elevated E/e' (>15) on echo Doppler is an established measure of elevated LAP.Unlike echo, cardiac MRI (CMR) has no non-invasive measure of LAP. Normally both the atrioventricular valves open simultaneously or the tricuspid valve opens earlier than the mitral valve due to a very short right-sided isovolumic relaxation time (IVRT). Elevated LAP shortens the left sided IVRT and therefore causes the mitral valve to open earlier than expected. Also, elevated LAP indirectly leads to elevation of right heart pressures causing lengthening of the tricuspid valve isovolumic relaxation time resulting in delayed tricuspid valve opening. We investigate the role of using the time differential of mitral and tricuspid opening as novel parameter of LAP measurement on CMR.We hypothesize that elevated LAP should lead to an increased positive time differential of the mitral and tricuspid valve opening times.CMR and echo Doppler studies in 32 patients were reviewed. Echo Doppler data were reviewed to measure the mitral E wave and septal e' velocities. The LAP was calculated using the following formula:LAP = (E/e' x 1.25) + 1.912 out of 30 patients met the criteria for an elevated left atrial pressure based on the E/e' ratios and the remaining 20 patients had normal LAP.On CMR, the mitral and tricuspid valve opening times (in milliseconds) were calculated using the 2D short axis cine phase contrast images obtained at the level of the AV valves. The velocity versus time graphs and cine images were used to calculate and differences in valve opening times.The correlation between the CMR derived mitral and tricuspid valve time differential and echocardiographic E/e' derived LAP values was calculated using Spearman's rank correlation.Our study showed that there is significant correlation between the echo derived LAP using E/e' and mitral and tricuspid valve opening time differential. Spearman's rank correlation was 0.39 (p=0.028). A positive time differential  had high specificity in detecting elevated LAP (85%). However, the sensitivity was poor (50%). The positive and negative predictive values were 67% and 74%, respectively.Time difference between the openings of the atrioventricular valves is a highly specific marker of elevated left atrial pressure. This marker merits further testing to determine if it can provide quantitative information on the degree of left atrial pressure elevation."}
+{"text": "Specifications TableValue of the data\u2022The raw data files will allow future scientists to re-analyze the data in single- or meta-analyses.\u2022The raw dataset will allow future scientists to extend statistical analyses.\u2022The data fills a major gap in knowledge regarding changes that underlie bald scalp-specific manifestations in AGA.\u2022The data is linked to transcriptional profiling and functional and pathway based analyses to clarify underlying mechanisms of disease.1The raw data files (CEL files) obtained from microarray analysis, that were used in the analysis and interpretation of our related report are available in Sample IDs are:AG5011DAG5011NAG7003DAG7003NAG7007DAG7007NAbbreviations:AG=Androgenetic alopeciaN: haired scalpD: bald scalpRNA was extracted from frozen biopsies of haired and bald scalp samples from 3 AGA-patients. Genome-wide gene expression analysis was performed using the microarray platform: Human Genome U95Av2 GeneChip  according to manufacturer\u05f3s protocols. Biotinylated probes were fragmented and hybridized to the microarray chips . Default parameters were used to import the gene expression data to Partek Genomics Suite v6.6 . Raw data preprocessing included log2 transformation, quantile normalization, RMA background subtraction and median polish and was used for probeset summarization to scale mean expression values of all 6 arrays. The preprocessed dataset was subsequently processed to establish differentially expressed genes between bald and haired scalp using the \u201cGene Expression\u201d tool within Partek Genomic Suite"}
+{"text": "The axial periodicity of rat arachnoid and dura mater collagen fibrils exposed to 910 MHz for 2 h/day for 30 consecutive days was measured by means of image analysis of electron-optical data. Such measurements were compared with those from sham-exposed animals. These measurements reveal that on exposure, the intermolecular interactions during collagen fibril assembly are affected."}
+{"text": "Bacteroidales gene markers with human sewage and animal fecal samples  from Tha Chin and Chao Phraya watersheds. Annealing locations of PCR primers were illustrated by maps of 16s rRNA Bacteroidales genes. We also summarized previously published work on the performance of the PCR assays. For further discussion of the data presented here, please refer to Somnark et al., Performance evaluation of Bacteroidales genetic markers for human and animal microbial source tracking in tropical agricultural watersheds, Environ. Pollut. 236 (2018) 100\u2013110.We reported modified endpoint PCR results analyzed by universal and human-, swine-, and cattle-specific  Specifications TableValue of the data\u2013Bacteroidales-modified endpoint PCR markers could be compared with microbial source tracking (MST) studies in other geographic areas for further development of region-specific MST methods.PCR results of \u2013Bacteroidales PCR primer maps could offer an insight into annealing regions of primers for further design of new primers or evaluating currently available primers with their performance.\u2013A summary of PCR assays that are originally designed and adopted to other regions could serve as a database for comparing the MST method performance in different geographical areas.1Bacteroidales genetic markers from both studies that originally designed the assays and studies that adopted the designed assays to be used in another geographic location  after 50\u2013100\u2009mL human sewage filtration was performed with a ZR Fecal DNA MiniPrep kit . DNA concentrations were measured using a NanoDrop spectrophotometer .2.2PCR primers targeting universal and human-, swine-, and cattle-specific fecal markers were selected from both endpoint and quantitative PCR platforms . A 10-\u03bcL"}
+{"text": "Pure Sertoli cell tumours (SCTs) represent less than 1% of testicular neoplasms and malignant forms are rare. We present a unique case of a 69-year-old man who initially underwent inguinal orchidectomy for a malignant SCT. He then subsequently developed a paraumbilical cutaneous lesion which was histologically identical to the primary tumour. SCTs rarely metastasise. This is the first case of SCT with cutaneous metastasis described in the literature."}
+{"text": "The tumor suppressor p53 is a well-characterized transcription factor that can bind gene promoters and regulate target gene transcription in response to DNA damage. Recent studies, however, have revealed that p53 binding events occur predominantly within regulatory enhancer elements. The effect of p53 binding on enhancer function has not been systematically evaluated. Here, we perform a genome-scale analysis of enhancer activity from p53-bound sequences using a series of massively parallel reporter assays (MPRAs) coupled with the assay for transposase-accessible chromatin (ATAC-Seq). We find that the majority of sequences examined display p53-dependent enhancer activity during the DNA damage response. Furthermore, we observe that p53 is bound to enhancer elements in healthy fibroblasts and poised for rapid activation in response to DNA damage. Surprisingly, our analyses revealed that most p53-bound enhancers are located within regions of inaccessible chromatin. A large subset of these enhancers become accessible following DNA damage indicating that p53 regulates their activity, in part, by modulating chromatin accessibility. The recognition and activation of enhancer elements located within inaccessible chromatin may contribute to the ability of the p53 network to function across the diverse chromatin landscapes of different tissues and cell types. The tumor suppressor p53 is a master regulator of the DNA damage response and a central line of defense against genomic instability \u20136. FolloDrosophila uncovered an additional intergenic p53 binding site that functions as an enhancer element  and quantified the regulatory capacity of p53-bound sequences during the DNA damage response. Moreover, we have incorporated the use of the assay for transposase-accessible chromatin (ATAC-Seq) and profiled the regulatory activity of p53 binding sites in their endogenous genomic contexts. Collectively, these data demonstrate that p53 modulates the activity of hundreds of enhancer elements throughout the genome.In addition to confirming that many p53 binding sites function as enhancer elements during the DNA damage response, our analyses uncovered several previously unappreciated aspects of genome regulation by p53. We observe that p53 is bound to enhancers in healthy fibroblasts and is poised for rapid activation in response to DNA damage. Intriguingly, we find that most p53-bound enhancers reside within regions of inaccessible chromatin. The chromatin surrounding many of these enhancers becomes accessible in response to DNA damage indicating that p53 regulates their activity, in part, by modulating chromatin accessibility. Altogether, our results provide strong evidence that the regulation of enhancer accessibility and activity by p53 is an integral component of the p53 network.Human fetal fibroblasts GM06170 (Coriell Cell Repositories) were cultured in Dulbecco's Modified Eagle's Medium (DMEM) supplemented with 15% fetal bovine serum (Life Technologies). Fibroblasts were cultured with 500 nM doxorubicin for 6 h in MPRA experiments and 12 h in ATAC-Seq experiments to induce DNA damage.Lipofectamine 3000 (Life Technologies) was used to deliver MPRA plasmid pools into fibroblasts as per the manufacturer's instructions. Fibroblasts were plated in six-well dishes at a density of 50K cells/well. Fibroblasts were transfected with MPRA plasmid pools (1 \u03bcg/well) 24 h after plating. Culture medium was replaced 24 h after transfection with fresh medium containing 500 nM doxorubicin (Sigma) to induce DNA damage. Fibroblasts were harvested 6 h post-treatment for RNA and protein isolation.Cell pellets were lysed and protein concentrations were quantified by BCA assay (Pierce). Western blots were performed on protein lysates (30 \u03bcg/well). Primary antibodies used were \u03b1-p53  and \u03b1-GAPDH (Santa Cruz). Protein was visualized with horseradish peroxidase-conjugated protein A (Life Technologies) and Supersignal developing solution (Pierce).RNA from treated fibroblasts was isolated using TRIzol (Life Technologies) as per the manufacturer's instructions. For each sample, 2\u2009\u03bcg of RNA was reverse transcribed using SuperScript III Reverse Transcriptase (Life Technologies). RNA was treated with DNase I (Worthington) prior to reverse transcription. qPCR was performed on an ABI7900HT real-time PCR (Applied Biosystems) using FastStart Universal SYBR Green Master-Rox (Roche). Primers for TBP mRNA were supplied by Applied Biosystems. Primers for p21 were designed using Primer3. Only those primer sets that showed linear amplification over several orders of magnitude were used for quantification. Primers and PCR conditions are listed in ChIP experiments were performed as previously described . \u03b1-p53 (MPRA targeted sequencing libraries were generated directly from 50% of each cDNA reaction using PfuUltra II Fusion HS DNA polymerase (Agilent). Libraries were size-selected using Agencourt AMPure XP beads (Beckman Coulter). Prior to sequencing, the quality and concentration of each library was assessed using the Bioanalyzer (Agilent). Primers and PCR conditions are listed in MPRA targeted sequencing libraries were generated such that the first 10 bases of each read corresponded to the 10-base tag used to uniquely identify individual oligonucleotides in the MPRA library. Only those sequencing reads in which the first 10 bases matched perfectly to a tag in the MPRA library and the following 26 bases matched the expected MPRA reporter sequence were used for quantification. Expression driven by each variable sequence in the library was defined by the sum of the reads mapping to each of the 10 distinct tags corresponding to the respective variable sequence. Differential expression between untreated and doxorubicin-treated fibroblasts was assessed using DESeq2 . For anaN appeared at position i was normalized by the frequency at which base N appeared at position i. Activity contributions were rescaled such that the maximum calculated activity contribution was equal to 1.To determine the activity contribution of each nucleotide at each position within the variable region of the MPRA library, the sum of the activity (absolute fold-change in response to doxorubicin treatment) for each element in which base \u00b0C for 45 min. Transposed DNA was isolated using the MinElute PCR Purification Kit (Qiagen). ATAC-Seq libraries were generated from transposed DNA using NEBNext High-Fidelity 2X PCR Master Mix (NEB). Libraries were size-selected using Agencourt AMPure XP beads (Beckman Coulter). Prior to sequencing, the quality and concentration of each library was assessed using the Bioanalyzer (Agilent). Primers and PCR conditions are listed in Fibroblasts were treated with 500 nM doxorubicin for 12 h to induce DNA damage. Following treatment, \u223c100K cells were resuspended in transposition reaction mix  and incubated at 37ATAC-Seq reads were aligned to the human hg19) genome using Bowtie2 . Aligned genome uRNA sequencing reads were mapped to UCSC known genes and our previously described catalog of noncoding RNAs using TopHat2 with default options ,21. DiffP-values were corrected for multiple hypothesis testing using the Bonferroni method. Significance analysis of transcription factor binding site co-occurrence within pioneering sites was calculated using the hypergeometric distribution given the number of pioneering sites overlapped by each factor under comparison and the total number of pioneering sites in the genome. Resulting P-values were corrected for multiple hypothesis testing using the Bonferroni method.Enrichment of transcription factor (TF) binding within pioneering sites was calculated using the formula: enrichment = (s/S)/(g/G); where s = the number of TF peaks overlapping a pioneering site, S = the number of nucleotides covered by pioneering sites/the number of nucleotides covered by TF peaks, g = the number of TF peaks in the genome, and G = the number of nucleotides in the genome/the number of nucleotides covered by TF peaks. To calculate statistical significance of enrichment the labels of all TFs were randomly shuffled and the analysis was repeated 100 times. The resulting Human transcription factor binding sites were obtained through the transcription factor ChIP-Seq Clusters Version 3 track from the UCSC Genome Browser.To systematically evaluate the capacity of p53-bound sequences to function as regulatory enhancer elements during the DNA damage response we designed and performed a series of massively parallel reporter assays (MPRAs). The MPRA is a high-throughput sequencing-based method for simultaneously characterizing the regulatory potential for thousands of defined DNA sequences in a single experiment ,23. For For the MPRA oligonucleotide pool we designed 5,700 oligonucleotides with variable regions corresponding to the genomic sequences of 570 p53 binding sites throughout the human genome Figure . In paraTo determine which of the variable regions in the MPRA oligonucleotide pool can function as enhancer elements we designed an expression vector system in which the variable regions are placed immediately upstream of a reporter gene promoter . In this two-step cloning approach the oligonucleotide pool is first cloned into an empty (no reporter gene) plasmid backbone Figure . The resTo measure the regulatory activity of variable regions within the MPRA oligonucleotide pool during the DNA damage response the Promoter\u2013Proximal MPRA vector pool was transfected into GM06170 primary human fibroblasts. Transfected fibroblasts were then cultured in the presence of 500 nM doxorubicin for 6 hours to activate the p53 response to DNA damage. Treatment with doxorubicin resulted in a robust increase in the expression of p53 protein Figure . FurtherIn order to monitor expression levels from the Promoter-Proximal MPRA vector pool we next performed targeted RNA-Seq. We generated sequencing libraries by amplifying the region of the GFP reporter transcripts containing the unique barcode sequences. The representation of each barcode within the sequencing library provides a digital readout for the regulatory activity of the upstream genomic element. As a positive control we evaluated the regulatory activity of sequences within the MPRA pool corresponding to the p53 binding site within the p21 promoter. Treatment with doxorubicin resulted in a significant increase in expression from Promoter-Proximal MPRA vectors containing the endogenous sequence of this p53 binding site Figure . In contInterestingly, we observed that expression from Promoter-Proximal MPRA vectors containing the endogenous p21 promoter sequence was higher than their scrambled counterparts even in untreated fibroblasts Figure . This obWe next evaluated the expression from all of the sequences represented within the Promoter-Proximal MPRA vector pool. We found that the vast majority of sequences corresponding to p53 binding sites display increased regulatory activity in response to DNA damage Figure . This reTo further understand the sequence properties of p53-bound regions that drive regulatory activity we calculated the sequence activity contribution of each nucleotide in each position of the MPRA oligonucleotide pool. Our analysis identified the p53 recognition motif as the primary determinant of regulatory activity Figure . We searEnhancer elements can be separated from the genes that they regulate by varying genomic distances. To evaluate the ability of p53-bound sequences to function as enhancers when located more distant from transcription start sites we designed a Promoter\u2013Distal MPRA vector pool. In this design the MPRA oligonucleotide pool is cloned \u223c800 nt downstream of the transcription start site of a GFP reporter gene Figure . As a reThe Promoter-Distal MPRA vector pool was transfected into GM06170 primary human fibroblasts, which were subsequently cultured in the presence of 500 nM doxorubicin for 6 h to activate the p53 response to DNA damage. We then performed targeted RNA-Seq to monitor expression from the Promoter-Distal MPRA vectors. As a positive control for enhancer activity we again focused on sequences within the MPRA pool corresponding to the p53 binding site within the p21 promoter. Expression from Promoter\u2013Distal MPRA vectors containing the endogenous sequence of this p53 binding site was significantly increased in response to doxorubicin treatment, although not as robustly as with the Promoter\u2013Proximal MPRA Figure . PromoteWe next monitored the regulatory activity from all of the sequences represented within the Promoter\u2013Distal MPRA vector pool. We observed that most of the sequences corresponding to p53 binding sites display increased enhancer activity in response to DNA damage Figure . This inTo further understand how the distance between a p53-bound sequence and a reporter gene promoter affects enhancer activity we compared the results from the Promoter\u2013Proximal and Promoter\u2013Distal MPRAs. In general, we found that the magnitude of enhancer activation in response to doxorubicin treatment was less pronounced using the Promoter\u2013Distal MPRA approach Figure . HoweverHaving established that p53-bound sequences have the capacity to function as enhancer elements using MPRA enhancer screens, a transient reporter approach, we next characterized the regulatory potential of endogenous p53 binding sites using the assay for transposase-accessible chromatin using sequencing (ATAC-Seq). Briefly, ATAC-Seq utilizes transposon integration in live cells as a method for assaying chromatin accessibility . FollowiWe cultured GM06170 fibroblasts in the presence of 500 nM doxorubicin for 12 h to activate the p53 response to DNA damage and performed ATAC-Seq. Across three biological replicates we achieved an average sequencing depth of 42 million mapped reads per sample in untreated fibroblasts and 62 million mapped reads per sample in doxorubicin-treated fibroblasts. In addition, <10% of the mapped reads in each sample aligned to mitochondrial DNA, a common contaminant in many ATAC-Seq experiments. Our analyses identified three distinct classes of chromatin accessibility profiles surrounding p53 binding sites Figure . We founSurprisingly, we found that 62%  of p53 binding sites occur within regions of the genome that are inaccessible in both untreated and doxorubicin-treated fibroblasts Figure  and\u00a0B. TTo further understand how pioneering activity at p53 binding sites relates to pioneering activity across the genome we performed a global analysis of DNA damage-induced pioneering sites. We identified 8,219 regions in the genome that displayed clear signs of pioneering activity, 275 of which are bound by p53 Figure . BecauseTo characterize potential interactions between transcription factors bound to pioneering sites we next evaluated transcription factor binding site co-occurrence between all factors that are significantly enriched within pioneering sites. For 36 of the 37 factors analyzed we observed significant co-occurrence with two or more additional factors at pioneering sites Figure . AlthougTo confirm that p53 has the capacity to function as a pioneering factor we used existing ATAC-Seq datasets to profile changes in chromatin accessibility at p53 binding sites in IMR90 fibroblasts treated with nutlin . ImportaTo characterize the relationship between chromatin accessibility and regulatory activity in response to DNA damage we integrated our MPRA enhancer screens with ATAC-Seq profiles. Of the 570 genomic regions represented in our MPRA library 34 corresponded to regions of constitutively accessible chromatin, 445 corresponded to regions of constitutively inaccessible chromatin, and 91 corresponded to pioneering sites. An example of three proximal pioneering sites bound by p53 is shown in Figure We then compared chromatin accessibility profiles with the activity of endogenous p53 binding sites by evaluating expression changes for nearby genes in response to DNA damage. Specifically, we incorporated our previously described analysis of differential gene expression in response to treatment with doxorubicin and compared expression changes for genes with transcription start sites that occur within 2 kb (upstream or downstream) of p53 binding sites  13). Co. Co13). As an alternative method for monitoring endogenous enhancer activity we used existing datasets to profile enhancer RNA (eRNA) production at p53 binding sites. Briefly, eRNAs are noncoding RNA transcripts derived from enhancer elements and their expression is positively correlated with enhancer activity . A genomTo evaluate basal enhancer activity we compared eRNA expression levels in DMSO-treated cells at regions corresponding to p53 binding sites profiled in our study . We founOur previous analyses of both Promoter-Proximal and Promoter-Distal MPRA approaches, and more specifically at the p21 promoter, revealed that p53 is bound to response elements in untreated cells . To deteFinally, we used our MPRA enhancer screen data to compare the regulatory potential of p53 binding sites based on their endogenous chromatin accessibility profiles. We found that Promoter-Proximal MPRA vectors containing sequences located at pioneering sites display significantly greater induction in response to DNA damage than those containing sequences located within regions of constitutively accessible chromatin Figure . InteresThe regulation of gene expression by p53 has been studied extensively in the context of binding events that occur within gene promoters. Several recent studies, however, have found that p53 binding sites occur predominantly within regulatory enhancer elements ,13,14. TIn our MPRA enhancer screens we found that the vast majority of the genomic sequences that are bound by p53 display some level of enhancer induction in response to DNA damage. This enhancer activity is preserved regardless of the distance between the p53-bound sequence and the transcription start site of the reporter gene being regulated. While we did observe differences in the degree of enhancer activity between the many sequences we investigated, we were unable to identify any specific sequence features that explain these variations. In fact, the only distinguishable sequence property associated with enhancer activity during the DNA damage response was the presence of a p53 recognition motif. In the absence of a p53 recognition motif responsiveness to DNA damage was completely ablated, further demonstrating that p53 is the sole factor that modulates enhancer activity. Supporting our observations, an independent report published during the course of our study described the use of multiplexed reporter assays to profile enhancer activity from p53-bound regions and identified a large class of enhancers that are characterized by single p53 binding sites .Interestingly, our enhancer screen revealed that p53 is poised on response elements prior to the induction of DNA damage. We confirmed at two independent endogenous loci (one promoter and one enhancer) that p53 is indeed bound prior to the induction of DNA damage. Previous reports have shown that p53 binds to a specific subset of gene promoters and recruits components of the transcription initiation complex in healthy cells ,30,31. OWhile our MPRA enhancer screens succeeded in uncovering novel aspects of p53 biology, there were also some clear distinctions between the enhancer activities from MPRA expression vectors and endogenous p53-bound sequences. Specifically, we observed that many sequences in our MPRA oligonucleotide pool that exhibited significant enhancer induction in response to DNA damage actually corresponded to genomic regions located within constitutively inaccessible, thus inactive, chromatin. These differences demonstrate that the MPRA is a powerful tool for evaluating the functional potential of DNA sequences, but the actual regulatory capacity of an endogenous genomic sequence is ultimately dictated by the surrounding chromatin landscape. These are important considerations to take into account during the design and interpretation of MPRA-based approaches.Perhaps the most striking discovery in our study was that p53 appears to function as a pioneering factor, binding to response elements located within inaccessible chromatin and modulating changes in chromatin accessibility in response to DNA damage. In contrast to previous reports demonstrating that p53 can bind to genomic regions with high nucleosome occupancy in response to DNA damage, we observe that p53 is stably bound within inaccessible chromatin in healthy cells ,32. WhetWe propose that p53 is poised within inaccessible chromatin in an inactive state and that p53 activation  in response to DNA damage promotes chromatin remodeling Figure . In thisFinally, we present several lines of evidence demonstrating that p53 binding sites associated with pioneering activity comprise a highly potent class of p53-regulated enhancers. We find that genes located near p53-bound pioneering sites display significantly higher levels of induction in response to DNA damage as compared to genes near constitutively accessible or constitutively inaccessible binding sites. Furthermore, we observe significant increases in eRNA expression from p53-bound pioneering sites following p53 stabilization. Lastly, our MPRA screens revealed that the sequences of p53-bound pioneering sites display significantly greater enhancer activity during the DNA damage response as compared to the sequences of constitutively accessible p53 binding sites.The potent enhancer activity from p53-bound pioneering sites could not be attributed to the presence of binding sites for any specific regulatory co-factors or other sequence properties. Rather, we hypothesize that constitutively accessible genomic regions contain binding sites for a large array of regulatory factors and that p53 must compete with all of these factors to modulate enhancer activity. Conversely, sequences located within inaccessible chromatin are less likely to contain response elements for as many regulatory factors. Therefore, the elevated enhancer activity from sequences located within pioneering sites may result from the lack of regulatory competition with other factors as opposed to the presence of any single co-factor. This regulatory competition would also explain the overall variation in the enhancer activity we observed in our MPRA enhancer screens.In conclusion, our findings have shown that p53 binding sites throughout the genome can function as DNA damage-responsive enhancer elements. Moreover, we have uncovered a previously unappreciated role for p53 in the modulation of chromatin accessibility at enhancers during the DNA damage response. The ability to bind and activate regulatory elements located within inaccessible chromatin may explain how p53 can effectively mediate cellular stress responses across a wide variety of tissues and cell types that harbor diverse chromatin landscapes.The Gene Expression Omnibus accession number for the MPRA and ATAC-Seq data reported in this paper is GSE83780.Supplementary DataClick here for additional data file."}
+{"text": "A 38-year-old woman with a history of recurrent deep venous thromboses (DVTs) on chronic anticoagulation presented with acute left leg swelling. The patient was diagnosed with an acute left lower extremity (LLE) DVT in the setting of May-Thurner syndrome for which treatment with unfractionated heparin was started. Her hospital course was complicated by a new diagnosis of heparin-induced thrombocytopenia (HIT), with an incidental discovery of a large tricuspid valve mobile mass on a transthoracic echocardiogram (TTE). Subsequent imaging confirmed multiple right atrial thrombi along with LLE venous stent thrombosis and a new right LE acute DVT. Anticoagulation with argatroban for HIT thrombosis was started. She underwent a right atrial percutaneous thrombectomy and bilateral lower extremity thrombectomy with directed angioplasty and stent placement. This presentation is a rare manifestation of HIT with extensive intracardiac and deep venous thrombi, with successful staged interventions. HIT is an adverse immune reaction to heparin characterized by systemic platelet consumption and paradoxical thrombotic complications. HIT is mediated by immunoglobulins directed against platelet factor 4 (PF4) bound to heparin, which also activate platelets leading to thrombosis . The incA 38-year-old woman with a history of recurrent LLE DVTs in the setting of pregnancy and travel presented with new left leg swelling. She had a negative hypercoagulable workup and was previously treated with rivaroxaban. She had previous exposure to unfractionated heparin with no complications. Heparin infusion was started for her new LLE DVT. CT imaging revealed effacement of the left common iliac vein by the right common iliac artery suggestive of May-Thurner syndrome. Subsequent venogram revealed complete occlusion of the left external iliac vein and left common femoral vein for which thrombolysis with tissue plasminogen activator (tPA) was administered, followed by angiography with stent placement.\u03bcL to 133K/\u03bcL). Platelets continued to decline on heparin to a nadir of 52K/\u03bcL on hospital day 9  against PF4/heparin complexes is the pathophysiologic mechanism of greatest clinical concern . Platele\u03bcL when apixaban was started for lifelong anticoagulation given her risk for recurrent DVT. She received a loading dose of 10\u2009mg twice daily for 7 days, transitioned as an outpatient to a maintenance dose of 5\u2009mg twice daily. She remained without evidence of recurrent thrombosis at her 2-week and 3-month follow-ups.The use of novel oral anticoagulants (NOAC) in the management of HIT is an emerging subject of study. Clinical experience, though as yet limited, has shown good platelet count responses and tolerability in patients with HIT transitioned to NOAC, both directly after heparin discontinuation and after argatroban therapy , 9. Our This patient was incidentally found to have an anatomic predisposition to venous thrombi when CT revealed evidence of left common iliac vein compression against her fifth vertebral body by her right common iliac artery. This finding is suggestive of May-Thurner syndrome, a pathologic condition characterized by LLE venous insufficiency secondary to left iliac vein compression. As the compression is usually physiologic, May-Thurner syndrome is rarely considered during the workup of recurrent DVTs; indeed the syndrome presents as DVT in only 2-3% of cases . HoweverStudies suggest that endovascular correction of pathologic insufficiency via venous stenting may improve symptoms , 13. PreHIT is an important consideration in patients hospitalized for thrombotic events with the delayed onset of thrombocytopenia while on heparin therapy. Despite the onerous potential consequences of HIT in this patient with extensive thrombosis in the setting of an anatomical predisposition to DVT, her relatively young age and excellent baseline functional capacity facilitated successful staged endovascular management of both her intracardiac thrombi and her acute DVTs."}
+{"text": "In this video the Wright et al.  demonstrOn the flipside evidence from studying changes in the operated kidney using MAG3 renal scan also supports the notion that not every minute of ischemia counts and renal parenchyma preservation plays a more important role in renal function preservation if the warm ischemia time can be limited to less than 25-30 minutes . FurtherHomayoun Zargar, MDDepartment of UrologyRoyal Melbourne Hospital300 Grattan St, ParkvilleVIC 3050, Australiahomi.zargar@gmail.comE-mail:"}
+{"text": "We further showthat cells which have switched to [+PSI] haveimproved viability during chronological ageing which requires active autophagy.[+PSI] stains show increased autophagic fluxwhich correlates with increased viability and decreased levels of cellularprotein aggregation. Taken together, our data indicate that the frequency of[+PSI] prion formation increases duringyeast chronological ageing, and switching to the[+PSI] form can exert beneficial effects via thepromotion of autophagic flux.Ageing involves a time-dependent decline in a variety of intracellular mechanismsand is associated with cellular senescence. This can be exacerbated by priondiseases which can occur in a sporadic manner, predominantly during the laterstages of life. Prions are infectious, self-templating proteins responsible forseveral neurodegenerative diseases in mammals and several prion-forming proteinshave been found in yeast. We show here that the frequency of formation of theyeast [ Biological ageing involves a progressive decline in the ability of an organism tosurvive stress and disease. It is a complex process which is influenced by bothgenetic and environmental factors C) into a prion form (PrPsc) that is amyloidogenic.The amyloid form of the protein can subsequently convert other soluble moleculesinto the prion form thus resulting in the accumulation of the aberrant proteins inneuronal cells 6PSI+] and [PIN+], whichare formed from the Sup35 and Rnq1 proteins, respectively 9PSI+] is the altered conformation of the Sup35protein, which normally functions as a translation termination factor during proteinsynthesis. The de novo formation of[PSI+] is enhanced by the presence of the[PIN+] prion, which is the altered form of the Rnq1protein whose native protein function is unknown Prions are aberrant, infectious protein conformations which can self-replicate de novo [+PSI] prion formation14316We have previously shown that autophagy protects against Sup35 aggregation andPSI+] prion formation using the yeast CLS model andfound that the frequency of prion formation is increased during ageing. Furthermore,this frequency is elevated in an autophagy mutant suggesting that autophagy normallyacts to suppress age-dependent prion formation. We show that the prion-status ofcells influences CLS in an autophagy-dependent manner suggesting that prions can bebeneficial in aged populations of yeast cells.Yeast cells can survive for prolonged periods of time in culture and have been usedas a model of the chronological life span (CLS) of mammals, particularly for tissuescomposed of non-dividing populations 19+PSI] appearance during ageing. Cultureswere grown to stationary phase in liquid SCD media and prion formation measuredover time. [PSI+] prion formation was quantifiedusing the ade1-14 mutant allele which confers adenineauxotrophy and prions differentiated from nuclear gene mutations by theirirreversible elimination in guanidine hydrochloride (GdnHCl). The frequency ofde novo [PSI+] prion formationin a control[PIN+][-psi] straingrown to stationary phase was estimated to be 1.1 x 10-5 comparableto previously reported frequencies 12PSI+] prionformation in an atg1 autophagy mutant. Atg1 is aserine/threonine kinase which is responsible for the initiation of autophagy13PSI+] prionformation was further elevated in the atg1 mutant compared witha wild-type strain, suggesting that autophagy normally acts to suppress[PSI+] prion formation during ageing .We examined yeast CLS to determine whether there is an increased frequency of[PSI+] prion status of cells influenceslongevity. For this analysis, flow cytometry was used to monitor propidiumiodide uptake to assess yeast cell death PIN+][PSI+] strainshowed a modest increase in maximal lifespan compared with a[PIN+][psi-] strain. Additionally, cell death was lower in the[PIN+][PSI+] strainover the entire lifespan compared with the[PIN+][psi-] strainsuggesting that the [PSI+] prion improves viabilityduring ageing. To verify this difference in ageing between[PIN+][PSI+] and[PIN+][psi-]strains, viability was monitored using colony formation assays. Whilst lifespanmeasured using the colony forming assay was shorter compared with the propidiumiodide uptake assay, it confirmed that the [PSI+]strain maintained viability longer and had an increased lifespan compared withthe [psi-] strain .We next examined cell survival to determine whether the[PSI+] and all known prions. Curing the[PIN+][PSI+] strainwith GdnHCl dramatically decreased maximal lifespan to 10 days suggesting thatprions are beneficial during CLS . It should be noted however, thatGdnHCl treatment can also potentially affect Hsp10-related processes which areunrelated to prions. Autophagy is known to be required for chronologicallongevity and for example loss of ATG1 reduces CLS ATG1 reduced CLS in the 74D-694 yeast strain used for ourstudies . Interestingly, longevity was comparable in the[PIN+][PSI+],[PIN+][psi-] andcured strains indicating that active autophagy is required for prion-dependenteffects on longevity.Treating cells with GdnHCl blocks the propagation of most yeast prions byinhibiting the key ATPase activity of Hsp104, a molecular chaperone that isabsolutely required for yeast prion propagation 25+PSI]-prion status of cells affectsCLS in an autophagy-dependent manner, we examined whether autophagy is alteredin [+PSI] cells. We utilized a GFP-Atg8 fusionconstruct to follow the autophagy-dependent proteolytic liberation of GFP fromGFP-Atg8, which is indicative of autophagic flux PIN+][PSI+] straincompared with the[PIN+][psi-] andcured [pin-][psi-]strains indicative of increased autophagic flux . By day three, therewas also an increase in autophagic flux in the[PIN+][psi-] andcured [pin-][psi-]strains detected as an increase in free GFP. As expected, no autophagic activitywas observed for the atg1 knockout mutants. This suggests thatcells carrying the [+PSI] prion have increasedautophagic activity which may be beneficial during CLS.Given that the [PIN+][PSI+] strainaffects amorphous protein aggregation, which seemed likely given the previousstudies which have suggested that autophagy plays a role in the clearance ofmisfolded and aggregated proteins 16PIN+][PSI+] straincompared with the[PIN+][psi-] andcured [pin-][psi-]strains . This reduction in protein aggregation required autophagysince the levels of protein aggregation were comparable in theatg1-mutant version strains.We next examined whether the increased autophagic activity in the[de novo [+PSI] formation duringyeast chronological ageing, with the frequency of spontaneous formation increasedapproximately 40-fold in aged cells. Yeast has emerged as a powerful model toinvestigate the stochasticity of the ageing process and its contributing factors.The yeast CLS model more closely resembles the ageing of non-dividing cells such asneurons de novo formation of [+PSI] wasexacerbated in an atg1 mutant suggesting that autophagy normallyacts to suppress spontaneous prion formation during chronological ageing. Similarly,loss of autophagy has been found to cause neurodegenerative diseases in mice 16The majority of prion disease cases in humans occur in a sporadic manner,predominantly manifesting during later stages of life PSI+] prionconfers a beneficial advantage during yeast chronological ageing, which correlateswith enhanced autophagic flux. Given that the[PSI+]-status of cells improves viability during ageing,this may result in selection for [PSI+] in aged cells.Our data indicate that the presence of the [PSI+] prionacts to simulate autophagy which results in improved viability during ageing. Thereis previous evidence to suggest that the increased formation and accumulation ofprotein aggregates may exert a stimulatory effect on the autophagy pathway. Forexample, there is a correlation between the accumulation of PrPSC and theenhanced activity of quality control pathways including endoplasmic reticulumchaperones, the unfolded protein response and autophagy PSI+] strain, suggesting thatautophagy provides a beneficial effect during chronological ageing by removingpotentially harmful protein aggregates, including both amorphous and amyloid forms.Increasing autophagic flux would also presumably act to prevent further amyloidaggregation, potentially protecting against any negative impact of[PSI+] aggregation altering translation terminationefficiency.We found that that the presence of the [PSI+] prion causes a loss of function phenotypewhere translation termination activity is reduced due to the aggregation of thenormally soluble Sup35 protein PSI+] prion is thought to allow cells toreprogram gene expression such that new genetic traits become uncovered which mayaid survival during altered conditions 3132PSI+] prion can improve viability during ageing viamodulation of autophagic flux. It is unclear what triggers the increased frequencyof [PSI+] prion formation during ageing. One possibilityis oxidative stress, since ROS-induced protein aggregation and mitochondrialdysfunction is a common feature in age-related diseases 34PSI+] formation observed during chronologicalageing. Further research will be required to elucidate the exact signaling pathwaysand the range of quality control mechanisms that may be modulated through the directand indirect action of the [PSI+] prion during yeastageing.The [+PIN][PSI+],[+PIN][psi\u2212] and[-pin][psi\u2212]derivatives of the wild-type yeast strain 74D-694  were used for all experiments. Thestrain deleted for ATG1 (atg1::HIS3) has beendescribed previously  prion formation was scored by growth in theabsence of adenine as described previously PSI+] formation was calculatedbased on the mean of at least three independent biological repeatexperiments.[CLS experiments were performed according to Protein extracts were electrophoresed under reducing conditions on SDS-PAGEminigels and electroblotted onto PVDF membrane (Amersham Pharmacia Biotech).Bound antibody was visualised using WesternSure\u00ae Chemiluminescent Reagents(LI-COR) and a C-DiGit\u00ae Blot Scanner (LI-COR). Insoluble protein aggregates wereisolated as previously described 38"}
+{"text": "Five datasets were constructed from ligand and bioassay result data from the literature. These datasets include bioassay results from the Ames mutagenicity assay, Greenscreen GADD-45a-GFP assay, Syrian Hamster Embryo (SHE) assay, and 2 year rat carcinogenicity assay results. These datasets provide information about chemical mutagenicity, genotoxicity and carcinogenicity. Specifications TableValue of the data\u2022This article contains the largest public collection of ligands and results for the GreenScreen GADD\u03b1-45 and Syrian Hamster Embryonic Cell Transformation assays collated from previous literature to date.\u2022A benchmark dataset of pharmaceutically relevant ligands for use in rat carcinogenicity QSAR models is presented and compared with ligands from regulatory domains.\u2022Physiochemical descriptors were calculated from the SMILES structures and selected for QSAR model performance.1in vivo carcinogenicity datasets in this article are solely rat carcinogenicity outcomes due to previous literature finding the rat carcinogenicity bioassay produces better endpoint reliability in comparison to the mouse carcinogenicity bioassay. This article presents two rat carcinogenicity datasets from the regulatory toxicology and pharmaceutical safety chemical domains.The creation of a QSAR model for the 2-year rodent carcinogenicity bioassay is highly desirable since it is the gold standard for assessing potential chemical carcinogenicity. However, previous modelling efforts have been hampered due to data availability and reliability issues stemming from bioassay limitations such as low throughput, high cost, and modest reproducibility between laboratories and rodent species. The in vitro bioassays with larger libraries of screened molecules in comparison to in vivo rodent carcinogenicity bioassay data. QSAR models capable of utilizing this data in combination with rodent carcinogenicity data may address the limited applicability domain of the in vivo data. The data was exhaustively collated from the in vitro GreenScreen GADDin vivo rodent carcinogenicity outcomes. The Ames Bacterial Mutagenicity Benchmark Dataset has also been included for comparison.Genotoxicity occurs from chemicals acting with genomic mechanisms of toxicity and this has been associated with potential carcinogenicity. This endpoint type features many 22.1in vivo rat carcinogenicity from ISSCAN: 854 chemical database of in vivo rodent carcinogenicity results on pharmaceutical chemicals from PHARM: GreenScreen: 1415 GADD-45a-GFP assay results from Syrian Hamster Embryonic: Data on 1415 chemicals extracted from Ames: 6512 Ames results from 2.2SMILES structures were generated using ChemAxon JChem for Office from CAS Numbers or chemical names.These structures were curated using ChemAxon Standardizer to remove salts and solvents and aromatized.2.3The CfsSubsetEval algorithm 2.4knn-based distance The applicability domain of each dataset compared to the PHARM dataset was quantified using leverage, Euclidean distance from centroid, and a variable 2.5Attribute Importance Scores were calculated from each RandomForest QSAR model , Table 7"}
+{"text": "Mycobacteriumtuberculosis.We read this report with interest,The pulmonary nodules identified by CT chest in the index patient (case 1) may have cavitated as part of an immune reconstitution syndrome. It would be useful to know if any respiratory symptoms developed during the admission or subsequently; the timing of the original CT in relation to the immune reconstitution syndrome; if any additional chest imaging occurred; and if respiratory specimens were obtained for mycobacterial culture at any stage.,Patients with HIV infection may be sputum culture positive despite a normal chest x-ray.M. tuberculosis transmission during aerosol generating procedures, including the irrigation of abscesses.There have been previous reports of M. tuberculosis is probably from individuals with pulmonary disease not yet on effective treatment (largely undiagnosed).A better mechanistic understanding of which procedures are potentially aerosol generating might help guide practice. Ruling-out pulmonary disease is non-trivial, particularly in the context of HIV co-infection. Most transmission of DAB is funded through a Wellcome Trust PHD studentship grant ref 105165/Z/14/A.Conflict of interest: None declared."}
+{"text": "Objectives: Tourette Syndrome (TS) and Obsessive-Compulsive Disorders (OCD) share many clinical similarities and show a strong comorbidity. Current theories view a frontal-striatal dysfunction as the underlying cause of many clinical aspects of both disorders.This study sought to investigate mechanisms of conceptual integration and attention in both disorders. We hypothesized that the processing of stimuli with interfering aspects would be altered in a similar way while attentional mechanisms could differ.Methods: Event-related brain potentials (ERPs) were recorded in a modified STROOP-paradigm in groups of TS and OCD patients and in a control group. The paradigm involved the presentation of color words in a range of different colors. The subjects had to respond to words of matching word content and color and to ignore mismatching stimuli.Results: Incongruent stimuli elicited a frontal negative component (\u201cN450\u201d) which was enhanced in amplitude and prolonged in latency in both patient groups. Matching stimuli evoked enhanced N2 and P3b components representing target evaluation mechanisms. The OCD group alone displayed a larger P3b amplitude in comparison to both other groups.Conclusions: The data are interpreted to indicate that frontal inhibitory mechanisms are altered alike in TS and OCD. In contrast, only the OCD group showed evidence for aberrant target evaluation."}
+{"text": "Blood lactate concentration (BLC) is widely used to guide resuscitation in critically ill patients . MusculaAn adult patient presented with a total body surface area burn of 70% after a suicide attempt by self-immolation. A triple-lumen central venous catheter (CVC) with an integrated microdialysis function was placed in the left internal jugular vein. A second CVC was placed in the right femoral vein. Figure\u00a0To summarize, this case illustrates that continuous monitoring could allow sensitive detection of rapid and short-lasting changes in BLC after a 500-ml RL infusion. This could be used to assess lactate clearance. Further studies are needed to validate this concept."}
+{"text": "E. coli) followed by repeated rounds of nickel column affinity chromatography, failed to generate recombinant amelogenin at single band purity. This was because following an initial round of nickel column affinity chromatography, subsequent cleavage of the His-tag was not 100% efficient. A second round of nickel column affinity chromatography, used in attempts to separate the cleaved His-tag free recombinant from uncleaved His-tagged contaminants, was still unsatisfactory as cleaved recombinant amelogenin exhibited significant affinity for the nickel column. To solve this problem, we used preparative SDS PAGE to successfully purify cleaved recombinant amelogenins to single band purity on silver stained SDS PAGE. The resolving power of preparative SDS PAGE was such that His-tag based purification of recombinant amelogenin becomes redundant. We suggest that acetic acid extraction of recombinant amelogenin and subsequent purification using preparative SDS PAGE provides a simple route to highly purified His-tag free amelogenin for use in structure-function experiments and beyond.Recombinant protein technology provides an invaluable source of proteins for use in structure-function studies, as immunogens, and in the development of therapeutics. Recombinant proteins are typically engineered with \u201ctags\u201d that allow the protein to be purified from crude host cell extracts using affinity based chromatography techniques. Amelogenin is the principal component of the developing enamel matrix and a frequent focus for biomineralization researchers. Several groups have reported the successful production of recombinant amelogenins but the production of recombinant amelogenin free of any tags, and at single band purity on silver stained SDS PAGE is technically challenging. This is important, as rigorous structure-function research frequently demands a high degree of protein purity and fidelity of protein sequence. Our aim was to generate His-tagged recombinant amelogenin at single band purity on silver stained SDS PAGE for use in functionality studies after His-tag cleavage. An acetic acid extraction technique (previously reported to produce recombinant amelogenin at 95% purity directly from  Amelogenesis involves the incremental secretion of an extracellular protein matrix by ameloblasts. Amelogenin, present as a range of related molecules generated through extracellular proteolysis of several alternatively spliced gene products, comprises ~90% of the total extracellular protein matrix and is essential for normal enamel biomineralisation. Amelogenin mutations can lead to amelogenesis imperfecta (AI) in humans  mutation promotes intracellular amelogenin retention, stalls the secretory pathway, and triggers the UPR to switch into pro-apoptotic mode resulting in ameloblast death, thus classifying this case of AI as a conformational disease  on amelogenin aggregation/assembly and ameloblast secretory trafficking. Wild-type (WT) amelogenin begins to self-assemble during transit through the ameloblast secretory pathway  is via recombinant technology.E. coli based expression systems are the most widely used methodology for producing recombinant amelogenin even though post translational phosphorylation of serine 16 will be absent. Baculo virus . Once the cells reached an optical density of 0.6\u20131.2 recombinant protein expression was induced by adding isopropyl \u03b2-D-1-thiogalactopyranoside (IPTG). Induction of expression was confirmed by analytical SDS PAGE. After shaking overnight incubation at 37\u00b0C, the cells were harvested by centrifugation and amelogenin-enriched fractions obtained by extraction in acetic acid as previously reported  modified with a HRV 3C protease site in Rosetta DE3 Lyophilized crude extracts of recombinant amelogenin were dissolved in a minimum volume of nickel column binding buffer , loaded on to a nickel affinity chromatography column  up to a maximum protein load of 40 mg and eluted at a flow rate of 4 mL/min. Unbound proteins (column flow through) were collected. Bound recombinant amelogenin was eluted by increasing the imidazole concentration to 200 mM. The recombinant amelogenin was then buffer exchanged into 125 mM formic acid using size exclusion chromatography  and the fractions containing recombinant amelogenin collected and lyophilized. Fractions were analyzed by analytical SDS PAGE and anti-amelogenin Western blotting using rabbit IgGs raised against a peptide corresponding to the amelogenin hydrophilic C-terminal . The His-tag was removed enzymatically by adding recombinant restriction grade protease  at a concentration of 3 \u03bcL enzyme solution per mg recombinant protein. Cleavage was carried out over 20 h at 4\u00b0C. The resulting cleavage reaction mixture comprising cleaved recombinant, any uncleaved recombinant, free His-tag and other contaminants was finally buffer-exchanged into nickel column binding buffer by size exclusion chromatography ready for a second round of nickel affinity column chromatography.The lyophilized recombinant amelogenin, prepared as described above, was dissolved at 2 mg/mL in either 50 mM Tris-HCl, pH = 8 or 0.1 M NaA second round of His-tag cleavage was employed to remove cleaved His-tag and other contaminants present in the cleavage reaction mixture including any uncleaved recombinant. Cleavage products in binding buffer were loaded on to the nickel affinity column as described in the Section entitled Affinity Nickel Column Purification of His-Tagged Recombinant Amelogenins Extracted Using Acetic Acid. Unbound proteins (expected to contain the cleaved recombinant amelogenin) were collected in the column flow through. Bound proteins  were eluted using a stepped imidazole gradient  in order to optimize the separation. Fractions were analyzed by analytical SDS PAGE as described in the Section entitled Analytical SDS PAGE and Western Blotting.Analytical SDS PAGE was carried out based upon the method of Laemmli  except 2Following electrophoresis, proteins were detected using Coomassie Blue  or silver staining  or were transferred to nitrocellulose membranes  for Western blot analysis. After blocking and washing, the membrane was incubated with primary antibody  at a concentration of 5\u20137mg/1.5 mL. Preparative electrophoresis was carried out using a Model 491 Prep Cell . A 12% resolving gel was cast in the 28 mm internal diameter gel tube to a height of 9.5 cm with a 2 cm 4% stacking gel. The gel was run at a constant 12 W power at room temperature using the circulating cooling pump as recommended by the manufacturer. Once the tracker dye reached the bottom of the gel, 2.5 mL fractions were collected at a flow rate of 0.8 mL/min. Fractions of interest were identified by subjecting every third fraction to analytical SDS PAGE. All fractions of interest were then subjected to analytical SDS PAGE to accurately determine any fractions containing cleaved recombinant amelogenin at single band purity on silver staining.The methodologies described above are summarized in Figure E. coli both immediately after the addition of IPTG and 1 h post induction to determine the presence of any induced recombinant protein expression using analytical SDS PAGE and Coomassie Blue staining , free His-tag and the cleavage enzyme itself. Following analytical SDS PAGE, it was clear that that cleavage was only around 50% efficient at either pH 8 or 9 Figure . In an aGiven that a second round of nickel column purification failed to provide cleaved recombinant amelogenin at single band purity, we pursued an alternative strategy using preparative SDS PAGE. Fractions collected from preparative SDS PAGE were characterized using analytical SDS PAGE and silver staining Figure . Using tThe production of recombinant proteins is essential to the study of protein function and particularly in the case of amelogenins, which are difficult to purify from native tissue due to their aggregative behavior, multiplicity of isoforms and their degradation products and scarcity of material in the most commonly used animal models. In addition, without recourse to recombinant expression, it would be almost impossible to study the effects of specific mutations on amelogenin behavior.Despite much effort to obtain highly purified recombinant amelogenin using His-tag affinity chromatography we were unable to produce recombinant amelogenin of single band purity when analyzed by silver stained SDS PAGE. Apparent single band purity on SDS PAGE can be achieved by reducing sample load or by employing less sensitive gel staining techniques such as Coomassie Blue but this merely places any contaminants below the limit of stain detection. SDS PAGE is a standard technique for assessing degrees of protein heterogeneity in sample mixtures but additional analyses such as isoelectric focusing or mass spectroscopy would be needed to confirm absolute purity. With that caveat in mind, our goal was to produce recombinant amelogenin exhibiting single band purity on silver stained SDS PAGE gels. The challenges were twofold: (i) removing contaminating bacterial proteins and (ii) separating contaminating His-tagged recombinant amelogenin from His-tag-free recombinant amelogenin following His-tag cleavage, which is <100% efficient.E. coli at >95% purity in a single purification step  that are commonly co-purified when using immobilized metal affinity chromatography due to their metal chelating properties or clusters of exposed histidine residues  to a second round of nickel column affinity chromatography. In theory, the cleaved recombinant amelogenin should have little affinity for the column after removal of the His-tag ligand and would be easily collected in the flow through or at low imidazole concentration while the uncleaved recombinant amelogenin, free His-tag and HRV3C cleavage enzyme (which is itself His-tagged) would remain bound to the nickel column. However, cleaved recombinant amelogenin still exhibited significant affinity for the nickel column. This may be due to the high histidine content of amelogenin which includes a tri-histidine domain (Snead et al., To solve this problem we decided to employ preparative SDS PAGE rather than using nickel column affinity chromatography. This method was able to separate cleaved recombinant amelogenin from all contaminants to single band purity on analytical silver stained SDS PAGE. Substituting nickel column affinity purification with preparative SDS PAGE reduces the number of steps and leads to a much purer end product. Indeed, the excellent resolving power of preparative SDS PAGE, coupled with the acetic acid extraction technique makes the need for nickel column purification of His-tagged recombinant amelogenin redundant. We suggest that recombinant amelogenin without any His-tag could be purified to single band purity using preparative SDS PAGE Figure . In compThe preparative electrophoretic equipment employed here is not restricted to purifying proteins using SDS PAGE which separates proteins based on their molecular size. Separations can also be achieved using native PAGE buffer systems where proteins, in the absence of SDS, are separated based on their net charge which in turns depends on pH. The manufacturer's instructions provide a range of buffer formulations covering the pH range 3.8\u201310.2 which can be further adapted by the addition of chaotropic agents and uncharged detergents to aid protein solubility. Although, this additional flexibility is not required in the application reported here, it may prove useful if using preparative electrophoresis for other application such as purifying native enamel proteins extracted from developing enamel.SB, JK and CG made substantial contributions to the conception and analysis of data; drafted the paper and/or revised it critically for intellectual content; provided final approval of the version to be published; agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. CG acquired the data.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Angiomyolipoma is a well described but relatively uncommon benign renal neoplasm composed of varying admixtures of mature adipose tissue, smooth muscle, and thick-walled blood vessels.[1] The incidence of angiomyolipoma is about 0.3% overall.[2] It frequently occurs in patients with tuberous sclerosis. Even more uncommon is the simultaneous occurrence of angiomyolipoma and renal cell cancer in the same kidney in a patient without tuberous sclerosis."}
+{"text": "The recent elucidation of the mechanistic basis for transpersulfuration in the CsdA-CsdE model system has paved the way for a better understanding of its role under oxidative stress. Herein we present the crystal structure of the oxidized, inactivated CsdE dimer at 2.4 \u00c5 resolution. The structure sheds light into the activation of the Cys61 nucleophile on its way from a solvent-secluded position in free CsdE to a fully extended conformation in the persulfurated CsdA-CsdE complex. Molecular dynamics simulations of available CsdE structures allow to delineate the sequence of conformational changes underwent by CsdE and to pinpoint the key role played by the deprotonation of the Cys61 thiol. The low-energy subunit orientation in the disulfide-bridged CsdE dimer demonstrates the likely physiologic relevance of this oxidative dead-end form of CsdE, suggesting that CsdE could act as a redox sensor in vivo.Sulfur trafficking in living organisms relies on transpersulfuration reactions consisting in the enzyme-catalyzed transfer of S atoms  Escherichia coli comprises two large gene systems termed ISC (Iron-Sulfur Clusters) and SUF (Sulfur Mobilization) . Cys61 alpha carbon atom is shown as a yellow sphere.(MP4)Click here for additional data file.S8 Fig(PDF)Click here for additional data file.S9 Fig(PDF)Click here for additional data file."}
+{"text": "An 84-year-old female status post-Mohs micrographic surgery (MMS) presented to the emergency department (ED) for evaluation after a syncopal episode. Surgical excision of a scalp basal cell carcinoma occurred immediately prior to arrival . HemostaPoint-of-care cardiac ultrasound suggested acute air embolism with right heart strain as the cause of the patient\u2019s syncope. An air embolism is a rare but serious complication of any procedure that may involve venous or arterial vasculature. Air emboli in the setting of MMS has previously been cited in a dermatology case report.6To our knowledge, this is the first case within the ED setting to capture acute air emboli causing hemodynamic compromise on point-of-care ultrasound (POCUS). We placed the patient in reverse Trendelenburg while providing supplemental oxygen which lead to real-time clinical improvement with echocardiographic evidence . Compute6CPC-EM CapsuleWhat do we already know about this clinical entity?Acute air emboli may result in coronary or cerebral infarct, cardiovascular collapse and death without appropriate diagnosis and treatment.What is the major impact of image(s)?To our knowledge, these are the first ED ultrasound images to capture air emboli causing hemodynamic compromise as well as real-time clinical improvement with echocardiographic evidence.How might this improve emergency medicine practice?EM physicians must consider air embolus when approaching a hemodynamically unstable patient, particularly after procedures involving venous or arterial vasculature."}
+{"text": "A 23-year-old female was involved in a motor vehicle collision with multiple injuries, including a right acetabular fracture, but no pelvic fracture. Urology consultation was obtained due to difficulty placing a urethral catheter. Examination revealed a longitudinal urethral tear with vaginal laceration extending 2 cm from the urethral meatus proximally toward the bladder neck. The longitudinal urethral tear was repaired primarily. Traumatic female urethral injury in the absence of a pelvic fracture is an exceedingly rare occurrence."}
+{"text": "However, more evidence is necessary to in order verify the role of the NMDA receptor subunit NR1 and ROS in anesthetic-induced neurodegeneration.Prolonged exposure of developing mammals to general anesthetics affects the N-methyl-D-aspartate (NMDA)\u2013type glutamate or \u03b3-aminobutyric acid (GABA) receptor systems and enhances neuronal toxicity. Stimulation of immature neurons by NMDA antagonists or GABA agonists is thought to increase overall nervous system excitability and may contribute to abnormal neuronal cell death during development. Although the precise mechanisms by which NMDA antagonists or GABA agonists cause neuronal cell death are still not completely understood, up-regulation of the NMDA receptor subunit NR1 may be an initiative factor in neuronal cell death. It is increasingly apparent that mitochondria lie at the center of the cell death regulation process. Evidence for the role of oxidative stress in anesthetic-induced neurotoxicity has been generated in studies that apply oxidative stress blockers. Prevention of neuronal death by catalase and superoxide dismutase"}
+{"text": "The tractography showed absence of major crossing pathways within the pons and midbrain, and normal interhemispheric connections in the corpus callosum (A 13-year-old patient was referred for surgical treatment of scoliosis. Her neurological examination revealed the complete loss of horizontal eye movements with normal vertical gaze, suggesting diagnosis of horizontal gaze palsy and progressive scoliosis. The magnetic resonance imaging revealed a hypoplastic pons and medulla with a prominent midline cleft, therefore resulting in characteristic \u201cbutterfly\u201d configuration.callosum . Surgicacallosum .Horizontal gaze palsy with progressive scoliosis is a rare autosomal recessive disorder characterized by congenital absence of normal horizontal eye movements and progressive scoliosis during childhood and adolescence. Heterozygous mutations in ROBO3 are reported as a cause of this disorder."}
+{"text": "Polycomb-based repressive chromatin.The first genome-wide examination of the chromatin landscape at the periphery of the plant cell nucleus reveals substantial enrichment of heterochromatin and  Arabidopsis NUCLEOPORIN1 (NUP1) protein, an inner subunit of the nuclear pore complex (NPC) [The cell nucleus is a highly structured subcellular organelle that functionally houses the genome. The double-membrane nuclear envelope provides a physical interface that contributes to the compartmentalization of chromosomal domains that have distinct chromatin states and activities within the nuclear space. Our knowledge of chromatin organization and function in plant systems is rapidly expanding, and the roles of different nuclear peripheral components in structuring chromatin are also beginning to emerge . In metaex (NPC)  responsiArabidopsis cells, most heterochromatin typically aggregates around the centromeric and peri-centromeric regions, forming conspicuous subnuclear foci referred to as chromocenters which are thought to tether transposable elements (TEs) from distant genomic domains [Arabidopsis chromocenters are usually located near the nuclear periphery [Arabidopsis NPCs enhanced its expression [CAB (CHLOROPHYLL A/B-BINDING PROTEINS) genes are repositioned from the interior to the periphery of Arabidopsis cotyledon nuclei when induced by light signaling [In  domains   are frequently involved in long-range interactions between distant loci in plants [Arabidopsis chromosomes also form nucleolus-associated domains (NADs) that are enriched in transcribed ribosomal DNA genes and telomeric regions. Interestingly, NADs also contain heterochromatic TEs and silent protein-coding genes that might be sequestered in the nucleolus away from the RNA Pol II machinery (reviewed in [The integration of genome-wide ChIP-seq and Chromosome Conformation Capture 3C) approaches has recently extended linear epigenomic information on successive chromatin states towards a three-dimensional model of intra-chromosomal associations in n plants  and mammn plants . ArabidoC approacThe study by Bi and colleagues  offers aArabidopsis CAB genes [Polycomb-repressed genes (Fig.\u00a0Bi and colleagues also report that NUP1 RE-CHIP pulled down chromatin fragments that were enriched in acetylated histone H3 and other chromatin modifications characteristic of transcribed genes. The proximity between transcribed genes and NPCs might facilitate mRNA export via the so-called 'gene-gating process' proposed both for animal cells  and for nes Fig.\u00a0. DetermiArabidopsis. On the one hand, the association of transcriptionally active chromatin with NPCs can promote efficient mRNA surveillance and export [Polycomb-repressed silent regions at the nuclear periphery may provide an efficient way to organize or stabilize higher-order chromatin architecture. A potential contribution of H3K27me3-marked domains in tethering long-range euchromatin interactions around the nuclear periphery offers a novel and exciting working hypothesis for further investigations.The study by Bi and colleagues  adds to d export  while, oArabidopsis nuclei. PRC2 subnuclear foci are not exclusively enriched at the nuclear periphery, neither is RNA Polymerase II excluded from this area [A further question that is raised is whether there is a gradient of transcriptionally active chromatin domains from the interior to the periphery in his area , possiblhis area . This mohis area . AdditioArabidopsis to be extended, and uncover the molecular drivers of plant nuclear architecture diversity.Cell cycle and cellular responses to endogenous and environmental signals trigger dramatic changes in nuclear architecture whose functional impact on genome expression programs remains poorly understood. Future investigations of peripheral chromatin dynamics during cellular transitions thus offer exciting perspectives that can be used to unravel the functional plasticity of plant cell nuclear organization. Exploration of how plant lamina-like components and chromatin-bound factors mediate the anchoring of distinct chromosomal domains in plant species with diverse genomic and chromosomal arrangements should additionally allow the work of Bi and colleagues in"}
+{"text": "Mycobacterium avium subsp. paratuberculosis (Map) is a potential human pathogen known to be present in raw milk from infected dairy herds. Current pasteurisation regimes do not totally inactivate Map resulting in the possibility of viable cells being present in pasteurised milk used for Cheddar cheese production. A laboratory-based method, ensuring strict safety precautions, was developed to manufacture 800-g Cheddar blocks, experimentally contaminated (postpasteurisation) with two different strains of Map. The composition of the model Cheddar produced was consistent with commercial product. Syneresis of the cheese curd caused a 1 log10 concentration of Map numbers from milk to cheese for a strain isolated from pasteurised milk. The type strain NCTC 8578 did not show a similar concentration effect, but did however survive the Cheddar manufacturing process. A small percentage (<5%) of the Map load for each strain was recovered in the whey fraction during the process."}
+{"text": "This study aims to understand the relative roles of external forcing versus internal climate variability in causing the observed Barents Sea winter sea ice extent (SIE) decline since 1979. We identify major discrepancies in the spatial patterns of winter Northern Hemisphere sea ice concentration trends over the satellite period between observations and CMIP5 multi-model mean externally forced response. The CMIP5 externally forced decline in Barents Sea winter SIE is much weaker than that observed. Across CMIP5 ensemble members, March Barents Sea SIE trends have little correlation with global mean surface air temperature trends, but are strongly anti-correlated with trends in Atlantic heat transport across the Barents Sea Opening (BSO). Further comparison with control simulations from coupled climate models suggests that enhanced Atlantic heat transport across the BSO associated with regional internal variability may have played a leading role in the observed decline in winter Barents Sea SIE since 1979. The relative roles of external forcing versus internal variability in the Barents Sea winter sea ice decline since 1979 remain unconstrained. Here, the authors show that enhanced Atlantic heat transport into the Barents Sea associated with regional internal variability may have played a leading role. The decline of Arctic sea ice over the satellite period has often been attributed in large part to anthropogenic climate warming. Were the observed decline to continue at its recent rate, the Arctic would likely become nearly ice-free during summer within the next decade12Meanwhile, substantial multi-decadal/centennial variability of Arctic sea ice cover has been inferred from high-resolution multi-century algal proxy681014161318The Barents Sea is located on one of the main corridors of Atlantic inflow entering the Arctic. Strong coupling between winter Barents Sea SIE and the Atlantic heat transport into the Arctic through the Barents Sea Opening (BSO) are found in both observations and modelling studies1319202123In this study, we would like to address the following questions: What are the relative roles of changes in external radiative forcing versus internal variability in causing the observed winter Barents Sea SIE decline over the satellite period? Are there any substantial discrepancies between the observed and CMIP5-simulated externally forced response in winter NH sea ice decline, particularly given that the internal variability of Atlantic heat transport into the Arctic is largely removed in the CMIP5 multi-model ensemble mean forced response? The work presented here aims to provide insights on these questions by comparing observations with the CMIP5 multi-model ensemble simulations forced by changes in external radiative forcing as well as with long pre-industrial control simulations under constant radiative forcing. We show that the CMIP5 externally forced winter NH sea ice concentration (SIC) trend in individual regions  differs substantially from that observed. Our analysis suggests that enhanced Atlantic heat transport into the Barents Sea associated with regional internal variability may have played a leading role in the observed winter Barents Sea SIE decline since 1979.2 per 37 years) is weaker than that observed (\u22121.51 million km2 per 37 years), but still accounts for a substantial part (68%) of the observed declining trend. On the other hand, the observed March Barents Sea SIE declining trend is not well captured by the CMIP5 multi-model ensemble mean. Both the observed March Barents Sea SIE declining trend and anomalies often stay outside of the \u00b11 s.d. of the CMIP5 multi-model ensemble mean (2 per 37 years) is much weaker than that observed (\u22120.36 million km2 per 37 years), accounting for only a modest part (28%) of the observed declining trend.In this study, we included 79 ensemble members from 32 CMIP5 models (\u2018Methods' section), and the multi-model ensemble mean represents the response to changes in external radiative forcings in the models, as the internal variability in individual ensemble members tends to cancel out in the multi-model ensemble mean. The CMIP5 multi-model ensemble mean March NH SIE shows a gradual decline over the 37-year period from 1979 to 2015 due to changes in external radiative forcing . The obsble mean . The CMIDespite the weaker than observed declining trends in March NH and Barents Sea SIEs in the CMIP5 multi-model ensemble mean, the annual global mean SAT simulated by the CMIP5 multi-model ensemble mean displays a warming trend (0.86\u2009K per 37 years) stronger than that observed (0.51\u2009K per 37 years) . Both thWhy does the CMIP5 externally forced response account for a substantial part of the observed March NH SIE trend, but only a modest part of the observed March Barents Sea SIE trend ? We inter=\u22120.2) between annual global mean SAT trends and March Barents Sea SIE trends over the 37-year period across the CMIP5 ensemble members (BSO)  between the trends in annual mean net upward surface heat flux integrated over the Barents Sea region (FSFC) and trends in HTBSO, and strong anti-correlation (r=\u22120.64) between trends in FSFC and trends in March Barents Sea SIE, over the 37-year period across the CMIP5 ensemble members. Hence, an enhanced HTBSO leads to a reduced winter sea ice cover in the Barents Sea, and more net upward surface heat flux is released into the atmosphere through larger winter open water area in the Barents Sea2026SFC provide a negative feedback to changes in winter Barents Sea SIE. The positive correlation between HTBSO and FSFC trends and the negative correlation between FSFC and March Barents Sea SIE trends suggests that at multi-decadal time scales, changes in HTBSO are forcing changes in Barents Sea SIE and FSFC in the models, not the other way around. If the net upward surface heat flux (FSFC) were driving the winter Barents Sea SIE changes, one would expect a positive correlation between them , which is opposite to the behaviour simulated in the models.There is no significant anti-correlation  is thus too small to cause the observed decline in winter Barents Sea SIE  due to regional internal variability is necessary to explain the dramatic decrease of winter Barents Sea SIE seen in recent decades, in addition to the externally forced response. Here internal HTBSO changes could be affected both by local variability in surface winds through changes in volume transport across the BSO, as well as by remote variability in the large scale ocean circulation, such as AMOC, through changes in both volume transport across the BSO and ocean temperature of the Atlantic inflow.The CMIP5 multi-model ensemble mean forced response in HTter plot . This is Sea SIE . Based o Sea SIE , we estiBSO), we seek insights from long-term pre-industrial control simulations that are available from three coupled climate models . As discussed in the previous section, we estimate that an increase in HTBSO on the order of 30\u2009TW per 37 years due to regional internal variability is necessary to explain the dramatic decrease of winter Barents Sea SIE seen in recent decades. The simulated March Barents Sea SIC declines in response to a positive trend of HTBSO  in all three models due to internal variability , respectively. Even for GFDL CM3, only 38 out of all 3,564 available 37-year segments have such large HTBSO trends (\u2a7e30\u2009TW per 37 years), suggesting a rare occurrence. The implications are that either current climate models have unrealistically small amplitudes of low-frequency internal variability in HTBSO, or the recent observed decline of March Barents Sea SIE is a remarkably rare event. We speculate that it is more likely that models have unrealistically small amplitudes of low-frequency internal variability in HTBSO due to common systematic model deficiencies and mean state biases, rather than that the recent observed decline is a rare event. The underestimation of mean state HTBSO is implied from the simulated excessive mean state winter Barents Sea SIE  in CMIP5 models . It also exhibits a weak declining trend over a broader region in the NH, and thus opposite to the observed increasing trend in central Arctic. Hence, the CMIP5 externally forced response in March Barents Sea SIE exhibits a large discrepancy  compared to that observed, but the discrepancy is less severe in March NH SIE because the discrepancies in the spatial pattern are partially masked by summing over the entire NH. The large discrepancies in the spatial pattern of March NH SIC trends and in March Barents Sea SIE trend suggest that the observed winter NH sea ice trend over the satellite period cannot be well explained by the externally forced response alone, and that the observed rapid declining trend in winter Barents Sea SIE is not predominantly due to external radiative forcing.BSO) has played a key role in March Barents Sea SIE decline, while the warming in global mean SAT has been relatively unimportant for March Barents Sea SIE decline in individual CMIP5 ensemble members. We identify a significant high anti-correlation between winter Barents Sea SIE trends and HTBSO trends throughout individual CMIP5 ensemble members. This suggests that at multi-decadal time scales, changes in HTBSO are forcing changes in Barents Sea SIE and in net upward surface heat flux over the Barents Sea in these models. The CMIP5 externally forced HTBSO increase is too small to cause the observed decline in winter Barents Sea SIE. Based on CMIP5 results and observations, we estimate that a total 35\u2009TW per 37 years trend in HTBSO is needed to explain the observed winter Barents Sea SIE decline over the satellite period. Among this, an increase in HTBSO on the order of 30\u2009TW per 37 years due to regional internal variability is necessary to explain the majority of the observed winter Barents Sea SIE decline seen in recent decades and its discrepancies with the CMIP5 multi-model mean forced response. Results from long pre-industrial control simulations of three coupled models show that the simulated March Barents Sea SIC declines in response to a positive trend of HTBSO  are much larger than the CMIP5 multi-model ensemble mean forced response and are on the same order as that observed.Our analysis further suggests that an enhanced Atlantic heat transport across the BSO  from the National Snow and Ice Data Center (NSIDC)The observed global mean SAT is derived from the averaged SAT of three reanalysis data sets: NCEP/NCARBSO) using monthly mean ocean velocities and potential temperature (reference temperature being 0\u2009\u00b0C) from the selected CMIP5 ensemble members.To compare with the observations, we combined CMIP5 twentieth century all-forcing  simulations with CMIP5 representative concentration pathway (RCP) 4.5 future emission scenario simulations to cover the period from 1979 to 2015. The RCP4.5 pathway is chosen from among the four available future emission scenarios to represent the period after 2005, noting that these scenarios deviate little from each other during the short period 2006\u20132015. A total of 79 ensemble members from 32 CMIP5 models are selected, based on the criteria that all variables needed in our analyses are available in a selected ensemble member, and that the ensemble member has both historical and RCP4.5 simulations so that the they can be combined. Due to the large number of selected ensemble members, the multi-model ensemble means represent the response to changes in external radiative forcings in the models, as the internal variability in individual ensemble members tends to cancel out in the multi-model ensemble means. In this study, both observed and CMIP5-simulated anomalies are referenced to climatological means for 1979\u20132015. The correlation between March and November\u2013April averaged Barents Sea SIE trends over the 37-year period across CMIP5 ensemble members is 0.94, and the correlation between March and February\u2013April averaged Barents Sea SIE trends over the 37-year period across CMIP5 ensemble members is 0.99. These confirm that trends in March SIE are representative for trends in the winter SIE in this study. To study the oceanic impact on the Barents Sea winter SIE, we calculated the annual mean advective Atlantic heat transport across the BSO   Coupled Model version 2.1 (CM2.1)36BSO, 500 random samples of 37-year segments (same length as 1979\u20132015) are drawn from the control simulations, and the 500 pairs of 37-year trends in SIC and HTBSO are obtained for each model, respectively. Then SIC trends are regressed onto HTBSO trends for each grid point to obtain the spatial pattern of SIC changes associated with HTBSO changes due to simulated internal variability in each model.Additionally, long-term control simulations available from three coupled climate models under constant pre-industrial radiative forcing are employed to assess the impact of internal variability in HThttps://pcmdi.llnl.gov/search/cmip5. NSIDC sea ice satellite sea ice can be downloaded from http://nsidc.org/data/NSIDC-0051. NCEP/NCAR reanalysis data can be downloaded from http://www.esrl.noaa.gov/psd/data/gridded/data.ncep.reanalysis.html. Other data and code are available from the authors on request.All CMIP5 model output are available from How to cite this article: Li, D. et al. On the discrepancy between observed and CMIP5 multi-model simulated Barents Sea winter sea ice decline. Nat. Commun.8, 14991 doi: 10.1038/ncomms14991 (2017).Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations."}
+{"text": "Aspergillusflavus to displace aflatoxin-producers during crop development. The displacement results in lower aflatoxin concentrations in harvested grain. The current study evaluated in field performances of two atoxigenic strains of A. flavus endemic to Italy in artificially inoculated maize ears and in naturally contaminated maize. Co-inoculation of atoxigenic strains with aflatoxin producers resulted in highly significant reductions in aflatoxin concentrations (>90%) in both years only with atoxigenic strain A2085. The average percent reduction in aflatoxin B1 concentration in naturally contaminated maize fields was 92.3%, without significant differences in fumonisins between treated and control maize. The vegetative compatibility group of A2085 was the most frequently recovered A. flavus in both treated and control plots . A2085 was therefore selected as an active ingredient for biocontrol products and deposited under provisions of the Budapest Treaty in the Belgian Co-Ordinated Collections of Micro-Organisms (BCCM/MUCL) collection (accession MUCL54911). Further work on development of A2085 as a tool for preventing aflatoxin contamination in maize produced in Italy is ongoing with the commercial product named AF-X1\u2122.Since 2003, non-compliant aflatoxin concentrations have been detected in maize produced in Italy. The most successful worldwide experiments in aflatoxin prevention resulted from distribution of atoxigenic strains of  Data on aflatoxin B1 and percent reduction were ln and arcsin transformed, respectively, prior to analyses. Fields with aflatoxin B1 concentrations below 1 \u03bcg/kg in both treatments were not considered for the analyses. Aspergillus flavus populations in the maize flour are reported as log (10) transformed colony forming units (CFU)/g dry maize flour.Percent reduction in aflatoxin B"}
+{"text": "Heart failure (HF) is a condition characterized by increased filling pressures in the left ventricle due to altered cardiopulmonary blood flow. However, there are no clinically available non-invasive quantitative methods to measure filling pressures in HF. The pulmonary blood volume variation (PBVV) indexed to stroke volume (SV) by cardiac magnetic resonance (CMR) could be a novel non-invasive measure of HF. However, the relationship between PBVV/SV and increased filling pressures has not been validated. We have previously shown that the effect of increased filling pressures and redistribution of pulmonary blood flow can objectively be quantified using perfusion gradients derived from ventilation/perfusion single-photon emission computed tomography (V/P SPECT). V/P SPECT perfusion gradients have a high positive predictive value to diagnose decompensated HF.The aim of this study was therefore to investigate the relationship between the PBVV/SV and perfusion gradients in patients with heart failure.Fifteen patients with HF  were included. All patients underwent CMR at 1.5T and V/P SPECT. Four patients were under consideration for heart transplantation and 11 patients were candidates for cardiac resynchronization therapy. By measuring the blood flow in the pulmonary trunk and in one pulmonary vein, the PBVV was calculated, defined as the maximum cumulative difference in pulmonary blood volume over one heart beat. The SV by CMR was measured as the integral of the flow measurement over one heart beat in the pulmonary trunk. Dorso-ventral perfusion gradients (%-counts/cm) were automatically derived from V/P SPECT images using a user independent algorithm previously developed and validated in our department.There was a positive relationship between PBVV/SV and perfusion gradients Figure  suggestiPBVV/SV measured by CMR, as well as perfusion gradients by V/P SPECT have the potential to serve as non-invasive measures of HF. Further validation work with comparison to invasive pressure measurements are needed to assess the accuracy of the methods."}
+{"text": "Clinical scales to detect large vessel occlusion (LVO) may help to determine the optimal transport destination for patients with suspected acute ischemic stroke (AIS). The clinical benefit associated with improved diagnostic accuracy of these scales has not been quantified.We used a previously reported conditional model to estimate the probability of good outcome  for patients with AIS and unknown vessel status occurring in regions with greater proximity to a primary than to a comprehensive stroke center. Optimal rapid arterial occlusion evaluation (RACE) scale cutoff scores were calculated based on time-dependent effect-size estimates from recent randomized controlled trials. Probabilities of good outcome were compared between a triage strategy based on these cutoffs and a strategy based on a hypothetical perfect LVO detection tool with 100% diagnostic accuracy.In our model, the additional benefit of a perfect LVO detection tool as compared to optimal transport-time dependent RACE cutoff scores ranges from 0 to 5%. It is largest for patients with medium stroke symptom severity (RACE score 5) and in geographic environments with longer transfer time between the primary and comprehensive stroke center.Based on a probabilistic conditional model, the results of our simulation indicate that more accurate prehospital clinical LVO detections scales may be associated with only modest improvements in the expected probability of good outcome for patients with suspected acute ischemic stroke and unknown vessel status.The online version of this article (10.1186/s12883-018-1021-8) contains supplementary material, which is available to authorized users. Patients with acute ischemic stroke (AIS) due to large vessel occlusion (LVO) have better outcomes if they receive endovascular therapy (EVT) in addition to thrombolysis.  It is cuOur analysis is based on a probabilistic model built to estimate the probability of good outcome  for patients with AIS and unknown vessel status as a function of stroke severity, transport times to the nearest PSC and CSC, and transfer times between PSC and CSC. Details of the model have been published previously.  Briefly,Absolute probabilities of good outcome using a prehospital triage strategy based on optimal RACE cutoff scores are displayed in Fig.\u00a0p of LVO: ~\u200950%; corresponding binary Shannon entropy -p x log2 p \u2013 (1-p) x log2 (1-p): ~\u20091.00; Additional\u00a0file\u00a0We quantify the clinical benefit potentially achievable with improved prehospital LVO detection scales. Depending on stroke symptom severity, the geographic environment, and the location of stroke incidence relative to the surrounding stroke centers, the probability of good outcome increases by 0\u20135%. The largest difference is seen for medium severity strokes  the relatively large number of patients with mild stroke symptoms in an unselected sample who are less likely to have LVO and have a higher absolute probability of good outcome and b) the fact that the sensitivity of existing LVO detection scales is already high (85% for a RACE cutoff score\u2009\u2265\u20095). Availability of clinical scales with better discriminatory power would be nonetheless highly desirable. First, each falsely negative triage decision to a PSC may be associated with delayed access to EVT and permanent disability for an individual patient and should therefore be avoided. Second, from a societal perspective, a hypothetical scale with perfect accuracy would eliminate negative consequences of prehospital triage caused by low specificity and negative predictive value of currently available LVO detection scales, such as overburdening of CSCs with non-LVO infarcts, intracerebral hemorrhages and stroke mimics and deskilling and deprioritizing of PSCs due to lower patient volume. , 13The limitations of our model have been described previously.  Briefly,In conclusion, our results indicate that more accurate prehospital clinical LVO detections scales may be associated with only modest improvements in the expected probability of good outcome for patients with suspected acute ischemic stroke and unknown vessel status. Development of LVO detection scales with higher specificity could help to minimize the negative effects on patient distribution and resource use associated with currently available triage scales.Additional file 1:Panel A: Displayed are distributions of point-wise differences between the estimated probabilities of good outcome  associated with a prehospital triage strategy based on a hypothetical perfect large vessel occlusion (LVO) detection tool and the estimated probabilities of good outcome associated with a prehospital triage strategy based on optimal rapid arterial occlusion evaluation (RACE) scale cutoff scores, for different stroke severities and different transfer time settings . Panel B: Displayed are distributions of point-wise differences between the estimated probabilities of good outcome  associated with a prehospital triage strategy based on a hypothetical perfect LVO detection tool and the estimated probabilities of good outcome associated with a prehospital triage strategy based on a RACE cutoff score \u2265 5, for different stroke severities and different transfer time settings . Colors represent different treatment scenarios, with the possibility for treatment options defined by standard treatment time windows: symptom onset-tothrombolysis \u2013 270 min; symptom onset-to-groin puncture \u2013 360 min): I, both thrombolysis at the comprehensive stroke center (CSC) under the mothership approach and secondary transfer for endovascular therapy (EVT) under the drip and ship approach possible. II, thrombolysis at the CSC under the mothership approach not possible, secondary transfer for EVT under the drip and ship approach possible. III, thrombolysis at the CSC under the mothership approach possible, secondary transfer for EVT under the drip and ship approach not possible. IV, neither thrombolysis at the CSC under the mothership approach nor secondary transfer for EVT under the drip and ship approach possible. Horizontal lines indicate means. (TIFF 2376 kb)Incremental benefit of a hypothetical perfect large vessel occlusion detection scale according to treatment scenario I \u2013 IV. Additional file 2:-p x log2 p - (1-p) x log2 (1-p). Here, p denotes the probability of the presence of LVO among patients with ischemic stroke in a given RACE score category. Incremental benefits of a hypothetical perfect LVO tool correspond to average values in a geographic environment with a transfer time between PSC and CSC of 120 minutes. Labels indicate RACE score categories. (TIFF 1292 kb)Relationship between the uncertainty with regards to the presence of large vessel occlusion and the incremental benefit of a hypothetical perfect large vessel occlusion detection tool over optimal rapid arterial occlusion evaluation scale cutoff scores. Uncertainty with regards to the presence of large vessel occlusion (LVO) among patients with ischemic stroke in each rapid arterial occlusion evaluation (RACE) scale score category is quantified using the Shannon entropy"}
+{"text": "Treatment-resistant schizophrenia (TRS) is a major cause of disability and functional impairment worldwide. Approximately 30% of patients with schizophrenia will develop TRS at some point during their illness course. Despite the staggering financial and emotional costs associated with TRS, this severe disorder is poorly understood. The pathophysiological basis of TRS is posited in part to have neurodevelopmental roots. If early brain development (<2 years of age) influences TRS, then cortical gyrification, which is often complete by 2 years of life, could be abnormal in TRS when compared to non-TRS subjects. Subtle but diffuse pathological changes that occur during early development are postulated to disrupt the maturational relationship (covariance) among brain regions, even if no localised morphological changes are seen in adult life. The disrupted structural covariance resulting from diffuse developmental dyscoordination in early life can be quantified using gyrification-based connectomes obtained using graph theory. We applied this method to baseline MRI data collected during first contact with mental health services for psychosis to predict the emergence of TRS in the next 5 years.70 patients with first episode schizophrenia spectrum disorder who presented to mental health services between 2005 and 2010 were followed up for 5 years using electronic case notes. Psychopathology was assessed at baseline with the Positive and Negative Syndrome Scale (PANSS) and symptom dimensions were derived using Wallwork\u2019s model. TRS was defined according to Health and Clinical Excellence guidelines. Structural MRI images were obtained at baseline, with minimal exposure to antipsychotics (<3 months). Local gyrification indices were computed using Schaer\u2019s method for 68 contiguous cortical regions (34 in each hemisphere) using Freesurfer\u2019s Desikan atlas. After adjusting for age, gender and intracranial volume, group-based structural covariance was estimated (68x68 correlation indices) and each subject\u2019s contribution to the covariance was quantified using a jack-knife procedure, providing one distance matrix for each subject. These matrices were used to construct distance-based gyrification connectomes using Graph Analysis Toolbox. We used a functional data analysis approach across a range of cost-thresholds to reduce multiple testing when comparing TRS and non-TRS groups.17 (24.3%) of patients with first episode schizophrenia spectrum disorder met criteria for TRS at the end of the 5 years of follow up; 53 (75.7%) were non-TRS. TRS subjects had a significant reduction in small-worldness compared to non-TRS group  and reduced clustering coefficient  with increased path length .The positive symptoms were positively correlated  with higher small-worldness  suggesting that a predominantly hyperdopaminergic status that induces positive symptoms may relate to preserved small-worldness seen in non-TRS individuals, while subtle developmental changes resulting in reduced small-worldness may underlie TRS.These changes suggest that in the presence of TRS, the cortex-wide covariance in folding patterns become less organized, with reduced regional segregation as well as reduced overall integration of the morphological connectome. Such an effect may result from weakening of the tensions that arise from inter-regional connectivity in the neonatal brain. The emergence of TRS may be characterised by a neurodevelopmentally driven abnormality in structural organisation of the human cortex in those who develop schizophrenia."}
+{"text": "The TRT data consists of measured inlet and outlet temperatures, fluid flow and injected heat rate recorded every 10\u202fmin. The field dataset is made available to enable model verification studies.This data article comprises records from five Thermal Response Tests (TRT) of quadratic cross section pile heat exchangers. Pile heat exchangers, typically referred to as energy piles, consist of traditional foundation piles with embedded heat exchanger pipes. The data presented in this article are related to the research article entitled  Specifications TableValue of the data\u2022Each TRT is presented in an individual Excel sheet.\u2022These data can be used to validate thermal models of pile heat exchangers.\u2022There are not publicly available full-scale TRT datasets for pile heat exchangers.\u2022Sharing data will support the development of this type of ground heat exchangers.\u2022These data can supplement other data sets to assist the development of thermal dimensioning guidelines for pile heat exchanger foundations.1Dimensioning of Ground Source Heat Pump installations typically relies on thermal response testing (TRT) of one or more ground heat exchangers. The dataset of this article provides raw TRT data of several precast pile heat exchangers, described in 2During the TRT, the heat carrier fluid (water) is circulated in the ground heat exchanger while being continuously heated at a specified rate. Heat dissipates to the ground heat exchanger and subsequently to the ground. The test records fluid inlet- and outlet temperatures, the fluid flow rate and energy consumption and logs them in 10-min intervals for at least 48\u202fh.The shared data consists of five TRTs of square cross section precast pile heat exchangers. The five energy piles have different lengths and pipe configurations. The tests have been carried out at two different locations in Denmark.0 [\u00b0C], the average soil thermal conductivity \u03bbs [W/m/K] over the length of the heat exchanger and the thermal resistance the ground heat exchanger Rb [K\u202fm/W] Model interpretation of the measured TRT temperatures yield estimates of the undisturbed soil temperature T3], inlet temperature T1 [\u00b0C], outlet temperature T2 [\u00b0C], flow [l/h] and injection heat rate or effect [kW]. Notice the data is given from the closest in time to the most distant.The TRT sets are compiled in a single Excel file, separated in sheets named by the pile IDs (refer to Table 2 in The TRT equipment is produced by UBeG, Ref."}
+{"text": "This exhaustion, accompanied by increased cell surface expression of check point inhibitors was originally attributed to chronic TA-driven stimulation of CD8+ tumor infiltrating lymphocytes (TILs)[+ TILs, directed to antigens not present within the TME, contradicts this notion but rather points towards a different mechanism.At least in experimental animals the efficacy of active immunotherapy of cancer can be increased by metabolic reprogramming of tumor antigen (TA) specific CD8ycolysis . In a nues (TILs). Exhaust+ T cells that survive the harsh TME and are still present in advanced tumors have managed to switch from glucose to FA catabolism [T cells during activation in the periphery switch to glycolysis to meet their demand for energy and biomass production. Upon entering solid tumors they encounter an environment that is metabolically challenging and provides opposing cues. Lack of oxygen due to insufficient vessel formation in rapidly growing tumors increases signaling through the hypoxia-induced factor (HIF)-1a pathway, which promotes glycolysis. Glycolysis obviously requires consumption of glucose, which is commonly scarce in solid tumors, as it is also the cancer cells' preferred fuel. As a result, T cells conditioned towards glycolysis may starve within the TME. The interstitial fluid of solid tumors is commonly rich in fatty acids (FAs), which activate signaling through the peroxisome proliferator-activated receptor (PPAR)-\u03b1, a transcription factor that augments lipid metabolism. Indeed CD8tabolism .+ T cells within the TME during tumor progression suggests that many T cells are unable to make this crucial metabolic switch. Like in any war it helps to train the troops before sending them into battle. CD8+ T cells taught to gain energy through FAs rather than glucose before they enter the TME fare better that those that are untutored; their functions remain preserved and they are more effective at delaying tumor progression [The loss of activated CD8gression .There are many ways to change a cell's metabolism. Knockdown of HIF-1\u03b1 or other key factors of the glycolysis pathway reduces a cell's reliance on glucose. The same effect could be achieved by reinforcing PD-1 signaling, which through blockade of the Akt/mTor pathways decreases glycolysis and increases lipid catabolism. FAO can be enhanced directly through strengthening PPAR-\u03b1 signaling or genetically increasing the activity of rate-limiting steps of FAO, such as Carnitine Palmitoyltransferase (CPT 1), an enzyme that is essential to transfer long-chained FAs into mitochondria. Production of ketone bodies, which may provide crucial nutrients in hypoglycemic and hypoxic solid tumors, could be intensified by knock-in of 3-Hydroxy-3-Methylglutaryl-CoA Synthase (HMGCS) 2, the rate-limiting enzyme of ketogenesis.+ T cells stimulated in mice treated with fenofibrate are more efficacious at reducing tumor burden than those activated without the drug. Fenofibrate upon entering mitochondria reversibly inhibits complex I of the electron transfer chain[+ T cells and should thus be explored further (unpublished)*.Our efforts thus far have focused in fenofibrate , a PPAR-fer chain. In seru+ T cells to better prepare them for the hostile conditions of a TME. Treatment would need to be targeted to the unique metabolic conditions with different types of cancer.Recent years have shown tremendous progress in active immunotherapy of cancers through TA-specific vaccines, adoptiv"}
+{"text": "A 66-year-old woman presented with 4 years of progressive speech difficulty. She had nonfluent speech with phonemic errors but intact single-word comprehension and object knowledge. Her grammar was impaired in both speech and writing, and she exhibited orofacial apraxia. A clinico-radiologic see  diagnosi1 It is most frequently due to tau pathology, and clinicians should be alert to the potential development of progressive supranuclear palsy or corticobasal syndrome.2Nonfluent variant primary progressive aphasia is a neurodegenerative disease within the spectrum of frontotemporal dementia, characterized by the typical language and brain atrophy patterns seen here."}
+{"text": "Deviation in level of intrinsic neural activity  is observed in psychosis. Neurophysiological models have proposed this physiological indicator as a genetically mediated core deviation in psychosis. Translational models of intrinsic activity deviations promise to identifying multiple distinct physiological mechanisms for psychosis manifestation. Intrinsic activity deviations may masquerade as higher levels of neural response in sensory cortices, but ultimately may lead to poor signal-to-noise ratios, particularly when psychosis cases are required to identify stimulus salience.Why do we not hear more about intrinsic activity as a core biomarker for any psychosis variation? An explanation is provided by the current project. The Bipolar-Schizophrenia Network for Intermediate Phenotypes (B-SNIP) published a means for categorizing psychoses by neurobiological homology via use of multiple biomarkers (psychosis Biotypes) rather than by clinical features. B-SNIP demonstrated the superiority of Biotypes versus DSM diagnoses for capturing neurobiological similarity through multiple external validating measures . Independent analyses since the initial publication have provided additional support for the usefulness of psychosis Biotypes.For this project, we analyzed ongoing neural activity from 64 EEG sensors during 150 intervals of 10 sec duration from over 1450 B-SNIP subjects. These data (never before published) were from the inter-trial interval (ITI) of an auditory paired-stimuli task used in Biotypes construction (these ITI data themselves were not used). Although the subjects were engaged in a task (counting the number of stimulus pairs), the data used here were not part of the task itself. Data were evaluated for single trial power  as a function of frequency of neural oscillations (from 2\u201350 Hz) over the whole head. Data were then averaged over single trials to yield an estimate of the overall strength of nonspecific (unrelated to sensory processing) neural activity.When evaluated by DSM diagnoses , the 95% confidence intervals for all groups overlapped the healthy group means across all frequencies. When considered by psychosis Biotypes, differences were obvious and statistically significant. In comparison to healthy persons, Biotype-2 probands  were notably high on nonspecific neural activity, and Biotype-1 probands  were notably low. Group separations on this metric were better than those obtained with original intrinsic EEG measure used in psychosis Biotypes construction, indicating this more pure intrinsic activity measure is capturing a meaningful component of Biotype neurophysiology. This was true across a range of oscillatory frequencies for the probands. The first-degree relatives of the Biotype probands showed similar patterns, although higher frequency oscillations (above 20 Hz) better differentiated relatives from healthy persons.Intrinsic activity deviation is a promising biomarker for translational research programs aimed at differential treatment development, but using DSM psychosis diagnoses would obscure its importance for understanding psychosis."}
+{"text": "Candida albicans is a virulent human opportunistic pathogen. It evades innate immune surveillance by masking an immunogenic cell wall polysaccharide, \u03b2-glucan, from recognition by the immunoreceptor Dectin-1. Glucan unmasking by the antifungal drug caspofungin leads to changes in the nanostructure of glucan exposure accessible to Dectin-1. The physical mechanism that regulates glucan exposure is poorly understood, but it controls the nanobiology of fungal pathogen recognition. We created computational models to simulate hypothetical physical processes of unmasking glucan in a biologically realistic distribution of cell wall glucan fibrils. We tested the predicted glucan exposure nanostructural features arising from these models against experimentally measured values. A completely spatially random unmasking process, reflective of random environmental damage to the cell wall, cannot account for experimental observations of glucan unmasking. However, the introduction of partially edge biased unmasking processes, consistent with an unmasking contribution from active, local remodeling at glucan exposure sites, produces markedly more accurate predictions of experimentally observed glucan nanoexposures in untreated and caspofungin-treated yeast. These findings suggest a model of glucan unmasking wherein cell wall remodeling processes in the local nanoscale neighborhood of glucan exposure sites are an important contributor to the physical process of drug-induced glucan unmasking in C. albicans. Candida albicans is a normal commensal fungus living on various human mucosal surfaces. It is also an opportunistic pathogen that can cause superficial or systemic infections. Healthcare costs associated with treatment of candidiasis exceed $1 billion annually in the US alone . Given that, we chose to simply use the random unmasking model  in subsequent studies as it seemed to better mimic the experimental processes we expected might be present. The above values were calculated from n = 100 runs for each condition.(TIF)Click here for additional data file.S2 FigCellwall represents the 200 x 200 pixelated simulation space . Boundary collects the  boundary pixels of existing glucan exposure sites within the masked stripes. Masked keeps track of which pixels are available to be chosen, however, only those in non-fixed regions cover masked glucan and so can be exposed. The actual MATLAB algorithm was written in such a way that it can be run on multiple processors simultaneously.(DOCX)Click here for additional data file."}
+{"text": "Here, we presented new original data on the effects of iron depletion on the circulating lipid profile in B6HCV mice, a murine model of HCV-related dyslipidemia. Male adult B6HCV mice were subjected to non-invasive iron depletion by low iron diet. Serum iron concentration was assessed for evaluating the effects of the dietary iron depletion. Concentrations of circulating triglycerides, total cholesterol, Low Density Lipoproteins (LDLs), High Density Lipoproteins (HDLs) were analyzed and reported by using stacked line charts. The present data indicated that low serum iron concentration is associated to i) lower serum triglycerides concentrations and ii) increased circulating LDLs. The presented original data have not been published elsewhere. Specifications TableValue of the data\u2022The presented data indicated that low-iron diet i) reduced serum triglycerides concentrations and ii) increased levels of circulating LDLs in HCV transgenic mouse model. No differences have been found on cholesterol and HDLs concentrations in low iron feed mice respect to controls.\u2022These data are the further evidence on the interplay between the iron and lipid metabolism.\u2022The data in this article could be useful to optimize further clinical trials to evaluate the potential therapeutic effect of dietary iron depletion on dyslipidaemia in patients with Hepatitis C infection and hepatic iron overload.1Mice were fed a low-iron diet for thirty days and reduction in blood iron concentration was assessed by biochemical analysis . During 2To date, many evidences showed that iron overload plays a causal role in the hepatic fat accumulation. In particular, studies on HCV (hepatitis-C-virus) transgenic mice fed an excess-iron diet demonstrated that hepatic iron overload exacerbates the imbalance of lipid metabolism by both lipogenesis activation and reduced oxidation activity of fatty acids 32 asphyxiation and blood collected by post-mortem cardiac puncture. No animals became severely ill or died prior to the experimental endpoint. Euthanasia in mice was performed by carbon dioxide asphyxiation.B6HCV transgenic mice were from Markus Heim laboratory at Department of Biomedicine University Hospital of Basel t-test. The statistical significance of correlation was determined by the use of a simple regression analysis. A P value of 0.05 was considered to be significant.Blood biochemical analysis were performed on an automated hematology analyzer using mouse-specific algorithms and parameters (ProCyte DX IDEXX and Abaxis VetScan5). Total cholesterol was measured by the CHOD-PAP method adapted to automated analyzer (Chem 400), non-complexed HDL was measured using the CHOD-PAP method. For triglyceride determinations GPO-PAP method was used. Quantitative values are expressed as mean\u00b1SD . Data beMIUR Ministero dell\u2019Universit\u00e0 e Ricerca Scientifica .This work was supported by grants from"}
+{"text": "Atypical porcine pestivirus (APPV) was recently reported to be associated with neurologic disorders in newborn piglets. Investigations of 1,460 serum samples of apparently healthy pigs from different parts of Europe and Asia demonstrate a geographically wide distribution of genetically highly variable APPV and high APPV genome and antibody detection rates. Flaviviridae. The recently discovered atypical porcine pestivirus (APPV) is capable of inducing neurologic disorder in its host, like other pathogens of this family . Several recently published reports demonstrate that APPV is a prominent cause of virus-induced congenital tremor in pigs  3 encoding region and confirmed specificity of amplification by gel electrophoresis . Genome We used individual samples with high genome loads to generate amplicons in a seminested PCR and subsequently performed Sanger sequencing . We generated 20 different APPV NS3 sequences from apparently healthy pigs of all countries (sequences deposited into GenBank under accession nos. MF279213\u201332). Genetic differences reflect geographic origin to a low degree ; genetic,In addition to the NS3 fragments, we determined APPV complete coding sequences (CDS) from 1 sample from a healthy pig from China (deposited into GenBank under accession no. MF167292) and 2 samples (accession nos. MF167290 and MF167291) obtained from pigs during outbreaks of congenital tremors in Germany ,.rns antibody ELISA, as described (>60% of the animals showed intermediate to high reactivity in the antibody ELISA (We applied an indirect APPV Edy ELISA , which idy ELISA . We founOur findings indicate that the recently discovered APPV is abundant on several continents. APPV must be regarded as a pig pathogen of likely worldwide relevance.Additional information from genetic analysis of atypical porcine pestivirus in animals from Europe and Asia"}
+{"text": "Intracranial arteriovenous malformations can be further complicated by the development of aneurysms, which themselves carry the\u00a0risk of rupture and hemorrhage. New endovascular techniques allow for more treatment options for these lesions in the setting of arteriovenous malformations. Here we present the case of a patient who developed an aneurysm in the setting of an arteriovenous malformation and subsequently underwent successful endovascular treatment via percutaneous access of the vertebral artery along with reviewing the literature on further treatment options and developments. Intracranial arteriovenous malformations (AVMs) are rare vascular lesions associated with a risk of hemorrhage of up to 4% per year . AVMs caA 63-year-old female with no significant past medical history presented to our facility with headache and neck stiffness. The headache progressed to being the most severe pain she had ever experienced. She was also mildly lethargic but did not exhibit any focal deficits. She denied history of trauma or use of aspirin or blood thinners. Initial brain computerized tomography (CT) demonstrated evidence of scattered subarachnoid hemorrhage and diffuse cerebral edema which was most prevalent within the posterior fossa. Subsequent brain magnetic resonance imaging (MRI) with and without contrast demonstrated persistent right superior cerebellar hemisphere subarachnoid hemorrhage with associated stable parenchymal hematoma and evidence of a distal flow-related right superior cerebellar artery aneurysm secondary to an underlying posterior fossa AVM. Cerebral angiography showed two ruptured flow-related aneurysms on an enlarged branch of the right superior cerebellar artery associated with a small tectal AVM Figure .However, initial attempts at endovascular treatment were unsuccessful due to profound tortuosity of the\u00a0left vertebral artery, which was the only potential transfemoral or transradial access to the flow-related aneurysm Figure .Given the marked tortuosity of the vessels, the patient underwent treatment of the flow-related aneurysms beginning with percutaneous access of the vertebral artery at the C1 level, obtained using roadmap guidance from selective catheterization of the ostia of the left vertebral artery Figure\u00a0.Using a standard microcatheter system over a microcatheter guidewire, a super-selective catheterization of the two flow-related aneurysms was performed Figure .Multiple detachable platinum coils were then deposited into the aneurysmal branch resulting in occlusion of the vessel. Final control angiography revealed marked stasis in the two flow-related aneurysms well into the venous phase suggesting that they will rapidly thrombose Figure .The patient subsequently underwent surgical resection of the AVM and made complete neurological recovery. Repeat angiographic evaluation at six months showed no evidence of vascular abnormality Figure .The incidence of AVM-associated aneurysms has been reported in the literature ranging from 2.7 to 58% with a prevalence of 10-20% being cited in the largest case series -5. It isAVM-associated aneurysms are a rare but dangerous complication of AVMs. The emergence of new endovascular techniques has allowed for broader management of\u00a0AVM-associated aneurysms. Prompt treatment is necessary to prevent aneurysmal rupture, hemorrhage, and fatality. The patient we presented underwent successful endovascular treatment for an AVM-associated\u00a0aneurysm using a novel approach. It is important for physicians\u00a0to recognize and\u00a0treat AVM-associated aneurysms promptly while taking into account the unique neurovascular anatomy for each patient in order to avoid potentially\u00a0dangerous complications."}
+{"text": "To assess accuracy and precision of the positron emission tomography-computed tomography (PET-CT) carotid standardized uptake values (SUV) of 18F\u2013fluorodeoxyglucose (18FDG) as an inflammatory biomarker for determining cerebrovascular diseases such as stroke, methodology and statistical issues should be taken into account. Otherwise, misleading messages will be the main outcome of such research. Briefly, confusing accuracy and precision will mainly produce misleading messages.18F\u2013fluorodeoxyglucose (18FDG) have been proposed as an inflammatory biomarker for determining cerebrovascular diseases such as stroke. Consideration of varying methodological approaches and software packages is critical to the calculation of accurate SUVs in cross-sectional and longitudinal patient studies. They aimed to investigate whether or not carotid atherosclerotic plaque SUVs are consistent and reproducible between software packages [18FDG-PET SUVs of carotids were taken in 101 patients using two different software packages [n\u00a0=\u00a023) of the ROI locations, the differences between the SUV measurements from each software package were found to be statistically significant. They highlighted the importance of standardizing all aspects of methodological approaches to ensure accuracy and reproducibility.I was interested to read the paper by Giannotti N and colleagues published in the Dec 2017 issue of EJNMMI Res [However, reproducibility  and accuracy  are two completely different methodological issues \u20138. The m"}
+{"text": "Carcinosarcomas are rare tumours containing both malignant mesenchymal and epithelial elements. This reports presents a 70-year-old man with carcinosarcoma of the urinary bladder, which is proven histologically."}
+{"text": "A 61-year-old alcoholic man presented to the emergency department because of vomiting and dyspnea after discharged from hospital due to appendectomy two days ago. He smoked heavily and his past medical history revealed gastritis. On the examination, he was hypotension (50/00 mmHg) and lethargy. Cardiopulmonary resuscitation was initiated aggressively. His chest x-ray showed right-sided tension pneumothorax (A). Chest drainage tube was inserted immediately and his clinical status improved spectacularly. On the fifth hospital day, the presence of food particles  (red arrows) in the chest tube was found accidentally (B). Suspecting for esophageal perforation, the oral methylene blue test showed that the fluid in the chest tube turned bluish (C). Boerhaave's syndrome was established. An operation undertaken revealed a perforation of lower esophagus which was marked with nasogastric tube (yellow arrow) (D). However, his condition became worsen with nosocomial infection and died after that. The contents in the chest tube which can be an important diagnostic clue should be checked closely in the clinical practice."}
+{"text": "With significant improvements in percutaneous coronary intervention (PCI) technology, complex high risk PCI is increasingly offered to patients with limited revascularization options. Percutaneous mechanical circulatory support devices are often utilized for hemodynamic support during these complex procedures. Veno-arterial extracorporeal membrane oxygenation (ECMO) allows full hemodynamic support and provides systemic oxygenation. We describe a case of left main bifurcation stenting performed at our center with ECMO support in an awake patient without general anesthesia.\u00a0 Significant improvements in percutaneous coronary intervention (PCI) technology has led to complex high-risk PCI being offered to patients with limited revascularization options. Percutaneous mechanical circulatory support (MCS) devices, including veno-arterial extracorporeal membrane oxygenation (VA-ECMO), are often utilized for hemodynamic support during these complex procedures. VA-ECMO provides cardiopulmonary support and is comprised of a venous cannula to drain the deoxygenated blood, centrifugal nonpulsatile pump, membrane for gas exchange and an arterial cannula to return the oxygenated blood to the body . This alThe definition of high-risk PCI is currently evolving. Patient, lesion and clinical presentation risk factors need to be considered when making the decision about need for percutaneous hemodynamic support . CommonlA 54-year old male with a history of ischemic heart disease and hypertension presented with an acute coronary syndrome (ACS). Coronary angiography demonstrated a left dominant system with a 90% stenosis in the distal left main (LM) extending into the left circumflex (Cx) and left anterior descending (LAD) arteries, in addition to a previously documented 100% mid-LAD occlusion Figure , 1B. LefThe patient was lightly sedated with midazolam and fentanyl. PCI was performed via the right femoral artery using a 7F sheath. ECMO cannulation Figure  was via \u00a0With significant improvements in PCI technology, complex high-risk PCI is increasingly offered to patients with limited revascularization options. Percutaneous MCS devices are often utilized for hemodynamic support during these complex procedures.IABP is the most common type of MCS used during PCI, mainly due to its ease of use. A single double lumen catheter with a balloon at the end is inserted and attached to a pump. Helium inflates the balloon at the beginning of diastole. IABP increases diastolic blood pressure and coronary artery perfusion\u00a0decreases afterload and myocardial oxygen consumption and may increase cardiac output slightly . AdvantaAnother type of MCS is the Impella , which is a device placed across the aortic valve. When optimally positioned, it propels blood from the LV to the aorta. The Impella decreases end-diastolic wall stress while increasing diastolic compliance as well as aortic and intracoronary pressures and coronary flow velocity reserve .\u00a0 AdvantWhile traditionally, IABP and Impella are used, the former might not provide adequate hemodynamic support  and the Percutaneous mechanical circulatory support devices, including awake VA-ECMO, can be safely performed in appropriate cases of high-risk PCI."}
+{"text": "A feared complication of ventricular access for drainage or shunting is ventriculitis. Early diagnosis and treatment is vital to prevent morbidity and mortality. Efficacy of directed antibiotic therapy in ventriculitis is limited by increasing multidrug resistant microorganisms and insufficient systemic antibiotic absorption into the cerebrospinal fluid. Treatment may involve intravenous and/or intrathecal antibiotics as well as external ventricular drainage.We present the first case report suggesting a potential role of a novel technique \u2013 direct ventricular catheter-mediated continuous saline irrigation and serial prone patient positioning \u2013 to treat a fulminant bacterial ventriculitis. This novel technique promotes egress of purulence from the ventricles and may result in more rapid control of intraventricular infectious burden. Ventriculitis is a feared complication associated with cerebrospinal fluid (CSF) diversion and invasive intracranial pressure monitoring . A largeFirst-line empiric treatment for ventriculitis includes a third generation cephalosporin in addition to vancomycin . UnfortuHerein, we report the case of 48-year-old man with hydrocephalus and a history of numerous ventriculoperitoneal shunt (VPS) placements and revisions. He developed ventriculitis after undergoing VPS placement and required removal of the VPS and placement of temporary CSF diversion. We present a novel technique of catheter-mediated direct continuous saline irrigation into the ventricle paired with intrathecal antibiotic administration and serial prone positioning to promote ventricular drainage.The patient is a 48-year-old man who presented with recurrent, worsening symptoms of hydrocephalus following failed endoscopic third ventriculostomy. He subsequently underwent placement of a right frontal VPS. On post-operative day 4, the patient developed a high fever and altered mental status and underwent a shunt tap revealing grossly purulent fluid Figure . UltimatAt this time, we provided a novel treatment strategy for the patient that involved the following:1. Placement of bilateral  EVDs.2. Preservative-free normal saline was instilled in the right frontal EVD at 20 cc/hr with the left frontal EVD left open at 2 cm H2O.3.\u00a0Intraventricular gentamicin 8 mg daily was administered with both EVDs clamped for one hour after administration of the gentamicin.4. Gentamicin to be administered intrathecally daily until three to five days after culture clearance.5. Serial prone positioning for 30 minutes every three hours was carried out.6. Care was taken to pad all pressure points well and a standard face cushion was applied which was identical to the cushion utilized in prone positioned cases in the operating room.At the outset of therapy, a computed tomography (CT) scan of the brain was obtained  so the bilateral EVD were removed and a new shunt was implanted on Day 14. IV ceftriaxone was ultimately continued for a total of 21 days. The patient had no untoward effects from his bilateral EVD placement, intrathecal antibiotic administration, or serial prone positioning.Bacterial ventriculitis is linked to significant morbidity and mortality following shunt surgery. Rapid drainage of purulent material may be beneficial in curtailing inflammation. Indeed, insufficient drainage may raise intracranial pressure and exacerbate intracranial infection . This isThere have been previous reports of intraventricular irrigation utilized to treat ventriculitis. A case report by Wada, et al. in 2000 reported a\u00a0successful use of multiple intraventricular lavages for the\u00a0treatment of post-traumatic ventriculitis in a 44-year-old male following traumatic brain injury . In addiThis is the first report of the use of intraventricular catheter-mediated continuous saline irrigation paired with intraventricular antibiotic administration and serial prone patient positioning in the treatment of ventriculitis. Our case report demonstrates the safety and efficacy of this technique."}
+{"text": "TSC2. A number of androgen-regulated genes generate alternatively spliced mRNA isoforms, including a prostate-specific splice isoform of ST6GALNAC1 mRNA. ST6GALNAC1 encodes a sialyltransferase that catalyses the synthesis of the cancer-associated sTn antigen important for cell mobility. Genetic rearrangements occurring early in prostate cancer development place ERG oncogene expression under the control of the androgen-regulated TMPRSS2 promoter to hijack cell behaviour. This TMPRSS2\u2013ERG fusion gene shows different patterns of alternative splicing in invasive versus localised prostate cancer. Alternative AR mRNA isoforms play a key role in the generation of prostate cancer drug resistance, by providing a mechanism through which prostate cancer cells can grow in limited serum androgen concentrations. A number of splicing regulator proteins change expression patterns in prostate cancer and may help drive key stages of disease progression. Up-regulation of SRRM4 establishes neuronal splicing patterns in neuroendocrine prostate cancer. The splicing regulators Sam68 and Tra2\u03b2 increase expression in prostate cancer. The SR protein kinase SRPK1 that modulates the activity of SR proteins is up-regulated in prostate cancer and has already given encouraging results as a potential therapeutic target in mouse models.Changes in mRNA splice patterns have been associated with key pathological mechanisms in prostate cancer progression. The androgen receptor (abbreviated AR) transcription factor is a major driver of prostate cancer pathology and activated by androgen steroid hormones. Selection of alternative promoters by the activated AR can critically alter gene function by switching mRNA isoform production, including creating a pro-oncogenic isoform of the normally tumour suppressor\u00a0gene  Alternative mRNA isoforms have important roles in normal development and physiology. Almost every human gene produces more than one mRNA isoform, vastly expanding the information content of the human genome  and alternative utilisation of both 5\u2032 and 3\u2032 splice sites to insert exons of different sizes. Alternative mRNA isoforms can also be generated by the selection of different promoters and different polyadenylation sites. Each of these pathways produces mRNA splice variants that can impact on prostate cancer development or response to treatment . The prostate is a small gland located just below the bladder that produces seminal fluid components. Prostate cancers typically do not cause symptoms, but in some more advanced stages can block urine flow from the bladder, invade the adjacent seminal vesicles and metastasise more distantly to bone. Primary prostate cancer leads to a breakdown in the normal glandular structure of the prostate gland. Prostate cancer is classified histologically by morphological features using the Gleason scoring system  and one in the NDUFV3 gene that encodes a mitochondrial respiratory protein (this NDUFV3 exon was repressed by androgens). Although these ZNF121 and NDUFV3 exons changed splicing in response to androgens, their clinical importance is not known, nor if these genes are direct targets for the AR. However, this same study also identified a number of androgen-dependent mRNAs made from alternative promoters, including an alternative mRNA isoform of the normally tumour suppressor TSC2 (Tuberous Sclerosis 2) gene that is transcribed from an internal promoter (so only contains downstream TSC2 exons). The well-characterised full-length TSC2 protein represses cell growth via the mTOR pathway. The androgen-driven alternative TSC2 mRNA isoform encodes a shorter  TSC2 protein that promotes rather than represses cell growth  antigen  of the ST6GALNAC1 mRNA in the prostate. The presence of this extra exon causes an alternative start codon to be utilised, resulting in the shorter version of the ST6GalNac1 protein  are associated with more advanced forms of prostate cancer progression. ERG is a proto-oncogene that plays a key role in the pathology of prostate cancer. ERG encodes a transcription factor that controls the expression of many genes during normal development  and epithelial\u2013mesenchymal transitions (EMT) crucial for prostate cancer cell metastasis  encodes an in-frame peptide sequence. Inclusion of this 72-nucleotide exon might affect the interactions of the encoded ERG protein with transcription factors and other nuclear proteins, since it is immediately adjacent to the region of the ETS gene that encodes a protein\u2013protein interaction domain called the sterile alpha motif (SAM)/pointed domain (http://pfam.xfam.org/family/SAM_PNT).The The primary therapeutic strategy for advanced prostate cancer treatment is to block androgen signalling through androgen deprivation therapy or AR blockade, thereby halting tumour progression. Abiraterone is a drug that inhibits androgen biosynthesis and so reduces the levels of androgens within prostate cancer cells. Enzalutamide is a drug that antagonises the interaction of androgens with AR protein. Although prostate tumours initially respond to androgen deprivation therapy, later stages of the disease can develop into a treatment-resistant form of the disease called castration-resistant prostate cancer. Mechanisms of prostate cancer cell resistance cross over, so a prostate cancer cell developing resistance to enzalutamide will also show a reduced (~20%) response to abiraterone, and vice versa  that lack ligand-binding domains, frequently as a result of splicing inclusion of cryptic exons (abbreviated CE), making them independent of androgen control. Some AR-V protein variants translocate into the nucleus even in the presence of enzalutamide  site, thus creating a truncated AR mRNA that lacks coding information for the Ligand-Binding Domain (abbreviated LBD). As a result, ARv7 encodes a short yet constitutively active isoform of the AR (active in the absence of androgens). While full-length AR protein is dependent on androgen binding via its LBD to translocate into the nucleus and control transcriptional activity, ARv7 protein is constitutively present in the nucleus even in the absence of androgens and so can provide AR activity in androgen-depleted prostate cancer cells  patients, but less frequently in primary tumours  and NF\u03ba\u03b22, both of which increase expression in prostate cancer . The ARv567es protein isoform regulates the transcription of genes involved in cell cycle control and particularly activates the expression of the oncogene UBE2C. UBE2C is a ubiquitin-conjugating protein active during mitosis, as part of the anaphase-promoting complex (APC) that inactivates the mitotic checkpoint control. UBE2C protein is highly expressed in solid tumours and promotes cell proliferation. Transcriptional activation by the ARv567es AR isoform occurs via a DNA looping mechanism that involves interaction with the transcription factor MED1 , and within castration-resistant but not hormone-responsive prostate cancer  do increase in hormone-resistant prostate cancer compared to primary prostate cancer . However, it is worth noting that other HSP90 inhibitors have been reported to have different effects on ARv7 splice isoform variant production . SRRM4 is a splicing factor normally needed in the body (outside of the prostate gland) for neural differentiation. SRRM4 up-regulation drives splicing switches towards neuronal splicing patterns and the trans-differentiation of prostate cells towards neuroendocrine prostate cancer cells , BCLx (controlling splice isoforms important in cell death via apoptosis) and CCND1 (controlling splice isoforms important in the cell cycle) [Fig.\u00a0CD44 pre-mRNA towards the production of more metastasis-associated splice isoforms [including CD44 exon v5  mRNA which is important for angiogenesis. SRSF1 switches VEGF splicing patterns between pro- and anti-angiogenic mRNA splice isoforms via selection of an alternative 3\u2032 splice site  and the International Cancer Genome Consortia . Increased understanding of mRNA splice isoforms in prostate cancer will also come from integrating RNAseq data with peptide data from mass spectroscopy, thus enabling direct correlation of alternative isoforms and their encoded proteins (Evans et al. Investigation of splicing in prostate cancer is currently undergoing methodological change with the incorporation of analysis from big data sets, particularly with the global discovery of new splice isoforms. Future research in this area is likely to include comparison of large \u201c-omics\u201d level datasets to detect many splice isoform changes between different grades of prostate cancer tissue in parallel. Already, RNAseq datasets from patients with prostate cancer are available on sites like The Cancer Genome Atlas (TCGA, Integrating data from system-wide approaches will also be helpful for understanding how these splice isoforms are generated in prostate cancer cells. Transcriptome-wide binding maps of RNA splicing regulator proteins in cancer cells can be used to identify splicing targets important for therapy and diagnostics (Best et al. CHK1 mRNA might specifically kill cancer cells that rely on CHK1 in the absence of other checkpoints to control replication stress (Best et al. Although research in this area has been very productive, still remaining open in this field is a full understanding of how alternative splicing programmes impact on prostate cancer pathology. Research in the past few years shows that splicing patterns change during prostate cancer progression and in response to therapeutic intervention. Some splicing changes enable prostate cancer cells to grow in limiting concentrations of androgens, and some cause the production of more oncogenic proteins contributing to disease pathology. Understanding these splicing changes, and the mechanisms driving them, opens up new possibilities for developing diagnostic and therapeutic strategies to treat prostate cancer. As a result of these investigations, future therapies might aim to target specific splice isoforms, for example using antisense oligonucleotide and morpholino techniques that have been developed for other diseases including Duchenne muscular dystrophy and spinal muscular atrophy (Aartsma-Rus and Krieg"}
+{"text": "Purpose. To introduce a clinical sign on spectral domain optical coherence tomography (SDOCT), which may indicate high risk for full-thickness macular hole formation after internal limiting membrane (ILM) peeling. Methods. The preoperative SDOCT images of two patients\u2014one with multilaminar hemorrhage from ruptured retinal artery macroaneurysm and one with serous retinal detachment and severe macular schisis from optic pit maculopathy\u2014who developed full-thickness macular hole (FTMH) after ILM peeling were evaluated retrospectively. Results. On the preoperative SDOCT images of both patients there was a thin bridge of tissue on either side of the foveal center with an outer retinal defect. The photoreceptors were displaced laterally away from the foveal center to create an \u201comega-\u201d shaped configuration of the remaining tissue. Conclusion. \u201cOmega-\u201d shaped configuration on SDOCT may represent a higher risk of FTMH following ILM peeling. Vitreoretinal surgeons may wish to consider this sign in the process of their surgical decision making. Peeling of the internal limiting membrane (ILM) has become a preferred technique in the surgical treatment of miscellaneous macular disorders . HoweverIn this report we introduce a clinical sign on spectral domain optical coherence tomography (SDOCT) which may indicate high risk for FTMH formation after ILM peeling.A 91-year-old hypertensive woman presented with sudden onset of central scotoma and 20/200 vision due to multilaminar hemorrhage from ruptured retinal artery macroaneurysm OD. Subretinal blood extended beneath the fovea. Arthritis limited face-down positioning for pneumatic displacement, so pars plana vitrectomy (PPV) and subretinal tissue plasminogen activator injection were performed. The ILM was peeled to liberate trapped sub-ILM hematoma. A 66-year-old woman presented with serous RD and severe macular schisis from optic pit maculopathy OD. Her visual acuity was finger counting and she complained of a central scotoma for several years. Pars plana vitrectomy, ILM peeling, and long-acting gas tamponade were performed with face-down positioning postoperatively. omega sign.\u201d Preoperative recognition of this sign on SDOCT should warn surgeons against ILM peeling over the fovea, which may result in FTMH. Although the report of the bridging tissue is not novel, the risk of creating a macular hole by peeling it has not been well described. The more common situation for the bridging tissue is tractional foveoschisis in myopic eyes. In the study conducted by Kim et al., among the 17 eyes, macular hole was found in two eyes, where one of these eyes developed a macular hole with retinal detachment at 16 months after ILM peeling [Both cases demonstrate the necessity of the MCC for structural integrity of the fovea when a prominent outer retinal defect and localized serous or hemorrhagic RD are present. The bridging tissue over the foveola and lateral displacement of the photoreceptor band produced a horseshoe-shaped configuration that we termed the \u201c peeling . Similar peeling . Intraop peeling .Vitreoretinal surgeons may wish to consider \u201comega sign\u201d in the process of their surgical decision making and surgical planning. This may reduce the threshold for ILM peeling in these patients."}
+{"text": "Spinning top urethra (STU) denotes a particular urethral configuration that is a dilated posterior urethra mainly seen in young girls or women. STU deformity arises secondary to detrusor instability, leading to a rise the intravesical pressure against a closed sphincter. We describe a case of spinning top urethra in a 30-year-old woman who presented with lower urinary tract symptoms and left flank pain."}
+{"text": "Recently developed high throughput molecular techniques such as massively parallel sequencing and phylogenetic microarrays generate vast datasets providing insights into microbial community structure and function. Because of the high dimensionality of these datasets, multivariate ordination analyses are often employed to examine such data. Here, we show how the use of phylogenetic distance based redundancy analysis provides ecological interpretation of microbial community differences. We also extend the previously developed method of principal response curves to incorporate phylogenetic distance measure, and we demonstrate the improved ability of this approach to provide ecologically relevant insights into temporal alterations of microbial communities. Because these experimental platforms generate large datasets of measured values such as sequence read counts or microarray probe hybridization signals, multivariate statistical analyses are usually employed to interpret the acquired data4. Unconstrained ordination analyses such as principal coordinate and component analyses are frequently used to assess the variability in the datasets and distribute samples in lower dimensional space according to the matrix of measured values. While useful, these exploratory techniques do not provide a direct assessment of how different explanatory variables such as environmental gradients, sample groups, or patient metadata  contribute to the observed patterns in microbial community variability. To provide such assessment, the use of constrained methods is advocated3. The two widely used approaches, redundancy analysis (RDA) and canonical correspondence analysis (CCA), utilize Euclidean and \u03c72distances, respectively, to calculate the relationships among samples6. Neither distance measure takes into consideration the phylogenetic makeup of microbial communities and thus is not able to take advantage of this ecologically important information. Phylogenetic trees closely resemble clusters obtained on the basis of shared gene content7, and the microbial phylogeny and function were shown to be linked for many microbial traits9 . Thus, the microbial community composition and function are dependent to at least some degree on the phylogeny of its members12. In this report we show that phylogenetic distance based constrained analyses provide ecological interpretation of microbial community datasets.Recent advances in high-throughput massively parallel sequencing and phylogenetic microarrays have led to a bloom of studies in the field of microbial ecology14 to utilize the phylogenetic UniFrac (UF) distance-based matrix of (dis)similarities among samples in a dataset as has been done in several previous studies18. UniFrac distance is computed by calculating the fraction of branch lengths of a combined phylogenetic tree that are not shared between two communities19. Thus, two communities that mostly have members of phylogenetically distinct clades would have large a UF distance, whereas communities that consist of different members of the same phylogenetic clade  would have a small UF distance. By incorporating the abundance estimates of each taxon in different samples, a weighted UniFrac measure (wUF) can also be calculated. To compare the performance of wUF-dbRDA with several other commonly used constrained ordination analysis including Euclidean and Bray-Curtis distance-based RDAs as well as CCA, we designed a small synthetic microbial community consisting of a dozen bacterial members known to reside in the human gastrointestinal tract. We chose to use a synthetic dataset at this stage over an actual example of microbial community in order to reduce overall dataset variance and limit noise arising due to many low-abundance members typically present in most microbial communities20. Response variables were counts of each species\u2019 abundance simulated manually with random noise  as shown in Fig.\u00a0Fusobacterium nucleatum, a gut bacterial species that has been associated with human colorectal cancer21. Within each group, we introduced further dichotomy between \u201cgenders\u201d by varying which species of Clostridium and Bacteroides they harbored red Fig.\u00a0. The oveups Fig.\u00a0, and becups Fig.\u00a0. Both caups Fig.\u00a0 and instups Fig.\u00a0. Thus, wet al. study22. The dataset comprised phylogenetic microarray based abundance values for 775 phylotypes of human gut microbiota profiled in two cohorts of teenagers: healthy group (designated kHLT) and those diagnosed with diarrhea-predominant irritable bowel syndrome (designated kIBS). Group , gender, and age served as explanatory variables in our UF-dbRDA analysis see Fig.\u00a0. The fulsee Fig.\u00a0. Bray-Cuges Fig.\u00a0.Figure 229. The study described fecal microbiota changes in three patients with Clostridium difficile associated disease following fecal microbiota transplantation (FMT) from a healthy donor. The results of the wUF-dbPRC analysis are presented in Fig.\u00a0et al. study based on the K-means cluster analysis29, and additionally provide the ability to quantitatively establish the main determinants of community alterations.We then applied the wUF-dbPRC analysis to the time-series measurements of microbiota composition taken from the study by Shankar and co-workersWhile our synthetic datasets were designed specifically to show the potential differences in outputs between traditional and weighted UniFrac distance-based RDA and PRC analyses, the above comparisons provide compelling evidence for the advantages of phylogenetic distance based constrained ordination analyses in the study of microbial communities.vegan package30. Specifically, distance-based redundancy analysis was performed using the vegan function capscale. Principal response curves analysis was performed using the prc function. Analysis of variance was performed using the anova.cca command. The R code to run both dbRDA and dbPRC analyses is provided in Supplementary File\u00a0The constrained ordination techniques were performed in R using the Supplementary \u00a0Information"}
+{"text": "We report of a 57-year-old female patient who underwent a hemipelvectomy with a hemipelvic replacement in 1992. In 2013 the implanted material had to be partially removed due to a periprothetic infection. At that time a palacos spacer was implanted which penetrated two years later into the colon cavity.  Penetration of implanted material has been reported after different surgical procedures like endovascular aortic repair (aortoenteric fistula), gastric banding (penetration into the stomach) or total hip replacements (penetration into the pelvis). Here, we report a case of colon penetration after a total hip replacement.A 57-year-old female patient presented in 2/2015 in our outpatient clinic with mild, but therapy-refractory constipation since four weeks.This patient received a right inner hemipelvectomy with a hemipelvic replacement in 1992 because of a malignant schwannoma of the right iliac bone. In 1995, the patient suffered a traumatic right-sided femur fracture, which was treated with a plate osteosynthesis. During the following years she developed a non-irritated chronic fistula underneath her surgical scar. In 2013, the chronic fistula became infected and cumulated in a deep gluteal abscess (measuring 4x4 cm) extending to the hemipelvic prosthesis. An explantation of the pelvic replacement was recommended but was initially declined by the patient. She received antibiotics in concordance with the wound culture and sensitivity swab.\u00ae spacer, as well as a gentamycin chain , three wire cerclages, a Palacos\u00ae spacer inside her rectal cavity  showed the head of the implanted PalacosThe first step in our department was the removal of the foreign body under general anesthesia through the anus without complications  [A bowel perforation by implanted foreign material  is a rare complication. The complete absence of symptoms or only mild symptoms accompanying this process is even rarer. The penetration of foreign material into the gut usually causes severe complications like pain, melena respectively hematemesis or sepsis like in case of aortoenteric fistulas after endovascular repair via prosthesis . There a\u00ae) . HoweverThe authors declare that they have no competing interests."}
+{"text": "A number of psychological symptoms have been found to predict psychosis. Many studies have found no specificity to separate symptoms predicting non-psychotic psychiatric disorders from those predicting psychotic disorders. We were able to conduct prospective study comparing adolescent symptoms predicting non-psychotic psychiatric disorders and psychotic psychiatric disorders.Members of the of the Northern Finland Birth Cohort 1986 were asked to fill in PROD-screen questionnaire at age 15\u201316 years. PROD-screen includes 21 items both measuring positive prodromal symptoms, negative prodromal symptoms and general symptoms.We were able to follow 6,514 participants using Finnish Hospital Discharge Register detecting new hospital treated mental disorders till 23 years.The highest prevalence of positive symptoms in the PROD-screen were in the group of subjects who developed psychotic disorder (65% over the cut off) compared to subjects who developed non-psychotic disorder , and to subjects without any disorder . Respective figures for negative symptoms were 55% in the group of psychotic subjects compared to 30% in subjects with non-psychotic disorder  and 24% in the \u2018healthy\u2019 .When comparing separate symptoms in those having psychiatric hospital treatments, we found four positive symptoms and one negative symptom predicting specifically psychotic disorders.In this large prospective population sample both positive and negative symptoms in adolescence associated specifically with development of first episode psychosis."}
+{"text": "Influenza A virus (IAV) infection can be severe or even lethal in toddlers, the elderly and patients with certain medical conditions. Infection of apparently healthy individuals nonetheless accounts for many severe disease cases and deaths, suggesting that viruses with increased pathogenicity co-circulate with pandemic or epidemic viruses. Looking for potential virulence factors, we have identified a polymerase PA D529N mutation detected in a fatal IAV case, whose introduction into two different recombinant virus backbones, led to reduced defective viral genomes (DVGs) production. This mutation conferred low induction of antiviral response in infected cells and increased pathogenesis in mice. To analyze the association between low DVGs production and pathogenesis in humans, we performed a genomic analysis of viruses isolated from a cohort of previously healthy individuals who suffered highly severe IAV infection requiring admission to Intensive Care Unit and patients with fatal outcome who additionally showed underlying medical conditions. These viruses were compared with those isolated from a cohort of mild IAV patients. Viruses with fewer DVGs accumulation were observed in patients with highly severe/fatal outcome than in those with mild disease, suggesting that low DVGs abundance constitutes a new virulence pathogenic marker in humans. Influenza A viruses are the causative agents of annual epidemics, sporadic zoonotic outbreaks and occasionally pandemics. Worldwide, acute respiratory infections caused by influenza A viruses continue to be one of the main causes of acute illness and death. The appearance in 2009 of a new H1N1 pandemic influenza strain reinforced the search to identify viral pathogenicity determinants for evaluation of the consequences of virus epidemics and potential pandemics for human health. Here we identify a new general virulence determinant found in a cohort of severe/fatal influenza virus-infected patients, a reduced accumulation of viral defective genomes. These molecules are incomplete viral genome segments that activate the innate immune response. This data will contribute to the prediction of influenza disease severity, to improved guidance of patient treatment and will enable the development of risk-based prevention strategies and policies. Acute respiratory infections are a main cause of severe illness and death worldwide. Influenza A virus (IAV) causes annual epidemics and occasional pandemics with potentially fatal outcome ; the gloin vivo murine model  are shown in yellow. RNA viral promoter is shown in blue.(TIF)Click here for additional data file.S15 FigStructure of the dimer polymerase complex in Protein Data Bank (PDB) under accession 3J9B has been used as template for structural localization of PA mutations with UCSF Chimera 1.10.2. PA mutations described in the severe-fatal case viruses in the present study (PA 529 and PA 312) are shown in red. RNA viral promoter is shown in blue.(TIF)Click here for additional data file.S1 Table(XLSX)Click here for additional data file.S2 TableEpidemiological data, including comorbidities information, reported by the National Epidemiological Influenza Center are shown for the 2012\u20132013 Spanish influenza seasons.(TIF)Click here for additional data file.S3 Table(TIF)Click here for additional data file."}
+{"text": "Despite intensive rehabilitation efforts, most stroke survivors have persistent functional disability of the paretic arm and hand. These motor impairments may be due in part to maladaptive changes in structural and functional connections between brain regions. The following early stage clinical trial study protocol describes a noninvasive brain stimulation approach to target transcallosally mediated interhemispheric connections between the ipsi- and contralesional motor cortices (iM1 and cM1) using corticocortical paired associative stimulation (ihPAS). This clinical trial aims to characterize ihPAS-induced modulation of interhemispheric connectivity and the effect on motor skill performance and learning in chronic stroke survivors.  A repeated-measures, cross-over design study will recruit 20 individuals post-stroke with chronic mild\u2013moderate paretic arm impairment. Each participant will complete an active ihPAS and control ihPAS session. Assessments of cortical excitability and motor skill performance will be conducted prior to and at four time points following the ihPAS intervention. The primary outcome measures will be: TMS-evoked interhemispheric motor connectivity, corticomotor excitability, and response time on a modified serial reaction time task. NCT02465034. The findings from this single-site early stage clinical trial will provide foundational results to inform the design of larger-scale, multisite clinical trials to evaluate the therapeutic potential of ihPAS-based neuromodulation for upper limb recovery after stroke. This trial is registered with  Motor ir stroke . In roder stroke . In healr stroke . In indir stroke . Specifir stroke  and assor stroke . This exr stroke , 11. AltOne possible explanation for this limited progress in improving stroke rehabilitation outcomes is that abnormal IHI and hemispheric balance after stroke have been targeted indirectly and nonspecifically. Promising neuromodulatory rehabilitation approaches can elicit neuroplastic change using noninvasive brain stimulation TMS). However, traditional rTMS approaches target a single cortical site with limited effectiveness in restoring the balance of interhemispheric activity or meaningfully improving arm function in chronic stroke , 13. TheIf STDP can be induced noninvasively by targeting direct transcallosal connections between M1s in the human brain, then this approach could offer a neuromodulation approach to restore the balance of interhemispheric activity after stroke. Using an interhemispheric (ih)PAS paradigm to target transcallosal motor circuits in healthy individuals, STDP was induced in both local and interhemispheric neuronal circuits  and corrHAND representations will: (1) induce STDP that increases cortical excitability of the targeted region (iM1HAND) and reduces abnormal IHI from cM1HAND to iM1HAND and (2) enhance motor skill performance and learning of a modified serial reaction time task (SRTT) after STDP induction.In this early-stage clinical trial protocol, we will explore ihPAS as a novel noninvasive brain stimulation approach to induce STDP in interhemispheric motor connections to transiently modify IHI and ipsilesional cortical excitability targeting cortical pathways implicated in mediating chronic stroke-related arm motor impairment. The aims of the trial are to: (1) characterize STDP induction in intracortical and transcallosal circuits by ihPAS and (2) investigate the effect of ihPAS on motor skill acquisition and learning. We hypothesize that ihPAS of transcallosal connections between M1Twenty individuals with subcortical stroke aged 40\u201385 in the chronic stage of recovery (>6 months) with mild\u2013moderate impairment of the paretic arm  scan and baseline assessments of cognition, upper extremity physical impairment, motor function, and hand dexterity. Next, enrolled participants will complete two sessions of ihPAS, each with a 24-hour retention test, over 2 weeks. Assessments of cortical excitability using electromyography (EMG) and electroencephalography (EEG) of TMS-evoked cortical responses and motor skill performance will be conducted before ihPAS and then at three time points following ihPAS to evaluate the immediate time course of effects . Followi1 scan  will be performed on a Siemens Trio TIM 3T whole-body MRI scanner housed within the Center for Systems Imaging, a core facility at Emory University. The study team will have direct and immediate access to the data using Emory University's secure network server.A high-resolution TArm motor behavior will be evaluated by a licensed physical therapist during the first visit with the Wolf Motor Function Test (WMFT), shown to be a valid and reliable test of motor function in stroke , the uppParticipants will be seated comfortably in an adjustable reclining chair for all procedures. To reduce within- and between-session variability, the coil location and trajectory for the M1 stimulation site will be recorded and monitored in real-time with a stereotactic neuronavigation system  using the T1-weighted anatomical scans acquired for each participant. TMS will be delivered using a 70\u2009mm hand-held figure-of-eight coil over the iM1 and a 50\u2009mm branding iron coil over the cM1. Each coil will be connected to a monophasic stimulator ) using navigated TMS and evoked responses in the FDI will be measured with EMG  . Resting motor threshold (RMT) (% of maximum stimulator output) will be determined bilaterally using standard protocols . If an MHAND and iM1HAND at a frequency of 0.2\u2009Hz for ~8.3\u2009min [HAND stimulation preceding suprathreshold (SP120) iM1HAND stimulation at a fixed interpulse interval of 8\u2009ms [HAND) and decreased IHI from left M1HAND onto right M1HAND have been observed in healthy individuals [One hundred pairs of pulses will be delivered over cM1~8.3\u2009min  with sub of 8\u2009ms . This in of 8\u2009ms . When apividuals . Controlividuals . The ordSingle TMS suprathreshold (SP120) pulses will be delivered over the M1 representation for the FDI (frequency jittered from 0.1\u20130.25\u2009Hz) while the participant is seated quietly with eyes open and FDI at rest to assess general levels of corticospinal excitability . IHI wilSP120) will be the primary dependent measure of local iM1 excitability. For the IHI condition, MEP ratio (conditioned MEP/unconditioned MEP) will be calculated as the primary outcome measure characterizing IHI.For each TMS assessment, 30 pulses will be delivered to maximize within- and between-session reliability  and stor\u03bcV/bit resolution) during TMS assessments of cortical excitability. TMS-induced auditory artifacts will be reduced by using earplugs and frequency-specific noise to mask the audible TMS coil click [Electroencephalography (EEG) data will be recorded during all TMS assessments. TMS-evoked cortical responses can be used to directly assess intracortical neuronal circuit excitability and connectivity between distinct cortical regions \u201334. Elecil click . CorrectTMS-evoked EEG responses will be used to quantify abnormal interhemispheric connectivity after ihPAS intervention via imaginary phase coherence analysis (as detailed in ). All daWe will assess motor skill performance of each participant using a serial reaction time task (SRTT). Paretic arm motor function will be evaluated on a 3-item abbreviated version of the WMFT. Each assessment will be performed at each time point .Participants will perform a modified version of the SRTT  while seSkill will be defined as the difference between the average RT during the last 50 sequential trials and average RT during the second set of random trials within each block  Figure . To evalDue to time constraints of the experimental design, three items of the WMFT will be used to evaluate functional motor performance at each assessment time point. Streamlined versions of the WMFT have been shown to be useful in evaluating poststroke motor function across the continuum of recovery , 42. TheStroke is the leading cause of adult disability in the U.S. and its prevalence is expected to rise by 20% over the next 20 years, with tripled stroke-related costs . InnovatNoninvasive brain stimulation (NIBS) using repetitive activation of circumscribed brain regions with magnetic or electrical stimulation has shown promise as a potential alternative and/or augmentative therapeutic approach to traditional physical therapy after stroke with few side effects , 47. HowTaken together, ihPAS may offer an innovative and promising neuromodulatory approach to target mechanisms fundamental to stroke recovery requiring systematic investigation. The proposed project will be the first step in determining the clinical utility of ihPAS to improve functional outcomes after stroke. If successful, ihPAS could provide a novel neuromodulation technology to augment current clinical rehabilitation strategies to improve stroke outcomes. Regardless of the outcome, findings from this study will provide important information for refining or reconceptualizing neurobiologically based models of persistent arm impairment after stroke. The principal long-term objective of this work is to conclusively define the salient neuroplastic signatures of stroke recovery that can be leveraged into improved therapeutic outcomes and quality of life for each stroke survivor."}
+{"text": "Despite technical advances and accumulated experience, complications continue being aconcern for patients implanted with permanent pacemakers. Several leadless pacemakersystems have now been developed in order to reduce the rate of complications inpatients implanted with conventional transvenous pacemaker.A 75-year-old female patient with a background of systemic arterial hypertension,chronic atrial fibrillation with an episode of peripheral arterial embolism in theright upper limb and rheumatic valve disease, underwent mitral and aortic valvereplacement receiving two mechanical valve prosthesis in combination with leftatrial appendage occlusion. Six months after surgery, pharmacologic therapy toachieve heart rate control was very difficult and inadequate and the patient wasscheduled for permanent pacemaker implantation. In order to avoid lead or pocketcomplications, the Micra transcatheter leadless pacemaker  was implanted through the femoral vein using a steerablecatheter delivery system with the use of a 23-French introducer. The procedure wasperformed under uninterrupted acenocoumarol therapy with therapeutic internationalnormalized ratio (INR 2.5). Sedation and local anesthesia was applied and theimplant was successful upon initial device positioning at the mid-septum of theright ventricle with no complications. Access site closure was performed using asubcutaneous venous figure-of-8 suture. The pacing capture threshold at implant was0.38 V measured at 0.24 ms, the R-wave sensing amplitude was 8.8, and the pacingimpedance was 730 ohms. There were no complications and the patient was dischargedhome the next day after chest X-ray showed the device was positioned perfectly and elec1 They are particularly related to the device or as a result from transvenous leadplacement . Early performance and safety data for the Micratranscatheter leadless pacemaker are positive3 and leadlesspacemakers represent a promising alternative for many patients, eliminating the mainsources of complications associated with conventional transvenous pacemakerimplantation.In spite of technological advances and the enormous accumulated experience,conventional pacemaker therapy continues to be associated with a great variety ofpotential complications either in the short and long-term.Patients with mechanical heart valve prosthesis might represent a subgroup ofpatients for whom this new therapy can bring higher benefits due to the need forlifelong anticoagulation and the serious consequences of permanent transvenouspacemaker system infections."}
+{"text": "Infection with human immunodeficiency virus (HIV) influences the outcome and natural disease progression of hepatitis C virus (HCV) infection. While the majority of HCV mono-infected and HCV/HIV co-infected subjects develop chronic HCV infection, 20\u201346% of mono- and co-infected subjects spontaneously clear HCV infection. The mechanism underlying viral clearance is not clearly understood. Analysis of differential cellular gene expression (mRNA) between HIV-infected patients with persistent HCV infection or spontaneous clearance could provide a unique opportunity to decipher the mechanism of HCV clearance.Plasma RNA from HIV/HCV co-infected subjects who cleared HCV and those who remained chronically infected with HCV was sequenced using Ion Torrent technology. The sequencing results were analyzed to identify transcripts that are associated with HCV clearance by measuring differential gene expression in HIV/HCV co-infected subjects who cleared HCV and those who remained chronically infected with HCV.We have identified plasma mRNA, the levels of which are significantly elevated  <0.05) before HCV infection in subjects who cleared HCV compared to those who remained chronically infected. Upon further analysis of these differentially expressed genes, before and after HCV infection, we found that before HCV infection 12 genes were uniquely upregulated in the clearance group compared to the chronically infected group. Importantly, a number of these 12 genes and their upstream regulators  are associated with innate immune response functions.These results suggest that subjects who spontaneously clear HCV may express these unique genes associated with innate immune functions. IL28B) and IP-10 have been implicated in mediating host susceptibility/resistance to HCV infection and disease progression [Hepatitis C virus (HCV) infection is the leading cause of hepatocellular carcinoma in the United States . Due to gression \u201317. In Hgression . HoweverDifferential cellular gene expression in HIV-infected subjects has been shown to be associated with HIV disease progression . TherefoPathogenic changes occurring in any tissues or organs are expected to leave footprints in the blood. Consequently, measurement of certain target RNA in the plasma has been explored or used for diagnosis of a number of diseases and cancers \u201324. We hIn this study we identified plasma mRNA, the levels of which are significantly increased  in the HCV clearance group compared to chronically HCV infected patients. Upon further analysis of these differentially expressed genes, we have identified 12 genes that are upregulated only in clearance group before HCV infection. Moreover, some of these 12 genes and their upstream regulators are associated with innate immune functions.Frozen plasma samples were obtained from 13 HCV seroconverters who were infected with HIV for more than 10\u00a0years before HCV seroconversion in the Multicenter AIDS Cohort Study (MACS) . MACS isTotal nucleic acids were extracted from l ml of frozen cryopreserved plasma using an automated NucliSens EasyMag nucleic acid extraction machine  followed by removal of DNA from the nucleic extract with Qiagen AllPrep DNA/RNA mini kit and ribosomal RNA by a Low Input RiboMinus System (Life Technologies). The cDNA Library was then constructed using an Ion Torrent Total RNA-Seq Kit (Life Technologies) for whole transcriptome libraries and Barcodes 1 through 8 from an Ion Xpress 1\u201316 barcoding kit were used (Life Technologies) for each individual sample. cDNA libraries were quantified by qPCR using an Ion Library Quantitation Kit (Life Technologies) to determine a suitable template dilution factor for subsequent emulsion PCR and sequencing.Four barcoded samples were combined for one sequencing reaction. Template preparation for sequencing was conducted using the OneTouch Ion\u2122 Template Kit in the OneTouch machine (Life Technologies). Ion Torrent sequencing was conducted using the Ion Proton Sequencing Kit (Life Technologies) on an Ion Proton Machine (Life Technologies) using a P1(v2)-chip (Life Technologies). The constructed cDNA was also used for HIV viral load measurement using a quantitative-real time PCR for HIV gag RNA, with a sensitivity of 10 copies/mL .Raw sequencing reads in FastQ format were assessed for quality using CLC Genomics Workbench 7. Reads were accepted based on the length (longer than 25 nucleotides) and number of ambiguous bases . Quality trimming was performed. The mean numbers of reads from different groups after trimming ranged from 3.2 million to 8.4 million. The trimmed reads were then mapped to Homo sapiens gene sequences based on Homo sapiens (hg19) mRNA.www.genecards.org).Bioconductor edgeR in R package was employed to perform the differential expression analysis. A general linear model was applied on the subjects before and after HCV infection to accommodate the multifactor design of the experiment. The model incorporates the main effect for HCV infection plus interactions with patients and viral clearance, thus allowing us to identify genes differentially expressed in HCV cleared and chronically infected patients before and after HCV infection. To ensure there were sufficient counts for each gene in the test, genes with mean read counts higher than 10 were kept in the analysis. Genes with Benjamini-Hochberg adjusted FDR <0.05 and fold change greater than 1 were considered as significant genes. The significance and function networks of the detected differentially expressed genes were analyzed using Ingenuity Pathway Analysis software. The gene function information was obtained from GeneCards Human Gene Database ): six gene products (18%)  are related to signal transduction pathways and innate immune response,. eight gene products (24%)  are involved in metabolism and protein trafficking, and five gene products (15%)  are RNA/DNA binding proteins involved in gene regulation  before HCV infection, 19 DEGs have known biological functions  are RNA/DNA binding proteins involved in gene regulation   are known to participate in, or to be related to, signal transduction pathways and innate immune responses, twelve DEG gene products (21%)  are involved in metabolism and protein trafficking and eight DEG gene products (14%)  and cytotoxic NK-cells (P\u2009=\u20090.005), compared to patients who became chronically infected [The availability of sequential plasma samples with defined onset and disease outcomes of HCV infection in highly characterized HIV-infected subjects from the MACS  providedinfected . In addiinfected . FurtherPlasma RNA sequencing has identified the transcripts that are significantly associated with HCV clearance and are found to be expressed prior to infection. Some of the transcripts are involved in innate immune function. These results suggest that subjects who spontaneously clear HCV may have the transcripts that modulate forms of immunity that confer resistance to chronic infection with HCV. Further studies with longitudinal samples from HCV infected patients who cleared HCV infection, and those who became chronically infected may provide more definitive information about the nature of these inherited traits."}
+{"text": "OtheWe addressed this possibility by examining the distributions of fiber-types and MU fibers in small muscles of the rat hindlimb for comparison with those in large muscles. Six months after nerve transection and repair, all the nerve fibers reinnervated the denervated rat muscle but, in contrast to the restored mosaic distribution of reinnervated MU fibers and fiber-types in well reinnervated large cat muscles, the reinnervated rat MU muscle fibers were mostly confined within 1-3 muscle fiber clumps; the MU fibers were clumped in parallel with a corresponding fiber-type grouping in the muscle cross-sections .both small and large muscles [Each MU muscle fiber is normally surrounded by an average of 6 non-MU muscle fibers and all the MU muscle fibers are confined to a \u2018muscle territory\u2019 that is bounded by the outermost MU fibers Figure . The ter muscles . The siznot increase in size from normal [It is only when few nerve fibers regenerate into a denervated large muscle and each nerve fiber branches to reinnervate 5-8 times as many muscle fibers as normal, that each motor nerve fiber innervates adjacent muscle fibers; MU fibers and fiber-types exhibit clumping within MU territories which do m normal . This pam normal . The cluis also indicative of extensive partial denervation as in large muscles [both sprouting after extensive nerve damage and muscle reinnervation after damage that severs all the nerve supply whether or not all the nerves regenerate and reinnervate the denervated muscle. In large muscles on the other hand, fiber-type grouping indicates sprouting after extensive nerve damage whether or not there is partial or complete nerve injury.These findings and arguments indicate that fiber-type grouping in reinnervated muscles is not inevitable as has been generally supposed. Fiber-type grouping only occurs in large muscles after extensive partial denervation and when fewer than 20% of the original nerve supply reinnervate muscle after complete nerve transection and surgical repair . In smal muscles  but, clu muscles . Hence fThe enlarged MUAPs that are frequently recorded from muscles have been and continue to be used as indicators of muscle reinnervation , 3. It i"}
+{"text": "Purpose: To present a case with posterior segment findings in a patient with cloudy corneas secondary to immunotactoid glomerulonephritis (ITG).Methods: A 57-year-old female was known to have bilateral cloudy corneas diagnosed 12 years ago secondary to immunotactoid glomerulonephritis. Clinically, fundus examination was difficult to visualise due to the density of her corneal opacities. Results: B-scan ultrasound revealed significant retino-choroidal & non-inflammatory scleral thickening. The macula also showed signs of thickening in both eyes. Optical coherence tomography (OCT) showed thinning of the inner retinal layers and significant choroidal folds in both eyes. Electrodiagnostic tests (EDT) concluded loss of retinal ganglion cells with preservation of retinal function in both eyes.Conclusion: This case widens the spectrum of findings seen in patients diagnosed with Immunotactoid Glomerulonephritis and alerts us to undertake detailed posterior segment examination where possible. Ocular coherence tomography (OCT) and B-scan ultrasonography are important adjuvants to help assess the posterior segment in patients with corneal opacities secondary to ITG.  Corneal involvement in patients diagnosed with immunotactoid glomerulonephritis (ITG) is well described in literature. ITG is characterised by deposition of abnormal monoclonal protein in patients with paraproteinemia and lymphoproliferative disorders. We present interesting posterior segment findings in a patient with cloudy corneas secondary to immunotactoid glomerulonephritis.A 57-year-old female was referred to the corneal clinic with a one-week history of seeing a \u2018black spot\u2019 in front of her right eye. Her past ocular history revealed bilateral cloudy corneas diagnosed 12 years ago secondary to ITG. She was reviewed on an annual basis but as she was asymptomatic with visual acuity 6/6 (LogMAR 0.0) both eyes and the appearance of her corneas had remained unchanged over seven years; she was discharged back to primary care. Her medical history revealed ITG following a renal biopsy carried out 20 years ago. 6 years ago, she was diagnosed with end stage renal failure and was on haemodialysis and continuous ambulatory peritoneal dialysis. She was also known to suffer with haemolytic anaemia and hypertension.On examination, her best-corrected visual acuity was recorded as 6/7.5 (logMAR 0.2) and near vision N6 in both eyes. Corneal examination revealed full thickness limbal to limbal opacification in both eyes Figure 1 . The cenOCT examination showed a hazy view but thinning of the inner retinal layers and choroidal folds was noted in both eyes. Photoreceptor layer appeared to be intact including the outer nuclear layer Figure 2 . B-scan In both eyes, visual evoked potential (VEP) to flash stimulus was essentially normal. Her visual field testing showed non-specific defects and Ishihara colour vision test was normal. The patient refused penetrating keratoplasty due to the risks attached but elected to consider this option at a later stage. We decided to observe this patient on a regular basis and carry out serial OCT scans. The patient was asked to report any changes to her vision. At 6-month follow-up, patient was asymptomatic and visual complaints of seeing a \u2018black spot\u2019 in her right eye resolved completely.Immunotactoid glomerulonephritis (ITG) is a rare renal deposition disease and the diagnosis is based on analysis of renal biopsies. The primary differential diagnosis of this condition includes membranoproliferative or mesangiocapillary glomerulonephritis (MPGN). Both these glomerular diseases typically present with nephrotic syndrome. In ITG, the exact mechanism is unknown but deposition of immunoglobulin, particularly IgG \u03ba and \u03bb light chains and complement, suggests an immune system dysfunction. MPGN is a group of immune complex-mediated disorders characterized by subendothelial and mesangial deposition of immune complexes. Most of these patients progress to develop end stage renal failure. Corneal involvement in various systemic paraproteinemias or monoclonal gammopathies is well established and various morphological characteristics mimicking hereditary and degenerative corneal disorders have also been described , 2]. Th. Th2]. TThe choriocapillaris, Bruch\u2019s membrane and RPE complex have been proven to have similar morphological characteristics as the glomerulus and there is histopathological evidence that immune complexes can get deposited at these sites , 5]. Mo. Mo5]. MIn our patient, renal biopsy showed deposits of IgG kappa and C3 at the tips of some glomerular loops and based on electron microscopy, a diagnosis of ITG was made. Subsequently, our patient developed generalized full thickness cloudiness of both her corneas. As her visual acuity continued to remain stable and the patient was asymptomatic, the need for detailed fundus examination was overlooked and patient was discharged to primary care. Her recent presenting complaint of \u2018black spot in vision\u2019 did not correlate with her cloudy corneas and it was then that the patient underwent an OCT scan. Choroidal folds seen on OCT both eyes are presumably a result of retino-choroidal & scleral thickening as confirmed by B-scan. We feel that this is an immune related process related to ITG as there were no signs of intraocular inflammation & \u2018T-sign\u2019 was absent on B-scan. One could argue that choroidal thickness is possibly altered as a result of chronic renal failiure and following haemodialysis but evidence shows that the average choroidal thickness decreases significantly in such patients  whereas To our knowledge, this is the first case describing retino-choroidal & scleral thickening in a patient with ITG. This case widens the spectrum of findings seen in patients diagnosed with ITG and alerts us to undertake detailed posterior segment examination in patients with corneal opacities. Corneal changes might not be the only cause of visual symptoms in patients with ITG. OCT and B-scan USG are useful tools for posterior segment assessment in these patients. This case also highlights the need for further studies on a cohort of patients diagnosed with ITG to assess their posterior segment findings.The authors declare that they have no competing interests."}
+{"text": "Transfusion-related acute lung injury (TRALI) is the leading cause of transfusion-related fatalities and is characterized by the onset of acute respiratory distress within six hours following blood transfusion. In most cases, donor antibodies are suggested to be involved, however, the pathogenesis is poorly understood. A two-hit model is generally assumed to underlie TRALI pathogenesis where the first hit consists of a patient predisposing factor such as inflammation and the second hit is due to donor antibodies present in the transfused blood. We recently demonstrated that the acute phase protein C-reactive protein (CRP) could enhance murine anti-major histocompatibility complex (MHC) class I-mediated TRALI. Whether CRP is increased in human TRALI patients which would support its role as a risk factor for human TRALI, is currently unknown. For that purpose, we measured CRP levels in the plasma of human TRALI patients and found CRP levels to be significantly elevated compared to transfused control patients. These data support the notion that CRP may be a novel first hit risk factor in human TRALI and that modulation of CRP levels could be an effective therapeutic strategy for this serious adverse event of transfusion. Transfusion-related acute lung injury (TRALI) is the leading cause of transfusion-related mortality and is characterized by acute respiratory distress within six hours following blood transfusions , 2. AparWe recently demonstrated that C-reactive protein (CRP), an acute phase protein widely used as a clinical biomarker of infections and inflammation, enhances anti-major histocompatibility complex (MHC) class I-mediated TRALI in BALB/c mice . MechaniIn light of these findings in mice, we assessed whether CRP levels are indeed increased in human TRALI patients which is an essential step to establish if CRP may be a risk factor for TRALI induction and if modulation of CRP levels in humans could be a therapeutic approach to combat TRALI.CRP levels were measured in plasma samples from human TRALI patients n=12) and in control orthopedic surgery patients that had not been hospitalized nor had infections within one month prior to surgery and received allogeneic blood transfusions post-operatively without any pulmonary transfusion reactions (n=10). TRALI samples were collected for CRP analysis within 24-48 hours upon transfusion and for the control group blood samples were collected within 24 hours following transfusion (which occurred on post-operative days 3-4). The patient characteristics and clinical features are listed in Table 2 and in The finding that CRP levels are significantly elevated in human TRALI patients Figure  suggestsCRP is member of the pentraxin family and is composed of 5 identical, nonglycosylated 206 amino acids protomers which together form a noncovalently linked annular symmetrical pentameric molecule . PentamePlatelets are classically known for their hemostatic function but have been suggested to play a pathogenic role in TRALI , 24. It In summary, our data indicate that CRP levels are significantly upregulated in the plasma of TRALI patients and thus monitoring CRP levels prior to transfusion may be useful and down-regulating CRP levels could be a novel therapeutic approach to explore in TRALI.Human TRALI samples were diagnosed and obtained with approval from Sanquin Diagnostic Services, Amsterdam, The Netherlands (Dr. L. Porcelijn). All TRALI samples were obtained and collected strictly under the following conditions : 1) Newly developing acute respiratory distress: PaO2/FiO2 ratio  < 300 mmHg or arterial oxygen saturation < 90% at room air; 2) Newly developed or worsened bilateral pulmonary infiltrates indicative of pulmonary edema on chest X-ray; 3) Emergence of all symptoms within 6 hours upon blood transfusion; 4) Exclusion of cardiac ischemia and transfusion associated circulatory overload (TACO).If patients had major risk factors for acute lung injury, such as pneumonia, sepsis, aspiration, multiple fractures or pancreatitis, they were excluded from this study except if the patient was stable and the risk factor did not appear to cause acute lung injury and the onset of acute lung injury was triggered by the blood transfusion.Human transfused control samples were obtained from Dr. M. T. Rondina . Patient characteristics and clinical features for both TRALI and transfused control samples are described in Table TRALI samples were collected for CRP analysis within 24-48 hours upon transfusion and for the control group blood samples were collected within 24 hours following transfusion, which occurred 3-4 days after the orthopedic surgery. CRP was measured from plasma using a standardized immunoturbidimetric assay, in which the human CRP from the samples agglutinates when incubated with latex particles coated with polyclonal rabbit anti-human CRP antibodies . The aggregrates were subsequently determined turbidometrically using the Beckman AU680, Beckman Coulter, USA."}
+{"text": "This study used the Deese-Roediger-McDermott paradigm [34] to investigate the direction and the extent to which emotional valence in semantic word lists influences the formation of false memories (FM). The experimental paradigm consisted of 1) a study phase , 2) a free recall phase, and 3) a recognition phase. Participants had to indicate whether the displayed item was \"new\" (new item or non-studied CL) or \u201cold\u201d (studied list item). CL associated with negative word lists elicited significantly more FM than CL associated with neutral word lists. This finding is in contrast to previous work showing that emotional words elicit fewer FM than neutral words. The results of our study also suggest that valence is capable of influencing emotional memory in terms of encoding and retrieval processes."}
+{"text": "Independent replication is vital for study findings drawn from Electronic Health Records (EHR). This replication study evaluates the relationship between seasonal effects at birth and lifetime cardiovascular condition risk. We performed a Season-wide Association Study on 1,169,599 patients from Mount Sinai Hospital (MSH) to compute phenome-wide associations between birth month and CVD. We then evaluated if seasonal patterns found at MSH matched those reported at Columbia University Medical Center. Coronary arteriosclerosis, essential hypertension, angina, and pre-infarction syndrome passed phenome-wide significance and their seasonal patterns matched those previously reported. Atrial fibrillation, cardiomyopathy, and chronic myocardial ischemia had consistent patterns but were not phenome-wide significant. We confirm that CVD risk peaks for those born in the late winter/early spring among the evaluated patient populations. The replication findings bolster evidence for a seasonal birth month effect in CVD. Further study is required to identify the environmental and developmental mechanisms. External replication and validation are essential to medical research145Recently, two of the co-authors (Boland and Tatonetti) developed a method called SeaWAS: Season-Wide Association Study that reveals relationships between birth month  and lifetime disease riskTo perform a proper replication study, we sought to follow the original SeaWAS study as closely as possibleWe extracted all individuals born between 1926 and 2000 inclusive  who were treated at MSH (between 1979\u20132015), demographics given in We are especially interested in cardiovascular condition \u2013 birth month associations because they represent the novel findings from the original SeaWAS studyhttps://github.com/maryreginaboland/SeaWAS) to fit the database schema of MSH. We first performed a phenome-wide exploration of all birth month \u2013 disease associations for conditions with at least 1000 patients (1433 conditions). We employed the Benjamini-Hochberg method to correct for multiple hypotheses and control for the false discovery rate (FDR)We modified the SeaWAS algorithm obtained from the public domain . We assess statistical significance by comparing the actual correlation between the two institutions to an empirically derived null distribution. We generated empirical null distributions for each condition by randomizing the birth month\u2013disease risk curve from MSH. We then computed the Pearson correlation for the random curve and CUMC\u2019s birth month-disease risk curve. We repeated this procedure 1000 times producing 1000 random correlation results. We determined the empirically derived p-value as the proportion of random correlations greater than the actual correlation between true MSH data and true CUMC data divided by 1000. If this value is zero then the p-value is reported as \u201cp\u2009<\u20090.001.\u201det al. 2004To place our findings in the context of biological mechanisms deemed important in birth month associations, we obtained peak flu season data obtained from the Centers for Disease Prevention and Control (CDC) data on flu activity from 1982\u201383 through 2013\u201314We used SeaWAS to mine birth month associations at MSH for all 1433 conditions with at least 1000 individuals born between 1926 and 2000, inclusive. We applied multiplicity correction using FDR to adjust the p-values. We limited our analysis to only the circulatory system conditions (as defined by the ICD-9 codes) that were found in both datasets, allowing us to compare the patterns of birth month-disease risk between the two institutions. SeaWAS-CUMC analysis found 9 circulatory system conditions were associated with birth month at an FDR threshold of 0.05 computed phenome-wide (1433 conditions) . Four ofWe performed pattern analysis of the birth month \u2013 disease risk curves for the circulatory system conditions between MSH and CUMC (set of 108 conditions). This was done to ascertain whether or not the birth month \u2013 disease relationship was the same between the two institutions. We found that seven of nine CUMC findings had significantly similar patterns at MSH . More dehttp://www.cdc.gov/flu/about/season/flu-season.htm) containing the number of times each month was the peak month for a given flu season. This data was aggregated from 1982\u201383 through 2013\u201314We overlaid data on seasonal variation in vitamin D levels and flu diagnosis levels to identify trends that could imply a biological rationale for observed cardiovascular \u2013 birth month association patterns. Replication of novel research findings is critical to biomedical research1457Coronary arteriosclerosis, essential hypertension, angina and pre-infarction syndrome were all significantly associated with birth month at the phenome-wide level at both MSH (after adjusting for 1433 tests) and CUMC (after adjusting for 1688 tests). Their seasonal patterns were also significantly correlated , Fig. 2 Three conditions, atrial fibrillation, cardiomyopathy, and chronic myocardial ischemia, were significantly correlated between CUMC and MSH but were not significantly associated with birth month at the phenome-wide level at MSH. These conditions could be associated with birth month through their common comorbidities, namely essential hypertension, angina, coronary arteriosclerosis and pre-infarction syndromeThere are several additional reasons why results from CUMC and MSH may differ. Firstly, many of these circulatory system conditions are comorbid with one another Several mechanisms have been proposed previously that could explain the relationship between cardiovascular conditions and birth month24et al.et al.A limitation of our approach includes the exclusive use of diagnosis codes collected during the clinical encounter and recorded in EHRs. Therefore, we know that these patients were diagnosed with a cardiovascular condition, but they may not necessarily have had cardiovascular disease. We used only diagnosis codes in order to properly validate the original results presented in Boland The condition most correlated between MSH and CUMC was coronary arteriosclerosis , which iIn this replication study, we study the cardiovascular condition \u2013 birth month relationship at another institution (MSH) with the same climate and urban setting as CUMC (both located in NYC). We found that seven of nine cardiovascular conditions associated with birth month at CUMC were also significantly correlated with the patterns revealed at MSH. These findings support the relationship between risk for cardiovascular conditions and birth month. We describe two leading putative mechanisms behind this relationship: maternal infection and low vitamin D levels. We also discuss the possibility of a combined mechanism  underlying the disease \u2013 birth month observations. Further study is required to identify the particular environmental and developmental mechanisms driving the observed associations.How to cite this article: Li, L. et al. Replicating Cardiovascular Condition-Birth Month Associations. Sci. Rep.6, 33166; doi: 10.1038/srep33166 (2016)."}
+{"text": "Despite a vast literature examining semantic impairment in Alzheimer's disease (AD), consensus regarding the nature of the deficit remains elusive. We re-considered this issue in the context of a framework that assumes semantic cognition can break down in two ways: (1) core semantic representations can degrade or (2) cognitive control mechanisms can become impaired [1]. We hypothesised and confirmed that the nature of semantic impairment in AD changes with disease severity. Patients at mild or severe stages of the disorder exhibited impairment across various semantic tasks but the nature of those deficits differed qualitatively for the two groups. Commensurate with early dysfunction of the cognitive control, temporoparietal-frontal-cingulate network, characteristics of deregulated semantic cognition were exhibited by the mild AD cases. In contrast, the severe AD group reproduced features of additional degradation of core semantic representations. These results suggest that spread of pathology into lateral anterior temporal lobes in later stage AD produces degradation of semantic representations, exacerbating the already deregulated system. Moreover, the dual nature of severe patients\u2019 impairment was highlighted by disproportionately poor performance on tasks placing high demand on both conceptual knowledge and control processes\u2013e.g., category fluency."}
+{"text": "Legionella pneumophila we uncovered that the host metabolic checkpoint kinase Mechanistic target of rapamycin (MTOR) is a central regulator of the pathogen niche expansion program.A ruptured bacteria-containing organelle within the cytosol of an infected eukaryotic cell frequently initiates host defense responses that restrict pathogen replication. Therefore, source for lipids must be found to accommodate the organelle membrane expansion required to support bacterial replication. How host cells are manipulated to provide lipids for the expansion of pathogen-occupied organelles is not well understood. By investigating the interaction between macrophages and the human pulmonary pathogen  Legionella suppress MTOR to promote inflammation through a host-driven mechanism. In our recent study :e1006088) we identified the Toll-like Receptor (TLR) adaptor Myeloid differentiation primary response gene 88 (Myd88) as a critical factor mediating the host-induced MTOR suppression in Legionella infected BMMs. Deletion of Myd88 unmasked an unexpected ability of L. pneumophila to activate and sustain MTOR function even in the absence of growth factors or TLR stimulation. BMMs harboring pathogenic L. pneumophila elicited robust phosphorylation of the ribosomal S6 protein (a downstream substrate of the MTOR pathway) that was sustained for the entire intracellular replication cycle of the bacterium. In sharp contrast, uninfected neighboring cells remained quiescent . Further investigation revealed that one or more protein(s) encoded by L. pneumophila is translocated through the bacterium Type IVb secretion system (T4bSS) directly into the host cytosol to activate MTOR in a phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)-dependent manner. The Legionella T4bSS manipulates host functions through delivery of ~300 bacterial effector proteins into the host cytosol and is critical for virulence. Thus, it appears that in L. pneumophila-infected macrophages the host and the pathogen are locked in a molecular tug-of-war over MTOR function, where suppression favors the host and activation likely favors the pathogen.Previously, we uncovered that mouse bone marrow-derived macrophages (BMMs) infected with pathogenic Legionella was revealed in part because in MTOR studies cells are generally serum-starved prior to stimulation. Under those conditions, membrane biogenesis requires de novo lipogenesis or lipids recycling through autophagy. Blocking MTOR function in Legionella infections through various approaches destabilized the Legionella-containing vacuole (LCV), led to its premature rupture and the release of bacterial products into the host cytosol, which in turn activated a host cell death response. Culture supplementation with serum but not delipidated serum maintained LCV integrity and blocked the host cell death response implicating a lipids shortage as the likely cause for the loss of LCV integrity under MTOR suppression conditions. Because Legionella efficiently blocks autophagy through LC3 delipidation, the role of MTOR-dependent de novo lipogenesis was investigated. The transcription factors Serum Response Element Binding Protein 1 and 2 (SREBP1/2) are key lipogenesis regulators downstream of MTOR. Legionella infection induced Srebf1 expression as well as SREBP1/2-regulated genes in infected macrophages. Similarly to MTOR suppression, SREBP1/2 inhibition produced a LCV instability phenotype, which was complemented by dietary lipids. Taken together these data indicates that Legionella manipulates the PI3K-MTOR-SREPB1/2 axis to sustain MTOR-dependent lipogenesis to accommodate LCV expansion for optimal intracellular replication.The benefit of sustained MTOR activity for de novo lipogenesis are functionally redundant for LCV growth in mammalian macrophages one might wonder why Legionella has retained the capacity to activate MTOR? MTOR anabolic regulation is conserved in unicellular amoebae, the natural hosts for Legionella, which inhabit aquatic environments and lack constant source of dietary lipids. MTOR inhibition reduced Legionella intracellular replication in Acanthamoeba castellanii but only moderately. This observation raises the question if Legionella could manipulate host lipogenesis independent of MTOR and SREBPs or perhaps LCV expansion can be accommodated from pre-existing membranes . In principle, fusion with other membrane-bound organelles could facilitate LCVs expansion. Indeed, Legionella T4bSS effectors repertoire include proteins that promote recruitment and fusion of the LCV with the early secretory pathway as well as the endoplasmic reticulum. The ER is a major biosynthesis compartment for most cellular lipids and its large membrane reservoir could potentially accommodate some LCV expansion even in the absence of de novo lipogenesis. Considering that we identified a number of Legionella species that replicate intracellularly but do not activate MTOR it would be important to determine the different mechanisms by which LCV compartments expand.If dietary lipids and Legionella infections could be an excellent model system to decipher how MTOR controls SREBP1/2 and lipogenesis - a key cellular process that is still poorly understood in primary macrophages. Our work points to a rapamycin-insensitive MTOR-dependent mechanism although additional work is needed to elucidate which MTOR complex is involved and the precise mechanism. Host membranes are key features for successful intracellular survival of vacuolar pathogens and we uncovered that subversion of MTOR by L. pneumophila is one mechanism by which the host membrane biogenesis program can be manipulated for niche homeostasis."}
+{"text": "Cardiac MRI is frequently used in the diagnosis of cardiac amyloidosis. Feature tracking is a novel method of analyzing myocardial strain at the myocardial borders. We investigated myocardial deformation mechanics of both the right and left ventricles in patients with Multiple myeloma with suspected cardiac amyloidosis.Comprehensive strain analysis was performed in 46 patients with multiple myeloma with suspected cardiac amyloidosis. MRI strain by feature tracking was measured using 2D cardiac performance analysis MR software . Global longitudinal strain (GLS) was obtained obtained from averaging longitudinal strains of apical 4-, 2- and 3-chamber views. Global circumferential strain (GCS) was obtained from averaging circumferential strains of the basal, mid and apical short axis views. Endocardial and epicardial contours were analyzed separately. Right ventricular GLS was derived from apical 4 chamber view, only endocardial contour was analyzed.Table 1 depicts the MR characteristics of the cohort. Normal LV wall thickness was present in 47% with biopsy proven cardiac amyloidosis. GLS and strain rate were significantly reduced in the epicardial and endocardial layers. There was no statistically difference in radial and circumferential strain as well as right ventricular GL strain. Segmental GL strain analysis showed typical apical sparing pattern in the endocardium but not in the epicardium.This feature tracking MRI analysis sheds light on strain mechanics in a cohort of early cardiac amyloidosis with a significant number of cases with normal LV wall thickness. Global longitudinal strain was affected earlier than radial and circumferential strain. Based on the pattern of apical sparing, amyloidosis affects epicardial strain earlier and without segmental variation compared to endocardial strain."}
+{"text": "Investigators from four European tertiary care hospitals  performed a case-control study of children and adolescents aged 6 to 17 years diagnosed with primary headaches in the emergency department by a pediatric neurologist using the validated ICHD-3 criteria. Investigators from four European tertiary care hospitals  performed a case-control study of children and adolescents aged 6 to 17 years diagnosed with primary headaches in the emergency department by a pediatric neurologist using the validated ICHD-3 criteria. They enrolled 648 controls and 424 cases (257 patients with migraine and 167 with tension-type headache). Investigators masked to a patient\u2019s group allocation diagnosed functional gastrointestinal disorders using the Rome III diagnostic criteria. Eighty-three (32%) children and adolescents in the migraine group were diagnosed with functional gastrointestinal disorders compared with 118 (18%) in the control group (p<0\u00b70001). Multivariable logistic regression showed a significant association between migraine and three gastrointestinal disorders: functional dyspepsia, irritable bowel syndrome and abdominal migraine. The authors concluded that correct recognition would have an impact on the diagnosis and therapeutic management of these pediatric gastrointestinal disorders. [COMMENTARY. This well conducted multicenter trial included all functional gastrointestinal disorders defined according to ROME III criteria. However, among digestive afflictions, celiac disease (CD) deserves particular attention. CD patients may exhibit a myriad of extra-intestinal symptoms, which includes neurological symptoms such as migraine. Studies report a high frequency of migraines in patients with CD and vice versa, and describe the beneficial effect of a gluten-free diet in these cases . Also, tOn the other hand, recent findings regarding the role of the gastrointestinal microbiota in the gut-brain axis suggests that an unbalanced gut flora (i.e. dysbiosis) can be associated with neurological diseases like migraine. Enhanced pro-inflammatory immune responses have been reported with intestinal disorders associated with dysbiosis and increased intestinal permeability (just like IBS and celiac disease) as well as in migraine patients . Evidenc"}
+{"text": "A 60-year-old Polish male was admitted into our hospital with complaint of right-sided lower extremity weakness. CT of head showed a left frontal 2.6 \u00d7 1.5 cm mass. Staging work-up did not show any other associated lesions in the chest or abdomen. Brain tumor was resected with histology consistent with large cell neuroendocrine carcinoma with most likely lung primary because of TTF-1 positivity. Following recovery from surgery, he had external beam radiation therapy to the brain and systemic chemotherapy with four cycles of cisplatin/etoposide. Patient is alive and doing well 6 months post diagnosis with no evidence of recurrence. Large cell neuroendocrine carcinomas (LNECs) are rare malignant high-grade neuroendocrine tumors with clinical outcomes that mirror that of small cell carcinomas. LNEC of the lung is still classified under non-small lung cancers according to WHO classification but they are managed in a similar manner as small cell lung cancer (SCLC) because of poor clinical outcomes compared to other non-small cell lung cancer (NSCLC).There are few case reports of metastatic neuroendocrine tumor of the brain without radiologically detected primary. These together with metastatic neuroendocrine tumors of other sites with unknown primary are said to arise from occult clinically undetected primary sites like lung and GI.This case highlights the different ways of presentation of these tumors and also management challenge in terms of further systemic chemotherapy for resected oligometastatic disease with no primary lesion detected.A 60-year-old Polish male presented to our hospital because of worsening right lower extremity weakness for about a month. He has had chronic low back pain ongoing for a couple of years. No problems with bowel or bladder movement were found. He has 20-pack-pear history of cigarette smoking.Physical examination was significant for mildly reduced power in his right lower extremity with positive Babinski bilaterally.CT of head showed a left frontal 2.6 \u00d7 1.5 cm mass , 2. MRI Further staging work-up which includes CT of chest and abdomen, MRI of cervical and thoracic spine and CT of lumbar spine was unremarkable aside degenerative disease of lumbar and cervical spine. He was also noted to have an elevated PSA of 55 ng/mL as part of outpatient work-up for chronic lower back pain.He was started on intravenous steroids and eventually had MRI-guided stereotactic left parietal craniotomy with tumor resection.Pathologic examination of resected tumor showed large cells growing in sheets and nests  There waThis patient, however, did not have any lung lesion noted on imaging. He did not have any significant pulmonary symptoms either.He had external beam radiation therapy once recovered from surgery. He also had four cycles of cisplatin/etoposide after completion of radiation therapy.MRI of brain done 3 and 6 months post diagnosis has not shown any evidence of recurrence.The patient also had prostate biopsy which showed prostatic adenocarcinoma Gleason 4 + 3 = 7. He was started on androgen deprivation therapy while being treated for metastatic neuroendocrine tumor and will start radiation therapy soon for prostate cancer.LNEC is a rare high-grade neuroendocrine tumor that has been described in the lungs and other extra pulmonary sites -3. In 19Neuroendocrine tumors of unknown primary constitute less than 5% of all cancer of unknown primary sites and 10-13% of all neuroendocrine tumors -11. MostFew cases of metastatic neuroendocrine tumor of the brain without radiologically detected primary have been described in the literature -14. SomeMetastatic neuroendocrine tumors of unknown primary are said to be from occult clinical undetectable primary sites like lung, GI and other sites. Some patients with these kinds of tumors (isolated lymph node metastasis) constitute a distinct group with unknown primary carcinoma with relatively favorable prognosis .Survival after diagnosis of cerebral metastasis is dependent on some parameters that include age, performance status, extent of extracranial disease as well as the primary diagnosis . The lat"}
+{"text": "Interventricular septal hematoma is a rare complication of retrograde chronic total occlusion (CTO) percutaneous coronary interventions (PCI) with a typically benign course. Here we report two cases of interventricular septal hematoma and coronary-cameral fistula development after right coronary artery (RCA) CTO-PCI using a retrograde approach. Both were complicated by development of ST-segment elevation and chest pain. One case was managed actively and the other conservatively, both with a favorable outcome. Interventricular septal hematoma is a rare complication of retrograde chronic total occlusion (CTO) percutaneous coronary interventions (PCI) with a typically benign course . Here weA 46-year-old female with Canadian Cardiovascular Society (CCS) class IV angina symptom despite maximal medical therapy was referred for coronary angiogram and was found to have right coronary artery (RCA) chronic total occlusion (CTO) .RCA CTO percutaneous intervention was performed using right radial and right femoral artery dual catheter approach. The RCA was engaged with 6 French Judkins right guide catheter; the right femoral artery was cannulated with a 6 French sheath and the left main was engaged with a 6 French XB 3.5 guide catheter. With standard antegrade wire escalation technique, the CTO could not be crossed . The treAfter removal of retrograde Corsair and guidewire, angiogram of the LAD and RCA revealed Ellis Type III cavity spilling perforation of the second septal branch into the right ventricle (RV) Figures . The patThe next morning, she was taken back to the cardiac catheterization lab and repeat coronary angiography appeared unchanged. Given the patient's symptom and tachycardia, the decision to proceed with exclusion of the septal artery to RV perforation was made. Bilateral femoral access was obtained and similar guide catheters were used to engage the left and right coronary systems. The perforated collateral septal branch was accessed with workhorse type coronary guidewires from the LAD and RCA. Corsairs were then advanced into the proximal segment of the collateral vessel and negative suction was applied for approximately ten minutes . This maA 66-year-old male with known coronary artery disease and a chronically occluded mid right coronary stent presented with non-ST-segment elevation myocardial infarction. The culprit lesion was the RCA proximal to the remotely deployed and chronically occluded bare metal stent resulting in right ventricular ischemia. An attempt to recanalize the RCA was unsuccessful. He was treated medically but had persistent Canadian Cardiovascular Society (CCS) class III angina and was referred for RCA CTO-PCI.The antegrade approach was unsuccessful because the wire repeatedly tracked beside the stent; therefore, the retrograde approach was used. The in-stent lesion was successfully crossed with reverse cart technique in the proximal RCA . The RCAOn the night after his PCI, he developed severe chest pain, anterior ST-segment elevation, and nonsustained ventricular tachycardia . Repeat The following day, a contrast enhanced transthoracic echocardiogram confirmed a new large interventricular hematoma. The end systolic dimensions were 5.3 \u00d7 2.6\u2009cm . There wTen days after PCI he was clinically stable and angina-free. An echocardiogram revealed a smaller intramyocardial septal hematoma (3.6 \u00d7 1.3\u2009cm) with a fistulous tract in the septum that entered the apical right ventricle. At 3 months a subsequent echocardiogram showed resolution of the interventricular septal hematoma  and the CTO-PCI frequency is increasing . In a reSeptal collateral perforation and hematoma formation is a rare complication after retrograde CTO-PCI  and beliWhile the management of these cases remains controversial and undefined by large experience some guidance is needed as the frequency of CTO-PCI and the retrograde approach increases. Taking our observations together with previous reports we suggest the following when retrograde CTO-PCI results in septal hematoma formation . InpatiePatients who remain asymptomatic can be managed conservatively and dismissed 24\u201348 hours after CTO-CPI. Among those with symptoms of hematoma expansion, those without hemodynamic compromise can also be monitored with serial echocardiography and dismissed after 3-4 days of additional observation in the absence of additional evidence of hematoma expansion or significant shunt formation. We recommend more aggressive management with hematoma exclusion for those with hemodynamic compromise, evidence of additional hematoma expansion, pericardial effusion, tamponade, or significant shunt development (Qp/Qs > 1.5\u2009:\u20091). Early dismissal after definitive management is not unreasonable and may be useful in avoiding prolonged inpatient observation, but the long term outcome of this approach is unknown. After successful CTO-PCI, exclusion of septal hematoma can be accomplished by local occlusion of the contributing septal perforator or occlusion of the origin of the septal with a covered stent. Both the donor and recipient vessel side of the collateral must be occluded to prevent flow into the hematoma. After unsuccessful CTO-PCI only the donor limb of the collateral needs to be occluded. Local occlusion of either limb of the septal can be accomplished with aspiration (as in Case 1) through a microcatheter or coiling with a bailout strategy of covered stenting. We preferentially use aspiration and coils in an effort to avoid the long term risk of covered stent restenosis or thrombosis which is as high as 30% in some series . AdditioSeptal hematoma formation is an unusual but potentially dangerous complication of the increasingly used technique of retrograde CTO-PCI. The case reports to date provide some clues as to the best management of this event. We propose an observation and treatment algorithm and recommend serial imaging with contrast echocardiography to assist in the decision-making during these rare but important events.RCA CTO PCI was complicated by large interventricular septal hematoma \u201c5.3 \u00d7 2.6\u2009cm\u201d at end systole (video 1), with coronary-ventricular fistula (5\u2009mm in diameter) (Video 2). At 3 months post PCI a subsequent echocardiogram showed resolution of the hematoma (Video 3)."}
+{"text": "Two patients with longitudinally extensive myelopathy were initially biopsied for suspected spinal cord tumors. Both patients were later diagnosed with neuromyelitis optica spectrum disorders (NMOSD) supported by their AQP4-seropositivity. Pathological review of both biopsies revealed demyelinated lesions with thickened vessel walls and tissue rarefaction. Immunohistochemical staining demonstrated findings compatible with acute NMOSD lesions in one case while the other case exhibited findings consistent with chronic NMOSD lesions. A pre-biopsy differential diagnosis of longitudinally extensive spinal cord tumors should include NMOSD. Specific biopsy features, such as cystic changes with vascular wall thickening and astrocyte injury, should raise suspicion for NMOSD. No clinical response was observed with high-dose methylprednisolone.A 14-year-old girl presented with bilateral lower limb paresthesia and weakness that progressed over a few days. Nine months later, she developed upper extremity weakness with sensory dysfunction at the level of C7 that worsened in a step-wise manner over a period of 3 months to paraplegia, sensory loss and sphincter dysfunction. Spinal MRI  showed tRe-assessment of the biopsied spinal cord specimen  revealedA 47-year-old woman presented with left shoulder pain, motor weakness and paroxysmal spasms in her left upper extremity over a month period. Spinal cord MRI demonstrated an edematous T2 hyper-intense lesion extending from the medulla to C7 with central contrast enhancement. Brain MRI was normal. She was treated with high-dose methylprednisolone for five days with a partial recovery. Four months later, acute transverse myelopathy developed over a few days with paraparesis, loss of sensation in both legs and sphincter dysfunction. A second spinal MRI revealed a caudal extension of the lesion to the T2 level with marked swelling and gadolinium enhancement . The patRe-assessment of the spinal cord specimen  revealedThese two case reports highlight the importance of a proper diagnostic work-up in patients with acute LETM to differentiate inflammatory myelitis from spinal tumors. Serum testing for AQP4 antibodies should be considered before invasive procedures.7 Spinal cord-biopsied lesions in patients with NMOSD are uncommon for obvious reasons, and the opportunity to evaluate NMOSD pathology features in vivo is rare. We identified only one prior case report of a biopsied patient with LETM and AQP4 antibodies, and these authors did not perform a detailed pathological study to analyze features of NMOSD.8Most of our understanding of NMOSD pathology derives from post-mortem studies.7 NMOSD findings are quite distinct from multiple sclerosis (MS) lesions and clearly indicate immune-mediated astrocytopathy.9 The pathological findings in the first case are good examples of the active NMO lesions associated with complement activation and granulocyte infiltration described in a recently published study identifying six lesion types.10 In contrast, the second case only demonstrated pathological findings compatible with the chronic NMOSD lesions in post-mortem cases, and the differential diagnosis of NMOSD based solely on the pathological findings is challenging because of the similarity of chronic NMO lesions to another demyelinating diseases such as MS. The elevated expression of AQP4 in the demyelinated lesions is indicative of reactive fibrous astrogliosis that can also be observed in MS, whereas speckled necrotic spots with decreased AQP4 staining and vascular hyalinization are consistent with astrocyte dystrophy found in NMO. This sample may have been taken from the periphery of the active lesion, or the biopsied area may have been affected by a previous attack.Acute NMOSD lesions are characterized by an extensive loss of AQP4 and GFAP staining with activated complement and IgG deposition in perivascular regions, in addition to relatively preserved myelinated fibers. In regions with severe inflammation, necrotic changes and perivascular cuffing are observed, predominantly including neutrophils, eosinophils, lymphocytes and macrophages.Although we do not under any circumstances recommend using spinal cord biopsy as a substitute for AQP4-antibody testing to diagnose NMOSD, the AQP4-antibody result may be false negative with some assays and the diagnosis may be arrived at incidentally during the work-up of spinal tumors. NMOSD should be suspected in biopsies with features such as cystic changes with vascular wall thickening and astrocyte rarefaction. The findings can range from the very acute to chronic inactive lesions depending on the evolutionary stage of the biopsied area. Nevertheless, additional immunohistochemistry staining is required to identify other features compatible with the typical pathological findings described in NMOSD."}
+{"text": "Tuberculosis (TB) occurring in solid organ transplantation (SOT) is associated with significant morbidity and mortality usually due to delays in diagnosis, drug toxicity encountered with antimycobacterial therapy, and drug-drug interactions. TB in SOT patients may mimic other infectious and noninfectious posttransplant complications such as posttransplant lymphoproliferative disorder (PTLD) and systemic cytomegalovirus infection. Immune reconstitution inflammatory syndrome (IRIS) is a host response resulting in paradoxical worsening of an infectious disease which occurs after the employment of effective therapy and reversal of an immunosuppressed state. We describe the development of immune reconstitution inflammatory syndrome (IRIS), a unique complication occurring during the treatment of extrapulmonary tuberculosis occurring after transplant which resulted from decreasing immunosuppression in a patient who received Alemtuzumab induction therapy. Although (IRIS) has been originally described in HIV/AIDS patients receiving highly active antiretroviral therapy (HAART), solid organ transplant recipients with diagnosed or occult TB whose immune system may undergo immune reconstitution during their posttransplant course represent a new high risk group. SOT recipients have a high risk of developing TB during the posttransplant period usually due to reactivation of latent infection , 2. ExtrA 32-year-old Asian woman received a successful two-antigen mismatched deceased donor renal transplant. She underwent Alemtuzumab and Methylprednisone induction. The immediate posttransplant course was uncomplicated. She was discharged with a nadir serum creatinine of 0.9\u2009mg/dL. Immunosuppression consisted of Mycophenolic acid delayed release (MMF) 720\u2009mg twice daily and Tacrolimus therapy (target trough 9\u201312\u2009ng/mL). Three months after transplant the patient developed elevated liver enzymes associated with fever of 102\u00b0F. Initial blood cultures, CMV, parvovirus B-19 and EBV by quantitative polymerase chain reaction were negative. Computed tomographic imaging studies (CT) revealed periaortic lymphadenopathy . Liver bFever, abdominal pain, and fullness slowly resolved over the course of therapy. Repeat CT imaging of the abdomen revealed resolving iliopsoas fluid collections . After 4SOT recipients have a high risk of developing TB during the posttransplant period usually due to reactivation of latent infection , 2, 4. MRifampin induces hepatic and intestinal CYP3A4 resulting in protracted difficulty in maintaining therapeutic drug levels of calcineurin inhibitors (CNI), inhibitors of the mammalian target of Rapamycin (MTOR), and corticosteroids , 12. RifIRIS can be described as a pathological hyperinflammatory host response when reversal of either pathogen or iatrogenic immunosuppression occurs resulting in paradoxical worsening of disease during effective antimicrobial therapy . IRIS haIn SOT undergoing treatment for active TB, IRIS usually occurs within 3 months . Risk faAlthough a working paradigm of the pathophysiology of IRIS occurring in the posttransplant setting has not been established, current evidence suggests an imbalance between pathogen directed host inflammatory Th1, Th17) and anti-inflammatory  effector cells resulting in hyperinflammatory response to a pathogen with ensuing tissue damage . Both MT and antiIt is important to also consider epidemiological data involving TB to further examine high risk population subgroups within which our patient resides. According to the Centers for Disease Control and Prevention (CDC), one-third of the world's population is infected with TB . In 2015Immune Reconstitution Inflammatory Syndrome (IRIS) has primarily been studied in the context of HIV/AIDS-associated paradoxical exacerbation of infection symptoms after recovery of an immunosuppressed state. Although there have been increasing reports of IRIS occurring in the setting of SOT and infections with MTB and a variety of opportunistic infections, we believe that IRIS is an underrecognized complication in this high risk group. This report demonstrates the difficulties encountered when IRIS develops in a SOT recipient during the management of extrapulmonary MTB infection by reduction in immunosuppression and institution of appropriate antimycobacterial therapy. It is possible that decreasing immunosuppression may have further exacerbated the development of IRIS in this patient. The potential for the development of IRIS in SOT with MTB may have an impact on treatment strategies for physicians managing transplant immunosuppression. Clinicians should therefore be cognizant of the potential of IRIS not only in HIV/AIDS cases but also in solid organ transplant patients. Caution should be used in decreasing immunosuppression in SOT patients undergoing treatment for MTB. Developing greater awareness among treatment providers about the paradoxical nature of IRIS is essential for the safe and proper management of patients that have undergone therapeutic immunosuppression for transplantation. What is clear is that further investigation into IRIS associated with solid organ transplantation must be completed to develop not only our understanding but also appropriate treatment protocol for this complex phenomenon."}
+{"text": "Erdheim-Chester disease (ECD) is a rare non-Langerhans cell histiocyte disorder most commonly characterized by multifocal osteosclerotic lesions of the long bones demonstrating sheets of foamy histiocyte infiltrates on biopsy with or without histiocytic infiltration of extraskeletal tissues. ECD can be difficult to diagnose since it is a very rare disease that can affect many organ systems. Diagnosis is based on the pathologic evaluation of involved tissue interpreted within the clinical context. Patients who have the BRAF V600E mutation are treated first line with vemurafenib. For those without the mutation with symptomatic ECD, conventional or PEGylated interferon alpha is recommended. For patients who are either intolerant or nonresponsive to interferon alpha, systemic chemotherapy with or without corticosteroids can be used. We present a rare case of Erdheim-Chester disease with concurrent Langerhans cell histiocytosis which occurs in only one fifth of the cases and often presents as a diagnostic and therapeutic challenge. We present the case of a 47-year-old Caucasian male who initially presented to the primary care physician 6 years ago with the chief complaint of left ear fullness of 2 weeks' duration. The patient also noticed that the left ear fullness was associated with tearing from the right eye. The patient was initially treated conservatively, with no subjective improvement in his symptoms. He underwent imaging studies which revealed a left mastoid/middle ear fossa mass and a right orbital mass . Imaging2 weekly and prednisone 40\u2009mg/m2. Thereafter, he was started on monthly pulse prednisone and daily 6 mercaptopurine doses as maintenance therapy for 24 weeks.The surgical resection of the orbital mass was followed by six cycles of vinblastine 6\u2009mg/mThe patient was relatively stable until about three years ago when he started experiencing diplopia in the right eye. CT scans revealed extensive bilateral intraconal enhancing soft tissue, infiltrative soft tissue involving the right sphenoid wing with extension into the pterygopalatine fossa and right temporal fossa, and enhancing soft tissue identified within bilateral frontal sinuses . Right oThe patient was started on PEGylated interferon alpha to be given as 180\u2009mcg subcutaneously weekly. Repeated CT evaluations over the next 3 years demonstrated no evidence of progression of disease on PEGylated interferon alpha-2a therapy .About 6 months ago, the patient noticed a swelling on the frontal part of the scalp. MRI brain showed interval development of left calvarial mass lesion extending intracranially, associated with an epidural soft tissue component measuring 4\u2009\u00d7\u20091.5\u2009\u00d7\u20091.5\u2009cm . The patErdheim-Chester disease (ECD) is a rare form of non-Langerhans cells histiocytosis. Approximately 500 cases have been reported in the literature with far fewer cases occurring concurrently with Langerhans cell histiocytosis (LCH) . HoweverRecent studies have identified a high prevalence of the BRAF V600E mutation in patients with ECD. This gene is known to participate in oncogene-induced senescence . A 2014 The most common clinical manifestations of ECD depend on the site of involvement. Literature review of 259 patients diagnosed with biopsy-proven ECD identified the most common presentations including bone pain 26%), neurologic features 23%), diabetes insipidus (22%), and constitutional symptoms (20%) [%, diabet%, neurolPrognosis is generally poor, and no definitive cure for the disease is currently available. Cardiovascular and CNS involvement is usually associated with the worst prognosis . RetrospDefinitive diagnosis of ECD requires biopsy identifying infiltration of tissue by foamy mononucleated histiocytes with small nuclei. Rare multinucleated histiocytes known as Touton cells are also observed . Mild fiPrior to establishing treatment plans, patients require staging and genetic studies. Typical imaging consists of an MRI of the brain, an MRI or CT scan of the entire aorta, a cardiac MRI, a transthoracic echocardiogram, and a fluoro-d-glucose PET scan or CT scan of the chest, abdomen, and pelvis . RadioloIn the rare event of ECD diagnosis with asymptomatic disease with no objective evidence of CNS involvement or organ dysfunction, delaying treatment with adequate screening is reasonable . In patiPatients who carry BRAF V600E mutation should be considered for BRAF inhibitor therapy. Vemurafenib is a serine/threonine kinase inhibitor of activating point mutations in BRAF and was FDA approved for treatment of ECD on November 6, 2017 . EstimatPreviously regarded as first-line treatment, interferon alpha or PEGylated interferon alpha has the most robust supporting evidence for survival benefit in ECD . The larFor patients who are either intolerant or nonresponsive to interferon alpha therapy, alternative treatment options include systemic chemotherapy with or without corticosteroids. Typical regimens for LCH and theoretical treatment for ECD is a 24-week treatment plan comprising weekly vinblastine and etoposide for six weeks followed by vinblastine and etoposide every three weeks for the remaining duration of the treatment course . Use of Due to the rarity of the condition, only a limited number of drugs from clinical trials have become FDA-approved treatment regimens. Small case studies have noted the efficacy of anticytokine-directed therapy using agents such as anakinra (Il1 receptor antagonist), canakinumab (Il1 receptor antagonist), and infliximab (anti-TNF) \u201322. TociDisease monitoring is typically done at 3- to 6-month intervals with flouro-d-glucose PET scans. Once the disease stabilizes, PET scans can be done less frequently as per clinician discretion . As no bErdheim-Chester disease (ECD) is a rare non-Langerhans histiocyte disorder, most commonly characterized by multifocal osteosclerotic lesions of the long bones demonstrating sheets of foamy histiocyte infiltrates on biopsy with or without histiocytic infiltration of extraskeletal tissues. Since it is a very rare disease that can affect many organ systems, diagnosis can be challenging. Diagnosis is based on the pathologic evaluation of involved tissue interpreted within the clinical context. Not all patients with ECD require treatment at the time of diagnosis. Patients who are asymptomatic without evidence of central nervous system involvement or organ dysfunction can simply be observed. With vemurafenib becoming the first FDA-approved drug for the treatment of ECD, patients who possess BRAF V600E mutation should be considered for BRAF inhibitor therapy. In patients without the mutation or those who are intolerant to the drug, conventional or PEGylated interferon alpha is the recommended treatment. Further treatment options include the use of systemic chemotherapy with or without corticosteroids."}
+{"text": "Acute angle closure glaucoma (ACG) in the setting of polypoidal choroidal vasculopathy (PCV) is a catastrophic complication that has been documented infrequently in literature. Ours is the second only report that describes hemorrhagic choroidal detachment as an event leading to acute angle closure glaucoma in PCV patients and the first one to describe the use of diode cyclophotocoagulation (CPC) for this condition. The purpose of this article is to familiarize readers with this entity that has an extremely dismal visual prognosis. Ours is a descriptive case report of two patients with PCV complicated by sudden onset hemorrhagic choroidal detachment (CD) and acute ACG. Both patients had severe pain with no perception of light at presentation with an acute angle closure attack. Both underwent diode CPC for pain relief and control of intraocular pressure (IOP). Both our patients did not regain any vision, but their pain was relieved by diode CPC. Both eyes eventually became phthisical. Acute ACG following massive hemorrhagic CD is a rare but grave complication of PCV, not amenable to treatment. Diode CPC is an effective palliative modality of management to achieve pain relief in such cases. The initial description of polypoidal choroidal vasculopathy (PCV) was given by Yanuzzi  in 1982 A 67-year-old female presented in July 2012 with defective vision in the right eye for six months. She was a known hypertensive and diabetic on treatment for both conditions for the last 15 years. There was no history of trauma, blood dyscrasias or use of antiplatelet or anticoagulant therapy. On examination, her best-corrected visual acuity (BCVA) was counting fingers at face in the right eye and 6/6 in the left eye. Intraocular pressure (IOP) by non contact tonometry (NCT) was within normal limits in both eyes. Anterior segment examination was unremarkable except for bilateral pseudophakia. Fundus examination of the right eye showed three hemorrhagic pigment epithelial detachments (PED) surrounded by serosanguinous fluid, while the fundus in the left eye was within normal limits. OCT of the right eye showed notched hemorrhagic PEDs with underlying polyps and surrounding subretinal fluid (SRF) suggestive of PCV Figure 1 . Based oA 71-year-old female known diabetic and hypertensive over the last 20 years presented in February 2012 with the complaints of poor vision in the left eye for the past three months. She was diagnosed to have PCV on ICGA done at an outside institution. On examination, her BCVA was 6/12 in the right eye and 6/36 in the left eye. IOP was within normal limits. Anterior segment examination in the right eye showed anterior chamber intraocular lens and the left eye showed nuclear sclerosis grade III. Fundus examination revealed moderate non proliferative diabetic retinopathy in the right eye and a large parafoveal subretinal hemorrhage with hemorrhagic PED in the left eye suggestive of PCV. The patient underwent phacoemulsification with posterior chamber intraocular lens (PCIOL) implantation in March 2012 in the left eye. Following this, ICGA-guided PDT with ranibizumab was planned, but before she could undergo this treatment, she developed an acute episode of pain with vomiting in April 2012. Her visual acuity at this visit was NPL and applanation tension was 44 mm Hg. Slit lamp examination showed epithelial corneal edema, shallow anterior chamber, PCIOL, and hemorrhagic CD in the anterior vitreous face. Anterior chamber angles were closed on gonioscopy and B Scan ultrasonography revealed annular hemorrhagic CD with \u2018kissing choroids\u2019 (Figure 2b Spontaneous massive subretinal hemorrhage is a known complication of PCV arising from rupture of thin walled choroidal vessels. Polypoidal choroidal vasculopathy causing massive suprachoroidal bleed and appositional hemorrhagic CD resulting in secondary angle closure glaucoma has been reported only once before . Table 1The proposed mechanism for secondary angle closure is that annular hemorrhagic CD can result in the forward displacement of the lens-iris diaphragm causing an angle closure attack , 9]. Th. Th9]. TThe authors declare that they have no competing interests."}
+{"text": "Embolization of the Amplatzer Septal Occluder (ASO) device  after percutaneous closure of atrial septal defect (ASD) is a rare and potentially catastrophic complication. Percutaneous retrieval of the embolized device is gaining ground as an acceptable method, although these patients are usually subsequently referred for open surgical closure of the ASD. We present a unique case of percutaneous retrieval embolized ASO device and placement of newer larger ASO device in a single procedure.  A 75-year-old female patient with history of persistent atrial fibrillation after multiple failed cardioversions and septum secundum type of ASD presented with worsening exertional dyspnea of six-month duration. She was previously intolerant to amiodarone. She underwent elective catheter based atrial fibrillation ablation followed by closure of the ASD during a combined percutaneous procedure. ASD closure was performed using a 16\u2009mm Amplatzer Septal Occluder (ASO) device after measuring the diameter of the defect at 15.4 \u00b1 1.0\u2009mm  with sizThe incidence of occluder device embolization after ASD closure is 0.55%\u20131.4% . Nearly Percutaneous retrieval of the embolized ASO device is still not widely performed. Also, there is no consensus regarding the appropriate timing of the reclosure of the ASD percutaneously after the retrieval of embolized device. With proper planning, percutaneous retrieval and placement of newer device can be safely performed in single setting. We also believe that, in patients with atrial fibrillation and atrial septal defect, it is reasonable to perform atrial fibrillation ablation prior to ASD closure."}
+{"text": "This change reflects the outcome of a recent multicenter international study demonstrating that negative Xpert MTB/RIF Assay results from either one or two sputum specimens are highly predictive of the results of two or three negative acid-fast sputum smears.*The Food and Drug Administration (FDA) has cleared the Xpert MTB/RIF Assay  with an expanded intended use that includes testing of either one or two sputum specimens as an alternative to examination of serial acid-fast stained sputum smears to aid in the decision of whether continued airborne infection isolation (AII) is warranted for patients with suspected pulmonary tuberculosis (Mycobacterium tuberculosis complex (MTBC), and two serial Xpert MTB/RIF Assay results detected 100% of AFB smear\u2013positive/MTBC culture-positive patients. In the setting of an overall prevalence of culture-confirmed pulmonary tuberculosis of 22.4% (14.2% [88 of 618] in the United States and 37.1% [127 of 342] outside the United States), a single negative Xpert MTB/RIF Assay result predicted the absence of AFB smear\u2013positive pulmonary tuberculosis with a negative predictive value of 99.7% (99.6%% in the United States and 100% outside the United States); for two serial negative Xpert MTB/RIF Assay results, the negative predictive value was 100%. These findings confirm the results from earlier reports . In addition, one or two Xpert MTB/RIF Assay tests detected 55% and 69%, respectively, of sputum specimens that were AFB smear\u2013negative but culture-positive for MTBC.When compared with the results of two or three serial fluorescent-stained acid-fast sputum smears, a single Xpert MTB/RIF Assay result detected approximately 97% of patients who were acid-fast bacilli (AFB) smear\u2013positive and culture-confirmed as infected with Updated labeling for the Xpert MTB/RIF Assay includes the recommendation that the decision whether to test one or two sputum specimens in determining the need for continued AII should be based on specific clinical circumstances and institutional guidelines. Clinical decisions regarding the need for continued AII should always occur in conjunction with other clinical and laboratory evaluations, and negative Xpert MTB/RIF Assay results should not be the sole basis for infection control practices. The revised label also includes information demonstrating that Xpert MTB/RIF Assay performance is similar in human immunodeficiency virus (HIV)-infected and HIV-uninfected adults, although HIV-infected adults with pulmonary tuberculosis might be more likely to be AFB smear negative at presentation. The Xpert MTB/RIF Assay should not be used for decisions regarding the need for continued AII if MTBC has been detected by the Xpert MTB/RIF Assay or by other methods.MMWR report for additional information regarding the Xpert MTB/RIF Assay .Product labeling retains the recommendation that regardless of Xpert MTB/RIF Assay results, serial collection of sputum specimens for mycobacterial culture remains necessary because nucleic acid amplification testing does not detect all patients with pulmonary tuberculosis, and recovery of organisms for further characterization and drug-susceptibility testing is needed when MTBC is present. Concomitant acid-fast microscopy of serial sputum specimens is also needed when excluding nontuberculosis mycobacterial disease. Readers are encouraged to review the updated product labeling and the previous related"}
+{"text": "Rice hoja blanca tenuivirus. The sequenced isolate was obtained by insect vector transmission from a symptomatic rice sample grown in Colombia. Sequence data from the four RNA components were obtained by deep sequencing (Illumina), and infections were confirmed by enzyme-linked immunosorbent assay and Sanger sequencing.We describe here the complete genome of  Rice hoja blanca tenuivirus (RHBV) is a multipartite single-stranded, negative-sense RNA virus belonging to the genus Tenuivirus. It causes hoja blanca disease (HBD) in rice (Oryza sativa L.), which has been reported as affecting rice yield in Colombia since 1935. The virus was first described in 1983 (Tagosodes orizicolus M\u00fcir (Hemiptera: Delphacidae), which can also be infected by the virus . Compared to the GenBank nonredundant database using BLASTx and BLASTn searches, 33.33% of the total number of contigs showed significant similarity with different viral sequences reported for RHBV. RHBV encodes a typical tenuivirus genome arrangement compared to Rice stripe tenuivirus (RSV), the type species of the group  using g TRIzol , and deeassembly  and MAQ he group . It is cMG566074 (RNA1), MG566075 (RNA2), MG566076 (RNA3), and MG566077 (RNA4).The complete genome sequences reported here have been deposited at GenBank under the accession no."}
+{"text": "A two-year-old female presented to the emergency department with facial lacerations after an attack by the family canine (Boxer breed). The exam revealed a stellate laceration on the cartilage of her left pinna, blood in the ear canal, left-sided facial droop, and inability to close her left eye . ComputeTemporal bone fractures can result in facial nerve paresis/paralysis if CN VII is involved.4What do we already know about this clinical entity?The thin temporal bones of children are susceptible tohigh-pressure injuries associated with dog bites, often resulting in damage to important structures such as cranial nerve VII.What is the major impact of the image(s)?This image demonstrates that high-pressure injuries from canine teeth can result in significant intracranial pathology despite minimal skin defects.How might this improve emergency medicine practice?This image highlights the importance of imaging in cases of penetrating facial trauma from dog bites to avoid delayed diagnosis and facilitate early intervention."}
+{"text": "In this study, we demonstrate that a bioA mutant of Mycobacterium tuberculosis (Mtb\u0394bioA) is highly attenuated in the guinea pig model of tuberculosis when administered aerogenically as well as intradermally. Immunization with Mtb\u0394bioA conferred significant protection in guinea pigs against an aerosol challenge with virulent M. tuberculosis, when compared with the unvaccinated animals. Booster immunization with Mtb\u0394bioA offered no advantage over a single immunization. These experiments demonstrate the vaccinogenic potential of the attenuated M. tuberculosis bioA mutant against tuberculosis.Owing to the devastation caused by tuberculosis along with the unsatisfactory performance of the Bacillus Calmette\u2013Gu\u00e9rin (BCG) vaccine, a more efficient vaccine than BCG is required for the global control of tuberculosis. A number of studies have demonstrated an essential role of biotin biosynthesis in the growth and survival of several microorganisms, including mycobacteria, through deletion of the genes involved in  Mycobacterium bovis, has been widely administered since 1921. BCG protects children against severe forms of tuberculosis (TB) but demonstrates highly variable efficacy (0\u201380%) against adult pulmonary tuberculosis in different field trials with poor efficacy in high TB burden countries, in general  as early as 1 week post injection  bacillary load of Mtb\u0394bioA was observed in the organs when compared with BCG at 1 week post inoculation, the bacillary numbers of Mtb\u0394bioA rapidly declined to levels below that of BCG and were undetectable by 6 weeks. However, BCG showed some persistence in the spleen . Guinea pigs were challenged with aerosolized virulent M. tuberculosis Erdman strain at 12 weeks post primary immunization and protective efficacy was evaluated four weeks post challenge. The sham-immunized guinea pigs showed the maximum infection with a bacillary load of 6.85 log10 CFU in the lungs and 5.66 log10 CFU in the spleen  and in the spleen , when compared with sham-immunized controls. Mtb\u0394bioA vaccinated animals exhibited efficient control over the multiplication of virulent M. tuberculosis in the lungs and significantly reduced the bacillary burden by 1.504 log10 CFU (p <0.0001) when compared with sham-immunized animals  in the spleen when compared with the sham-immunized animals , the protection imparted was lower though not statistically different relative to single immunization  as compared to BCG vaccinated animals  average total granuloma score when compared with the animals vaccinated with BCG  when compared with sham-immunized animals  was shown to have contrasting replication capability in mice and primates .The figure depicts representative photographs of lungs, spleen and liver of guinea pigs following aerosol infection with (TIF)Click here for additional data file."}
+{"text": "The adequacy of vitamin D intake is necessary to optimize the bone health during the rapid growing phase of infancy. Vitamin D also affects many organs playing an important role in maintaining general health. Vitamin D deficiency may be associated with cardiovascular disease, diabetes, cancer, and autoimmune diseases .The incidence of vitamin D insufficiency and nutritional rickets has decreased in Turkey following the nationwide vitamin D prophylaxis programme undertaken by the Turkish Ministry of Health in 2005. This programme provides free vitamin D drops containing 400 IU daily for all children under 12 months of age . AlthougVitamin D prophylaxis dose might spark a debate in infants for maintaining general health. Further investigations would therefore be needed to clarify the optimal amount of vitamin D supplementation to the infants aged 0-12 months.Peer-review: Internal peer-reviewed.Financial Disclosure: The author declared that this study has received no financial support."}
+{"text": "Left ventricular myocardial strain has been described as a potentially useful technique for evaluation and risk stratification of a range of acquired and congenital heart diseases. Tagged acquisition by cardiac MRI has been considered the reference standard for determining myocardial strain; however, this method can be time consuming and the tagged lines may not be visible throughout the cardiac cycle. Tissue Tracking software (Circle Cardiovascular Imaging\u00ae) is a post-processing method which allows measurements of myocardial strain based on cine cardiovascular magnetic resonance images without the need for additional sequences. Augustine et al. (JCMR 2013) have previously reported reasonable agreement between Feature Tracking (Tom Tec\u00ae) measurements for circumferential strain and tagging. We aimed to perform a similar comparison between Tissue Tracking software and tagging on a small cohort of normal volunteers.Cardiac MRI studies were performed with a 1.5 T unit  on 7 normal volunteers. Short-axis tagged MR images of the left ventricle were analyzed using HARP software  by the same observer, blinded to results of the alternate method. Steady state free precession (SSFP) cine images were analyzed with Tissue Tracking software (Circle Cardiovascular Imaging\u00ae) by two observers in consensus. The 2D peak circumferential strain (%) obtained by both techniques were compared using Bland Altman analysis for each of the 16 cardiac segments based on the American Heart Association classification for short axis images.There was reasonably good correlation between tagged acquisition and Tissue Tracking software. A total of 94 data points were included. The Bland-Altman plot is shown in Figure Tissue Tracking software provides a good surrogate for calculating 2D peak circumferential strain (%). A larger cohort is needed to further validate this new capability."}
+{"text": "This is achieved by implementing a gallium grading towards the back contact into a CuInSe2 base material. We show that this modification significantly improves the open circuit voltage but does not reduce the spectral response range of these devices. Therefore, efficient cells with narrow bandgap absorbers are obtained, yielding the high current density necessary for thin film multi-junction solar cells.Multi-junction solar cells show the highest photovoltaic energy conversion efficiencies, but the current technologies based on wafers and epitaxial growth of multiple layers are very costly. Therefore, there is a high interest in realizing multi-junction tandem devices based on cost-effective thin film technologies. While the efficiency of such devices has been limited so far because of the rather low efficiency of semitransparent wide bandgap top cells, the recent rise of wide bandgap perovskite solar cells has inspired the development of new thin film tandem solar devices. In order to realize monolithic, and therefore current-matched thin film tandem solar cells, a bottom cell with narrow bandgap (~1\u00a0eV) and high efficiency is necessary. In this work, we present CuSe"}
+{"text": "Cancer cells secrete growth factors that induce proliferation, protect against apoptosis and the immune system or promote neo-angiogenesis . As theyA conceptual problem arises: a non-producer cell can exploit the growth factors secreted by its neighbouring producer cells without paying the cost of production; hence non-producers should have a proliferation advantage and spread in the population. How can intra-tumour cooperation be maintained then? Why do not non-producer mutants drive producer cells to extinction?In some cases, two clones producing one growth factor each can coexist if both are essential, because the two clones depend on each other , similarTargeted therapies aiming at impairing cooperation by blocking growth factors or their receptors  are pron"}
+{"text": "The goal of this study was to modify the BAC vector pBeloBAC11 so that genomic inserts contained in this vector could be subjected to bidirectional transposon-mediated nested deletions from the wild-type and mutant loxP 2272 site and a XhoI restriction enzyme sequence was designed and inserted at the SfiI restriction site located approximately 200 basepairs upstream of the lacZ gene in pBeloBAC11. Clones containing the desired insert were identified by XhoI restriction digests since an additional band was generated. This transposon-mediated deletion technology allows researchers to identify the boundaries of cis-acting elements and genes.An oligonucleotide containing a mutant  Fir. FirXhoIion Fig.  5]. Alt. AltXhoIe EBNA-1 . Utiliza* cannot be propagated in mammalian cells.pBeloBAC11 loxP"}
+{"text": "Retained intraocular foreign body (IOFB) is a major cause of visual loss following open globe injuries. Detecting the presence and accurate localization of IOFB in the setting of an open globe injury remains a challenge. There can be various mimics of intraocular IOFB on imaging including air, ocular calcifications, etc. Here, we describe a case of open globe injury wherein a retained perfluoro-n-octane bubble mimicked a retained intraocular foreign body. Retained intraocular foreign body (IOFB) is a major cause of visual loss following open globe injuries. Studies have shown that up to 40 percent of open globe injuries can have retained IOFB . Loss ofTo report a case of open globe injury wherein a retained perfluoro-n-octane bubble mimicked an intraocular foreign body necessitating a second surgery. A 10-year-old boy presented to the emergency with a history of blast injury. His visual acuity at presentation was 6/6 in the right eye and hand movements in the left. Ocular examination showed a full thickness corneal laceration measuring 10 mm passing through the center of the left cornea. He underwent corneal tear suturing with lens extraction as an emergency procedure by the cornea team Figure 1 . IntraopPenetrating injuries with a retained intraocular foreign body are an important cause of blindness among children. Studies have shown that the removal of intraocular foreign bodies within 24 hours from the time of trauma significantly reduces the risk of endophthalmitis . CT scanThis case emphasizes the need to exercise caution when making a diagnosis of an IOFB especially when the contours of the foreign body are smooth and regular.The authors declare that they have no competing interests."}
+{"text": "A 58 years old male with a long-standing history of HLA-B27 positive ankylosing spondylitis presented with increasing fatigue and dyspnea on exertion. He had left ventricular dysfunction and enlargement, flail right coronary leaflet of aortic valve with severe eccentric aortic insufficiency along with left ventricular non-compaction in echocardiography. The most common cardiac manifestations of ankylosing spondylitis are aortic insufficiency and conduction disturbances. Involvement of myocardium, in the form of dilated cardiomyopathy and restrictive cardiomyopathy, has also been reported. This case presents a very rare association of ankylosing spondylitis with non-compaction cardiomyopathy. More than half of patients also have peripheral joint involvement or enthesitis.+ ankylosing spondylitis presented with increasing dyspnea on moderate exertion and easy sense of fatigue. His joint pain was controlled effectively with non-steroidal anti-inflammatory drugs. He never smoked and the remaining of his medical history was unremarkable. Family history for cardiac or rheumatologic disorders was negative. On physical exam, he appeared tachycardic with a blood pressure of 135/60 mm Hg. Apical impulse was displaced to left and there was a diastolic murmur and S3 gallop on cardiac auscultation. In transthoracic echocardiography there was left ventricular enlargement with left ventricular end diastolic diameter of 7.2 cm and left ventricular end systolic diameter of 6.1 cm. Left ventricular ejection fraction was 32% (Supplementary Video 1). Right coronary cusp (RCC) of aortic valve (AV) was thick and fibrotic. RCC was flail causing significant defect in coaptation that yielded severe eccentric turbulent jet towards anterior leaflet of mitral valve (Supplementary Video 2). There was also biventricular non-compaction (A 58 years old male with a 16-year history of HLA-B27mpaction . Descend5 Cardiac involvement has long been recognized as an extra-articular manifestation of the disease and presents most commonly with aortic insufficiency and conduction abnormalities.5 Involvement of myocardium also reported, yet is not frequently encountered and remains less well recognized.7 Recently presence of left ventricular asynchrony has been shown in patients with ankylosing spondylitis.6 Cardiac involvement occurs more frequently in long-standing disease however they can precede skeletal symptoms.7 The prevalence of dilated cardiomyopathy in patients with ankylosing spondylitis is under-reported because it symptoms such as dyspnea on exertion may be attributed to the underlying disease. Restrictive cardiomyopathy secondary to amyloidosis has also been rarely been reported in patients with ankylosing spondylitis. Inflammatory processes and ensuing fibrosis have been implicated in the valvular dysfunction and conduction disturbances that associate with ankylosing spondylitis.8 In a recent study on patients with ankylosing spondylitis and no apparent cardiac involvement, increased aortic stiffness and decreased global myocardial performance have been reported which signifies the subclinical cardiac involvement in this group of patients.3Ankylosing spondylitis is a chronic inflammatory disease of the axial skeleton at large that predominantly affects young men.9 It is speculated that left ventricular non-compaction may happen as an adaptive mechanism to certain hemodynamic conditions. Chronic left ventricular volume overload may be a potential trigger for increased trabeculation of myocardium. It is unclear whether left ventricular non-compaction cardiomyopathy has occurred secondary to aortic insufficiency or independently in this patient. The association of non-compaction cardiomyopathy with ankylosing spondylitis remains exceedingly rare.Left ventricular non-compaction may arise from the arrest of trabecular remodeling that happens during early fetal life. It is an uncommon entity that may present in isolated form or in association with other cardiac or systemic conditions. Though it is commonly considered a congenital disorder, the acquired cases have also reported. Right ventricle is involved in less than 50% of cases. Three major clinical manifestations are heart failure, arrhythmias, and systemic embolic events.The local ethics committee approved the study.None.videos 1Click here for additional data file.videos 2Click here for additional data file.videos 3Supplementary file consists of videos 1, 2, and 3.Click here for additional data file."}
+{"text": "Semantic dementia (SD) implicates the anterior temporal lobes (ATL) as a critical substrate for semantic memory. Multi-modal semantic impairment can also be a feature of post-stroke aphasia (referred to here as \u201csemantic aphasia\u201d or SA) where patients show impaired regulatory control accompanied by lesions to the frontal and/or temporo-parietal cortices, and thus the two patient groups demonstrate qualitatively different patterns of semantic impairment [1]. Previous comparisons of these two patient groups have tended to focus on verbal receptive tasks. Accordingly, this study investigated nonverbal receptive abilities via a comparison of reality decision judgements in SD and SA. Pictures of objects were presented alongside non-real distracters whose features were altered to make them more/less plausible for the semantic category. The results highlighted a number of critical differences between the two groups. Compared to SD patients, SA patients: (1) were relatively unimpaired on the two alternative forced choice (2AFC) decisions despite showing a comparable degree of semantic impairment on other assessments; (2) showed minimal effects of the plausibility manipulation; (3) were strongly influenced by variations in the regulatory requirements of tasks; and (4) exhibited a reversed effect of familiarity\u2013i.e., better performance on less commonly encountered items. These results support a distinction between semantic impairments which arise from impaired regulatory processes  versus those where degraded semantic knowledge is the causal factor . SA patients performed relatively well because the task structure reduced the requirement for internally generated control. In contrast, SD patients performed poorly because their degraded knowledge did not allow the fine-grained distinctions required to complete the task."}
+{"text": "Hemidiaphragm paralysis secondary to phrenic nerve palsy is a well-recognised medical condition. There are few case reports in the literature documenting resolution of hemidiaphragm paralysis following cervical spine surgery. This case report documents our experience with one such case.  A 64-year-old man was referred to the orthopaedic service with right hemidiaphragm paralysis. He had a previous history of asbestos exposure and polio and was initially seen and investigated by the respiratory physicians. He also reported intermittent neck pain and an MRI scan showed right-sided cervical foraminal stenosis. He underwent posterior right C3/4 and C4/5 foraminotomies, and by three months postoperatively, his hemidiaphragm paralysis had resolved and his shortness of breath had also improved.  This report documents a unique case of resolution of hemidiaphragm paralysis following posterior unilateral cervical foraminotomies. The phrenic nerves (C3/4/5) supply motor function to the hemidiaphragms. The motor supply of each hemidiaphragm comes purely from the phrenic nerves, and so conditions affecting the phrenic nerve or its nerve roots cause hemidiaphragm paralysis. Hemidiaphragm paralysis secondary to phrenic nerve palsy is a well-recognised medical condition with multiple causes. However, there are few case reports in the literature documenting resolution of hemidiaphragm paralysis following the cervical spine surgery. The cases that have previously been described involve patients with concomitant tetraparesis treated with spinal cord decompression with or without foraminotomies. This case report documents resolution of hemidiaphragm paralysis and improved respiratory function with unilateral cervical nerve root decompression alone, a finding that has not previously been described.A 64-year-old man was referred to the orthopaedic service with right hemidiaphragm paralysis. He had initially presented to his general practitioner reporting subjective shortness of breath after stand-up paddleboarding. His past medical history was significant for asbestos exposure and polio. Chest radiograph revealed an elevated right hemidiaphragm Figures  and 2. AThe underlying cause for his hemidiaphragm paralysis, whether it was related to his cervical foraminal stenosis or postpolio syndrome, was indeterminant .After obtaining multiple subspecialist opinions, a decision was made to proceed with posterior right C3/4 and C4/5 foraminotomies accepting that this may not have any effect on his shortness of breath. Surgery proceeded uneventfully as did postoperative recovery. By three months postoperatively, his hemidiaphragm paralysis had completely resolved on chest radiograph, and his shortness of breath had also improved . CompariThe phrenic nerve originates from cervical nerve roots C3\u20135 with the dominant supply coming from C4. The phrenic nerves are the sole motor supply to the hemidiaphragms and also provide proprioceptive fibres to the central part of each hemidiaphragm. Common causes of phrenic nerve palsy include idiopathic, malignancy (primary lung tumour or metastatic disease), trauma , neuromuscular disease (polio or multiple sclerosis), inflammation (pneumonia or HSV), brachial plexus palsies, and direct compression (aortic aneurysm). However, the aetiology of diaphragmatic paralysis remains unidentified in more than two-thirds of patients .It is possible that these idiopathic cases are caused by unidentified nerve root compression in the cervical spine. Poliomyelitis can result in the degeneration of the anterior horn cells, innervating both hemidiaphragms and the accessory respiratory muscles. Additional damage to the axons of the surviving anterior horn cells as a result of nerve root compression may result in clinically significant respiratory dysfunction as was evident in this patient.Acute dyspnoea secondary to diaphragmatic paralysis can also occur following minor cervical trauma. Parke and Whalen described two patients with severe cervical myelopathy who developed respiratory insufficiency related to phrenic nerve palsy after cervical manipulation . Merino-Respiratory compromise is a known complication of acute cervical spinal cord injury but rarely is it considered in less acute settings such as in cases of degenerative cervical spondylosis.There are few case reports in the literature documenting resolution of diaphragmatic paralysis due to cervical nerve root compression following cervical spine surgery. Hayashi et al. reported on a 64-year-old man with dyspnoea who had bilateral hemidiaphragm paralysis secondary to cervical spondylosis . Buszek There are numerous studies in the literature that show impaired respiratory function in patients presenting with cervical pathology. Ishibe and Takahashi compared 84 patients with cervical pathology with an age-matched control group of patients without cervical pathology and found that those in the cervical group had significantly lower respiratory function  . Within Similar to other case reports in the literature, this report documents a case of resolution of right hemidiaphragm paralysis following C4 and C5 nerve root decompression via posterior cervical foraminotomies (C3/4 and C4/5 levels), a finding not previously described. Although rare, cervical nerve root compression as a cause of phrenic nerve palsy should be considered in patients presenting with hemidiaphragm paralysis and respiratory symptoms as surgical management can result in resolution of paralysis and potential improvement in respiratory symptoms."}
+{"text": "Small interfering RNA (siRNA) duplexes are short  double-stranded RNAs (dsRNAs) with several overhanging nucleotides at both 5\u2032- and 3\u2032-ends. It has been found that siRNA duplexes bind the RNA-induced silencing complex (RISC) and cleave the sense strands with endonucleases. In this study, for the first time, we detected siRNA duplexes induced by plant viruses on a large scale using next-generation sequencing (NGS) data. In addition, we used the detected 21 nucleotide (nt) siRNA duplexes with 2 nt overhangs to construct a dataset for future data mining. The analytical results of the features in the detected siRNA duplexes were consistent with those from previous studies. The investigation of siRNA duplexes is useful for a better understanding of the RNA interference (RNAi) mechanism. It can also help to improve the virus detection based on the small RNA sequencing (sRNA-seq) technologies and to rationally design siRNAs for RNAi experiments. RNA interference (RNAi) is a cytoplasmic cell surveillance system that recognizes double stranded RNAs (dsRNAs) and specifically destroys single and double stranded RNA molecules homologous to the dsRNA inducers, using small interfering RNAs (siRNAs) as guides . The abuOne important class of RNA fragments related to RNAi is siRNA duplexes, which contain perfectly base-paired regions with 2 nucleotide (nt) 3\u2032-end overhangs. Previous studies have shown that siRNA duplexes of 21\u201323 nt are the sequence-specific mediators of RNAi and post-transcriptional gene silencing (PTGS) . The actSince plant RNAi produces abundant siRNA duplexes and the mechanism of plant RNAi is comparatively clear, in this study we detected siRNA duplexes induced by plant viruses and analyzed their features. As far as we know, this is the first time siRNA duplexes have been detected and analyzed on a large scale using NGS data. This study aims to provide useful information for a better understanding of the RNAi mechanism. The analysis of siRNA duplexes can be used to improve the virus detection using sRNA-seq data and to rationally design siRNAs for RNAi experiments .Fourteen complete viral genomes including 17 nucleic acid sequences under the NCBI GenBank accession numbers JQ314457 , KT63405x\u2013nt duplex (x represents the duplex length) proportion is calculated as the read count of x\u2013nt siRNA duplexes with 2 nt overhangs divided by the count of viral reads. The program duplexfinder was developed to detect siRNA duplexes [The cleaning and quality control of sRNA-seq data were conducted using the pipeline Fastq_clean  that hasduplexes . Statistduplexes .All 17 viral genome sequences had genome coverages of more than 99% and average depths  varied fDrosophila melanogaster embryo lysates [Drosophila in vitro system [To reduce the statistical bias, we used seven nucleic acid sequences with higher average depths from four viruses to detect and analyze siRNA duplexes. The duplex lengths from 15 to 50 nt and the overhang lengths from 0 to 6 nt were used as parameters to count the duplex reads in the sRNA-seq data A. The re lysates . Among to system . These rIn this study, we also found genome coverages of the seven viral sequences calculated using aligned 21 nt siRNA duplexes with 2 nt overhangs were close to the genome coverages calculated using all aligned reads . IdenticBased on the detection results from the seven viral sequences, we constructed a dataset including 20,415 pairs of 21 nt siRNA duplexes with 2 nt overhangs for further analysis . Using tAnother controversial topic in RNAi studies is whether the RISC contains single- or double-stranded siRNAs. Previous studies have introduced a debate on the symmetry between sense and antisense strands of siRNAs . Using t"}
+{"text": "Pulmonary arterial hypertension (PAH) is a life limiting disorder resulting in progressive right heart (RV) failure. Cardiac MRI is the reference standard for RV assessment in PH and has known prognostic value in children. Symptoms of PAH are exacerbated or become apparent with exercise and cardiopulmonary exercise testing (CPET) is also prognostic in PAH.2. A combined approach using MR-CPET could provide a more sensitive method of assessing disease severity, the causes of exercise limitation and response to treatment. In this study we assessed the utility of MR-CPET in children with PAH.We have recently demonstrated the feasibility of MR augmented CPET (MR-CPET) in healthy adults. Using the Fick principle MR-CPET allows calculation of tissue oxygen extraction \u0394cO10 Children with PAH aged 8 to 16 years  and 10 healthy volunteers matched for age and sex underwent MR-CPET. Exercise was performed on a MRI compatible ergometer  CPET data was collected using a commercial respiratory gas-analyser  with a modified MR compatible sampling umbilical.Resting and peak exercise ventricular volumes and septal curvature were measured using a radial k-t SENSE real time sequence. Aortic flow was simultaneously continuously measured using a previously validated real-time UNFOLD-SENSE spiral PCMR sequence.MR data was used to derive CO, HR and SV curves during exercise. Arteriovenous oxygen content gradient (AVO2) curves (a measure of tissue oxygen extraction) were calculated by dividing the VO2 and CO curves Figure . RestingSubjects also completed a six-minute walk test, experience survey and exercise history.2 was significantly lower in the PAH group. This seems to be driven by both reduced tissue oxygen extraction and cardiac output although only reduced \u0394cO2 was of statistical significance. MR-CPET measures at rest and exercise are shown in Figure All children successfully completed the test without complication.Peak VORVEF was significantly lower in the PAH group both at rest and at peak exercise.There was a significant difference in the increase in estimated mPAP between the control and PAH groups. There was no significant difference in 6-minute walk test distance between the groups.MR-CPET is well tolerated in both healthy children and children with class I/II PAH. This study demonstrates that exercise intolerance in children with PAH is in part due to reduced tissue oxygen extraction and may open possibilities to study new pharmacological or exercise based therapeutic strategies."}
+{"text": "This research investigated the contribution of the dorsolateral prefrontal cortex (DLPFC) in the attentional resources in episodic encoding for both verbal and non-verbal material. Paired-pulse transcranial magnetic stimulations (TMS) were used to interfere transiently with either the left or right DLPFC during encoding under full attention (FA) or under divided attention (DA) in a recognition paradigm using words and random shapes. Participants recognized fewer items after TMS over the left DLPFC than over the right DLPFC during FA encoding. However, TMS over the left DLPFC did not impair performance when compared to sham condition. Conversely, participants produced fewer items after TMS over the right DLPFC in DA encoding compared to sham condition, but not compared to TMS over the left DLPFC. These effects were found for both words and random shapes. These results suggest that the right DLPFC play an important role in successful encoding with a concomitant task regardless of the type of material."}
+{"text": "Regenerative medicine is challenged by the need to conform to rigorous guidelines for establishing safe and effective development and translation of stem cell-based therapies. Counteracting widespread concerns regarding unproven cell therapies, stringent cell-based assays seek not only to avoid harm but also to enhance quality and efficacy. Potency indicates that the cells are functionally fit for purpose before they are administered to the patient. It is a paramount quantitative critical quality attribute serving as a decisive release criterion. Given a broad range of stem cell types and therapeutic contexts the potency assay often comprises one of the most demanding hurdles for release of a cell therapy medicinal product. With need for improved biomarker assessment and expedited measurement, recent advances in graphene-based biosensors suggest that they are poised to be valuable platforms for accelerating potency assay development. Among several potential advantages, they offer versatility for sensitive measurement of a broad range of potential biomarker types, cell biocompatibility for direct measurement, and small sample sufficiency, plus ease of use and point-of-care applicability. A wide range of novel Advanced Therapy Medical Products (ATMP) have been pursued intensively over the last decade. In addition to gene therapy medical products (GTMP) and tissue-engineered products (TEP), the application of stem cells has driven extensive research into somatic cell therapy medicinal products (CTMPs). Although the number of ATMPs in the centralised European Union (EU) Marketing Authorization (MA) phase has been described as low , 2, a nuWith regard to stem cell-based therapies, our growing understanding of one of the most actively investigated cell types, commonly known as human \u201cmesenchymal stem cell\u201d (hMSC), is fostering debate. Arising from studies of nonhematopoietic human bone marrow stromal cells (hBMSC), an authoritative view is that tissue-specific stem/progenitor cells, a subset of which are skeletal stem cells, are not to be confused with similarly named \u201chMSC\u201d derived from other tissue sources, especially for regeneration of bone or cartilage tissue . Rather,Complementing progress in understanding the diversity of stem cells are advances in large-scale production of therapeutic cells, including bioreactor systems for mesenchymal stem cells . Cell exAmong key requirements for cell-based therapy for regenerative medicine, current guidelines stipulate identity, safety , purity,The challenges to potency assay development are many: (i) inherent heterogeneity in the starting cell population; (ii) a limited cell product lot size and amount available for testing; (iii) limited viability and stability of cellular products; (iv) the difficulties in establishing the mechanism of action (MOA) considering the numerous intrinsic factors and active components; (v) the potential for both positive or negative interactions among active components; (vi) the difficulty of establishing reference standards; (vii) additional complexity if biomaterials are involved; (viii) the difficulty of accurately predicting the in vivo fate from external measurements made before cell administration to the patient.For the widely used hBMSC, starting material heterogeneity concerns not only identity and parity with minimal defining criteria , but alsNotably, clinical study data is not of practical use for establishing the potency assay. The potency assay predicts ability to cause functional effect rather than clinical effectiveness or outcome and needs to be capable of defining individual product lot release criteria. The emerging apparent contradiction is that potency assays benefit from being highly sophisticated yet technically simple. To date, many potency assays rely on definitive end points that match relatively clear phenotypes such as cell proliferation, differentiation, cell death, and ability to induce angiogenesis. Not all traditional assays measuring these phenotypes are necessarily equivalent however, especially for diverse therapeutic cell types and indications. Whereas proliferation may be a phenotype considered useful for evaluating the potency of autologous hematopoietic stem cells for bone marrow transplantation, interlaboratory reproducibility of commonly performed colony forming unit (CFU) assays is problematical . Sample Understandably, the high costs and investigative time needed for developing a suitable potency assay for cell-based products has hindered entry of biologicals into phase III or IV clinical trials. A potency assay needs to be one of the first considerations for any CTMP, yet there is currently a marked discrepancy between the number of phase I/II clinical safety trials and phase III or IV clinical trials that require a validated potency assay . For exa2 can suffice to cover the entire corneal surface of the patient's affected eye. Corneal epithelium that would otherwise be irrevocably damaged is replaced with epithelium with a reservoir of continually regenerating limbal stem cells that provide long-term normal corneal function. Marketing approval came eighteen years after initial proof-of-principle success in two patients [bright expression in the stem cell nuclei of holoclones could be linked to a good clinical outcome. Providing a potency reference, it was found that among the total number of clonogenic cells, presence of >3% holoclone-forming limbal stem cells correlated with successful transplantation [bright cells could serve as a key potency assay biomarker for this cell-based therapy.The first stem cell-based ATMP therapy granted marketing authorization by EMA, Holoclar, treats severe trauma induced limbal stem cell deficiency (LSCD) in adults . A recompatients  and a 20patients . Productantation . Thus, qSeveral other stem cell CTMP have resorted to quantitative ELISA methods in potency assays. Multistem\u00ae; an adult allogeneic bone marrow-derived product has shown beneficial effects in animal models of ischemic injury. For potency assays regarding complex indications, when an authentic bioassay is not feasible, surrogate in vitro assays identify biological activity analytically by correlation to a relevant product-specific causal activity. Angiogenic factors secreted by Multistem multipotent adult progenitor cell (MAPC) populations, measured by enzyme-linked immunosorbent assay (ELISA) correlated with induction of tube formation by endothelial cells in vitro for a proposed quantitative potency assay with predefined accept/reject criteria . A more \u03b1 (IL2R\u03b1) expression on activated T cells. Quantitative metrics included a concentration of at least 13\u2009pg TNFR1 per million MSCs and the ability of inhibiting at least 30% of IL2R\u03b1 expression in cocultured CD3/CD28-activated peripheral blood mononuclear cells (PBMCs) relative to control was considered sufficient in order to induce the desired therapeutic effect [An effective surrogate potency measure for the immunoregulatory activity of the Osiris Bone marrow adult mesenchymal stem cell product Prochymal\u2122 was an ELISA measure of tumor necrosis factor receptor 1 (TNFR1) levels in the cell therapy product, in combination with a qualitative measurement of the inhibition of the interleukin 2 receptor c effect .NCT03280056). Notably, microRNA profiling of MSC-NTF cells could distinguish them from matched origin MSC, characterisation that could be useful for a potency assay if biological response is dependent on a threshold number of MSC-NTF cells [The product NurOwn\u00ae consists of autologous ex vivo-propagated bone marrow-derived MSCs induced to secrete neurotrophic factors (MSC-NTF cells), currently undergoing a phase III clinical trial for the treatment of Amyotrophic Lateral Sclerosis (ALS). Biomarkers quantified for this stem cell-based therapy product include cell-secreted neurotrophic factors, inflammatory factors, and cytokines in the cerebrospinal fluid (TF cells .NCT02730299). An effective measurement of biological effect for this product was the time for neutrophil engraftment following transplantation [The NiCord\u00ae product consists of a cryopreserved stem cell product consisting of allogeneic ex vivo-expanded umbilical cord-derived hematopoietic CD34+ progenitor cells and the noncultured cell fraction of the same cord blood unit. Current phase 3 clinical trials include treatment of hematological malignancies such as acute lymphoid leukemia or myelodysplastic syndrome , hypertrophic pseudoarthrosis of long bones (NCT02230514) and femoral head osteonecrosis (NCT01605383). The product PneumoStem\u00ae consists of allogeneic ex vivo-expanded human umbilical cord blood-derived MSCs currently in phase 1/2 clinical trials for the prevention of bronchopulmonary dysplasia in premature infants (NCT02381366), as well as a phase II clinical trial for the treatment of intraventricular hemorrhage (NCT02890953). The results of these trials will be important to evaluate the safety and effectiveness of this approach [NCT02504619) plus severe aplastic anemia and myelodysplastic syndrome (NCT03173937). The product NeuroStem\u00ae consisting of allogeneic human umbilical cord-derived MSCs is undergoing phase 1/2 clinical trials for the treatment of Alzheimer's disease (NCT02054208). The product CartiStem\u00ae, allogeneic ex vivo-expanded umbilical cord blood-derived MSCs in combination with sodium hyaluronate, is under evaluation in two parallel clinical trials for the treatment of knee chondral defects (NCT01733186) and osteoarthritis (NCT01041001). Although a particular potency assay was not described and biological activity including inhibition of proinflammatory cytokines is poorly characterised, long-term benefit has been reported [Numerous other stem cell-containing cell-based therapy products are currently pending market approval or are undergoing clinical trial evaluation. Notably, the respective definitive potency assays are either proprietary or still a work in progress. Nonetheless, they serve as good examples for considering the scope of applications where graphene-based biosensors might be helpful in early stages of cell therapy development. The blood and tissue bank of Catalonia product XCEL-MT-OSTEO-ALPHA, representing autologous ex vivo-expanded MSCs fixed in allogeneic bone tissue, is currently being tested in phase 1/2 clinical trials for the treatment of spinal fusion  for cell product manufacture . Existin\u03b1 [\u03b3 [Although ELISA and PCR-based quantification seem to be the methods of choice in the current development of stem cell-based products due to their outstanding detection limits, the challenge of guaranteeing high quality measurements is increasingly being met by progress in biosensor design. Various functionalized forms of graphene and nanocomposites  can be u\u03b1  and IFN-\u03b1 [\u03b3 ) or apop\u03b1 [\u03b3 ), and pl\u03b1 [\u03b3 ). Graphe\u03b1 [\u03b3 .This versatility can help advance development of novel potency assays for future stem cell-based products . GraphenStem cells are characterised by a capacity for both self-renewal and asymmetric division that produces one identical daughter stem cell and a second distinct daughter cell equipped with the potential to commit to a lineage-specific differentiation program . Found iConsistent with providing improved conditions for monitoring stem cell performance, 3D GO-encapsulated gold nanoparticles could serve as nondestructive biosensors of neural stem cell (NSC) differentiation potential. An intrinsic property of graphene is enhanced adherence to molecules that contain aromatic structures. Highly unsaturated metabolites are predominant in undifferentiated stem cells so that Raman spectroscopy peaks of undifferentiated NSC on GO-encapsulated gold nanoparticles were 3.5 times higher than peaks obtained from control metal structures and clearly distinguishable from peaks obtained using differentiated cells that oxidize the metabolites upon differentiation . Given tNanomaterials may be particularly useful in enabling more specific measurements in vivo and this may help bridge the in vitro/in vivo divide, so that what is measured in vitro during cell expansion is genuinely more relevant for the desired therapeutic approach. Graphene oxide can be incorporated in a number of nanocomposites to serve as a platform that enhances electrical properties for biosensing applications in vivo . The uniAs highlighted by the examples above, among the enhanced healing qualities required from cell-based therapies , the fol\u22121 [For a definitive assay, cell death is a great endpoint. Governing the process of apoptosis or programmed cell death, a cascade of molecular events usually activates a cysteine-dependent aspartate directed protease (caspases), an enzyme family with multiple roles in regulating stem cell properties . GO coul\u22121 . Two pro\u22121 .Demonstrating the versatile manner by which graphene platforms can be used to detect potency assay-relevant molecules, a number of different biosensor types have been developed for the angiogenic growth factor VEGF. A field-effect transistor (FET) electronic platform conjugated with VEGF-specific RNA aptamers could recognize target molecules at an unprecedented 100\u2009fM concentration . Alterna\u22121, with a low detection limit of 1.6\u2009pg mL\u22121, and good reproducibility and stability, qualities that are key for good potency assays.Stem cell integration in tissues was not only critical for successful corneal recovery using limbal epithelial stem cells but was also found to be important for mesenchymal stem cells in cementogenesis, a process establishing regeneration of cementum for anchoring teeth to alveolar bone. Sorting periodontal ligament cells according to CD146 expression could homogenize cultures and enrich cells with high colony forming potential, capable of subsequently resurfacing dentin with a newly formed cementum-like layer, allowing improved integration in the dentin surface . Modifyi\u03bcL of plasma without sample processing [Immunomodulatory mechanisms achieved by mesenchymal stem cells remain to be investigated  and it iocessing .Bone repair is an intensively explored regenerative application for the most commonly employed hBMSC cell type under investigation in clinical trials. Cellular products in the form of allografts containing mesenchymal stem that are currently evaluated for safety and efficacy in many phase I/II clinical trials will require suitable potency assays for progression to subsequent clinical trial phases. Enhanced osteogenesis serves as a prime example where graphene-based biosensors present favourable qualities for improving potency assay development. New quantifiable gene expression biomarker candidates are emerging , 77 withAn important aspect for any potency assay is that it should fit cell expansion timelines and thus fast analysis is advantageous. The potency assays proposed by Murgia et al.  involvedDepending on the nature of the envisioned detection platform, integrating graphene with sustainable production methods will be important for obtaining highly reproducible molecular interactions with biological molecules . VariousGraphenic species are being tested to achieve market grade novel inks for 3D printing applications  and meanThe burgeoning number of stem cell clinical trials requiring a potency assay provides an excellent opportunity for advanced biosensor design to address valuable clinical applications pragmatically within a preclinical context. The versatility of graphene-based biosensors is well suited for the complex nature of potency assays that will be very specific for each therapeutic application. Different versions of graphene allow prospects for a choice of sensor types, especially given successful fabrication of nanoparticle composites allowing the electrochemical characteristics of graphene to enhance specialized sensing platforms. Graphene oxide presents advantages for water dispersion, biocompatibility, and versatile surface modification and electrochemical transduction of the signal allows miniaturization. This can help establish assays suited to limited cell product lot sizes and facilitate measurement prior to administration with point-of-care tools. Particular advantages for potency assays are likely to be derived from appreciating that stem cells are highly responsive to microenvironments; thus surrogate assays based on closer mimicry of the therapeutic situation are likely to provide better correlative measurement of potency biomarkers . Graphen"}
+{"text": "Vascular closure devices provide a safe and cost-effective method to achieve rapid hemostasis and early ambulation after angiographic procedures. Rarely, they can result in arterial injury with resultant stenosis or acute arterial closure requiring open surgical intervention. We report an Angio-Seal\u00ae vascular closure device-induced acute arterial closure successfully treated percutaneously with the SilverHawk\u00ae plaque excision system. This report discusses the possible mechanisms of Angio-Seal\u00ae induced arterial occlusion and various percutaneous options for treatment. Vascular closure devices (VCD) are increasingly used in place of manual compression to provide rapid hemostasis and early ambulation after angiographic procedures. They have been shown to reduce hospital stay and have been demonstrated to be cost-effective -2.\u00a0AlthoA 60-year-old Caucasian female with a history of coronary artery bypass surgery, diabetes mellitus, dyslipidemia, and chronic tobacco use was admitted to the hospital with Rutherford Class III exertional claudication in the bilateral hips and buttocks. Non-invasive workup, including a duplex sonogram, demonstrated distal aortic stenosis involving the aortoiliac bifurcation. She underwent an abdominal aortogram with bilateral lower extremity arterial run-offs. During the procedure, vascular access was obtained with #6 French short sheath, which was advanced into the right common femoral artery without complications. The arteriograms confirmed the presence of a distal aortic 70% calcific stenosis with the plaque involving the ostia of both common iliac arteries. The run-off vessels bilaterally were without significant stenosis. A staged percutaneous procedure was planned. An Angio-Seal\u00ae device was deployed successfully after an angiogram confirmed suitability for device placement Figure .\u00a0Immediately after the Angio-Seal\u00ae deployment, the patient developed leg discomfort with the loss of arterial pulses in the right leg. A duplex scan confirmed acute occlusion of the right common femoral artery (CFA). Immediate vascular access was obtained at the contralateral (left) CFA and an angiogram of right CFA confirmed a total occlusion Figure . A #7 FrTM filter device placed at the distal SFA. With multiple passes, the lesion was shaved off resulting in no significant residual stenosis  Anchor-induced dissection resulting from the dragging of the anchor along the arterial inner wall during deployment; 2) thrombosis induced by the intraluminal anchor or a portion of the collagen plug that prolapsed into the lumen; and 3) plaque rupture from device-induced trauma, resulting in worsening stenosis at the deployment site. The traditional management for VCD-induced vessel stenosis/occlusion is open surgery and has been well-described . BalloonIn the case presented, balloon angioplasty provided temporary relief likely because the local thrombogenic stimulus with anchor plug/ prolapsing collagen plug and associated dissection flap was still present intraluminally. The SilverHawk\u00ae atherectomy system was chosen with the thought that the atherectomy would remove the inciting stimulus (the plug or the anchor) as well as also any dissection flap, if present, and minimize the need for a stent in this unfavorable location. Furthermore, a failed atherectomy would likely not compromise a future open surgical repair.A distal filter device is strongly recommended to prevent the risk of distal embolization with the use of this atherectomy system -8. In thThe use of an Angio-Seal\u00ae VCD may rarely result in an\u00a0acute closure of the artery. Such a stenosis/occlusion may not be treated successfully with angioplasty alone. Although surgical intervention has been the traditional treatment, SilverHawk\u00ae plaque excision system can be used successfully and, thus, avoid open surgical repair. However, the use of a distal protection device is strongly recommended."}
+{"text": "Biological Psychiatry, Steven Woltering and colleagues demonstrate that children with externalizing behaviors who respond to cognitive behavioral therapy show electroencephalogram-defined neural markers of improved self-regulation  parent management training interventions to reward prosocial behaviors and to extinguish negative behaviors and (2)\u2009improving executive functioning through skills training and coaching, psychoanalytic approaches promote emotion regulation through communicating to the child the self-protective meanings of negative behaviors. This intervention alongside developmental help scaffolds the child\u2019s development of alternative emotion regulation capacities . As bothWoltering and colleagues\u2019 study provides a model for exploring this hypothesis. This study recruited 140 children aged 8\u201312 from outpatient treatment agencies with scores on the externalizing scale of the Child Behavior Checklist  within All children then engaged in an evidence-based cognitive behavioral therapy program with an integrated parent management training . This pThe Child and Adolescent Functional Assessment Scale  was appSeventy-one of the original 140 participants completed the treatment with usable data. Fifty-five percent (39 completers) were treatment non-responders, and 45% (32 completers) were responders. Non-responders, responders, and 24 age-matched children recruited from the community then repeated the go/no-go task under EEG.Treatment responders, but not non-responders, showed reductions in posttreatment relative to pretreatment EEG in needed cortical resources to regulate impulsive behavior during the go/no-go task. Specific findings included, a reduction in the magnitude of the N2 component of the event-related potential (ERP), a defined waveform associated with inhibition of prepotent responses , 15. ThiThis study suggests that successful as opposed to unsuccessful treatment normalizes aberrant biomarkers of executive functioning in children with externalizing behaviors and are associated with improved executive function performance on a go/no-go task.The study of ERPs is an ideal neurobiological modality to bridge the theoretical executive function and emotion regulation literature. Several studies examine ERPs in children with externalizing behaviors as both a neural correlate of emotion regulation , 17\u201319 aContemporary child psychoanalytic psychotherapy involves the interpretation of children\u2019s defenses against unwelcome affects , 21\u201323. An 8-week manualized psychoanalytic approach to children aged 6\u201312 with externalizing behaviors organized around defense analysis  is underThe author confirms being the sole contributor of this work and approved it for publication.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "The pattern of glomerular disease in adults varies considerably across the globe and haschanged within same geographical regions and clinical settings. Diagnosis of glomerularlesions on basis of biopsy remains a standard approach.The pattern of glomerular disease in adults varies considerably across the globe and has changed within same geographical regions and clinical settings. Diagnosis of glomerular lesions on basis of biopsy remains standard despite arguments of margins of error related with sampling in random fashion. Focal segmental glomerulosclerosis (FSGS) which emerged as separate clinic-pathological entity in 1970s has been reported commonest pattern in glomerular pathology  ExistencDuring last four decades IMN reported most common cause of nephritic syndrome in adults worldwide . Debate IgA nephropathy once reported most frequent cause of glomerulonephritis among patients who undergo renal biopsy. Prevalence of IgA nephropathy to some extent seems to be influenced by policy of proceeding with renal biopsy in all patients coming with microscopic hematuria . In our Minimal change disease (MCD) is less frequent cause of glomerular disease in adults; we have reported 5.8% adults biopsied for nephritic syndrome, acute nephritic syndrome, non-nephritic proteinuria, rapidly progressive glomerular disease and isolated hematuria . Study pSurprisingly FSGS remains very low on list in present study only 6.5% had FSGS as causative pathology. We have reported primary FSGS as most frequent pathological lesion in our studied population which happened to be a large group of 1793 patients. Recently over last 18-20 months we have observed sudden rise in mesangiocapillary pattern in our biopsy population of adult patients (unpublished data).The present study by Modugumudi et al  also claRN was the single author of the manuscript.The author declared no competing interests.Ethical issues  have been completely observed by the author.None."}
+{"text": "Tissues within the dipolar field of superparamagnetic contrast agents experience a frequency shift that enables positive contrast MRI with acquisition schemes using on-resonant saturation Figure . The admA cylindrical tube containing a concentrated suspension of 19 nm SPIONs was placed alongside the upper leg in human volunteers Figure , causingThe off-resonance area was selectively excited and visualized with a 0 s delay time Figure . Spins wFlow imaging with iron induced spin tagging (FLIRT) was achieved using external SPIONs which targeted the positive labeling of moving protons. The feasibility of this method was shown in vivo with preliminary data obtained in human volunteers. It allows for flow visualization in the vicinity of ferrimagnetic objects without contrast injection."}
+{"text": "We evaluated the influence of pack stock  use on meadow plant communities in Sequoia and Yosemite National Parks in the Sierra Nevada of California. Meadows were sampled to account for inherent variability across multiple scales by: 1) controlling for among-meadow variability by using remotely sensed hydro-climatic and geospatial data to pair stock use meadows with similar non-stock (reference) sites, 2) accounting for within-meadow variation in the local hydrology using in-situ soil moisture readings, and 3) incorporating variation in stock use intensity by sampling across the entire available gradient of pack stock use. Increased cover of bare ground was detected only within \u201cdry\u201d meadow areas at the two most heavily used pack stock meadows . There was no difference in plant community composition for any level of soil moisture or pack stock use. Increased local-scale spatial variability in plant community composition (species dispersion) was detected in \u201cwet\u201d meadow areas at the two most heavily used meadows. These results suggest that at the meadow scale, plant communities are generally resistant to the contemporary levels of recreational pack stock use. However, finer-scale within-meadow responses such as increased bare ground or spatial variability in the plant community can be a function of local-scale hydrological conditions. Wilderness managers can improve monitoring of disturbance in Sierra Nevada meadows by adopting multiple plant community indices while simultaneously considering local moisture regimes. High elevation meadows are a vital ecological component of mountain systems throughout western North America. They provide critical habitat for wildlife , 2, suppThe biophysical characteristics of meadows in the Sierra Nevada are highly variable, especially related to hydrologic regimes and associated plant community types . In the Here, we assessed meadow plant community responses to pack stock use while simultaneously controlling for multi-scale environmental factors known to influence variability of meadow hydrology and plant community structure. Specifically, we asked whether current levels (2004\u20132009) of pack stock use influence: total vegetation cover and bare ground, plant community composition, and local-scale spatial variability in plant community composition. We used a multi-step approach to: 1) control for large-scale, among-meadow variability by matching pack stock use meadows with non-pack stock reference meadows from a comprehensive database of remotely sensed estimates of hydro-climatic and geospatial attributes; 2) control for within-meadow variation in local hydrology by measuring in-situ soil moisture in all sampling plots and stratifying analyses by vegetation grouped to specific moisture regimes; and 3) control for variation in intensity of pack stock use by sampling across a large gradient in reported use.Pinus contorta), rocky outcrops, and scrub vegetation types interspersed with highly diverse and productive meadow habitats [The study was conducted in subalpine meadows within the Sequoia National Park section of the jointly managed Sequoia & Kings Canyon National Parks (SEKI) and Yosemite National Park (YOSE) in the Sierra Nevada, California . Researchabitats . The SieCarex scopulorum, Calamagrostis muiriana) and forbs , interspersed with moss in the understory. Subalpine meadows are also used by native herbivores including mule deer , voles (Microtus spp.), and pocket gophers (Thomomys spp.).Subalpine meadows generally occur at perennially wet locations where ground water is at or near the surface , and plaPack stock use in Sierra Nevada meadows offers an opportunity to investigate the role of disturbance on plant communities at a scale relevant to management. Many of the meadows used by pack stock occur within National Parks, where meadows are free from confounding influences of other domestic livestock, such as cattle or sheep grazing. And unlike many cattle grazing practices, pack stock use within meadows occurs intermittently throughout the summer season as groups travel through . Pack stTo understand if meadow plant communities were affected by stock use, we paired pack stock meadows to non-stock meadows using an ensemble of biophysical, geospatial, and hydro-climatic remote sensing data, which allowed us to compare sites that theoretically should have similar ecological conditions. Pack stock meadows were any meadow that received reported pack stock use within the past decade, whereas non-stock meadows had no reported pack stock use from any time period. The pool of potential meadows to select from was identified using park-wide meadow GIS layers . Use recThe twenty candidate stock meadows with highest number of stock nights from each park were matched to non-stock meadows, using the package \u2018Matching\u2019  in the RThe three highest ranked matched reference meadows were visited and assessed qualitatively based on similarities in meadow size, landscape position , elevation and proximity with the matched stock meadow. The one deemed the best match was then selected as the non-stock  meadow for sampling. This resulted in every stock meadow having one sampled non-stock control meadow totaling to 22 matched pairs, with 14 pairs (14 stock/14 non-stock) sampled during the 2011 and 2012 growing seasons in YOSE and 8 pairs (8 stock/8 non-stock) sampled during the 2012 growing season in SEKI. The YOSE meadows ranged in size from 1.15\u201322.14 ha with an average meadow size of 5.90 ha, and SEKI meadows ranged in size from 0.42\u201310.62 ha with an average meadow size of 2.60 ha. The maximum number of stock nights in a single year varied widely during 2004\u20132009: 10\u2013577 stock nights in YOSE, with an average of 134 per year; and 82\u2013271 stock nights in SEKI, with an average of 155 per year.2) sampling plots were established at 20 m intervals. Ocular aerial estimates of the total vegetation cover (%), litter cover (%) and exposed mineral soil cover  were recorded within each plot. Plant species composition was sampled at every third sampling plot along each transect with ocular aerial estimates of cover by species in eight 25 x 25 cm sub-plots arranged systematically within each 4 m2 plot. Soil moisture was recorded at every 4 m2 plot as volumetric water content (VWC) using a Field Scout Time Domain Reflectometer 100 soil moisture probe  to a depth of 12 cm. Readings were taken within 10 cm of the inside of each corner as well as the center of each plot. The soil VWC values were averaged within each plot.Each meadow was sampled once during the peak summer growing season (June\u2013August). Sampling occurred along 5-m wide belt transects spaced 40 m apart, running across the meadow width, perpendicular to the main meadow drainage. Along the centerline of each belt transect, 2 x 2 m (4 mClassification and Regression Tree (CART) analyses were used  as a noThree metrics were used as response variables: bare ground, species dissimilarity and species dispersion:r = -0.65; and bare ground and vegetation plus litter cover, Pearson\u2019s r = -0.84). We did not use vegetation or litter cover as response variables due to high Pearson\u2019s r values with bare ground.Bare ground\u2014Total cover of bare ground in each plot was used both as a direct measure of exposed soil and as an indirect measure of total vegetation cover. Bare ground and total vegetation cover (live and dead as litter) were negatively correlated  is more heterogeneous than a plot with lower species dispersion.Species dispersion\u2014There is a possibility that plant communities can maintain overall similar species composition and relative abundances, but differ in the spatial patterning and variability of those species . For exaing plot . Speciesing plot . A higheMean soil moisture (VWC) measurements for each plot were used to stratify the analyses across distinct vegetation community types associated with a different dominant soil moisture regime (see Explanatory Variables below). In order to ensure an adequate sample size, those vegetation community types that had less than three plots for any meadow in a pair of matched meadows were dropped from the analysis. Differences in average bare ground and differences in mean species dispersions were calculated by subtracting the bootstrapped means of the non-stock (control) meadow from the bootstrapped means of the paired stock meadow. Each procedure was run 1000 times to produce an estimated mean difference as well as 95% confidence intervals for each meadow pair. These were then used as the response variables in each CART analysis. Mean estimates and 95% confidence intervals for species dissimilarity between matched pairs were calculated based on bootstrapped estimates of mean values for each species within each vegetation community type. Similar to the bare ground response, the procedure was run 1000 times and a median value from the resulting distribution was taken as a mean estimate to be used in the CART analysis.Explanatory variables used in the CART analyses fell into three broad categories:Pack Stock Use\u2014Six measures of pack stock use based on NPS records from 2004\u20132009 were assigned to each matched pair: mean and maximum annual stock nights, mean and maximum annual stock density , and the standard deviation and coefficient of variation of annual stock nights across the six year period. We considered this six year period as a representative snapshot of contemporary use levels.Within-pair difference -The differences in physical attributes  within each stock and non-stock meadow pair were used to explain differences in vegetation between the pair. A large difference in each response due to Within-pair differences would suggest a weak pairing between stock and non-stock control meadows.Between-pairs difference\u2014The mean physical attributes of each meadow pair were used to evaluate how much the difference in vegetation between stock and non-stock meadows varies with the overall environmental context of the meadow pair .2 and that did not have ties in the covariates selected for the split. We used a bootstrapping method to quantify uncertainty in the estimates of meadow-scale differences between stock and non-stock meadows of each pair to better describe the specific relationships between stock use intensity and meadow responses (described under Response Variables above).Fourteen geospatial and hydro-climatic covariates derived from remote sensing data were used to measure within-pair and between-pairs differences . We exclNatural variability in soil moisture regimes known to influence coarse scale patterns of dominant vegetation within each meadow were addressed by stratifying all analysis across three vegetation community types reflective of local soil moisture conditions . To do this, patterns in the distribution of the 10 most dominant plant species were explored by plotting the mean plot level cover (computed as a running average) along the soil moisture gradient, taken as the mean plot level soil VWC standardized to individual meadow means. The moving average was calculated as a two-sided mean with a window width of 0.25 standard deviations. Vegetation community types were then delineated based on natural breaks and transitions in the distribution of species representative of dominant soil moisture regimes see ; Fig 2.Carex filifolia, a xeric vegetation type indicator species [Carex vesicaria and Carex scopulorom, both characteristic of wet meadow habitats [The top 10 most abundant species showed clear vegetation community changes along the soil moisture gradient . These d species . Carex vhabitats , were hiIndividual CART models were able to explain 58 to 93% of the variance in the difference between stock and non-stock meadows. However, the relative contributions of different classes of explanatory variables  differed among responses  and by vegetation community type . At the One third of cases showed a significant signal of stock use on vegetation differences among meadows when analyses were stratified by individual community types . These iThe previous analysis contrasts the relative contributions of pack stock use and a suite of coarse physical meadow attributes for explaining differences between stock and non-stock meadow pairs. We now evaluate the three cases where splits in the CART models were contributed to more by a Stock Use metric than any of the mean physical attributes. For each example, the individual bootstrapped differences between meadows were plotted against the most contributing Stock Use metric .Differences in bare ground cover within the Dry vegetation community type varied considerably across the entire range of maximum stock nights . Four meIn general, there was little difference in local-scale spatial variability in plant community composition (species dispersion) between stock and non-stock meadows across all stock use intensities for both the Wet and Dry vegetation communities , Fig 6. Sierra Nevada meadows are complex ecosystems that are routinely subjected to natural disturbances such as seasonal flooding from snowmelt , long-teFor bare ground cover, signs of potential impacts were restricted to the Dry vegetation community type. This suggests that current use levels may be having little impact on bare ground or vegetation cover across the majority of meadow plant communities (Wet and Intermediate). Furthermore, bare ground within the Dry vegetation community exhibited a non-linear relationship with pack stock, where only meadows with the highest use intensities (> 156 maximum stock nights/ha) had greater bare ground than their matched control meadows . Such a A contrasting, yet equally important result, was the lack of any observed difference (stock vs. non-stock) in bare ground within the Intermediate or Wet vegetation communities. Meadow soils within these community types stay consistently moist throughout the growing season making them more susceptible to compaction due to lower soil strengths . Soil coDifferences in the mean community composition (species dissimilarity) between paired stock and non-stock meadows was highly variable and showed no clear or consistent trend with stock use for any of the vegetation community types. Instead, results from the CART analysis suggest that hydro-climatic and geospatial attributes of meadow pairs were often the best predictors of large differences between stock and non-stock meadows. Our results support findings from NPS monitoring in SEKI where, over a 25-year monitoring period, meadows showed greater differences across meadow pairs than between individual paired stock and non-stock meadows . Closer Our results suggest that, under certain conditions, variability in plant community composition (as species dispersion) could be a more sensitive response to ecological stressors than mean metrics of vegetation cover or species composition often used in monitoring grazing practices\u201346. SimiA closer examination of the vegetation community types shows two very different patterns of variability across our study meadows. Dry vegetation communities exhibited lower species dispersion (increased homogenization) within meadows with the lightest use (< 8 maximum stock nights/ha). Decreased spatial variability in plant communities experiencing grazing disturbance is not a novel concept . Yet theWe expected that increased species dispersion would be extended into the Intermediate vegetation community because those areas tend to host more species, and therefore a greater potential for spatial variability among the species present. The failure to detect changes in species dispersion within the Intermediate vegetation community may be a matter of the spatial resolution sampled. Intermediate communities occupy a larger proportion of total meadow area compared to the Wet and Dry vegetation communities. As a result, this community type contains steep hydrologic gradients  with manThe overall transition of the plant communities along the soil moisture gradient  reflecteCompositionally, we observed no differences along the entire pack stock use gradient sampled. Instead, we noticed differences at the highest pack stock use levels for bare ground within Dry communities, and species dispersion within Wet communities. Such results must be placed within the context of contemporary pack stock use records, which are maintained by the NPS. Our study did not account for past impacts from periods when pack stock use levels were much higher than what is currently allowed. For example, historical accounts of Sierra Club outings from the early 1900s have descriptions of over 100 pack animals being used on single trips to the Sierra Nevada high country . With hiMonitoring dynamic ecosystems is challenging, and any measure of change is dependent upon the variables monitored. We demonstrated that using a single variable indicator such as vegetation cover or bare ground could fail to distinguish other changes occurring within the meadow. However, regardless of the variable measured, no differences between stock and non-stock meadows would have been detected if the meadows we surveyed were not evaluated within the context of local hydrologic conditions.S1 TableGeographical locations of study meadows. X, Y coordinates are meadow centroids projected in NAD 1983 UTM Zone 11N; Site refers to the National Park unit where each meadow is located; SampleYear refers to the year sampling occurred; matchGroup indicates the pairing results from the multivariate matching technique; Stock indicates whether a meadow was a pack stock meadow (1) or a non-stock meadow (0).(CSV)Click here for additional data file."}
+{"text": "Robotic assisted radical cystectomy (RARC) is an alternative to open radical cystectomy. As experience is gained with the RARC approach the technique is being applied to more complex surgical cases. We describe here our technique for RARC with intracorporeal ileal conduit urinary diversion for a renal transplant recipient.en bloc with the bladder specimen); identification of the transplanted ureter at the right bladder dome; posterior bladder and prostate dissection along Denonvilliers\u2019 fascia; development of the space of Retzius; ligation and transection of the bladder and prostate vascular bundles; apical prostate dissection and transection of urethra; left pelvic lymphadenectomy; ilium resection for creation of the ileal conduit; stapled enteric anastomosis; ureteroileal anastomosis; maturation of the ileal conduit stoma.The patient is a 60-year old man with high-grade muscle invasive bladder cancer. He has a history of renal failure due to polycystic kidney disease and received a deceased donor renal transplant in 2008. His hospital course at time of transplant was complicated by low-level BK virus viremia. Interestingly his trans-urethral bladder tumor resection specimen at time of bladder cancer diagnosis stained positive for SV40. His native kidneys were anuric so bilateral laparoscopic nephrectomy was performed in a staged fashion 2 weeks prior to RARC. Our surgical technique utilizes 6 trocars, of note a 12-mm assistant trocar is placed 1 cm superior to the pubic symphysis, and this trocar is solely used to pass a laparoscopic stapler to facilitate the excision of the ileal segment and the stapled enteric anastomosis. Surgical steps include: identification of native ureters bilaterally (removed The surgery had no intraoperative complications. Operative time was 443 minutes (7.4 hours). Estimated blood loss was 250 cc. Length of hospital stay was 5 days. The patient did not experience any postoperative complications. The patient maintained good renal graft function with no decline in eGFR to date.As surgeon comfort and experience with robotic assisted surgery grows, robotic surgery can successfully be applied to less frequently performed procedures. Here we successfully performed a robotic assisted radical cystoprostatectomy with intracorporeal ileal conduit urinary diversion for a renal transplant recipient."}
+{"text": "Recent meta-analysis revealed that elevated presynaptic striatal dopaminergic function is a robust feature of psychosis like schizophrenia. Considering increased dopaminergic capacity in psychotic disorders, it is not surprising that antipsychotic drugs, which primarily block dopaminergic neurotransmission, are mostly effective in the treatment of psychosis.However, it remains obscure what would happen to presynaptic dopaminergic function with antipsychotic treatment. This is an important issue addressing whether the current antipsychotic drugs are correcting the primary dopaminergic abnormality or not. In addition, the issue can give a clue regarding the mechanism of relapse in psychotic disorders.We measured presynaptic dopamine capacity using [18F]DOPA PET before and after the antipsychotic discontinuation in first episode psychosis. The binding potentials of [11C]raclopride were also measured after the discontinuation. Healthy controls had [18F]DOPA and [11C]raclopride scans at the corresponding date.First episode psychosis patients were carefully monitored in the aspects of symptomatic aggravations.The presynaptic dopamine capacity and the density of dopamine receptors showed significant group effect and the interaction between group and time (p<0.005)Dopaminergic function seems to play a critical role in relapse of first episode psychosis."}
+{"text": "The Abstract section is missing. The publisher apologizes for the error. The Abstract can be viewed here:in vivo remyelination were observed. Our data suggest that NG2 modulates oligodendroglial migration but is dispensable for successful remyelination after cuprizone-induced demyelination.The expression of the proteoglycan NG2 is characteristic for oligodendroglial progenitor cells (OPC). The protein has been reported to influence OPC behavior in different pathological models. Here we examined the function of NG2 in remyelination ensuing after cuprizone feeding of mice to induce demyelination. OPC isolated from NG2-deficient mice exhibited an increased chemotaxis compared to WT OPC, but no differences in proliferation, differentiation or"}
+{"text": "Alzheimer's disease (AD) and its transitional state mild cognitive impairment (MCI) are characterized by amyloid plaque and tau neurofibrillary tangle (NFT) deposition within the cerebral neocortex and neuronal loss within the hippocampal formation. However, the precise relationship between pathologic changes in neocortical regions and hippocampal atrophy is largely unknown.In this study, combining structural MRI scans and automated image analysis tools with reduced cerebrospinal fluid (CSF) A\u00df levels, a surrogate for intra-cranial amyloid plaques and elevated CSF phosphorylated tau (p-tau) levels, a surrogate for neocortical NFTs, we examined the relationship between the presence of Alzheimer's pathology, gray matter thickness of select neocortical regions, and hippocampal volume in cognitively normal older participants and individuals with MCI and AD (n\u200a=\u200a724). Amongst all 3 groups, only select heteromodal cortical regions significantly correlated with hippocampal volume. Amongst MCI and AD individuals, gray matter thickness of the entorhinal cortex and inferior temporal gyrus significantly predicted longitudinal hippocampal volume loss in both amyloid positive and p-tau positive individuals. Amongst cognitively normal older adults, thinning only within the medial portion of the orbital frontal cortex significantly differentiated amyloid positive from amyloid negative individuals whereas thinning only within the entorhinal cortex significantly discriminated p-tau positive from p-tau negative individuals.Cortical A\u03b2 and tau pathology affects gray matter thinning within select neocortical regions and potentially contributes to downstream hippocampal degeneration. Neocortical Alzheimer's pathology is evident even amongst older asymptomatic individuals suggesting the existence of a preclinical phase of dementia. Selective neurodegeneration of the cerebral cortex is a characteristic pathological feature of Alzheimer's disease (AD). Intracellular tau-associated neurofibrillary tangles (NFTs) and extracellular amyloid-\u00df (A\u00df) associated plaques show a characteristic laminar and regional pattern of distribution within gray matter, with greater involvement of the medial temporal lobe and heteromodal association areas than primary sensory or motor cortices in vivo assessment of neuropathologic changes underlying AD. Positron emission tomography (PET) studies examining fibrillar amyloid deposition with Pittsburgh Compound B (PiB) and MRI studies of functional and structural connectivity have observed a significant overlap in a number of neocortical regions that appear preferentially affected in the earliest stages of AD in vivo the effect of tau burden on atrophy in heteromodal and limbic cortices.Recent advances in neuroimaging and image analysis algorithms allow for the Cortical atrophy resulting from cellular shrinkage, dendritic spine loss, and axonal disruption is reflected as a loss of gray matter that diminishes cortical thickness www.loni.ucla.edu/ADNI). The ADNI is a large multi-site collaborative effort launched in 2003 by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, the Food and Drug Administration, private pharmaceutical companies and non-profit organizations as a public\u2013private partnership aimed at testing whether serial MRI, PET, other biological markers and clinical and neuropsychological assessment can be combined to measure the progression of MCI and early AD. The Principal Investigator of this initiative is Michael Weiner, MD, and ADNI is the result of many co-investigators from a broad range of academic institutions and private corporations, with subjects recruited from over 50 sites across the US and Canada. For more information, please see http://www.adni-info.org.All 724 participants were selected from the Alzheimer's disease Neuroimaging Initiative (ADNI) database (http://www.adni-info.org/index.php?option=com_content&task=view&id=9&Itemid=43). The institutional review boards of all participating institutions approved the procedures for this study. Written informed consent was obtained from all participants or surrogates. Briefly, experienced clinicians conducted independent semi-structured interviews with the participant and a knowledgeable collateral source that included a health history, neurological examination, the Mini-Mental State Examination Each participant from the ADNI cohort was formally evaluated using eligibility criteria that are described in detail elsewhere (As illustrated in CN (n\u200a=\u200a208) - Individuals who were cognitively normal at baseline and clinical follow-up (CDR 0).MCI (n\u200a=\u200a353) \u2013 Individuals with mild cognitive impairment (MCI) defined using the revised MCI criteria AD (n\u200a=\u200a163) \u2013 Individuals who met criteria for probable AD http://www.loni.ucla.edu/ADNI/Data/index.shtml). Parameter values vary depending on scanning site and can be found at http://www.loni.ucla.edu/ADNI/Research/Cores/.All ADNI MRI scans were acquired at multiple sites using either a GE, Siemens, or Philips 1.5T system. Multiple high-resolution T1- weighted volumetric MP-RAGE scans were collected for each subject and the raw DICOM images were downloaded from the public ADNI site , freely available at The neocortex of the brain on the MRI scans was then automatically subdivided into gyral-based regions of interest (ROIs). To accomplish this, a registration procedure was used that aligns the cortical folding patterns For longitudinal analysis, the baseline and one-year follow-up structural MRI scans were rigid body registered and an unbiased template volume was created From the current ADNI sample, a number of individuals (n\u200a=\u200a338) underwent lumbar puncture for CSF biomarker evaluation. Methods for CSF acquisition and biomarker measurement have been reported previously for this sample Spearman's rank correlation coefficients were first used to examine relationships between the mean thickness of the individual ROIs and total hippocampal volume. Separate linear regression models were constructed for the amyloid positive, amyloid negative, p-tau positive and p-tau negative MCI and AD individuals, with the baseline thickness of the individual ROIs as predictors for hippocampal atrophy rate. Logistic regression models and multivariate analysis of variance (MANOVA) were used to compare whether baseline thickness of the individual ROIs significantly differentiated amyloid positive from amyloid negative as well as p-tau positive from p-tau negative CN individuals. In all of the analyses performed, age, gender, education, and APOE-\u03b54 carrier status were additionally included.Overall, the hippocampus demonstrated the largest magnitude of correlation with the entorhinal cortex , temporal pole , inferior temporal gyrus  and the medial portion of the orbital frontal cortex  . The infLinear regression models amongst the MCI and AD individuals demonstrated that decreased A\u03b2 levels \u200a=\u200a\u22120.01 to \u22120.003, p<0.01) and increased p-tau levels  significantly predicted hippocampal atrophy rate. Within the amyloid positive MCI and AD individuals, baseline thickness of the entorhinal cortex  and inferior temporal gyrus  significantly predicted the atrophy rate of the hippocampus. Similarly, within the p-tau positive individuals, baseline thickness of the entorhinal cortex  and inferior temporal gyrus  significantly predicted the atrophy rate of the hippocampus . Within Logistic regression models amongst the CN cohort demonstrated that APOE-\u03b54 carrier status (Odds Ratio (OR)\u200a=\u200a0.08, 95% CI\u200a=\u200a0.02 to 0.27, p<0.0001) and thinning in the medial portion of the orbital frontal cortex  significantly differentiated the amyloid positive from amyloid negative older individuals whereas thinning of the entorhinal cortex  significantly differentiated the p-tau positive from p-tau negative older individuals . None ofOur results demonstrate that 1) amongst cognitively normal older participants and individuals with MCI and AD, select heteromodal association cortices correlate with hippocampal volume, 2) amongst MCI and AD individuals, gray matter thinning within the same two neocortical regions predicts longitudinal hippocampal volume loss in both amyloid positive and p-tau positive individuals and 3) amongst cognitively normal older adults, thinning within the medial portion of the orbital frontal cortex significantly differentiates amyloid positive from amyloid negative individuals whereas entorhinal cortex thinning significantly discriminates p-tau positive from p-tau negative individuals. Taken collectively, this indicates that cortical A\u03b2 and tau pathology is evident even among asymptomatic older individuals, affects gray matter thinning within select neocortical regions and potentially contributes to downstream hippocampal degeneration. These findings are in agreement with prior work indicating the value of CSF A\u03b2 as an early biomarker The four cerebral cortical regions that best correlated with hippocampal volume follow an interesting neurodevelopmental pattern. On architectonic grounds, the regions identified on the lateral hemisphere trace evolutionary lineage from the so-called \u2018paleocortical\u2019 trend whereas regions identified on the medial hemisphere are derived from the \u2018archicortical\u2019 trend Correlations between thickness of the individual regions and hippocampal volume may reflect underlying patterns of neuropathology. Thickness of the medial portion of the orbital frontal cortex, inferior temporal gyrus, entorhinal cortex, and the temporal pole demonstrated the strongest magnitude of association with the hippocampus amongst each of the three participant groups. In contrast, parietal, occipital, and lateral frontal cortices, correlated with the hippocampus only amongst cognitively normal older adults and MCI individuals. With AD onset, these regions failed to associate with the hippocampus. Of interest, these regions showed the largest magnitude of association with each other amongst each of the three participant groups , 4 and 5One explanation for these findings may involve the evolution of the neuropathologic cascade in AD. Amyloid deposits are first noted in the medial portions of the orbital frontal, basal temporal and entorhinal cortices and tau-associated NFTs initially affect the medial temporal and temporopolar cortices Another possibility is that associations between regions reflect underlying anatomic connections and the decreased correlation coefficients noted with AD onset represent a selective disruption in cortico-hippocampal connectivity. Though several studies have noted disruptions in anatomic connectivity with AD Significant reductions in CSF A\u03b2 levels and elevations in CSF p-tau levels coupled with thinning within select heteromodal regions predicts longitudinal hippocampal atrophy. Prior PiB studies have demonstrated a significant relationship between neocortical amyloid deposition and hippocampal atrophy in vivo evidence that amongst cognitively normal individuals tau pathology selectively affects the thickness of the entorhinal cortex. It is important to note that almost half (47%) of the p-tau positive individuals were additionally amyloid positive and future work will involve looking at the interaction between A\u03b2 and tau pathology.Amongst cognitively normal older adults, cortical thinning of the medial orbital frontal cortex significantly differentiated amyloid positive from amyloid negative individuals whereas thinning of the entorhinal cortex significantly discriminated p-tau positive from p-tau negative individuals. Consistent with neuropathology studies, which demonstrate early amyloid deposition within the medial orbital frontal cortex and early NFT accumulation within the entorhinal cortex The finding that amyloid positive individuals show selective thinning within the medial orbital frontal cortex is in agreement with one prior study demonstrating that older individuals with subjective memory complaints show significant correlations between gray matter atrophy and neocortical PiB increase within the medial orbital frontal/anterior cingulate cortex These findings have important clinical implications. Subtle gray matter disturbances in specific regions of the cerebral neocortex are present amongst a subset of asymptomatic older individuals and can be quantified using sensitive structural neuroimaging techniques. In combination with CSF A\u03b2 and tau, structural MRI measures can provide an indication of disease stage and have value in identifying those who will likely benefit from early therapeutic interventions. Our results also indicate the importance of administering anti-amyloid therapy early in the disease process (at a pre-MCI stage) in order to alter or delay hippocampal degeneration and thus progressive memory loss, the harbinger of clinical Alzheimer's dementia.Why does neurodegeneration affect select cerebral cortical regions? From a phylogenetic perspective, heteromodal and archicortical medial temporal regions constitute the oldest areas of the brain a priori anatomically defined regions with disease-based statistical methods to examine neocortical and subcortical areas in AD. Another limitation involves the use of CSF A\u03b2 and p-tau to assess the presence of amyloid and neurofibrillary pathology in the neocortex. Though amyloid load as measured using PiB and CSF A\u03b2 are highly correlated and likely reflect plaque deposition This study has several limitations. One issue involves the use of gyral-based neuroanatomic ROIs to examine specific neocortical regions. It is likely the case that Alzheimer's pathology does not follow the specific boundaries of these ROIs and affects areas within and across multiple ROIs. The use of regions of interest generated from a disease specific effect"}
+{"text": "Retroviruses are widely used to transfer genes to mammalian cells efficiently and stably. However, genetic elements required for high-level gene expression are incompatible with standard systems. The retroviral RNA genome is produced by cellular transcription and post-transcriptional processing within packaging cells: Introns present in the retroviral genomic transcript are removed by splicing, while polyadenylation signals lead to the production of ineffective truncated genomes. Furthermore strong enhancer/promoters within the retroviral payload lead to detrimental competition with the retroviral enhancer/promoter.in vitro it is possible to produce infectious retroviral particles carrying a high-level expression cassette that completely prohibits production of infectious retroviral particles by conventional methods.By exploiting a new method of producing the retroviral genome in vitro transcription of the retroviral genome by T7 RNA polymerase.We produced an expression cassette comprising a strong enhancer/promoter, an optimised intron, the GFP open reading frame and a strong polyadenylation signal. This cassette was cloned into both a conventional MMLV retroviral vector and a vector designed to allow in vitro produced uncapped retroviral genomic transcript into the packaging cells did not lead to any detectable GFP expression. However, infectious retrovirus was easily recovered, and when used to infect target primary human cells led to very high GFP expression \u2013 up to 3.5 times greater than conventional retroviral LTR-driven expression.When the conventional retroviral vector was transfected into packaging cells, the expression cassette drove strong GFP expression, but no infectious retrovirus was produced. Introduction of the in vitro transcribed retroviral genomic RNA. The applications of this technique are not limited to producing the higher levels of transgene expression demonstrated here. For example, novel reporters with alternatively spliced exon-intron configurations could readily be transduced into virtually any cell. Furthermore, because the in vitro transcripts are not translated within the packaging cells, retroviruses carrying genes lethal to the packaging cells can also be produced.Retroviral vectors carrying an optimized high-level expression cassette do not produce infectious virions when introduced into packaging cells by transfection of DNA. Infectious retrovirus carrying the same cassette is readily produced when packaging cells are transfected with  Retroviral vector systems are routinely used as delivery vehicles for efficient and stable gene transfer into mammalian cells . Since tin vitro generated RNA to nucleate retroviral virions, completely circumventing packaging cell genomic transcription and translation   promoter . This ex) Figure . pT is sWhen transfected into packaging cells, the standard retroviral vectors (pC) produced high levels of GFP expression as measured by flow cytometry Figure . Howeverin vitro transcription system based vectors (pT) carrying the same CMV expression cassette readily generated infectious virus following transfection of in vitro transcribed RNA genomes into packaging cells. The pT vectors produced no detectable GFP expression in the packaging cells, due to the lack of requisite translation signals (e.g. 5' cap) on the RNA transcripts, a notable advantage of the system . Primarin vitro-transcribed retroviral RNA genomes can be utilized to transfer a high-level expression cassette which includes genetic elements not compatible with commonly used retroviral packaging systems. Using this cassette we observe an increase in expression level of up to 3.5 times in primary human cells, reflecting the provision of an intron and the use of strong enhancer/promoter and polyadenylation signals. The ability to circumvent packaging cell transcription, post-transcriptional editing and translation of the vector genome, while maintaining assembly into virions, effectively addresses the shortcomings of current retroviral systems. Thus, this approach is based on standard molecular biology techniques, yet allows virtually any genetic sequence constellation to be manifested by the integrated retroviral provirus: Strong enhancers/promoters, introns and polyadenylation signals for boosting gene expression; gene reporters that encompass multiple exon-introns; post-transcriptional signal sequences to improve gene trapping; cytotoxic gene expression or shRNA expression cassettes that target essential genes.In this report we demonstrate how Vectors pT-cGreen/neerGc L311/L312) were based on vector L139 pT7RU5mcsSIN, a derivative of LB-G  were bas. A T7 poTo generate the uncapped retroviral genomic transcripts, MluI-linearized pT-vector DNA was transcribed with T7 polymerase . RNA was quantified  and the quality checked by denaturing agarose gel electrophoresis   were transfected into 293-based Phoenix A packaging cells by the standard protocol ,15 whichin vitro transcribed genomic RNA was introduced into the packaging cells using the cationic lipid DMRIE-C . The RNA was mixed with lipid at a ratio of 1 \u03bcg RNA to 3.5 \u03bcl DMRIE-C in a final volume of 250 \u03bcl of serum-free OptiMEM  and incubated at room temperature for 20 minutes. Subconfluent (80%) Phoenix-A packaging cells in poly-lysine coated 12-well plates were prepared by rinsing with serum-free medium and 360 \u03bcl OptiMEM was added per well. The RNA-lipid mixture was added dropwise to the cells and incubated for 2 hours before the cells were washed and incubated in complete medium. pT virus-containing medium (1 ml) was harvested 18 hours later. Titers were typically approximately 1 \u00d7 105 gfu/ml for infection of primary human endothelial cells [The al cells .Primary human umbilical vein endothelial cells  were cultured according to the supplier's recommendations. Cells were infected as described  . Viral sAll authors participated in the overall study design and writing of the manuscript. MB/DM conducted the experiments in the laboratory of JBL. All authors have read and approved the final manuscript."}
+{"text": "Fifty-three premenopausal patients presenting with advanced breast cancer have been treated with a potent new luteinising hormone-releasing hormone agonist Zoladex (ICI 118630) in a phase I clinical trial. On progression of disease 26 patients have undergone therapeutic oophorectomy. We present the clinical and endocrinological responses to treatment in 45 assessable patients. The response rate to Zoladex in this series was 31% and the ER status of the primary tumour was predictive of a response to the luteinising hormone-releasing hormone."}
+{"text": "Esculentoside A (EsA) is a saponin isolated from the roots of Phytolacca esculenta. Previous experiments showed that it had strong anti-inflammatory effects. Tumour necrosis factor (TNF) is an important inflammatory mediator. In order to study the mechanism of the anti-inflammatory effect of EsA, it was determined whether TNF production from macrophages was altered by EsA under lipopolysaccharide (LPS) stimulated conditions. EsA was found to decrease both extracellular and cell associated TNF production in a dose dependent manner at concentrations higher than 1 \u03bcmol/l EsA. Previous studies have showed that EsA reduced the releasing of platelet activating factor (PAF) from rat macrophages. The reducing effects of EsA on the release of TNF and PAF may explain its anti-inflammatory effect."}
+{"text": "A technique for growing colonies from single-cell suspensions of human tumour xenografts using agar in diffusion chambers is described. Modified Millipore diffusion chambers containing tumour cells in semi-solid agar-medium were implanted into the peritoneal cavity of pre-irradiated mice and provided standard culture conditions for the study of colony-forming cells. All 11 xenograft tumours so far studied produced colonies. The incubation period for colony growth ranged from 12 to 28 days and the plating efficiency ranged from 0-3% to 16% for different tumours, but both parameters were constant for each individual tumour. The reproducibility of the system provides a colony-forming assay which can be used to study the effects of irradiation and cytotoxic drugs on human tumour clonogenic cells and may therefore have some advantages over similar assays based on experimental animal tumours."}
+{"text": "Sister chromatid exchange (SCE) induction by two radiosensitizing platinum compounds (cis-dichloro-bis isopropylamine trans dihydroxy platinum IV (CHIP) and cis-platinum metronidazole2 Cl2 (FLAP] was studied in CHO cells in vitro. Both drugs induced SCE in a dose dependent manner. CHIP was a much more potent inducer of SCE than FLAP and produced almost 4 times as many SCE as FLAP at equimolar concentrations and twice as many at equitoxic dosage. Induction of SCE by a component of the FLAP molecule--metronidazole--was also examined. It did not cause any increase of SCE frequency over the control level when applied at 10 times the highest concentration of FLAP which was used."}
+{"text": "Bovine herpesvirus 1. We used a bioinformatics approach to distinguish authentic mature miRNA sequences from other classes of small RNAs and short RNA fragments represented in the sequencing data. Using this approach we detected 219 out of 356 known bovine miRNAs and 115 respective miRNA* sequences. In addition we identified five new bovine orthologs of known mammalian miRNAs and discovered 268 new cow miRNAs many of which are not identifiable in other mammalian genomes and thus might be specific to the ruminant lineage. In addition we found seven new bovine mirtron candidates. We also discovered 10 small nucleolar RNA (snoRNA) loci that give rise to small RNA with possible miRNA-like function. Results presented in this study extend our knowledge of the biology and evolution of small regulatory RNAs in mammals and illuminate mechanisms of small RNA biogenesis and function. New miRNA sequences and the original sequencing data have been submitted to miRNA repository (miRBase) and NCBI GEO archive respectively. We envisage that these resources will facilitate functional annotation of the bovine genome and promote further functional and comparative genomics studies of small regulatory RNA in mammals.MicroRNA (miRNA) and other types of small regulatory RNAs play a crucial role in the regulation of gene expression in eukaryotes. Several distinct classes of small regulatory RNAs have been discovered in recent years. To extend the repertoire of small RNAs characterized in mammals and to examine relationship between host miRNA expression and viral infection we used Illumina's ultrahigh throughput sequencing approach. We sequenced three small RNA libraries prepared from cell line derived from the adult bovine kidney under normal conditions and upon infection of the cell line with  MicroRNAs (miRNAs) are small 21\u201323 nucleotide regulatory RNAs that modulate gene expression in animals and plants. In animals regulation of gene expression by miRNAs is achieved by sequence-specific targeting of the 3\u2032 untranslated regions of messenger RNAs by the RNA induced silencing complex (RISC). This results in translational repression of protein synthesis and, in some cases, destabilization of messenger RNA Identification of comprehensive sets of miRNAs and other small regulatory RNAs in different organisms is a critical step to facilitate our understanding of genome organization, genome biology and evolution. The recently completed bovine genome is the first sequenced genome of ruminant mammal that displays a broad range of phenotypic characteristics that reflect adaptation to different habitats and domestication. The large number of cattle breeds selected for their commercially valuable traits (e.g. meat and milk production) and their ability to thrive in different environments make the bovine genome an attractive model to study genetic and epigenetics variations underlying diverse cattle phenotypes The latest release of the miRNA database (miRBase 13.0 March 2009) contains 356 bovine miRNA genes that code for 326 distinct mature miRNAs and eight sequences originating from the RNA hairpin arm opposite to the annotated mature miRNA containing arm, the so-called miRNA* Bovine herpesvirus 1 (BoHV-1). Illumina's ultrahigh throughput sequencing approach has been used successfully to identify new miRNAs and other classes of small regulatory RNAs in several recent studies We aimed to extend the known repertoire of small regulatory RNAs expressed in bovine tissues and identify miRNA that could be disregulated upon viral infection. We used a cell line derived from the adult bovine kidney under normal conditions and upon infection of the cell line with the To simplify the sequencing data, all identical sequence reads in each small RNA library were grouped and converted into sequence tags\u2013unique sequences with associated counts of the individual sequence reads. The resulting sets of non-redundant sequence tags for each library were mapped to the bovine and BoHV-1 reference genomes Following mapping of sequence tags to the reference bovine genome we analyzed small RNA sequences originating from known bovine miRNA loci listed in miRBase 13.0. We found that out of 356 known cow miRNAs 338 could be positioned onto assembled chromosomes; out of those 219 miRNA were detected in at least one of our three small RNA libraries, 190 amongst those were detected in either two or all three small RNA libraries  genomic loci annotated as known bovine miRNAs or as other classes of non-coding RNA were excluded; (2) to be considered for further analysis an individual locus had to be supported by at least two independent sequence reads originating from at least two small RNA libraries; (3) the loci lacking hairpin-like RNA secondary structures including the positions of the small RNA tags were eliminated. The resulting set of sequences and their respective RNA structures were analyzed further to distinguish genuine miRNA precursors from other RNAs that contain similar RNA structures , worms (Caenorhabditis elegans), and mammals (primates and rodents) de-novo identification of mirtrons we used methodology described earlier TPRG1L and DDX5 genes respectively and were expressed in all three small RNA libraries as evidenced by presence of sequence tags  is a class of evolutionary conserved non-coding RNAs present throughout the Eukaryotes Although analysis of snoRNA loci in the bovine genome is complicated by the current lack of comprehensive annotation of non-coding RNAs we analyzed bovine snoRNA loci that could be identified using human snoRNA annotations and syntenic alignment tool from UCSC genome browser . We idenThe source of bovine RNA, RNA sample preparation, and construction of small RNA sequencing libraries is described in supplemental methods . In brieApproximately 20 \u00b5g of total RNA isolated from MDBK cells either infected (MOI of 0.75 and 7.5) or mock inoculated with BoHV-1 was supplied to GeneWorks Pty Ltd  for construction of small RNA libraries and ultrahigh throughput sequencing. Sequencing was performed on the Illumina Genome Analyzer G1 according to the manufacturer's protocol.Bos Taurus v. 3 genome sequence assembly and annotations  http://www.ncbi.nlm.nih.gov/). To identify novel miRNA genes we identified all hairpin-like RNA structures encompassing small RNA sequence tags using RNAfold Individual sequence reads with the base quality scores were produced by GeneWorks Pty Ltd using Illimina's Data Analysis Pipeline software v.1.0. Subsequent sequence data analyses were carried out as described by Glazov et al. with some modification To identify the evolutionary conserved orthologs of the bovine miRNAs in other mammalian genomes we used bovine pre-miRNA sequences to search for highly similar sequences in human, mouse, dog, horse, and opossum genomes. The search was performed using BLAT Kent 2002 Known mammalian miRNA sequences were obtained from microRNA database at the Sanger center (miRBase 13.0 March 2009) http://microrna.sanger.ac.uk/registry/). Original sequence data generated in this study have been deposited to the NCBI Gene Expression Omnibus database (http://www.ncbi.nlm.nih.gov/geo/) under accession number GSE15450.All sequences identified as new miRNA precursors and the mature miRNA were submitted to the miRBase at the Sanger Centre (Table S1Summary of the expression data for known detected cow miRNA(0.16 MB XLS)Click here for additional data file.Table S2Sequence and genomic coordinates information for new miRNA* identified in this study.(0.03 MB XLS)Click here for additional data file.Table S3Summary of the expression data for newly detected cow miRNA(0.06 MB XLS)Click here for additional data file.Table S4Sequence and genomic coordinates information for new miRNA precursors(0.03 MB XLS)Click here for additional data file.Table S5Sequence and genomic coordinates information for new mature miRNA and miRNA*(0.03 MB XLS)Click here for additional data file.Figure S1Summary of phylogenetic relationships of the mammalian species discussed in this study.(0.06 MB PDF)Click here for additional data file.Figure S2Known miRNA with unusual small RNA processing pattern.(0.10 MB PDF)Click here for additional data file.Figure S3Bidirectional miRNA candidates.(0.10 MB PDF)Click here for additional data file.Figure S4Mirtrons(0.09 MB PDF)Click here for additional data file.Figure S5snoRNA-derived small RNAs(0.13 MB PDF)Click here for additional data file.Figure S6Bovine miRNA bta-mir-219(0.06 MB PDF)Click here for additional data file.File S1Supplemental methods.(0.03 MB PDF)Click here for additional data file."}
+{"text": "Bombesin-like peptides and their receptors are widely distributed throughout the gut and are potential mitogens for a number of gastrointestinal (GI) cancers. We have analysed the expression of bombesin-like peptides and their receptor subtypes in normal and neoplastic colorectal tissue. Expression was analysed by reverse transcription polymerase chain reaction (RT-PCR) using receptor and ligand subtype-specific primers and then expression localized by in situ hybridization (ISH) with riboprobes synthesized by in vitro transcription of cloned PCR products. Colorectal cancer tissue and matched normal mucosa from 23 patients were studied. Two of these patients had synchronous adenomatous polyps and two had synchronous hepatic metastases which were also studied. An additional two patients with adenomatous polyps were studied along with matched normal mucosa. Gastrin releasing peptide (GRP) receptor and ligand expression was present in all samples but with overall greater expression in the tumour samples. Neuromedin B (NMB) receptor expression was not detectable. NMB ligand was detected in all but one mucosal sample with overall overexpression in the tumour samples. Bombesin receptor subtype 3 (BRS-3) receptor expression was not detectable. These data support the possibility that GRP may be an autocrine growth factor in colorectal cancer. \u00a9 2000 Cancer Research Campaign"}
+{"text": "Treatment of ruptured Achilles tendons currently constitutes of conservative early functional treatment or surgical treatment either by open or minimal invasive techniques. We hypothesize that an experimental Achilles tendon suture in an animal model significantly deteriorates Achilles tendon microcirculation immediately following suturing.Fifteen Achilles tendons of eight male Wistar rats (275\u2013325 g) were included. After preparation of the Achilles tendon with a medial paratendinous approach, Achilles tendon microcirculation was assessed using combined Laser-Doppler and spectrophotometry (Oxygen-to-see) regarding:- tendinous capillary blood flow [arbitrary units AU]- tendinous tissue oxygen saturation [%]- tendinous venous filling pressure [rAU]The main body of the Achilles tendon was measured in the center of the suture with 50 Hz. 10 minutes after Achilles tendon suture (6-0 Prolene), a second assessment of microcirculatory parameters was performed.Achilles tendon capillary blood flow decreased by 57% following the suture . Tendinous tissue oxygen saturation remained at the same level before and after suture . Tendinous venous filling pressure increased by 33%  after suture.Achilles tendon suture in anaesthetised rats causes an acute loss of capillary perfusion and increases postcapillary venous filling pressures indicating venous stasis. The primary hypothesis of this study was confirmed. In contrast, tendinous tissue oxygen saturation remains unchanged excluding acute intratendinous hypoxia within the first 10 minutes after suture. Further changes of oxygen saturation remain unclear. Furthermore, it remains to be determined to what extent reduced capillary blood flow as well as increased postcapillary stasis might influence tendon healing from a microcirculatory point of view in this animal setting. Achilles tendon ruptures are currently treated either conservatively with an early functional rehabilitation programme or surgically with varying suture techniques. Besides the conventional open approach with its known inherited potential adverse effects such as infections and extensive scaring minimal-invasive percutaneous techniques are becoming popular. Current scientific studies adress biomechanical properties of different suture techniques for tendon ruptures. -3 FurtheAs tendon healing is often prolonged and associated with a less than optimal outcome, current studies aim at ameliorating the conditions for tendon healing. ,7 HoweveWe therefore designed a preliminary animal study to investigate our hypothesis that an Achilles tendon suture significantly deteriorates Achilles tendon microcirculation immediately following the tendon suture.Experiments were approved by the local animal right protection authorities and performed in accordance to the NIH guidelines for the Care and Use of Laboratory Animals .The study included 8 male Wistar rats (250\u2013350 g body weight (bw); Charles River Laboratories, Sulzfeld, Germany), housed 1/cage at 21\u00b0C with a natural light/dark cycle as well as water and standard laboratory chow ad libitum. Under pentobarbital sodium anesthesia , the rats were tracheotomized and mechanically ventilated . Furthermore, animals' right carotid artery was cannulated with polyethylene catheters . The cannulation allowed heart rate and blood pressure to be monitored. During the procedure, body temperature was maintained at 36\u201337\u00b0C by means of a heating pad. Systemic blood parameters and blood gas analysis were assessed before starting measurements using a Coulter Counter .Fifteen gastrocnemius and soleus muscles as well as Achilles tendons were surgically exposed by a medial approach down to the calcaneal insertion. Only 15 Achilles tendons of 8 Wistar rats could be used because of carotid cannulation dislocation with consecutive fatal bleeding and exitus letalis after measurement of a single tendon in one case.Tissue was allowed to stabilize for 10 minutes before investigating the tendinous microcirculation using a non-invasive combined Laser-Doppler- and Photospectrometry-system . Each tendon was measured 10 minutes after preparation of the Achilles tendon as well as ten minutes after tendon suture at the same location. Measurements at baseline and 10 minutes after tendon suture always started at the right Achilles tendon. 15 minutes after initiation of measurement of the right Achilles tendon of one rat, the contralateral Achilles tendon was measured at baseline.We used a fixation apparatus for the probe in order to minimize measurement artefacts due to vibration figure . BaselinThe determination of hemoglobin and the principle of blood flow measurement are combined in the O2C system. The optical method for measuring both, blood flow by Laser-Doppler technique and hemoglobin oxygenation and hemoglobin concentration in tissue by spectrometric techniques, has been described in detail elsewhere.  The loca\u2022 tendinous capillary blood flow \u2022 tendinous tissue oxygen saturation [%]\u2022 tendinous venous filling pressure [AU]We have recently described the use of the O2C-system in measurements of increased capillary blood flow at the point of pain in patients with insertional and mid-portion tendinopathy of the Achilles tendon compared to healthy subjects as well as the influence of permanent and intermittent application of cooling and compression on microcirculation of Achilles tendons in healthy humans. ,9 A 5% iIndependent samples t-test was applied for comparison of baseline measurement of right vs. left Achilles tendon. Paired t-test was used for comparison of pre- vs. post-interventional microcirculatory changes. A p-value less than 0.05 was considered to indicate statistical significance. The SPSS statistical software package 16.0 for Windows  was used for statistical analysis.Achilles tendon mid-portion capillary blood flow was 70 \u00b1 30 arbitrary units at rest without tendon suture. There were no significant differences in capillary blood flow between right and left Achilles tendon at baseline . 10 minutes after suturing the tendon's mid portion, capillary blood flow significantly decreased to 31 \u00b1 16 arbitrary units by 57% . Oxygen saturation did not significantly change within ten minutes following the suture of the Achilles tendon and remained at 77 \u00b1 22% . The postcapillary filling pressure significantly increased ten minutes after the Achilles tendon suture to 72 \u00b1 20 AU  may exert positive effects on tissue healing, a process highly dependent upon adequate circulation. IPC is a treatment based on the passive increase of blood flow by cycling external pressure. The biomechanical effects include reduced venous stasis, decreased venous pressure and increased arterial blood flow.  IPC is uFurthermore, in vivo transient limb ischemia releases a low molecular weight, hydrophobic, circulating factor which induce a potent protection against myocardial ischemia/reperfusion injury in Langendorff perfused hearts and isolated cardiomyocytes in the same species. This cardioprotection is transferable across species, independent of local neurogenic activity, and requires opioid receptor activation. A commonAchilles tendon suture in anaesthetised rats causes an acute loss of capillary perfusion and increases postcapillary venous filling pressures indicating venous stasis. In contrast, tendinous tissue oxygen saturation remains unchanged excluding acute intratendinous hypoxia within 10 minutes after suture. Reduced capillary blood flow as well as increased postcapillary stasis might influence tendon healing from a microcirculatory point of view at least in this animal experiment. Nevertheless, the consequences of our findings remain unclear and must be an issue of further studies.Ethical Board Review statement: Experiments were approved by the local animal right protection authorities and performed in accordance to the NIH guidelines for the Care and Use of Laboratory Animals .The authors declare that they have no competing interests.RK carried out the data assessment. RR performed preparation of the tendons and supplied materials. RK, JL and KK drafted the manuscript. RK and KK participated in the design of the study. RK and JL performed the statistical analysis. PMV conceived of the study, participated in its design and coordination and helped to draft the manuscript. All authors read and approved the final manuscript."}
+{"text": "However, repeat dearterializations for 60 min in portal deviatedrats induced irreversible liver damage and all rats died in a few days. Repeated dearterializationsfor 60 minutes alone retarded the tumour growth as efficiently (p = 0.007). Simultaneousocclusion of the hepatic artery and the portal vein for 30 minutes with a side-side porto-cavalshunted  did not affect tumour growth (p = 0.154). Liver aminotransferases(ASAT and ALAT) were substantially increased following dearterialization for 30 min inrats with either an end-side or a side-side porto-caval shunt. Dearterialization for 60 min in ratswith end-side porto-caval shunts gave a further release of ASAT and ALAT.As liver tumours receive some of their blood supply from the portal vein, we wanted to illustratethe influence of portal blood flow in combination with dearterialization in the treatment of livertumours. Forty male, inbred Wistar/Furth rats with an adenocarcinoma transplanted to the liverwere treated with various inflow occlusions repeated daily for 5 days. Deviation of the portalblood flow alone with an end-side porto-caval shunt did not alter the tumour growth (\t\tIn conclusion, portal deviation did not augment the therapeutic benefit of repeat dearterializationsfor the treatment of this experimental liver tumour. Repeat dearterializations aloneseemed to be a feasible and efficient therapy for liver tumours."}
+{"text": "The monoclonal antibody CL21 recognizes a determinant present on the surface ofleukocytes, but not on erythrocytes or nonhemopoietic tissue. The CL21 antigen wasfirst expressed at 48 hr of development at 20\u00b0C (stage 28) on embryonic cells culturedfrom lateral plate mesoderm. Based on immunofluorescence staining and flowcytometric analysis, the distribution of fluorescence intensity of larval thymocytes andsplenocytes was unimodal. Distributions of dull and bright cells were detected in bothadult thymocytes and splenocytes. These different subpopulations appeared during thelate perimetamorphic period. Adult splenocytes were metabolically activated whencultured in the presence of mAb CL21 bound to a substrate but not in the presence ofmAb CL21 in suspension. Immunoprecipitation and SDS-PAGE under nonreducingconditions revealed that a single 180-kD molecule was expressed on thymocytes.Analysis of splenocytes demonstrated the presence of two molecules having similarmolecular mass that resolved to a single band under reducing conditions."}
+{"text": "Hepatic artery thrombosis is a devastating complication after orthotopic liver transplantation often requiring revascularization or re-transplantation. It is associated with considerably increased morbidity and mortality. Acute cognitive dysfunction such as delirium or acute psychosis may occur after major surgery and may be associated with the advent of surgical complications.Here we describe a case of hepatic artery thrombosis after living-donor liver transplantation which was not preceded by signs of liver failure but rather by an episode of acute psychosis. After re-transplantation the patient recovered without sequelae.This case highlights the need to remain cautious when psychiatric disorders occur in patients after liver transplantation. The diagnostic procedures should not be restricted to medical or neurological causes of psychosis alone but should also focus vascular complications related to orthotopic liver transplantation. Hepatic artery thrombosis (HAT) is the most frequent arterial complication in orthotopic liver transplantation (OLT) occurring in 2.5-6.8% of adult transplant recipients including adult living donor liver transplant recipients -3 with aA 42-year-old male patient underwent a living-donor liver transplantation (LDLT) for progressive hepatitis B, cirrhosis with 7 points on the Child-Turcotte-Pugh scale and a model for end-stage liver disease score of 10. He was placed on the waiting list for transplantation because of suspected hepatocellular carcinoma. He had no history of psychiatric disorder. The donor was his 43-year-old brother who had no major medical problems. The clinical match was appropriate infection the patient also received 103 units of hepatitis B immunglobuline at reperfusion and intravenous infusion of piperacillin/tazobactam at surgery until the 3rd POD but no antimycotics or prophylactic CMV therapy (both donor and recipient had experienced CMV infection).At the time of transplantation the patient received induction immunosuppression consisting of 500 mg methylprednisolone and 20 mg basiliximab, the latter was repeated on the 4th post-operative day (POD). Immunosuppression was maintained with oral mycophenolat mofetil from the first POD at 2 \u00d7 1 g daily and oral prednisolone with an initial daily dose of 75 mg. The latter was tapered by 5 mg every two days. On the 5th POD oral tacrolimus was added to the immunosuppressive regimen starting with 0.5 mg on the first day and increasing daily dose by 1 to 2 mg to achieve trough plasma level of 4-10 In the postoperative course serum transaminases peaked on the first and 4th POD but then decreased continuously as prothrombin time increased (coagulation factors were not substituted). Albeit a gradual increase in total bilirubin plasma levels only a mild graft dysfunction was suspected because bile flow over the T-drain increased. Daily doppler sonography of hepatic vessels showed unaltered graft perfusion. Overall the patient had an uncomplicated postoperative without signs for infection or organ dysfunction. The clinical course and laboratory findings did show mild a graft dysfunction but neither rejection nor acute graft failure were indicated.On the 9th POD the patient suffered from acute paranoid psychosis, being alert but agitated and physically aggressive. He was mistrustful and afraid of being harmed by people around him. The patient became unmanageable and had to be sedated with an intramuscular injection of 5 mg haloperidol and an intravenous injection of 20 mg diazepam. Due to this unusual presentation of postoperative delirium a diagnostic workup was initiated. Patent hepatic artery could not be shown in doppler sonography and subsequent angiography. Explorative laparotomy on the same day revealed a complete thrombosis of the donor hepatic artery and gross ischemic infarction in all liver segments. Because progression of infarction and subsequent graft loss was to be expected the patient was placed on the transplant waiting list for re-OLT.An acceptable organ was offered from an 18-year-old heart-beating donor on the following day and the patient underwent re-OLT 10 days after the LDLT. The hepatic artery of the new graft was reanastomosed to the old conduit. The immunosuppressive regimen was reinitiated as described above including tacrolimus (see Figure Here we describe a case of HAT after LDLT preceded not by signs of an liver failure but by acute paranoid psychosis. At transplantation the patient required a complex arterial reconstruction with an interposition graft which is a known risk factor for HAT ,8. WhethPsychiatric disorders are not uncommon in the postoperative course of the liver transplant patient . Like otPsychiatric disorders may also be drug induced. Immunosuppressive drugs like tacrolimus and corticosteroids are known causative agents of psychiatric reactions -16. NeurBecause of elevated bilirubin we also suspected impaired graft function could cause acute psychosis in our patient. In chronic liver failure manifestations of encephalopathy are common and may reach from mild obtundation with dementia and movement disorders to deep coma . In the Besides infection and sepsis surgical complications are the most likely cause of graft dysfunction in the early post-transplant period. Therefore we initiated further diagnostic work-up. Abdominal sonography showed no flow in the hepatic artery and subsequently HAT was confirmed by angiography. During explorative laparotomy the liver was found to be with gross infarction and we decided to evaluate the patient for re-transplantation. Luckily we obtained a graft within 24 hours and after re-transplantation psychosis resolved without sequelae.We propose that in the described patient HAT is the most likely cause of an acute liver failure although laboratory findings indicated only mild graft dysfunction. Acute liver failure was accompanied by hepatic encephalopathy apparent as acute delusional psychosis.This case highlights the need to remain suspicious when psychiatric disorders occur in patients after liver transplantation. The diagnostic procedures should not be restricted to medical or neurological causes of psychosis but should also focus vascular complications of OLT.The authors declare that they have no competing interests.ADG and TL collected and analyzed the data and wrote the article. GR, HB and AO contributed substantially to the process of analyzing the data and writing the paper. All authors read and approved the final manuscriptThe pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2482/10/7/prepub"}
+{"text": "Childhood neuroblastoma tumours of the sympathetic nervous system show a remarkable clinical heterogeneity ranging from spontaneous regression to unfavourable outcome despite intensive therapy. Favourable neuroblastomas often express high levels of trkA mRNA, encoding the tyrosine kinase receptor for nerve growth factor. We have investigated mRNA expression for the neurotrophin receptor trkC in 23 primary neuroblastomas using a sensitive RNAase protection assay. TrkC expression was detected in 19 of these tumours at highly variable levels with a 300-fold difference between the highest and lowest values. Significantly higher levels of trkC mRNA were found in tumours from patients with favourable features such as low age (P < 0.012), favourable tumour stage (P < 0.012) and favourable prognosis (P < 0.05). Children with intermediate or high trkC mRNA expression had better prognosis compared with those with low or undetectable levels . Further characterisation of trkC mRNA expression by reverse transcriptase-polymerase chain reaction (RT-PCR) showed that mRNA encoding the full-length cytoplasmic tyrosine kinase domain of the receptor was only expressed in a subset of favourable tumours. These data show that favourable neuroblastomas may express the full trkC receptor while advanced tumours, in particular MYCN-amplified neuroblastoma, seem to either express no trkC or truncated trkC receptors of as yet unknown biological function. These data are suggestive of a role for trkC and its preferred ligand neutotrophin-3, NT-3, in neuroblastoma differentiation and/or regression."}
+{"text": "During the last years the analysis of microRNA expression patterns has led to completely new insights into cancer biology. Furthermore, these patterns are a very promising tool for the development of new diagnostic and prognostic markers. However, most human tumour samples for which long term clinical records are available exist only as formalin-fixed paraffin-embedded specimens. Therefore, the aim of this study was to examine the feasibility of microRNA profiling studies in routinely processed formalin-fixed paraffin-embedded human breast cancer specimens using fluorescence labelled bead technology.A statistically highly significant correlation  was observed for the expression of 319 microRNAs in routinely processed FFPE breast cancer specimens and paired fresh frozen tissue samples (n = 5). Results were confirmed in a larger series analyzing a selection of 10 microRNAs reported to be deregulated in breast cancer (n = 12). The expression pattern of 3 microRNAs was independently validated in this cohort using real-time RT-PCR technology.Comprehensive microRNA expression patterns can be reliably derived from routinely processed FFPE breast cancer specimens using fluorescence labelled bead technology. Formalin-Fixed, Paraffin-Embedded (FFPE) tissue samples represent an invaluable source for the study of human disease. Millions of blocks are archived world wide with corresponding well-documented clinical histories and histopathological reports. The potential value of these archives for retrospective molecular studies has been well recognized . HoweverThe analysis of microRNA expression patterns in human tumour specimens promises to provide completely new insights into tumour biology. In addition, it may contribute to the development of new diagnostic or predictive markers ,3. But tThe quantification of microRNA expression levels using LNA probes coupled to fluorescence labelled beads offers several advantages: No amplification step is required which may introduce a potential bias and the hybridization of probes and target sequences takes place in a homogeneous system .So far, no systematic comparison of microRNA profiles obtained from fresh-frozen and corresponding FFPE samples using the fluorescence labelled bead technology is described.In this study we examined the expression pattern of 319 microRNAs in routinely processed formalin-fixed paraffin-embedded breast cancer specimens and paired fresh-frozen specimens from the very same tumours. For this purpose the fluorescence labelled bead technology from Luminex  was employed.The integrity and quality of the RNA preparations was analysed using the microcapillary fluid device form Agilent . The mean \"RNA integrity number\" (RIN) for all The mean fluorescence intensity, the highest fluorescence intensity, and the sum of all fluorescence intensities were not reduced in any of the FFPE samples compared to the corresponding fresh-frozen sample (data not shown). Therefore, no reduction in microRNA recovery due to formalin-fixation was observed.The expression level of 319 microRNAs (FlexMir panel version 8 from Luminex) was measured in 5 fresh-frozen breast cancer specimens and corresponding formalin-fixed paraffin-embedded tissue samples from the very same tumour. The measurements showed a very good correlation for all 5 paired samples Fig. . The Spe10 individual microRNAs were selected from the literature as most frequently deregulated in primary human breast cancer  was measured in all samples (12 fresh frozen and 12 FFPE) using the stem-loop primer real-time PCR methodology from ABI . Overall, the expression pattern (miR-10b versus miR-145 and miR-10b versus miR-21) obtained with this completely different technique is quite similar: The expression level of miR-145 is only slightly higher than the expression level of miR-10b whereas miR-21 is much stronger expressed than miR-10b  than using the bead-based methodology (mean: approx. 40-fold).The systematic comparison of paired fresh-frozen and formalin-fixed paraffin-embedded tissue specimens from the very same tumour shows that reliable microRNA expression pattern can be obtained from routinely processed breast cancer specimens using the fluorescence-labelled bead-based technology from Luminex. However, a disadvantage of the current microRNA profiling methodology from Luminex is the requirement of quite large amounts of total RNA (2.5 \u2013 5 \u03bcg) which is clearly not available for every interesting case.The much stronger overexpression of miR-21 as measured by real-time PCR in comparison to the bead-based methodology could be due to slight differences in amplification efficiencies for these two microRNAs. These slight differences in efficiency create a considerable difference in expression level after 25 or 30 cycles due to the exponential nature of the amplification process. Additional sources of differences between the methods compared are the completely different RNA processing (cDNA synthesis versus direct biotin-labelling) and differences in analytical sensitivity . But nevertheless, the overall pattern is the same using both techniques.Leaving out all signals below 100 arbitrary units improved the correlation quite significantly for three out of five samples, clearly indicating that most of the variability between paired samples are due to fluctuations of the signals of very weekly expressed microRNAs.Nelson et al.  analysedLi et al.  publishe2 = 0.86 \u2013 0.89). However, no corresponding pairs of routinely processed human tissue samples were analyzed. Only a single archival human colon cancer specimen for which no corresponding fresh-frozen material was available was analyzed.Xi et al.  studied Wang et al.  mention Lawrie et al.  showed iT) values and the shift in CT values, a direct comparison with the correlation coefficients obtained by us using a different methodology is not possible. However, both technical approaches seem to provide reliable data.The recently published study from Hoefig et al.  represenFinally, the evaluation of different microRNA isolation procedures recently published by Doleshal et al. , containThe data presented in this study convincingly show that routinely processed human FFPE tissue specimens are suitable for large-scale as well as small-scale microRNA profiling projects using fluorescence labelled bead technology. Therefore, this methodology can now be used for large retrospective studies utilizing stored archival FFPE samples together with the corresponding clinical and histopathological records.Note added in proof:During the revision of this manuscript Zhang et al. published the comparison of microRNA expression patterns from fresh-frozen and corresponding FFPE lymph node specimens (n = 7) using the Agilent microarray platform .  These au12 fresh frozen breast cancer specimens and corresponding formalin-fixed paraffin-embedded tissue samples from the very same tumours were retrieved from the archives of the Institute of Pathology, Medizinische Hochschule Hannover in an anonymous fashion following the guidelines of the local Ethics committee. Tumour cell content was controlled on an HE stained serial section and above 80% for all cases.Total RNA was isolated from fresh-frozen specimens using TRIZOL\u2122 reagent  following the protocol supplied by the manufacturer. Isolation of total RNA from FFPE specimens was performed as described previously.  FollowinAn aliquot of 150 ng of every RNA preparation was checked for integrity in an Agilent 2100 Bioanalyzer . Sample preparation and analysis were performed following the manufacturer's instruction.Quantification of microRNAs hybridized to fluorescence labelled beads was performed with a BioPlex 200\u2122 from Biorad  using the software Luminex IS\u2122, version 2.3 from Luminex . All beads coated with LNA probes complementary to mature microRNAs were purchased from Luminex .Prior to hybridization total RNA is labelled with biotin which is later bound to a streptavidin-phycoerythrin conjugate. For this purpose the FlexmiR\u2122 MicroRNA Labeling Kit from Luminex was used. For the comprehensive profiling of 319 microRNAs  2.5 \u03bcg total RNA were labelled, for the analysis of 10 selected microRNAs (FlexmiR\u2122 Select) 0.5 \u03bcg were labelled following the protocol provided by the manufacturer. Subsequent washing, hybridization and analysis of samples were performed exactly as described in the protocols provided by Luminex.The system was calibrated using the xMAP\u2122 calibration control reagents from Luminex following the recommendations of the manufacturer. Every run contained a negative control for background subtraction (water instead of RNA) and a positive control . For data normalization the background value for every individual microRNA bead was subtracted from every corresponding measurement. Subsequently, all corrected mean fluorescence intensities were normalised to pool 1 using the average correction factor for the four normalization controls included in all five pools as recommended by the manufacturer (The 319 different microRNA beads are divided into 5 pools because there are not enough different fluorescence labels available to distinguish more than 70 \u2013 80 beads in a single tube.). These normalised net mean fluorescence intensities were directly compared between paired samples. All control and normalization beads  were left out for these comparisons.For the measurement of the expression levels of selected microRNAs  the real time-RT-PCR-based detection methodology from ABI  was used. Relative expression levels were calculated using the constitutively expressed small RNAs RNU24 and Z-30 as endogenous controls. All primers and probes were purchased from ABI. cDNA synthesis and real-time PCR were performed following the protocols supplied by the manufacturer.The distribution of the microRNA expression data did not pass the test for normality (\u03b1 = 0.05) for any specimen. Therefore, Spearman rank correlation factors were calculated (two-tailed). For all calculations the software package GraphPad Prism  was used. p-values < 0.05 were considered statistically significant.FFPE: formalin-fixed paraffin-embedded; LNA: locked nucleic acid.UL and HK conceived the study, BH and UL performed all measurements and evaluated the data, MC and UL performed the statistical analysis and drafted the manuscript, HK selected and evaluated all cases, UL wrote the manuscript with support from HK and MC. All authors read and approved the final manuscript.Comparison of expression levels of 319 microRNAs in 5 paired fresh-frozen and formalin-fixed paraffin-embedded human breast cancer specimens. The data provided represent the correlation analysis of the microRNA expression levels measured in the paired specimens BrC1 \u2013 BrC5 (fresh-frozen versus FFPE). The results for BrC1 are also shown in Fig. Click here for fileComparison of expression levels of 319 microRNAs in 5 paired fresh-frozen and formalin-fixed paraffin-embedded human breast cancer specimens leaving out weak signals. The data provided represent the correlation analysis of the microRNA expression levels measured in the paired specimens BrC1 \u2013 BrC5 (fresh-frozen versus FFPE) leaving out all signals below 100 arbitrary units (see main text for further details).Click here for fileComparison of expression levels of 10 selected microRNAs in BrC1 \u2013 BrC6. The data provided represent the relative expression levels of 10 microRNAs reported to be deregulated in human breast cancer (see Table Click here for fileComparison of expression levels of 10 selected microRNAs in BrC7 \u2013 BrC12. The data provided represent the relative expression levels of 10 microRNAs reported to be deregulated in human breast cancer (see Table Click here for file"}
+{"text": "Background: Chronic intestinal schistosomiasis is rare in the United Kingdom. The symptoms arenonspecific and may mimic several other gastrointestinal conditions. We present a case of chronicintestinal schistosomiasis in a West Indian woman presenting to a genitourinary clinic.        Case: The patient presented with chronic lower abdominal pain and dysuria. A sexually transmitteddisease (STD) screen was negative and midstream urine cultures were sterile. A rectal biopsyrevealed a non-necrotizing granulomatous reaction around the ova of Schistosoma. Her symptomsresolved with anti-schistosomiasis therapy.            Conclusion: This case illustrates that physicians should be aware of chronic schistosomiasis in thedifferential diagnosis of chronic lower abdominal pain in women who have come from or visitedareas where schistosomiasis is endemic."}
+{"text": "Growth factor activity which stimulates anchorage-independent growth (AIG) in a rat fibroblast line, was detected in human premalignant adenoma tissue from familial polyposis coli colectomy specimens and in serum-free culture supernatant from an adenoma cell line PC/AA. The activity extracted from adenoma tissue was compared quantitatively in the AIG bioassay with extracts of normal mucosa from split thickness colorectal tissue. Adenoma tissue yielded three times the amount of acid-extractable protein g-1 wet wt and adenoma extracts consistently had significantly greater specific activity over a wide protein concentration range. Activity extracted from adenoma tissue and from the derived cell line PC/AA were compared qualitatively after fractionation by gel filtration. Both extracts showed almost identical profiles of biological activity after assay of individual fractions for AIG stimulation, suggesting that the factor(s) originates from the epithelial component of the adenoma tissue since PC/AA is a pure epithelial cell line. Activity eluted as two major peaks with apparent mol. wts of 9 kd and 20-25 kd (relative to standards) in both cases. This report demonstrates for the first time that elevated production of a growth factor may be an early change in the evolution of human colorectal cancer from small, premalignant adenomas."}
+{"text": "An 11-year-old girl with rapidly enlarging bilateral breast lumps is reported. It was diagnosed as a case of juvenile fibroadenoma following fine needle aspiration cytology and confirmed on histopathological examination of the excised specimens. Bilaterally symmetrical giant juvenile fibroadenomas are very rare in prepubertal girls.2 The lesAn 11-year-old premenarche girl presented with bilateral, rapidly increasing breast lumps for two months . There wFNAC showed aggregates of cohesive epithelial cells . A few bGiant juvenile fibroadenoma in the prepubertal age group is almost always benign and should be treated with breast conserving surgery.4 JuvenilVarious other conditions like lipoma, hamartoma, cysts should be kept in the list of differential diagnosis. Most of Giant juvenile fibroadenoma simultaneously occurring in both the breasts is rare. Isolated case reports are available in the English literature.11 Someti12"}
+{"text": "Vascular endothelial growth factor (VEGF) expression was examined by immunohistochemistry in 45 prostatic carcinoma specimens and ten benign prostatic tumours (BPH). The majority of carcinoma specimens exhibited cytoplasmic staining for VEGF and showed a trend of increasing expression with dedifferentiation (2p = 0.003). Immunoreactive VEGF was also seen in the prostatic carcinoma cell lines, the order of staining intensity was PC3 > DU145 > LNCaP. Intense granular cytoplasmic staining for VEGF was observed in neuroendocrine-like cells which were seen focally in many of the prostatic specimens. Consecutive sections were incubated with a chromogranin A antibody to confirm the neuroendocrine phenotype of these cells. A significant correlation (P < 0.0001) between the total number of intensely stained VEGF-positive cells and chromogranin A-positive cells was found. A subpopulation of neuroendocrine-like cells also showed intense immunoreactivity for transforming growth factor alpha . A correlation was observed (2p = 0.0092) between the intensity of VEGF and TGF-alpha immunostaining in carcinoma cells which were not of neuroendocrine differentiation. The presence of these two angiogenic factors may aid the neovascularisation of carcinomas and their increased expression in tumour-associated neuroendocrine cells may contribute to a more aggressive phenotype."}
+{"text": "Mitomycin-treated transplantable Moloney virus-induced lymphatic leukaemia cells (YC8) not only failed to stimulate normal allogeneic lymphocytes in one-way mixed leucocyte culture (MLC) but also exerted a strong inhibitory effect on the proliferative response of normal lymphocytes, in MLC and after stimulation by mitogens. Potentially inhibitory factors which could be released in the culture fluids by the YC8 cells were not found, but a YC8-derived adherent cell subpopulation was identified as being responsible for the in vitro suppression."}
+{"text": "The association of the atrophy-hypertrophy complex in monolobar Caroli\u2019s disease (Type I) is reportedin a 30 year old male who presented with recurrent cholangitis. Ultrasound and CT scan showedlocalised, right sided, saccular biliary dilatation in a normal sized liver. Severe right lobar atrophy wasdetected at operation and the resected right lobe weighed only 140 gms. Distortion of the hilar vascularanatomy and posterior displacement of the right hepatic duct orifice were problems encountered atsurgery."}
+{"text": "Inherited cardiomyopathy (CM) represents a diverse group of cardiac muscle diseases that present with a broad spectrum of symptoms ranging from benign to highly malignant. Contributing to this genetic complexity and clinical heterogeneity is the emergence of a cohort of patients that are double or compound heterozygotes who have inherited two different CM mutant alleles in the same or different sarcomeric gene. These patients typically have early disease onset with worse clinical outcomes. Little experimental attention has been directed towards elucidating the physiologic basis of double CM mutations at the cellular-molecular level. Here, dual gene transfer to isolated adult rat cardiac myocytes was used to determine the primary effects of co-expressing two different CM-linked mutant proteins on intact cardiac myocyte contractile physiology. Dual expression of two CM mutants, that alone moderately increase myofilament activation, tropomyosin mutant A63V and cardiac troponin mutant R146G, were shown to additively slow myocyte relaxation beyond either mutant studied in isolation. These results were qualitatively similar to a combination of moderate and strong activating CM mutant alleles \u03b1TmA63V and cTnI R193H, which approached a functional threshold. Interestingly, a combination of a CM myofilament deactivating mutant, troponin C G159D, together with an activating mutant, cTnIR193H, produced a hybrid phenotype that blunted the strong activating phenotype of cTnIR193H alone. This is evidence of neutralizing effects of activating/deactivating mutant alleles in combination. Taken together, this combinatorial mutant allele functional analysis lends molecular insight into disease severity and forms the foundation for a predictive model to deconstruct the myriad of possible CM double mutations in presenting patients. Inherited cardiomyopathies (CM) are the most prevalent genetic disorders of the cardiovascular system Some of the genetic complexity associated with CM can be attributed to environmental factors and genetic modifiers. However, emerging complexity in the form of multiple CM allele inheritance is also evident in vitro gene-dosage experiments One hypothesis explaining these findings is that a higher total dosage of CM mutant protein is causal for the increased disease severity or mitigate the functional cellular outcomes of either mutant allele when studied in isolation. A prediction of this model is that individuals inheriting two mutant CM alleles with opposing biophysical properties may paradoxically have a less severe outcome than either parent with only a single CM mutant allele. Adding to the complexity of CM is the realization there are \u223c467 CM-linked mutant alleles that have been reported in eleven different sarcomeric genes 2)\u2212467)/2]), with \u223c75,000  of those totaling the number of double heterozygous genotypes. The total number of compound heterozygous combinations was derived by the following formula: ((X2)\u2212X)/2, where X is the number of mutations identified for a given sarcomeric gene. This formula is calculated for total number of mutations within each sarcomeric loci and then summated to equal 33,737 possible genotypes.An alternative hypothesis explored here is that multiple CM mutant proteins cause allele-specific combinatorial primary effects that uniquely alter sarcomeric function and are not necessarily linked directly to total mutant gene dosage. Thus, our working hypothesis is that altered biophysical properties of double mutant sarcomeric proteins could interact to either heighten 2+ activating (thin filament activator) or Ca2+deactivating (thin filament deactivator) archetypes. Results derived from these archetypes could then inform a predictive model for extrapolation to all possible CM mutant combinations. The study employed CM mutant thin filament regulatory proteins as a proof-of-concept methodology to address this problem for three reasons. First, this family of sarcomeric proteins is highly amenable to acute genetic engineering and structure-function studies 2+ sensitivity and thin filament cooperativity thereby modifying myocyte force development and relaxation performance In light of the staggering number of potential compound/double genotypes, an examination of every possible double mutant combination is unfeasible. We reasoned that a predictive model, predicated on experimental data, could be implemented as an index of functional outcomes in multiple CM allele inheritance. To facilitate this undertaking we assumed that specific CM mutants could be categorized as CaTo derive a working model predicting the physiologic effects of multiple CM alleles, experiments combined CM alleles that separately cause mild, moderate or strong myofilament activation . A combi10\u20131012 pfu/ml.Adenoviral construction of AdGFP, AdLacZ, \u03b1TmE180G, \u03b1TmK70T, \u03b1TmA63V, cTnIR146G, and cTnIR193H were previously described 6 cells with 77% viability. The care and use of the laboratory animals for this study was in agreement with the guidelines set forth by the Internal Review Board of the University of Michigan Committee on the Use and Care of Animals. Veterinary care was provided by the University of Michigan Unit for Laboratory Animal Medicine.Rat hearts were excised from heparinized (1500 U/kg) and anesthetized  adult female Sprague Dawley rats . Ventricular cardiac myocytes were isolated via collagenase-hyaluronidase digestion as previously described Post digestion the myocytes were resuspended in DMEM (Dulbecco's Minimum Eagle Media) plus 5% fetal bovine serum (FBS) and approximately 20,000 cells were plated on laminin-coated coverslips and incubated for 2 hours. At which time the media is replaced with serum-free DMEM. Subsequently myocytes are transduced with recombinant adenoviral vectors. For single gene transfer myocytes were transduced with an experimentally predetermine optimal multiplicity of infection  based on the stoichiometric replacement for each vector and level of efficiency. For dual gene transfer two different recombinant adenoviruses were combined so that the total MOI was 500 and then simultaneously applied to the plated myocytes 6) were used for immunodetection. In some instances horseradish peroxidase-conjugated goat anti-mouse or goat anti-rabbit secondary antibodies were used for chemilumenescence detection  To assess the mutant cTnIs expression and incorporation into the sarcomere, cultured ventricular myocytes were scraped into Laemmli sample buffer and prepared for gel electrophoresis by boiling and sonication. As previously described, cardiac proteins were separated on a 4\u201320% gradient SDS-page gel  and prepared for Western blot analysis. A cTnI specific polyclonal antibody  and Tm specific monoclonal antibody  as previously described. A coverslip containing cultured myocytes was bathed in HEPES buffered medium 199  kept at 37\u00b0C. Myocytes were electrically paced at 40 volts with a frequency of 0.2 Hz. Ca2+ transient measurements were accomplished using the excitable Ca2+ indicator Sarcomere length measurements and CaTo validate the experimental design of dual mutant CM gene transfer, we determined the efficiency of adenoviral-based dual gene transfer using reporter genes . AcutelyWe tested three different CM mutant alleles shown previously and confirmed here to cause weak, moderate, or strong myofilament activation when tested individually . The pri2+ transients were simultaneously measured yielding results similar to mechanical relaxation  show evidence of a functional ceiling for some mutant combinations suggesting there are limits to mechanical dysfunction induced by compound mutations. We also studied in combination CM mutants with distinct activating and deactivating properties. A priori, such combination could result in a dominant effect or, alternatively, a hybrid functional outcome. Findings here show that combining CM mutants with opposing effects on myofilament function (activator + deactivator) produces a hybrid outcome and evidence of functional neutralization at the intact myocyte level. This finding raises the possibility that two CM mutant alleles, that in isolation markedly alter cell performance to cause CM, could in combination yield near normal cellular physiology. These data are used to develop a working model (detailed below) for predicting molecular outcomes on the >100,000 possible CM double mutant combinations.These results demonstrate that double cardiomyopathy mutants, with mild to strong myofilament activating properties combine to worsen cellular diastolic dysfunction. These additive effects on mechanical performance  plays in thin filament regulation.The cause and effect relationship for CM patients with multiple disease alleles is poorly understood due to a myriad of compounding factors including environment, genetic modifiers, increased mutant allele dosage, or allele-specific functional interactions that likely contribute to the severity of the disease presentation myocytes . It is w2+-mediated thin filament activation 2+ sensitivity and thus sarcomere relaxation 2+ concentrations when compared to their single mutant counterparts. This heightened activation manifests itself as a more severe cellular diastolic dysfunction, as the sarcomere remains contracted with decaying Ca2+ concentrations. While the A63V+R193H double activator combination slowed relaxation beyond that of either mutation studied in isolation, the net effect was not precisely additive on a one to one basis as the sum total of relaxation times for single R193H and A63V myocytes  was \u223c17% greater than those measured in A63V+R193H dual gene transfer myocytes (493 ms). This suggests that the A63V+R193H combination may reach a functional threshold or a physiologic limit in which additional mutant incorporation no longer alters thin filament activation similar to previous reports where extracting only a fraction of troponin complexes (as little as 5%) results in nearly maximal Ca2+ independent thin filament activation 2+ activation beyond this saturation point. The functional threshold attained by the A63V+R193H myocytes in this case could be ascribed to the lower gene dosage of both mutants attained in the dual gene transfer model. Perhaps with increased A63V Tm incorporation the alterations in diastolic dysfunction could be precisely additive. Alternatively, A63V mutant Tm and R193H mutant cTnI may overlap in terms of their biophysical roles in thin filament regulation and thus only combine to fractionally worsen diastolic dysfunction leaving open the question of possible compound CM mutant combinations that may encroach on a physiologic limit where the thin filament attains complete Ca2+-independent dis-inhibition and maximal tension generation during relaxation conditions. The R193H cTnI mutant alone encroaches on this limit as it has a dominant effect in all combinations to cause a Ca2+ independent diastolic tone In this study we ascribe the worsening of myocyte mechanical performance to the combined effects that gain of function mutations in cTnI and Tm have on enhancing CaAn equally important factor that likely impacts the additive effects of two activating mutant alleles is the combined incorporation of each mutant into the sarcomere given the central role thin filament stoichiometry and cooperativity plays in the regulation of contraction 2+ sensitivity A critical insight garnered from this study is that two CM mutant alleles in combination may not necessarily result in a more severe cellular dysfunction. This is evident from the deactivator + activator combination (cTnIR193H + cTnCG159D) in which the diastolic dysfunction characteristic of single cTnIR193H mutant was neutralized in part by cTnCG159D producing an intermediate activating phenotype. The G159D mutation appears to play a structural role in the troponin complex, but also interacts with cTnI's N-terminus In contrast to the mutant Tm and cTnI pairings, the modification of the thin filament with cTnCG159D and cTnIR193H is modeled with a different distribution pattern and higher percentage of double mutant regulatory units . It is cUsing experimental data from activating and deactivating sarcomeric CM mutants obtained here and elsewhere as foundations, a working model was developed to promote predictive insights into myocyte function of the theoretically possible tens of thousands of compound CM combinations. The model was constructed by categorizing single mutant CM alleles by their functional properties as myofilament activators or deactivators, and by the strength with which these properties have been altered. The activation properties of numerous single sarcomeric mutants in both the thick and thin filament have already been characterized This model also incorporates the neutralizing effects of activator and deactivator alleles in combination . Here, tFor experimental purposes we did not employ the more prevalent double heterozygous genotypes, which predominantly consist of MyHC and MyBP-C mutant allele combinations. As myosin is a vital ligand required for maximal activation of tension development In conclusion, our findings show at the cellular/molecular level double mutant thin filament proteins have direct and combinatorial effects to alter cellular diastolic function. The mechanistic basis for additive/mitigating effects cannot be solely due to total mutant gene dosage alone, but also appears to be highly dependent on the population and location of double mutant regulatory units along the thin filament and the biophysical properties of the effected sarcomeric protein in terms of the activating/deactivating nature and the strength of these mutant alleles. These results also underscore that the primary outcome for double heterozygous patients may not necessarily cause a worsening of the disease phenotype particularly in cases where the genotype produces an activating and a deactivating mutant myofilament protein."}
+{"text": "Orbital trauma usually affects the bony parts of the orbit; however, in rare cases foreign bodies are found within the orbit. In this report, we introduce a case with unusual large intraorbital foreign bodies (two parts of a brake lever) after a motorcycle accident. Although one of the foreign bodies was located in the posterior orbit, they required only one simple operation for retrieval. We will discus the management strategy. Intraorbital foreign bodies (FBs) usually occur after a high-velocity injury such as a gunshot or industrial accident.2 AlthougTraumatic eye injuries due to large foreign bodies are rare. There are few reports of unusually large intraorbital FBs such as an iron nut or wood.4 There iA 25-year-old man presented to our emergency clinic 6 h after a penetrating orbital injury with a brake lever in his right lower eyelid during a motorcycle accident . Both eyIntraorbital FBs can be associated with severe injuries leading to loss of vision or may lead to sight-threatening complications.2 A retai5Retained metallic intraorbital FBs are well tolerated and should be managed conservatively in the absence of specific indications for removal.2 When th125"}
+{"text": "Smoking is a known aetiological risk factor for cervical cancer. Smoking-related DNA damage (DNA adducts), in cervical epithelial cells, has recently been demonstrated to suggest a causal role in the development of cervical cancer. Human papillomavirus 16 (HPV 16) is a known oncogenic virus and is also implicated as a cause of cervical cancer. It has been suggested that both smoking and HPV may act synergistically in the development of cervical cancer. We have investigated the cervical DNA adduct level and the prevalence of HPV 16 (using polymerase chain reaction) in women who had normal cervical cytology. Both the DNA adduct assay and the HPV assay were carried out on exfoliated cervical cells recovered from cervical scrapes. In 87% of the cases there was enough DNA from the exfoliative cervical cells to analyse for DNA adducts. Smokers had higher DNA adduct levels than non-smokers (P = 0.002), confirming the previous data from cervical biopsy samples. Forty-two per cent of the specimens were found to be HPV 16 positive. There was no significant difference in smoking-related DNA damage (DNA adduct levels) between HPV-positive and HPV-negative smokers. This suggests that smoking DNA damage does not augment HPV infectivity. These results do not, therefore, support the molecular synergism theory."}
+{"text": "Angina pectoris early after aortic valve replacement surgery in patients with previously normal coronary arteries may be life threatening and has to be assessed immediately.12 weeks after aortic valve replacement surgery, a 60-year-old female patient was referred for evaluation of recent onset of severe chest pain on mild exertion and at rest. Coronary angiography showed severe stenosis nvolving the left coronary ostium and the left main stem. The patient was urgently referred for bypass surgery and had an uneventful postoperative recovery.A high degree of suspicion is needed for early recognition and aggressive management of this rare but serious complication. Unstable angina is rare, but may be life-threatening in patients in the early postoperative period following aortic valve replacement with normal preoperative coronary arteries.We report the case of a 60-year-old female patient undergoing valve replacement surgery for symptomatic aortic valve stenosis. Preoperative echocardiographic assessment revealed a severely calcified aortic valve with a calculated aortic valve area of 0.8 ccm. Mean pressure gradient was 55 mmHg and left ventricular ejection fraction was well preserved.The patient was free of angina and reported dyspnoea on exertion.Preoperative coronary angiography revealed normal coronary arteries.Valve replacement surgery was performed using a Sorin 23 mm mechanical valve prosthesis. Early postoperative recovery was unremarkable.12 weeks after surgery the patient was referred for evaluation of recent onset of severe chest pain on mild exertion and at rest.ECG revealed severe ST-segment depression in leads V2-5 during episodes of chest pain.Coronary angiography showed a 90% diameter reduction involving the left coronary ostium and the left main stem.The patient was urgently referred for bypass surgery and had an uneventful postoperative recovery.Angina pectoris early after aortic valve replacement surgery in patients with previously normal coronary arteries may be life threatening and has to be assessed immediately. A high degree of suspicion is needed for early recognition and aggressive management of this rare but serious complication.Unstable angina early after aortic valve replacement in patients with normal coronary arteries in the preoperative angiography is rare.Generally, possible differential diagnoses of postoperative angina pectoris in patients undergoing mechanical aortic valve replacement are coronary embolism, progression of coronary heart disease in patients with coronary atherosclerosis, graft occlusion in patients with concomitant aortocoronary bypass (ACBP) and iatrogenic coronary ostial/main stem stenosis.Many cases of iatrogenic coronary ostial/main stem stenoses have been reported since the late 1960ies, all cases showing similar patterns \u2013 sudden onset of angina pectoris 3\u20136 months postoperatively in patients without or with only mild coronary artery disease \u2013 and similar histologic findings \u2013 intimal fibrous proliferation of one or both coronary ostia [We report the case of a 60-year-old moderately obese female patient, who was referred for evaluation of recent onset dyspnea on exertion. Physical examination revealed a 3/6 crescendeo-decrescendo systolic murmur at the aortic valve.Electrocardiography showed regular sinus rhythm without additional findings Fig. 2 and a mean pressure gradient of 55 mmHg.Echocardiographic assessment revealed a severely calcified aortic valve with a calculated valve area of 0,80 cmLeft ventricular ejection fraction was well preserved with left ventricular wall thickness of 14 mm .Preoperative coronary angiography revealed completely normal coronary arteries Fig .The patient underwent aortic valve replacement surgery. The procedure was performed using mini-sternotomy with a single 2-stage venous cannula and normothermic cardiopulmonary bypass. The use of normothermic techniques has been reported to confer several advantages over conventional hypothermia, such as reduced bleeding and requirements for electrical defibrillation, shorter intubation times, and improved hemodynamic parameters postoperatively. Myocardial protection with cold antegrade and retrograde St. Thomas' cardioplegic (II) solution was obtained immediately after aortic cross clamping. The aortic valve is exposed through an oblique aortotomy incision made well above the orifice of the right coronary artery. The severely calcified stenotic aortic valve was excised, replaced with a Sorin 23 mm mechanical valve prosthesis, attached with subannular mattress sutures of 2-0 Ethibond .Early postoperative recovery was unremarkable.12 weeks after surgery the patient was referred for evaluation of recent onset of severe chest pain on mild exertion and at rest. ECG at admission showed inverted T-waves in leads V2 to V5 and in lead aVL Fig. .During episodes of chest pain ECG revealed severe ST-segment depression in leads V2 to V5 Fig .Coronary angiography showed a 90% diameter reduction involving the left coronary ostium and the left main stem Fig .The patient was urgently referred for bypass surgery with a left internal mammary artery graft to the LAD and a left radial artery graft to the circumflex artery.Postoperative recovery was unremarkable. Four months later she is doing well without chest pain or signs of myocardial ischemia.The present case underlines the importance of early diagnosis and treatment if angina pectoris occurs after aortic valve replacement.Coronary ostial stenoses can be detected in 0,1% of coronary angiographies in unselected patients ,11. AparIatrogenic coronary ostial stenosis is a well recognized, but uncommon and potentially life threatening complication of aortic valve replacement. Symptoms include chest pain during exercise or at rest, sudden onset of acute heart failure and acute pulmonary edema. Usually, symptoms occur within the first 6 months, though they may occur up to 30 months after the operation .Main stem stenosis after aortic valve replacement was first recognised in 1969 by Trimble et al . who desSeveral pathogenic mechanisms have been suggested: aortic root fibrosis secondary to turbulent flow around the prosthesis ; the preThere may also be a genetic predisposition for developing this complication since 70% of the affected individuals as compared to 10\u201315% in a control group had an epsilon 4 allele apolipoprotein E genotype .Instrumentation with minimal trauma of the left main stem is most likely the cause of early postoperative stenosis after aortic valve replacement surgery ,8,14.Avoiding cannulation of the coronary ostia for antegrade cardioplegia, but instead using retrograde delivery as an alternative method for myocardial perfusion during open heart surgery may reduce the risk of postoperative coronary ostial or left main stem stenosis ,15.If recurrent or newly onset angina pectoris occurs early after aortic valveReplacement, a high degree of suspicion os warranted to recognize this rare but life threatening complication of coronary ostial stenosis, even if preoperative coronary angiography did not show coronary heart disease.New operative techniques that reduce manipulation and consequently avoid trauma of the coronary vessels may prevent postoperative coronary ostial stenosis. Future studies in patients undergoing this procedure using retrograde cardioplegia only will have to prove this hypothesis.Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.The authors declare that they have no competing interests.SG was the main author and wrote the article. CKN was the surgical consultant, was involved in data collection and revised the manuscript. CS was the surgical consultant was involved in data collection and interpretation. JA was the cardiology consultant and gave final approval of the manuscript. All authors have read and approved the final manuscript."}
+{"text": "We report three fatal cases of bacteremia  caused by Vibrio cholerae O1 (Ogawa), which occurred in the context of a community outbreak of cholera diarrhea in Blantyre, Malawi. Only four cases of invasive disease caused by V. cholerae O1 have previously been reported. We describe the clinical features associated with these rare cases and discuss their significance."}
+{"text": "Blood lymphocytes from 47 patients with lung carcinoma have been tested for cytotoxicity against cells isolated from the autologous tumour. Significant cytotoxic potential was found in 15 cases. The effectors were also tested against allogeneic tumour targets from lung and other sites. Reactions were only rarely detected (2/32 positive against lung and 1/13 positive against non-lung cells). The restriction of cytotoxicity to the autologous combination was also apparent in in vitro-generated effectors. Blood lymphocytes were co-cultivated with autologous tumour and subsequently tested against autologous or allogeneic targets. Cytotoxicity was found in 13/17 lung tumours against autologous tumour, with no reactions recorded against allogeneic tumour targets, but one case positive against the K562 cell line. These data suggest either the expression of individually distinct antigens on human pulmonary neoplasms, or the requirement for histocompatibility between target and effector in cytotoxicity reactions in man, and therefore differ from previously described patterns of lymphocytotoxicity against human tumours."}
+{"text": "Thirty-one cervical biopsies of invasive carcinoma have been studied by immunohistochemical means using the monoclonal antibody Ki67 to determine tumour cell proliferation rates. A wide range (10-50%) in the extent of Ki67 staining (expressed as the percentage of labelled tumour cells) was observed indicating considerable variation on tumour growth rates. There was no significant relationship between the percentage of positive cells and conventional histological parameters such as cell type or tumour differentiation. Immunostaining with monoclonal antibody Ki67 therefore provides a new approach to the assessment of cervical tumour biopsies which will require long term clinical follow-up to establish its prognostic significance."}
+{"text": "A 58 year old woman with symptomatic severe bicuspid aortic valve stenosis underwent aortic valve replacement with a mechanical prosthesis. On post-operative day four, the patient developed sudden onset of sustained narrow complex tachycardia with a heart rate of 170 - 180 . She comInitial evaluation of the presenting arrhythmia  revealedAccelerated junctional tachycardia in the post-cardiac surgery period has been described in the pediatric and adult congenital populations, and has been associated with significant morbidity . HoweverIn conclusion, we report the case of a patient who developed incessant, accelerated junctional tachycardia few days after aortic valve surgery. This condition is self-limited and can be treated acutely with anti-arrhythmic medications such as amiodarone. Recognizing this condition and treating it conservatively are important to ensure a favorable clinical outcome."}
+{"text": "The ultrastructure of two lymphoblastoid cell lines derived from Marek's disease lymphomata has been studied. The cells varied from 5 to 12 mum in diameter and had large round or oval nuclei. A nucleolus was occasionally present and about 3% of cells showed projections of the nuclear envelope. The cytoplasm contained many ribosomes and several mitochondria but endoplasmic reticulum was sparse. A small number of cells contained annulate lamellae and crystalline structures were occasionally seen. Cells with immature intranuclear herpesvirus particles were rarely present. The cells had many ultrastructural features in common with Burkitt's lymphoma-derived cell lines."}
+{"text": "Post-partum choriocarcinoma is a rare complication of pregnancy. We have analysed a series of nine consecutive patients presenting with choriocarcinoma after a full-term non-molar pregnancy. All patients were managed at the Supraregional Trophoblastic Disease Screening and Treatment Centre at Weston Park Hospital, Sheffield between 1987 and 1996. All presented with persistent primary or secondary post-partum haemorrhage. Treatment with multiagent chemotherapy  was successful in all cases. Early diagnosis is important because this rare condition is potentially curable with appropriate chemotherapy. \u00a9 1999 Cancer Research Campaign"}
+{"text": "A slowly growing solid sarcoma was implanted subcutaneously on the anterior chest wall of mice. On reaching a predetermined size the tumours were locally irradiated using 240 kV x-rays with single doses of 0, 2000 or 5000 rad. The mice were sacrificed 12 weeks after irradiation and examined for lung metastases, which were found to be less frequent in those mice whose implanted tumours had received the most irradiation."}
+{"text": "PMN-dependent plasma leakage was equally well reduced by the different sulphated polymers. Vascular permeability induced by histamine or thrombin acting via a PMN-independent mechanism was not reduced. Fucoidan was the only polysaccharide able to suppress IL-1-induced PMN infiltration for 60\u201370%. Local administration of dextran sulphate had no effect on PMN-dependent plasma leakage. Differential inhibition of PMN recruitment was determined after injection of dextran sulphate or fucoidan depending on the type of insult. Therefore, these results suggest that different adhesion pathways are utilized during PMN recruitment in vivo in response to chemoattractants and IL-1.The selectin-mediated rolling of leukocytes along the endothelial cells is a prerequisite step followed by firm adhesion and extravasation into the inflamed tissue. This initial contact can be suppressed by sulphated polysaccharides. We have studied the effect of sulphated polysaccharides on the ultimate polymorphonuclear leukocyte (PMN) recruitment and plasma leakage in rabbit skin in response to intradermal injection of various inflammatory mediators. PMN infiltration evoked by various PMN chemoattractants (FMLP, C5a desArg, LTB"}
+{"text": "A comparison of this information tothe Ly5b allele sequence identifies 12 allele-specific nucleotide changes. These basesubstitutions correspond to five amino-acid changes within the extracellular domain ofthe LCA molecule. These amino-acid differences are clustered in a region that alsocontains the greatest divergence between mouse and rat LCA sequences. Thus, thesetwo mouse LCA alleles exhibit a pattern of sequence conservation that mimics thatfound over a much broader scale of evolution. Analysis of antigenicity profiles for eachof the allelic sequence changes reveals three molecular domains of altered antigenicitythat could account for observed serological differences between the two alleles.Sequence information from the 5' end of the Ly5a LCA gene, generated usingpolymerase chain-reaction techniques on genomic DNA, reveals eight additionalnucleotide differences between the Ly5a and Ly5b alleles.The family of leucocyte common antigen (LCA) transmembrane glycoproteins isexpressed in most hematopoietic cells. Molecular isoforms of the LCA molecule aregenerated by alternative splicing of a single gene encoded on the murine chromosome 1.Three LCA alleles with different antigenic reactivities have been identified in inbredmouse strains. To investigate the divergence between alleles, cDNA clones to the SJA(Ly5"}
+{"text": "The terrain is well explored regarding genes whose gene expression is up-regulated upon binding of thyroid hormone (TH) to its nuclear receptor. This regulation mechanism has been intensively studied and is well understood. In contrast, a lot of white spots remain on the map when it comes to target genes whose expression is down-regulated upon binding of TH to the thyroid hormone receptor (TR). Since no consistent mechanism has been proposed to explain ligand-dependent down-regulation of target gene transcription several working hypotheses favour different molecular mechanisms. Some working theories suggest a direct binding of TR to regulatory elements of target genes. Others favour models that are independent of a direct DNA binding event. However recent data suggested that a direct binding of TR to DNA is dispensable for TH-dependent negative gene transcription. Thyroid hormone regulates gene expression in a positive and negative manner. The mechanism of positively TH-regulated gene transcription has been intensively studied and is well understood. The thyroid hormone receptor (TR) binds to thyroid hormone response elements (TREs) which are located within regulatory elements of TH target genes. If the ligand  is present, liganded TR recruits a huge coactivator complex. This coactivator complex possesses or recruits several enzymatic activities which modify the chromatin of target genes generating an open structure allowing for transcription. If the ligand is absent the un-liganded TR undergoes a conformational change which releases the coactivator complex and recruits a corepressor complex. Again this corepressor complex integrates several enzymatic activities modifying chromatin toward a closed and transcriptional silent state. These processes are well documented and discussed in comprehensive and excellent review articles elsewhere; see e.g. -3.Besides positively TH-regulated target genes there are clearly those genes whose gene expression is negatively regulated upon administration of TH. The probably best known example is the down-regulation of thyrotropin (TSH) in the pituitary as part of the negative endocrine hypothalamus-pituitary-thyroid feedback loop. However also in other tissues (e.g. the liver) negative gene regulation is a well known regulation pattern in microarray analysis -8. The p(A) TR binds to specific negative thyroid hormone response elements (negative TREs). Due to the specific composition of these DNA response elements the TR undergoes specific conformational changes leading to a recruitment of a coactivator complex in the absence of TH. In contrast, binding of the ligand recruits a corepressor complex to the liganded TR. Of note, the functional readout is diametrically opposed compared to the readout for positively regulated genes (see above).(B) A second model suggests that TR does not bind to DNA directly but rather to another transcription factor via protein-protein interactions. Again, the un-liganded TR (bound to DNA via transcription factor X) recruits a coactivator complex whereas the liganded TR recruits a corepressor complex.(C) Finally, a third model suggests that a soluble, not DNA-bound TR sequesters cofactors away from other DNA-bound transcription factor-cofactor complexes. Sequestering of corepressor components from DNA-bound transcription factors finally leads to an activation of gene expression whereas sequestering of coactivators leads to a repression of gene transcription.Several pros and cons exist for all of the three models and no uniform model is in sight which takes in account all aspects of negative gene regulation.Several reports described negative TREs Figure , model AOne major support for the model of negative TREs came from experiments by Frederic Wondisford and colleagues. They investigated the double mutant E125G; G126S within TR\u03b2  which conserved the overall zinc finger structure of the DNA binding domain (DBD) but altered the DNA binding specificity . The GS If TR did not bind directly to DNA it might bind via protein-protein interactions to a transcription factor as a bridging factor in order to target TR to specific regulatory elements Figure , model BE457A knock-in mice harbouring a defective coactivator binding site demonstrated alterations in positively and \u2013 paradoxically \u2013 negatively regulated TH target genes [Following an alternative hypothesis TR might not bind to DNA at all (neither directly (model A) nor indirectly (model B)), but rather sequesters cofactors from DNA-bound transcription factor-cofactor complexes Figure , model Cet genes . On the et genes ,34. It rUp to now no convincing data have been presented doubtlessly supporting one particular model by discarding hitherto alternative models. Taking together recent data a direct binding of TR to negative TREs (model A) appears to be unlikely due to the lack of high-affinity binding sites for TR. Rather TR is involved in modulating the transcriptional activity of other transcription factors either directly (model B) or indirectly (model C). Clearly the DBD of TR participates in these processes independent of its function to bind DNA. Furthermore, cell-type and/or context-specific post-translational modifications might additionally contribute. Identification of TR binding sites by chromatin immunoprecipitation and correlation with adjacent DNA sequences (as successfully performed for the estrogen receptor ) are eagThe author declares that they have no competing interests."}
+{"text": "Merkel cell carcinoma is an uncommon skin malignancy that has a high propensity for metastatic spread. A systematic literature search identified 17 cases describing metastasis to the gastrointestinal tract, with 7 cases involving the small or large bowel. To the best of our knowledge, this is the only case described of Merkel cell carcinoma metastasising to the ileocaecal valve.We present a 74-year-old Filipino woman diagnosed with Merkel cell carcinoma of the skin with regional node involvement. Following excision and radiotherapy, the tumour recurred with metastasis to the ileocaecal valve. The patient died 28 months after the initial diagnosis.The prognosis of metastatic Merkel cell carcinoma is poor. Currently the optimal management for metastatic disease is unclear and lacks a firm evidence base due to the small number of cases reported. Merkel cell carcinoma (MCC) is an uncommon and highly aggressive skin malignancy. It arises from Merkel cells at the dermo-epidermal junction, which are of neuroendocrine origin. Since its first description by Toker in 1972 .The incidence of MCC is 0.23 per 100,000 in Caucasians . At preset al. described the case of a 62-year-old man with axillary lymphadenopathy and metastasis to the stomach and the descending colon. The patient had a skin lesion excision which was initially diagnosed as basal cell carcinoma  OR \"esophagus\" [All Fields] OR \"stomach\" [All Fields] OR \"duodenum\" [All Fields] OR \"jejunum\" [All Fields] OR \"ileum\" [All Fields] OR \"bowel\" [All Fields] OR \"intestine\" [All Fields] OR \"intestinal\" [All Fields] OR \"caecum\" [All Fields] OR \"rectum\" [All Fields] OR \"rectal\" [All Fields] OR \"colon\" [All Fields] AND \"merkel cell\" [All Fields].This produced 61 results on PubMed of which 17 are reports of metastatic Merkel cell carcinoma in the gastrointestinal tract (excluding the liver)."}
+{"text": "Con A acceptor glycoproteins from the human Molt 4 (T cell leukaemia) and HeLa  cell lines were purified by affinity chromatography and used for the preparation of rat antisera. Cross-absorption analysis showed that each antiserum contained antibodies which recognised cell surface antigens preferentially expressed by the donor cell line. Molt 4-associated antigens were fully expressed on T cell tumour lines and normal thymocytes, but not on non T cell tumour lines, peripheral blood lymphocytes or other blood cells. Immunofluorescence studies showed that the antigens were preferentially expressed on a sub-population of immature thymocytes. HeLa-associated antigens were only fully expressed on one other epithelial tumour cell in a panel of 17 cell lines. Immunofluorescence studies showed that the HeLa-associated antigens were expressed on normal endocervical adenoepithelium but not on ectocervical, endometrial or intestinal epithelia. Thus purified Con A acceptor glycoproteins of cultured tumour cell lines are potent immunogens for the generation of antibodies recognising lineage-associated differentiation antigens. These antigens should be useful in tumour classification and in the study of normal differentiation."}
+{"text": "The sampling rate of an injection every 3 min produces 20 results per hour from a flowing stream.An automated continuous monitoring system for the determination of inorganic and total mercury by flow-injection analysis followed by cold-vapour atomic absorption spectrometry is described. The method uses a typical flow-injection manifold where digestion and reduction of the injected sample takes place. Mercury is removed by aeration from the flowing stream in a specially designed air-liquid separator and swept into a silica cell for absorption measurement at a wavelength of 253.7 nm. A calibration curve up to 10 \u03bcg Hg ml"}
+{"text": "Xenopus of the MHCff genotype. The tumor cell can be transplanted in histocompatible larval ff hosts, but notin ff adults unless irradiated (3000 rad). The tumor is rejected by allogeneic hosts. Thetumor cells express neither markers of the B-cell lineage nor MHC encoded molecules;they express only markers of the T-cell lineage. Its lymphoid population is clonal asrevealed by the existence of a stable rearrangement pattern of the immunoglobulingenes. Cell lines growing continuously in vitro have been derived from the tumor.A spontaneous lymphoid thymus tumor was discovered in a male"}
+{"text": "The tumour specific transplantation antigen (TSTA) from a chemically induced rat sarcoma has been isolated as an electrophoretically homogeneous soluble material by affinity chromatography using a Sepharose bound antibody raised to the tumour in syngeneic rats. The TSTA is specific for the particular tumour used (the MC-1 sarcoma) and does not cross-react with material extracted from other rat sarcomata. In addition, a material with different physicochemical properties which cross-reacted with different sarcomata was also eluted from the antibody column and this may be the previously identified onco-embryonic antigen (OEA1) which is immunogenic in the syngeneic host.125I was used in a radioimmunoassay which detected soluble TSTA in rats bearing a MC-1 sarcoma. The assay shows that tumour transplantation is associated with a persisting release of soluble antigen into the circulation. This antigenic burden is present continuously and renewed as long as the tumour mass exists.The purified TSTA labelled with"}
+{"text": "An increasing number of renal dialysis-dependent patients with Arterio-Venous fistulae are undergoing cardiac surgery.The fistula has important effects on systemic hemodynamics in dialysis patients. The flow is significantly and positively related to cardiac output and cardiac index, and inversely related to pulmonary vascular resistance.Few problems are encountered on cardiopulmonary bypass despite left to right shunting of blood. We present an unusual case in which a large brachial Arterio-Venous fistula with large collaterals prevented weaning off cardiopulmonary bypass. Patients with chronic renal failure have a high prevalence of coronary artery disease and an increasing number are undergoing coronary artery bypass grafting. A-V fistula decreases mean systemic arterial pressure, effective systemic blood flow, total and pulmonary peripheral resistances, whereas it increases heart rate, total cardiac output, stroke volume, left atrial pressure, pulmonary arterial pressure ,2. In paIn these patients few problems are encountered on cardiopulmonary bypass despite left to right shunting of blood. We present an unusual case in which a large A-V fistula with large collaterals prevented weaning off cardiopulmonary bypass.2 and coronary angiogram showed significant two vessel disease involving the LAD and circumflex territory.A 77 yr old gentleman was admitted with an acute coronary syndrome with modest troponin rise. He was known to have aortic stenosis and coronary artery disease and the aortic gradient had accelerated by 50 mmHg over a 6 month period to 80 mmHg with good systolic but poor diastolic function. Valve area was calculated at 0.7 cmHe had End Stage Renal Disease for six years and was on chronic Haemodialysis via a surgical brachiocephalic Arterio-Venous fistula three times a week. The fistula was capable of flows averaging 400 ml/min during haemodialysis.Prior to surgery he became unstable and required an IABP necessitating urgent mechanical aortic valve and myocardial revascularization procedures.He had an uneventful anaesthetic induction and institution of cardiopulmonary bypass. During bypass it was noted that he required large doses of vasoconstrictors (pitressin infusion) to maintain perfusion pressure. He underwent a successful aortic valve replacement with a size 21 Tophat mechanical valve, reversed saphenous vein graft to obtuse marginal of circumflex and LIMA to LAD with a crossclamp time of 70 minutes.Detailed haemodynamic monitoring was performed from induction and cardiopulmonary bypass as depicted in figure.On attempting to wean him off bypass his diastolic pressure was very low which severely compromised coronary perfusion pressure and distended the Right ventricle. Three attempts were made to wean him off by-pass but all failed.P = 0.01) and systolic Pulmonary artery pressure .Temporary closure of the A-V access by a sphygmomanometer allowed successful weaning off bypass. The corresponding Pulmonary artery pressure and Cardiac Output values were compared before and after the A-V occlusion. Occlusion resulted in a transient decrease in cardiac output (from 11.4 \u00b1 0.6 to 5.3 \u00b1 0.5 l/min, Similar flow and pressure measurements were obtained on three separate occasions of closure and release of compression. Eventually the fistula was explored and tied off together with 3 large collateral vessels. Flow characteristics at baseline and with arterio-venous fistula occluded are shown in Figure The haemodynamic effects of arterio-venous fistulae are well known -3 but thIn practice most patients have distal radial-cephalic fistulae where the flow is lower than brachio-cephalic fistulae and these are successfully weaned off bypass without problems. However, as in this case proximal fistulas with extremely high flow rates can cause problems in combination with the effects of surgery and cardiopulmonary bypass on normal physiology including activation of complement and other plasma protein systems. This leads to low SVR and PVR which compounds the affect of the shunt. In this case the presence of three large collaterals linked to the fistula may have further augmented A-V access flow. These multiple interacting factors were clearly demonstrated and reproducible on temporary occlusion of the fistula and made weaning off cardiopulmonary bypass virtually impossible because of extremely low diastolic pressures leading to heart failure.Inadequate tissue perfusion and oxygenation was manifested by increased lactate production. The fistula may have contributed to this but other factors may have been responsible.This case serves to highlight a potential problem of cardiopulmonary bypass in patients with chronic large proximal A-V fistulae which have developed collaterals. In such cases it may be wise to measure fistula flow prior to surgery and place an uninflated sphygmomanometer in anticipation of temporary occlusion."}
+{"text": "The work presented here has concerned the study of early, as well as late, enzymic changes occurring during diethylnitrosamine-induced hepatocarcinogenesis and liver regeneration after partial hepatectomy in comparison with normal liver differentiation. Rank correlation analysis of the enzyme data suggested a step-wise retrodifferentiation i.e. that the liver during carcinogenesis first assumed a neonatal enzymic pattern before attaining a foetal enzymic state. Similar enzymic changes were observed in regenerating liver after partial hepatectomy; again there was a step-wise retrodifferentiation of enzymic pattern and at 3 days post hepatectomy the liver had an enzymic pattern similar to both foetal and neoplastic liver. However, in contrast to liver undergoing neoplastic change, the regenerating liver retained the capacity to undergo redifferentiation towards a normal adult biochemical pattern."}
+{"text": "Burkholderia pseudomallei was isolated from environmental specimens 1 year after an outbreak of acute melioidosis in a remote coastal community in northwestern Australia. B. pseudomallei was isolated from a water storage tank and from spray formed in a pH-raising aerator unit. Pulsed-field gel electrophoresis confirmed the aerator and storage tank isolates were identical to the outbreak strain, WKo97."}
+{"text": "DCC - and c-erbB-2 genes in disseminated breast cancer cells and actuarial relapse-free survival. Furthermore, increasing numbers of genomic imbalances measured in disseminated tumour cells were significantly associated with worse prognosis of recurrent disease. Logistic regression and Cox multivariate analysis led to the identification of genomic imbalances as an independent prognostic factor. Determination of disseminated tumour cells by genotyping of oncogenes and tumour suppressor genes seems not only to be a useful adjunct in follow up of carcinoma patients but provides also valuable additional individualized prognostic and predictive information in breast cancer patients beyond the TNM system. \u00a9 2000 Cancer Research Campaign http://www.bjcancer.comThe prognostic value of disseminated tumour cells derived from 353 breast cancer patients was evaluated. Disseminated tumour cells were purified from blood using a newly established method and nucleic acids were subsequently isolated. We investigated genomic imbalances (GI) such as mutation, amplification and loss of heterozygosity of 13 tumour suppressor genes and 2 proto-oncogenes using DNA from isolated minimal residual cancer cells. Significant correlations were found between genomic alterations of the"}
+{"text": "The objectives of this study were to better our understanding of the carcinogenesis of gestational trophoblastic tumours and to investigate the possible presence of mutational alteration of the p53 tumour-suppressor gene in these tumours. Amplification-based direct DNA sequencing was performed on 14 hydatidiform moles, six invasive moles, eight choriocarcinomas and ten normal early placental tissues. No mutation in exons 5-8 was detected in any of these 38 tissue specimens. These results suggest that a mutation in p53 tumour suppressor either does not exist or is a very rare event in gestational trophoblastic tumours. The gestational trophoblastic tumours probably involve a tumour-suppressor gene other than p53 gene or may follow a completely different pathway to their malignant phenotype."}
+{"text": "Doppler echocardiography is useful in the initial evaluation and long-term follow-up of patients with pulmonary artery hypertension. Aerosolised iloprost has been shown to reduce pulmonary pressure immediately after inhalation. We report the echocardiographic findings in a patient with severe pulmonary hypertension, before and after the inhalation of aerosolized iloprost. These findings illustrate the acute influence of iloprost in right and left ventricular hemodynamics and morphology. These findings were reproduced in subsequent echocardiographic evaluations. Doppler echocardiography is useful in the initial evaluation and long-term follow-up of patients with pulmonary arterial hypertension ,2.-1 with estimated right ventricular systolic pressure (RVSP) of 122 mmHg. She was then started on 5.0 \u03bcg of nebulized iloprost six times per day. At the 29th week of pregnancy Doppler echocardiography was repeated before and immediately after a single dose of 5 \u03bcg of iloprost. Postinhalation acute assessment revealed not only a remarkable reduction in RVSP but also an impressive change in cardiac morphology as is evident from figures A 21-year-old woman diagnosed with idiopathic pulmonary hypertension since she was eleven, responsive to calcium channel blockers, was referred for Cardiology consultation at 23 weeks pregnancy. She was on nifedipine and fraxiparine and Doppler echocardiography revealed a dilated and hypertrophied right ventricle and a peak tricuspid regurgitant jet velocity of 5.3 msThe findings that we describe showed the potential utility of echocardiography in the evaluation of the acute effects of drugs used in the treatment of pulmonary arterial hypertension.Two-dimensional parasternal view before iloprost inhalation. Two-dimensional parasternal long and short axis views before iloprost inhalation showing a small left ventricle with increased eccentricity index.Click here for fileTwo-dimensional parasternal view after iloprost inhalation. Two-dimensional parasternal long and short axis views after iloprost inhalation showing near normal morphology of both ventricles.Click here for fileThree-dimensional parasternal view before iloprost inhalation. Three-dimensional parasternal long axis view before iloprost inhalation showing a small left ventricle with increased eccentricity index.Click here for fileThree-dimensional parasternal view after iloprost inhalation. Three-dimensional parasternal long axis view after iloprost inhalation showing near normal morphology of both ventricles.Click here for file"}
+{"text": "A lymphocyte clonal assay developed to quantitate in vivo somatic cell mutations at the hypoxanthine-guanine phosphoribosyltransferase locus was modified in order to study resistance to methotrexate. Even though nucleoside-free culture conditions were used methotrexate was not lethal to lymphocytes plated into micro-wells at greater than 10(2) cells/well. HPLC analysis of supernatants from wells plated initially with 10(4) cells/well in 100 microM methotrexate revealed the presence of micro-molar levels of hypoxanthine and thymidine by the 5th and 8th day of culture respectively. When lymphocytes were plated at less than or equal to 10(2) cells/well in nucleoside free medium, methotrexate was cytotoxic and micro-molar levels of thymidine together with hypoxanthine protected lymphocytes cultured under these conditions from toxicity. Modulation of nucleic acid antimetabolite cytotoxicity by nucleosides and bases has been recognised for some years. Nucleoside free culture conditions have been advocated for studying cellular sensitivity to antifolates to avoid such interfering factors. However our results indicate that metabolites from dying or damaged cells can prevent methotrexate cytotoxicity, further complicating the development of a suitable clonogenic assay for investigating antifolate sensitivity."}
+{"text": "The effect of methotrexate on solid rodent tumours has been investigated using the spontaneous mammary adenocarcinoma of the female C3H/Bts mouse. As these tumours exhibit a wide range of volume doubling times, calculations of tumour response to methotrexate must be related to doubling time. When methotrexate is injected into the tumour a dose-dependent tumour response is obtained. Systemic citrovorum \"rescue\" prevents methotrexate lethalities but reduces tumour response by a factor of 2. Methotrexate-treated tumours have an increased volume doubling time post treatment."}
+{"text": "The effectiveness of cancer radiotherapy is compromised by the small proportion (approximately 5%) of patients who sustain severe normal tissue damage after standard radiotherapy treatments. Predictive tests are required to identify these highly radiosensitive cases. Patients with the rare, recessively inherited, cancer-prone syndrome ataxia-telangiectasia (A-T) sustain extremely severe normal tissue necrosis after radiotherapy and their cultured cells are also highly radiosensitive. Clinically normal carriers (heterozygotes) of the A-T gene have an increased risk of breast cancer, account for approximately 4% of all breast cancer cases and show a modest increase in cellular radiosensitivity in vitro. It has been suggested that a substantial proportion of highly radiosensitive (HR) breast cancer patients may be A-T heterozygotes, and that screening for mutations in the A-T gene could be used as a predictive test. We have tested this hypothesis in a group of cancer patients who showed adverse reactions to radiotherapy. Sixteen HR breast cancer patients showing mainly acute reactions (and seven HR patients with other cancers) were tested for ATM mutations using the restriction endonuclease fingerprinting assay. No mutations typical of those found in obligate A-T heterozygotes were detected. If the estimate that 4% of breast cancer cases are A-T gene carriers is correct, then ATM mutations do not confer clinical radiosensitivity. These early results suggest that screening for ATM mutations in cancer patients may not be of value in predicting adverse reactions."}
+{"text": "TP53 mutation has been found, was not significantly different to that of normal strains. This was in contrast to LF strains that carry TP53 mutations. Cytogenetic observations of numerical and structural chromosome abnormalities were made on Giemsa stained metaphases prepared at different times during the lifespan of strains. Five strains from different LF families showed significantly increased frequencies of abnormal cells during the last 10% of their lifetime compared with seven normal strains and three other LF strains fell outside the normal range but did not reach significance. Two LF strains fell within the normal range indicating heterogeneity of the phenotype in this subset of LF fibroblasts. Numerical aberrations were the major aberration type observed. These observations of genetic instability are similar, but generally less strongly expressed, to those seen in LF strains with TP53 mutations. The basis for genetic instability in LF strains without TP53 mutations is not known, but appears not to involve defects in either the G 1 checkpoint or the checkpoint kinase hChk2. \u00a9 2000 Cancer Research CampaignThe mean in vitro lifespan of dermal fibroblast strains derived from cancer-affected individuals belonging to families conforming to the classical Li-Fraumeni-syndrome or the Li-Fraumeni-like syndrome (LF strains), but in whom no"}
+{"text": "A cone beam circular half-scan scheme is becoming an attractiveimaging method in cone beam CT since it improves the temporalresolution. Traditionally, the redundant data in the circularhalf-scan range is weighted by a central scanning plane-dependentweighting function; FDK algorithm is then applied on the weightedprojection data for reconstruction. However, this scheme stillsuffers the attenuation coefficient drop inherited with FDK whenthe cone angle becomes large. A new heuristic cone beamgeometry-dependent weighting scheme is proposed based on the ideathat there exists less redundancy for the projection data awayfrom the central scanning plane. The performance of FDKHSCW schemeis evaluated by comparing it to the FDK full-scan (FDKFS) schemeand the traditional FDK half-scan scheme with Parker's fan beamweighting function (FDKHSFW). Computer simulation is employed andconducted on a 3D Shepp-Logan phantom. The result illustrates acorrection of FDKHSCW to the attenuation coefficient drop in theoff-scanning plane associated with FDKFS and FDKHSFW whilemaintaining the same spatial resolution."}
+{"text": "We describe an outbreak among drug users of severe soft-tissue infections caused by a clonal strain of group A streptococcus of M-type 25. Cases (n = 19) in drug users were defined as infections (mainly needle abscesses) due to the outbreak strain. Comparison with controls showed that infected drug users bought drugs more often at a specific place. Drug purchase and use habits may have contributed to this outbreak."}
+{"text": "Tumour stromal neovascularization was investigated in 114 invasive and 20 in situ carcinomas of the uterine cervix by staining representative sections with the specific endothelial marker anti CD31 . A digital image analyser was used to measure the immunoreactivity. The following parameters were determined in the 'hot spots': vessel counts, vessel perimeter and endothelial stained area (expressed per mm2). The results were correlated with clinical and histopathological data. There was no significant relationship between the histopathological findings  and the median vessel count. In a univariate analysis all angiogenesis parameters had prognostic value: a higher vascularity was associated with worse prognosis (P < 0.05). Multiple regression analysis showed that vascular permeation (P < 0.001) and the median vessel count (P = 0.005) were the most important prognostic indicators. In the future these criteria may be used for selection of patients for anti-angiogenesis therapy."}
+{"text": "Comparing the primary DCIS and the invasive or non-invasive recurrence, concordant histology was found in 62%, and identical marker expression in 63%. Although 11% of the recurrences developed at a distance from the primary DCIS, nearly all these showed the same histological and immunohistochemical profile. 5 patients developed well-differentiated DCIS or grade I invasive carcinoma after poorly differentiated DCIS. Although these recurrences occurred in the same quadrant as the primary DCIS, they may be considered as second primary tumours. Only 4 patients developed poorly differentiated DCIS or grade III invasive carcinoma after well differentiated DCIS. We conclude that in most cases the primary DCIS and its local recurrence are related histologically or by marker expression, suggesting that local recurrence usually reflects outgrowth of residual DCIS; progression of well differentiated DCIS towards poorly differentiated DCIS or grade III invasive carcinoma is a non-frequent event. \u00a9 2001 Cancer Research Campaign http://www.bjcancer.comWe have investigated primary ductal carcinomas in situ (DCIS) of the breast and their local recurrences after breast-conserving therapy (BCT) for histological characteristics and marker expression. Patients who were randomized in the EORTC trial 10853  and who developed a local recurrence were identified. Histology was reviewed for 116 cases; oestrogen and progesterone receptor status, and HER2/"}
+{"text": "Amplification and increased expression of many growth factor receptors, including the epidermal growth factor receptor (EGFR), has been observed in human tumours. One therapeutic strategy for overcoming EGF autocrine control of tumour growth is inhibition of EGFR protein tyrosine kinase (PTK). A series of low molecular weight molecules have been identified which inhibit the EGFR PTK in vitro and demonstrate antiproliferative activity against human cancer cell lines with high expression of EGFR. A significant growth delay in squamous cancer xenografts has been reported for one of these compounds, the tyrphostin RG13022. Based on these encouraging results, we sought to confirm the activity of RG13022 in vivo and relate the effects to the in vivo plasma disposition. RG13022 and three additional peaks were detected by HPLC following intraperitoneal administration of 20 mg kg-1 RG13022 in MF1 nu/nu mice. RG13022 demonstrated rapid biexponential elimination from plasma with a terminal half-life of 50.4 min. RG13022 plasma concentrations were less than 1 microM by 20 min post injection. A primary product was identified as the geometrical isomer (E)-RG13022. Both RG13022 and its geometrical isomer inhibited DNA synthesis in HN5 cells after a 24 h in vitro incubation (IC50 = 11 microM and 38 microM respectively). Neither RG13022 nor its geometrical isomer displayed significant cytotoxicity. RG13022 had no influence on the growth of HN5 tumours when administered chronically, starting either on the day of tumour inoculation or after establishment of tumour xenografts. The rapid in vivo elimination of RG13022 has potential significance to the development of this and other related tyrphostin tyrosine kinase inhibitors, as plasma concentrations fell below that required for in vitro activity by 20 min post injection. The lack of in vivo tumour growth delay suggests that a more optimal administration schedule for RG13022 would include more frequent injections or continuous administration. An improved formulation for RG13022 is therefore required before further development of this or other similar protein tyrosine kinase inhibitors can be made. Alternative strategies should also be sought which display longer lasting in vivo exposures."}
+{"text": "We introduced the origin-defective SV40 early gene into cultured human oesophageal epithelial cells by infection of a recombinant SV40 adenovirus vector. The virus-infected cells formed colonies 3-4 weeks after infection in medium containing fetal calf serum. When the cells derived from 'serum-resistant' colonies were then maintained in the serum-free medium with a low calcium ion concentration, some of them passed the cell crisis and kept growing for over 12 months. These cells, regarded as immortalised cells, resembled the primarily cultured oesophageal epithelial cells in morphology and had some of their original characteristics. Treatment of the cells with a high calcium concentration induced phenotypic changes. These cells still responded to transforming growth factor beta. When the immortalised cells were injected into severe combined immunodeficient mice, they transiently formed epithelial cysts, although the typical differentiation pattern of the oesophageal epithelium was not observed. These cysts regressed within 2 months without development into tumours. The results indicated that human oesophageal epithelial cells were reproducibly immortalised by infection with a recombinant SV40 adenovirus vector at relatively high efficiency. The immortalised cells should be useful in studies on oesophageal carcinogenesis and in assessing the cooperative effects with other oncogene products or carcinogens."}
+{"text": "Despite numerous studies in the past it is not possible yet to predict postoperative liver failureand safe limits for hepatectomy. In this study the following liver function tests ICG-ER(indocyaninegreen elimination rate), GEC  and MEGX-F(monoethylglycinexylidid formation) are examined with regard to loss of liver tissue andprediction of operative risk. Liver function tests were assessed in 20 patients prior to liverresection and on the 10th. postoperative day. Liver and tumor volume were measured byultrasound and pathologic specimen and the parenchymal resection rate was calculated. Inpatients without cirrhosis (n = 10) ICG-ER and MEGX-F remained unchanged afterresection, GEC was reduced but did not correspond to the resection rate. Patients withcirrhosis (n = 10) had a significantly lower ICG-ER and GEC before resection than patientswithout cirrhosis. After resection these tests were unchanged. Patients with liver relatedcomplications and cirrhosis (n = 5) had lower ICG-ER and GEC than patients with cirrhosisand no complications. In the postoperative course all liver function tests in these patients weresignificantly lower compared to preoperative results. Comparing liver function tests ICGserves best to indicate postoperative liver failure. Liver function tests do not correspond withloss of liver tissue."}
+{"text": "Estimation of tumour proliferation may allow the design of individualised radiotherapy schedules to optimise response. This prospective study correlates the tumour proliferation rate of cervical carcinoma with response to conventional radiotherapy. The potential tumour cell doubling rate (Tpot) was estimated following flash labelling of the tumours in vivo using the DNA precursor, bromodeoxyuridine (BrdUrd); samples were analysed by flow cytometry. Tumour ploidy, DNA index and mitotic count were also assessed as was histological grade and type. Multiple biopsies from each tumour were obtained from 121 women. The median Tpot was 4.0 days, median S-phase duration 12.8 h and median adjusted labelling index 9.8%. Higher BrdUrd labelling was seen in patients who developed pelvic tumour recurrence following radiotherapy. This was the only biological/histological parameter with univariate and multivariate significance in relation to locoregional recurrence (P = 0.006 and P = 0.034 respectively). This study represents the first assessment of Tpot in relation to long-term response of cervical tumours treated by radiotherapy treatment. The association of high BrdUrd labelling and poor pelvic disease-free survival indicates the need for further research into the potential of radiotherapy schedule alteration to reflect tumour proliferation. The predictive value may be enhanced by combination with other biological parameters."}
+{"text": "Objective: We sought to determine the effect of bacteria on fluorescence polarization (FPOL) testing of amniotic fluid.Methods:  Fusobacterium necrophorum and Escherichia coli were inoculated at concentrations of 103 and 106/ml in amniotic-fluid specimens from 4 patients with no clinical or laboratory evidence of infection. The FPOL results were obtained at inoculation and again at 24 h of incubation. The results were compared using analysis of variance (ANOVA).Results: The FPOL results from inoculated specimens were all within 2% of the uninoculated controls. The specimens incubated with bacteria showed a < 1\u201319% variation when compared with the time-zero uninoculated controls. However, uninoculated controls incubated for 24 h exhibited a 2\u201312% variation when compared with the time-zero controls, suggesting that the variation present was not secondary to the bacterial co-incubation.Conclusions: In vitro, neither bacterial inoculation nor prolonged co-incubation influences FPOL results beyond the effect of incubation alone. FPOL appears to be an appropriate test to assess fetal lung maturity in patients in whom intraamniotic infection is a concern."}
+{"text": "Cellular repopulation in Lewis carcinoma irradiated with 60Co gamma-rays was examined by performing sequential cell-survival estimations using an in vitro soft-agar-colony assay. Following local irradiation (15--35 Gy) two distinct types of colony were seen: compact colonies with tightly packed cells and diffuse colonies with widely dispersed cells. Maximal diffuse colony formation in vitro was only obtained in the simultaneous presence of adequate numbers of compact colonies. After whole-body irradiation only compact colonies were observed. Only-cell survival data from compact colony counts correlated with cell survival estimated by the lung colony assay and we conclude that compact colonies are produced by clonogenic tumour cells. Cytochemical and immunological evidence showed that diffuse colonies were composed of macrophages. After local irradiation the initial kill of clonogenic tumour cells was dose dependent. At each dose level, repopulation began immediately and proceeded with a doubling time of about 1 day. Macrophage colony-forming cells (macrophage progenitors) per tumour were initially reduced by about 3 decades, but recovered very rapidly to reach pretreatment levels within 2 days. We conclude that at least two populations of clonogenic cells are present in Lewis lung carcinoma, tumour cells that repopulate irradiated tumours by in situ proliferation and host-macrophage progenitors that repopulate locally irradiated tumours by infiltration. The hazards of confusing host and tumour cell colonies in in vitro assay systems are stressed."}
+{"text": "We report a patient with an implantable cardioverter defibrillator (ICD) for arrhythmogenic right ventricular dysplasia (ARVD) who received inappropriate shocks for atrioventricular node reentry tachycardia (AVRNT). Patient had multiple shocks for tachycardia with EGM characteristics of very short VA interval and CL of 300 msec. An electrophysiologic (EP) study reproducibly induced typical AVNRT with similar features. The slow AV nodal pathway ablation resolved the ICD shocks. Despite increasingly sophisticated discrimination algorithms available in modern ICDs, the ability to differentiate SVT from VT can be challenging. Our patient received inappropriate shocks for AVNRT. When device interrogation alone is not conclusive, an EP study may be necessary to determine the appropriate therapeutic course. Arrhythmogenic right ventricular dysplasia (ARVD) is an inherited degenerative disorder involving progressive replacement of the myocardium by fibro fatty tissue. This is seen predominantly in the right ventricle though left ventricular involvement is not uncommon. The fibrofatty replacement provides the substrate for life threatening arrhythmias such as monomorphic ventricular tachycardia, polymorphic ventricular tachycardia (torsades de pointes), ventricular fibrillation and / or electrical storm  are sophisticated devices with arrhythmia discrimination algorithms that reliably differentiate SVT from VT and provide appropriate therapy. We report a patient with ARVD who had inappropriate shocks for AVNRT.A 47-year old male presented with 3 ICD shocks for persistent ventricular tachycardia. He had known history of polysubstance abuse and coronary artery disease with angioplasty. Eight months prior to this admission he had presented with symptomatic monomorphic ventricular tachycardia (Cycle length 360 msec). A 2D-echo showed an ejection fraction of 40% followed by a coronary angiogram which showed non-obstructive disease with previously placed patent right coronary stent. Cardiac MRI confirmed a diagnosis of ARVD. He received a Biotronik Lexos DR ICD (model # 347000). Device interrogation during the current admission revealed a wide complex tachycardia (WCT) that received 3 ineffective shocks but resolved spontaneously. The WCT as shown by the Electrograms (EGMs) during ICD interrogation showed a short VA interval, a Cycle length (CL) of 300msec which were completely different from the VT seen during his initial clinical presentation . ICD shoDuring EP study, no arrhythmia was inducible at baseline. With RV stimulation and Isoproterenol (2mcg) provocation, a typical AVNRT with a pacing cycle length of 500 msecs and 3 extra stimuli of 290-280-270 ms, identical to the arrhythmia seen on ICD interrogation strips was easily and reproducibly induced . PresencOur patient presented with sustained monmorphic VT, was diagnosed as ARVD by cardiac MRI, requiring ICD implantation. Subsequently he had inappropriate shocks due to AVNRT . Due to differences in the characteristics of the two arrhythmias an appropriate diagnosis of the arrhythmia responsible for the inappropriate shocks could be established only with programmed electrical stimulation during an EP study.ARVD has an increased incidence of ventricular arrhythmias and SCD requiring ICD implantation. It has been estimated that about 20 percent of SCD among patients <35 years is due to ARVD .In spite of a high specificity, inappropriate shocks have been seen in ARVD patients with ICD especially with atrial arrhythmias. In a study of 653 arrhythmia episodes in patients with dual chamber ICDs, inappropriate detection of atrial arrhythmias (with a stable atrioventricular relationship) was seen in 42% of patients, of which atrial flutter or fibrillation were more often misdiagnosed [Most modern ICDs have sophisticated discrimination algorithms to differentiate atrial and ventricular arrhythmias. While ventricular arrhythmias are recognized and treated with precision, atrial arrhythmias can be misdiagnosed and receive inappropriate shock therapy. An EP study may thus be necessary in establishing an accurate diagnosis and delivering appropriate therapy."}
+{"text": "Antibodies directed against the antigen released from viable tumour cells during growth have been raised by cross-immunization of immunocompetent hairy litter-mates with serum from nude mice bearing pancreatic tumour xenografts. Antisera raised against the components released from a primary pancreatic tumour xenograft (WB) or from a tumour cell-line xenograft (GER) showed a titre greater than 1:625 against cultured pancreatic tumour cells by an I125-binding assay. Five out of 14 of the hairy litter-mates immunized with serum from the same tumour (GER) produced antisera that bound more strongly to pancreatic cancer cells than to 13 other non-pancreatic cell lines (binding ratio greater than 2). Absorption of the antisera with pure CEA reduced the level of binding by 11-25% without affecting the specificity for pancreatic tumour cells. The antibody response could be completely removed by absorption with pancreatic tumour cells, whereas 50% and 18% of the activity remained after absorption with normal pancreas homogenate and a mixed non-pancreatic tumour-cell pool, respectively. Immunofluorescent staining of pancreatic tumour sections indicated that the antibody was localized on the membrane of ductular epithelial cells. Challenge of immunocompetent mice using this procedure has produced a polyspecific antiserum with signs of selectivity for the circulating antigens released from pancreatic cancer cells, and may provide a route to the production of antibody against specific tumour components."}
+{"text": "Patients with neurogenic bladder due to spina bifida are considered to be at increased risk for aggressive bladder cancer. We present a unique case of a 32-year-old woman with spina bifida diagnosed with sarcomatoid urothelial carcinoma of the bladder and report diagnosis and management.A 32 year old woman with neurogenic bladder managed with intermittent self catheterisations, presented with gross hematuria. On cystoscopy, she had a bulky bladder mass on the posterior bladder wall. Bladder biopsies revealed sarcomatoid variant of bladder transitional cell carcinoma. Treatment included radical cystectomy with ileal conduit diversion and adjuvant chemotherapy with excellent intermediate term follow up.Patents with neurogenic bladder managed with intermittent self catheterisations need periodical follow up due to increased risk for aggressive bladder cancer. Immediate radical cystectomy with adjuvant chemotherapy is the suggested treatment approach. Patients with neurogenic bladder due to spina bifida (SB) are considered to be at increased risk for bladder cancer. These tumours are composed of urothelial, glandular or small cell component showing variable degrees of differentiation, while a small subset may have a prominent myxoid stroma . We repoA 32-year-old Greek white woman with neurogenic bladder due to spina bifida managed with intermittent self catheterizations since puberty; presented with gross hematuria and recurrent urinary tract infections. There was no history of bladder cancer in patient's family. Cystoscopy showed a bulky solid mass occupying the posterior bladder wall. Computed tomography didn't show nodal or distant metastases. Bladder biopsies revealed muscle-invasive sarcomatoid urothelial carcinoma with carcinoma in situ of the bladder neck. Radical cystectomy with anterior pelvic exenteration and ileal conduit formation was performed. Microscopically, the tumor was a high-grade urothelial carcinoma, Grade III according to the classification of the World Health Organization (WHO) of 1973, invading the whole bladder-wall and the pericystic lipoid tissue (stage pT3a). A large subset of the tumor assumed a spindle cell/sarcomatoid appearance with high mitotic rate and atypical mitoses. Immunohistochemically, the tumor cells were positive for the epithelial membrane antigen (EMA), cytokeratin 18 (CK18) and Vimentin. Some tumor cells were positive for CD117 (c-kit), whereas all of them were negative for CK7, CK20, Desmin and CD34  DD contributed in writing and revision of the manuscript. All authors read and approved the final manuscript."}
+{"text": "P < 0.001), although the two compartments were also significantly correlated with each other. Tumours with low proliferation at the invasive margin had a significantly poorer prognosis both in univariate (P = 0.014) and in multivariate survival analyses (P = 0.042). We conclude that Dukes' B colorectal cancers exhibit a systematic spatial heterogeneity with respect to proliferation, and tumours with low proliferation at the invasive margin had a poor prognosis. The present data independently confirm recent results from the authors, and provide new insights into the understanding of tumour cell proliferation in colorectal cancer. \u00a9 1999 Cancer Research CampaignThe conflicting results about the prognostic impact of tumour cell proliferation in colorectal cancer might be explained by the heterogeneity observed within these tumours. We have investigated whether a systematic spatial heterogeneity exists between different compartments, and whether the presence of such a systematic heterogeneity has any impact on survival. Fifty-six Dukes' stage B colorectal cancers were carefully morphometrically quantified with respect to the immunohistochemical expression of the proliferative marker Ki-67 at both the luminal border and the invasive margin. The proliferative activity was significantly higher at the luminal border compared with the invasive margin ("}
+{"text": "Superior vena cava (SVC) and inferior vena cava (IVC) pressures were measured serially duringlaparoscopic cholecystectomy in which the intra-abdominal pressure was maintained at12mmHg. The influences of alteration of position from 15 degrees head-down to 15 degreeshead-up and of the operative procedure of holding the gallbladder up to the right subphrenicspace on SVC and IVC pressures were mild. IVC pressure was maintained almost equal to theintra-abdominal pressure during prolonged continuous pneumoperitoneum lasting longer than60min, while SVC pressure did not change significantly during operation. The discrepancybetween SVC and IVC pressures underwent no change during continuous pneumoperitoneum."}
+{"text": "This study presents a retrospective review of chest radiography in children with Murphy stage III T-cell lymphoblastic lymphoma. All received a standard leukaemia-based protocol with intensive induction, consolidation and continuing chemotherapy. Neither initial thoracic disease bulk nor the presence of a pleural effusion predicted outcome. However a significant difference was found when the 50 patients in whom the chest radiograph returned to normal within 60 days of commencing treatment were compared with the 18 patients with persistent mediastinal abnormalities, for both event-free  and overall survival . It appears that this relatively simple estimate of chemosensitivity may identify a group of particularly good-risk patients in whom drugs associated with late morbidity such as anthracyclines may be reduced and conversely a higher risk group in whom further intensification of treatment would be justified."}
+{"text": "Bovine seminal ribonuclease (BSRNase) is an unusual member of the ribonuclease superfamily, because of its remarkable anti-tumour and immunosuppressive properties. We describe here the construction, expression, purification and characterization of a panel of six immunotoxins based upon this enzyme and show that we can increase its anti-tumour activity by over 2 x 10(4)-fold. This is achieved by improving tumour cell targeting using a single-chain Fv (scFv) directed against the oncofetal antigen placental alkaline phosphatase. As well as the simple scFv-BSRNase fusion protein, we have constructed five other derivatives with additional peptides designed to improve folding and intracellular trafficking and delivery. We find that the molecule most cytotoxic to antigen (PLAP)-positive cells in vitro is one that contains a C-terminal 'KDEL' endoplasmic reticulum retention signal and a peptide sequence derived from diphtheria toxin. All these molecules are produced in Escherichia coli (E. coli) as insoluble inclusion bodies and require extensive in vitro processing to recover antigen binding and ribonuclease activity. Despite incomplete ribonuclease activity and quaternary assembly, these molecules are promising reagents for specific chemotherapy of cancer and are potentially less harmful and immunogenic than current immunotoxins."}
+{"text": "To the Editor: Multidrug-resistant Shigella dysenteriae type 1 caused an extensive epidemic of shigellosis in eastern India in 1984 , and the characteristic colonies were identified by standard biochemical methods  yielded S. dysenteriae type 1 occurred in the northern part of West Bengal in eastern India among tea garden laborers from April 2002 to May 2002; 1,728 persons were affected (attack rate of 25.6%). Sixteen persons died. The isolated S. dysenteriae type 1 strains were found intermediately sensitive to fluroquinolones with an MIC of 2 \u03bcg/mL .A similar outbreak of This drug-resistant Shiga bacillus is highly likely to spread further and will certainly pose a major therapeutic challenge unless adequate preventive measures are immediately instituted to contain its spread. Appropriate awareness programs for the community and reorientation training for physicians and other health personnel would be helpful to prevent further transmission of these resistant organisms. Alternative drugs to treat drug-resistant cases and an effective vaccine are also needed."}
+{"text": "To our knowledge we report the first case of percutaneous mechanical thrombectomy used for the treatment of massive pulmonary embolism in the United Kingdom. Pulmonary embolism is a common disease process but can be difficult to diagnose. Massive pulmonary embolism presenting with profound hypotension, however, is rare. Both phenomena carry with them significant mortality. Traditionally those patients suffering haemodynamic compromise from pulmonary embolism are treated with intravenous or catheter-directed thrombolysis. When this is contraindicated surgical embolectomy or mechanical techniques via a right heart catheter are alternative options. The former is well established but the latter is less commonly utilised in clinical practice. Our aim is to highlight the effectiveness and relative safety of percutaneous mechanical thrombectomy as a therapeutic tool in massive pulmonary embolism.A 70 year-old gentleman presented with a 4-month history of dry cough and general malaise. Clinical examination along with routine chest radiograph confirmed a left pleural effusion which was drained. Computed tomography of the chest, abdomen and pelvis revealed a left renal mass consistent with renal cell carcinoma plus multiple metastatic subpleural nodules. Following planned thoracoscopy and pleural biopsy the patient became acutely dyspnoeic and hypotensive. Relevant investigations including computed tomography pulmonary angiogram confirmed a large saddle embolus extending in to the lobar branches of both left and right pulmonary arteries. There were several relative contraindications to thrombolysis and so the patient proceeded to have percutaneous mechanical thrombectomy with excellent results. The patient made a full recovery from the acute episode and was discharged home on warfarin with a view to planned cyto-reductive nephrectomy.We illustrate here that percutaneous mechanical thrombectomy can be a safe and effective method of treating massive pulmonary embolism when thrombolysis is relatively contraindicated. It may also be of use as an adjuvant therapy in those patients able to receive thrombolysis. In the future further evaluation involving a larger cohort of subjects is necessary to determine whether this treatment is superior to surgical embolectomy when thrombolysis cannot be performed. Pulmonary embolism (PE) is a common but under-diagnosed disease process with an estimated incidence of about 60\u201370 per 100 000 of the general population. Here theDespite a lack of robust data British Thoracic Society (BTS) guidelines published in 2003 clearly recommend the use of thrombolysis in massive PE; the earlier the better.[A 70 year-old male presented with a 4-month history of dry cough and general malaise. He had had a right arm melanoma excised 5 months previously but otherwise had no significant medical history. Clinical examination revealed a left pleural effusion confirmed by chest radiograph which subsequently drained blood-stained fluid positive for reactive mesothelial cells and lymphocytes. Cytology was negative for malignant cells. Computed tomography (CT) of his thorax and abdomen undertaken just prior to discharge from hospital revealed a left renal mass consistent with renal cell carcinoma (RCC) and multiple bilateral subpleural nodules. Renal function was normal at this stage.The patient was electively re-admitted a week later for planned thoracoscopy and pleural biopsy. Biopsy confirmed the subpleural nodules to be metastatic RCC deposits. Following repeat chest drain insertion the patient collapsed some hours later and became acutely dyspnoeic with oxygen saturations of 82% on room air and a systolic blood pressure of 96 mmHg. There was no clinical evidence of lower limb deep vein thrombosis. Arterial gases confirmed type I respiratory failure and an electrocardiogram revealed a sinus tachycardia with new right bundle branch block. Subsequent CT pulmonary angiogram (CTPA) demonstrated a large saddle embolus with thrombus extending into the lobar branches of both main pulmonary arteries Fig. . MassiveWe proceeded to rheolytic thrombectomy using the AngioJet system . Access was gained via 5-French (F) and 10F sheaths into the right femoral vein. A 4F sheath was also introduced into the right femoral artery for blood pressure monitoring. We confirmed the absence of thrombus in the inferior vena cava (IVC) angiographically before proceeding with right heart catheterisation. A 0.035-inch guidewire was placed in the right ventricle over which a 5F multipurpose-1 (MP-1) diagnostic catheter was fed. Pulmonary angiography via this catheter revealed filling defects in both pulmonary arteries  declare that they have no competing interests.AM assisted with the actual procedure, helped to acquire data and images for figure presentations, drafted the manuscript and revised it critically for important intellectual content. AA conducted the actual procedure and gave a critical appraisal of the draft manuscript. All authors read and approved the final manuscript.Selective pulmonary angiogram pre-thrombectomy. Selective pulmonary angiogram demonstrating evidence of thrombus material in the left main pulmonary artery prior to percutaneous mechanical thrombectomy.Click here for fileSelective pulmonary angiogram post-thrombectomy. Selective pulmonary angiogram demonstrating restoration of blood flow in the left main pulmonary arterial tree following percutaneous mechanical thrombectomy.Click here for file"}
+{"text": "When normal rat and mouse embryo cells were treated with a cell free extract of S37 ascites tumour, morphological transformations occurred in both. The transformed cells readily induced lymphosarcoma-type tumours in the mice inoculated when newborn or young adults (8-12 weeks old), but not so readily in rats.Various tests carried out with these cells strongly indicate the presence of an oncogenic and transmissible agent in S37 ascites tumour. This agent appears to be related to mouse sarcoma virus isolated from animals with Moloney leukaemia but differs in only producing characteristic lymphosarcoma-type tumours."}
+{"text": "Guinea pig and mouse peritoneal macrophages formed antibody-dependent rosettes with guinea pig L2C leukaemic cells, but were unable either to phagocytose the cells or to kill them extracellularly as judged by the retention of 51Cr. Macrophages previously activated by BCG in vivo also failed to exhibit phagocytosis or cytoxicity towards the antibody-coated cells. These failures could not be attributed to deficient function of the macrophages nor to antigenic modulation of the L2C cells. The antibodies involved were capable of mediating lysis by complement, and ADCC by human leukocytes. However macrophages were cytostatic to antibody-coated L2C cells in that uptake of 3H-thymidine or 3H-deoxycytidine was abruptly and in some cases completely inhibited upon cell contact being established. Antigenic modulation which had proceeded sufficiently to protect against lysis by complement did not protect against cytostasis. Syngeneic macrophages had greater cytostatic activity than did allogeneic or xenogeneic. Macrophage activation by BCG did not result in significantly increased cytostasis. A univalent antibody derivative Fab/c was also capable of mediating cytostatis by the macrophages."}
+{"text": "Metastatic malignancy to the thyroid gland is generally uncommon due to an unfavourable local thyroid micro-environment which impairs the ability of metastatic cells to settle and thrive. Metastases to the thyroid gland have however been reported to occur occasionally particularly if there has been disruption to normal thyroid tissue architecture.18F-FDG PET scan positive thyroid nodule which was subsequently confirmed at surgery to be a focus of metastatic rectal adenocarcinoma within a primary poorly differentiated papillary thyroid carcinoma.We report a patient with a history of surgically resected rectal adenocarcinoma who presents with a rising serum CEA level and an Subsequent treatment involved right hemi-thyroidectomy, pulmonary wedge resection of oligometastatic metastatic colorectal cancer and chemotherapy.Metastatic rectal carcinoma to the thyroid gland and in particular to a primary thyroid malignancy is rare and unusual. Prognosis is likely to be more dependent on underlying metastatic disease rather than the primary thyroid malignancy hence primary treatments should be tailored towards treating and controlling metastatic disease and less emphasis placed on the primary thyroid malignancy. Metastatic malignancy to the thyroid gland, although considered rare, occurs more frequently than expected. Microscopic metastases to the thyroid gland have been reported to occur in 4%\u20139% of autopsy studies,2, with A 52 year old man with a history of T3N1M0 (Dukes C) rectal adenocarcinoma treated with neo-adjuvant chemo-radiotherapy (5FU + radiotherapy) followed by anterior resection and adjuvant chemotherapy (5FU) presented 18 months post completion of therapy with rising serum CEA level  and a 15 mm left lower lobe pulmonary nodule on computerized tomography (CT), suggestive of a metastatic deposit (figure 18F-FDG whole body Positron Emission Tomography (PET) scan was performed to further evaluate the nature of the left lower lobe pulmonary nodule and to evaluate any other possible sites of metastatic disease. The whole body PET scan demonstrated significant 18F-FDG uptake in the left lower lobe pulmonary nodule compatible with a metastatic deposit (figure An t figure . An inteAn ultrasound guided fine needle aspirate of the right lower pole thyroid nodule was performed which revealed malignant cells with features suggestive of a primary papillary thyroid cancer. A right hemi-thyroidectomy was subsequently performed. Macroscopically, the resected thyroid specimen demonstrated a well-circumscribed dominant thyroid nodule measuring 32 mm in diameter with a pale tan capsule less than 1 mm in thickness. The cut surface had a variegated appearance with pale tan friable tissue intermixed with foci of yellow tissue and dark brown foci. Histological examination revealed cells typical of metastatic adenocarcinoma of the colon intermixed in a background of a poorly differentiated papillary thyroid carcinoma (figure A wedge resection of the left lower lobe pulmonary nodule was subsequently performed which confirmed metastatic colorectal adenocarcinoma figure . Serum CMetastatic lesions to the thyroid gland are generally considered rare, possibly due to a high oxygen and iodine environment which may impair the ability of metastatic cells to settle and develop. Abundant high velocity blood flow through the thyroid gland also possibly plays a role in impeding the ability for metastatic cells to gain a foothold. Perhaps18F-FDG PET, an increasing number of incidental cases of metastatic disease to the thyroid gland are likely to be detected. Well differentiated primary thyroid carcinomas such as papillary and follicular carcinomas are generally not 18F-FDG avid on PET scanning and usually only become 18F-FDG avid if they de-differentiate.With the advent of improved diagnostic imaging technology such as 18F-FDG avid primary thyroid malignancies are generally a more aggressive variant of primary thyroid cancer which harbour a higher rate of unfavourable prognostic factors and are often less well differentiated[18F-FDG avid.It has been reported in the literature incidentally PET detected To our knowledge there have been no cases of metastatic malignancy within a primary thyroid malignancy reported previously in the literature. As such, there is scant evidence in the literature regarding the most appropriate management strategy for such a patient. Conventional management of a primary thyroid malignancy usually involves total surgical thyroidectomy followed by radioiodine therapy to ablate the thyroid remnant, decrease risk of recurrence and enable adequate follow up using I-131 whole body scintigraphy and stimulated thyroglobulin levels -13.In our case, prognosis is more likely to be dependent on the patient's metastatic rectal adenocarcinoma rather than the primary thyroid malignancy. Stage IV metastatic rectal adenocarcinoma portends a poor prognosis, with five year survival rates of between 4%\u20138%,15. MoreAs a result, the primary treatment focus in our patient was tailored towards treating metastatic rectal carcinoma and less so the primary thyroid malignancy. It is also of note, many poorly differentiated thyroid carcinomas are not particularly radioiodine avid and it is quite possible the impact of radioiodine therapy on reducing recurrence rates may be greatly diminished in this setting.Metastatic rectal carcinoma to the thyroid gland and in particular to a primary thyroid malignancy is uncommon and to our knowledge has not been reported. Prognosis is likely to be more dependent on underlying metastatic disease rather than the primary thyroid malignancy hence primary treatments should be tailored towards treating and controlling metastatic disease and less emphasis placed on the primary thyroid malignancy.Written informed consent was obtained from the patient for publication of this Case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.The authors declare that they have no competing interests.MC conceived the idea, reported the PET scan, performed the literature search, provided the radiographic images and drafted the manuscript. MM administered chemotherapy, reviewed and revised manuscript, JS performed surgery, reviewed and revised manuscript, SS reported histopathology, provided histopathological images, reviewed and revised manuscript and DT treated patient, reviewed and revised manuscript. All authors have read and approved the final manuscript."}
+{"text": "Generalized lymphosarcomatosis (leukaemia) of non-thymic type occurs in mice bearing 90Sr or 239Pu or 226Ra. Tumours passaged from such mice have been tested for tumour-associated transplantation antigens that could provoke a protective immunity which would be expected if such antigens were determined by virus activated by the irradiation. Sub-threshold doses of living syngeneic tumour, large doses of living allogeneic tumour and large doses of killed syngeneic tumour were without protective effect. This suggests that viruses observed electron micrographically in such tumours are passengers and not causative."}
+{"text": "The relationship of testicular seminoma with several factors was explored using a case-control study. Previously recognized associations with cryptorchidism and infantile inguinal hernia were confirmed and relationships were also found with cycling and horse-riding. These findings represent the first relationships of testicular cancer with well-defined postnatal risk factors."}
+{"text": "Heat shock proteins have been reported to confer resistance to certain antineoplastic drugs. We investigated the impact of hsp70 overexpression on the efficacy of two new anti-cancer drugs, topotecan and gemcitabine. We used the fibrosarcoma WEHI-S cells stably transfected to overexpress the hsp70 cDNA from the constitutive SV40 promoter and appropriate control cells. After topotecan and gemcitabine treatment hsp70-overexpressing cells showed a marked elevation in cell survival, suggesting that hsp70 overexpression was sufficient to confer resistance to the drugs. In addition, hsp70-overexpressing cells were capable of starting cell proliferation after treatment with drug dosages that were lethal to control cells. Our results demonstrate that hsp70 overexpression represents a possible cause of drug resistance. In order to transfer these data to tumour cells constitutively expressing stress hsp70 due to the constitutive activity of the original hsp70 promoter we sought to supress the heat shock response pathway by the natural flavonoid quercetin, known to inactivate the heat shock transcription factor (HSF). Using a suitable cell line, we demonstrated the sensitising activity of quercetin. We found that antineoplastic drug concentrations exerting cytotoxic activity were markedly lower when cells were pretreated with quercetin. Concomitantly, hsp70 expression was strongly down-regulated under quercetin treatment. Our data indicate that quercetin may be useful as a sensitiser in chemotherapeutically treated patients suffering from hsp70-overexpressing tumours."}
+{"text": "Evidence increasingly shows that stream ecosystems greatly contribute to global carbon fluxes. This involves a tight coupling between biofilms, the dominant form of microbial life in streams, and dissolved organic carbon (DOC), a very significant pool of organic carbon on Earth. Yet, the interactions between microbial biodiversity and the molecular diversity of resource use are poorly understood.Using six 40-m-long streamside flumes, we created a gradient of streambed landscapes with increasing spatial flow heterogeneity to assess how physical heterogeneity, inherent to streams, affects biofilm diversity and DOC use. We determined bacterial biodiversity in all six landscapes using 16S-rRNA fingerprinting and measured carbon uptake from glucose and DOC experimentally injected to all six flumes. The diversity of DOC molecules removed from the water was determined from ultrahigh-resolution Fourier Transform Ion Cyclotron Resonance mass spectrometry (FTICR-MS). Bacterial beta diversity, glucose and DOC uptake, and the molecular diversity of DOC use all increased with increasing flow heterogeneity. Causal modeling and path analyses of the experimental data revealed that the uptake of glucose was largely driven by physical processes related to flow heterogeneity, whereas biodiversity effects, such as complementarity, most likely contributed to the enhanced uptake of putatively recalcitrant DOC compounds in the streambeds with higher flow heterogeneity.Our results suggest biophysical mechanisms, including hydrodynamics and microbial complementarity effects, through which physical heterogeneity induces changes of resource use and carbon fluxes in streams. These findings highlight the importance of fine-scale streambed heterogeneity for microbial biodiversity and ecosystem functioning in streams, where homogenization and loss of habitats increasingly reduce biodiversity. A growing body of reviews and meta-analyses has recently highlighted the functional consequences of biodiversity for ecosystem functioning In this paper, we report the results of an experiment designed to test the hypothesis that fine-scale physical heterogeneity in streamside flumes affects bacterial biodiversity and DOC resource use by benthic biofilms. Biofilms are matrix-enclosed and attached communities that dominate microbial life in streams where they can control key ecosystem functions \u22121). The resulting flow may be identified as shallow rough-bed flow typical for headwater streams. The flumes were continuously fed in a once-through mode to assure identical water chemistry and microbial inoculum. A header tank and tilting weirs ensured steady and spatially uniform flow. Nearly identical average flume-level velocities were achieved by adjusting flume slopes individually with repeated measurements of mean velocity by slug additions of NaCl-solutions Experiments were conducted in streamside flumes . Five flumes contained 38 triangular dune-shaped bedforms , respectSDRxyz, the standard deviation of Rxyz is the central independent variable and a surrogate for flow heterogeneity.Acoustic Doppler Velocimetry  described the 3-D flow fields and served to derive heterogeneity of flow as its spatial variation. In each flume, velocity was mapped over one entire bedform (\u223c5 mm above substrate) at nodes of a 5\u00d75 cm grid. For each node, we determined depth, mean length of the 3-dimensional velocity vector y TI see . 80 measa) and for bacterial community composition. Coupons were sampled four times over a growth period of 4\u20135 weeks during summer season. Biofilms reached stationary growth after approximately 3\u20134 weeks. Coupons from triplicate bedforms were processed as composite samples for bacterial community composition. To determine microbial biomass SYTOX-stained bacteria were counted and sized using a Cell-Lab-Quanta (Beckman Coulter). Chlorophyll-a was assayed as described elsewhere Sterile unglazed ceramic coupons (1\u00d72 cm) served as substratum for biofilm growth DNA from biofilm communities was extracted and purified with the UltraClean Soil DNA Isolation kit . Non-colonized ceramic coupons served as negative controls. The fluorescently labeled primers used for PCR of the 16S rRNA gene were FAM labeled 27F and JOE-labeled 1492R  q\u200a=\u200a1D)/ln(S)ln to study dynamics of complex DOC. This DOC from riparian vegetation mimics an important terrestrial subsidy, which can generate substantial pulses of DOC in headwaters \u22121 and 8 mg L\u22121 for glucose and DOC, respectively. Water samples were collected at the flume outlets, filtered and frozen immediately before analysis. Glucose was analysed with HPLC\u2013PAD (Dionex ICS3000) using a CarboPac PA20 column . DOC concentration was measured using a SIEVERS (Ionics Instruments) and a Shimadzu TOC-VCPH/CPN. Mass transfer coefficients  for glucose and bulk DOC were calculated from log-linear fits of concentration decline in time  from riparian vegetation (time see .100O80N5S. See SDRxyz). See DOC (2 L water samples) from the header tank (inflow) and from each flume after recirculation  was extracted using XAD-8 resin 5 permutations. All calculations were done in R We hypothesized biodiversity components and community composition as explanatory links between environmental heterogeneity and resource use. Because of the multivariate nature of most of the involved entities, we used causal modeling on dissimilarity matrices calculated from subsets of appropriate variables \u22121 to 6.3 cm s\u22121 across all six flumes (\u22121 which translates to a residence time of 8.8 min) and mean water depth (6.7\u00b10.4 cm) among flumes  whereas bacterial abundance did not . Thus, we could identify a relatively small but stable beta-component that is clearly related to the hydrodynamic microenvironment and largely relies on relative abundance patterns of frequent OTUs.T-RFLP analyses identified a total of 76 bacterial operational taxonomic units (OTUs) in the biofilm samples in all flumes with an average of 26\u00b113 (mean\u00b1SD) per flume. Total bacterial diversity at flume-scale  was partitioned into the two orthogonal independent components alpha (average diversity within microhabitats) and beta (among microhabitats) diversity, and into richness and evenness, respectively see . We emplTo explore the possible consequences of spatial flow heterogeneity and related biodiversity patterns for resource use as an ecosystem process, we first measured the uptake of experimentally added monomeric glucose and then of a complex DOC mixture by mature biofilms typical for baseflow in headwaters. We extracted DOC from riparian vegetation to simulate a major carbon input to streams during leaf litter fall in autumn vf, see vf is independent from scaling effects of velocity and flume depth; its product with concentration represents the average flux of a solute to the streambed. We found vf of glucose (vf-Glucose) and bulk DOC (vf-DOC) significantly increased with increasing flow heterogeneity  using ultrahigh-resolution Fourier Transform Ion Cyclotron Resonance Mass Spectrometry  exhibited less variation at higher flow heterogeneity, indicating more even  consumption across all compounds of the DOC mixture (To test whether the observed increase in  mixture . This wo mixture  indicaterIinflow) as a key predictor of compound-specific mass transfer coefficients (vf-indDOC) in individual flumes; followed by the O\u2236C ratio, H\u2236C ratio and aromaticity (rIinflow) are preferentially removed from the stream water \u2013 decoupled from their absolute uptake proportional to concentration . These results also suggest that more oxygenated compounds are removed more readily from the water. Specifically, regression coefficients of the O\u2236C ratio, H\u2236C ratio and aromaticity  decreased with increasing flow heterogeneity. Similarly, negative relationships between slopes of predictors (or predicted effect sizes) of individual flume models and flow heterogeneity were found for O\u2236C, aromaticity and nitrogen  with higher heterogeneity  or intrinsic chemical properties \u2014 at higher flow heterogeneity. Hence, we further used the model coefficients as a proxy for resource use diversity.In support of the evenness pattern , the strnitrogen . In the The typical way of qualitatively visualizing ultrahigh-resolution spectra are Van Krevelen diagrams showing compounds in a chemical space defined by H\u2236C versus O\u2236C vf-indDOC and rIinflow (as a proxy for resource use diversity), which correlates better with bacterial beta diversity than with flow heterogeneity  constant . Similarly, the standard deviation of vf-indDOC, an additional descriptor for resource use diversity, correlated with beta diversity . Neither gamma diversity nor gamma evenness explained the diversity in resource use.Our experiments revealed a significant positive relationship between bacterial biodiversity and the diversity of DOC compounds removed from the water. This is supported by the slope of the relationship between To formally test biodiversity and community composition as explanatory links between flow heterogeneity and resource use, we applied causal modeling on dissimilarity matrices  and compIn this study, we present evidence that the manipulation of fine-scale flow heterogeneity may affect bacterial biodiversity in benthic biofilms and their resource use. The more heterogeneous flow landscapes triggered larger bacterial biodiversity and structural differentiation of biofilms, ultimately resulting in a broader range of DOC compounds removed more rapidly by the biofilms. To our knowledge, this is the first study attempting to integrate microbial diversity with environmental heterogeneity and chemical diversity of DOC as the major resource for microbial heterotrophs.Ecological theory Our results from causal modelling indicate that complementarity as a mechanism underlying the relationship between biodiversity and resource use may be true for DOC as a complex resource but most likely not for glucose. Rather, we argue that glucose uptake is largely controlled by variables modulated by flow heterogeneity, such as turbulence In contrast, we postulate that DOC removal was most likely controlled by mechanisms related to biodiversity rather than just to flow. Several lines of evidence support this hypothesis. The increase of bacterial beta diversity across the gradient of flow heterogeneity suggests diversification of hydrodynamic microhabitats along bedforms to generate distinct local communities assembled from the same species pool in the streamwater vf-indDOC of 361 compounds) exhibiting less variation at higher flow heterogeneity, which indicates more even  consumption across all compounds of the DOC pool. This would translate into decreasing metabolic specialization as flow heterogeneity increases. Evenness patterns of the molecular composition of both the inflow and residual DOC pools  enabling them to maximize resource use and to maintain high biomass irrespective of the hydrodynamic conditions Patterns of bacterial abundance across the six heterogeneity landscapes did not parallel patterns of glucose and DOC removal, indicating no role of bacterial abundance as a driver of resource use. We did not quantify the architectural differentiation of biofilms across flumes, but it becomes obvious from the spatial variation of both chlorophyll-The observed gradients of mass transfer and resource use diversity were not generated by surface area effects in the flumes. In fact, mass transfer coefficients are expressions of uptake performance corrected for the water volume and streambed surface area in the various flumes. Furthermore, bedforms were sealed to avoid confounding effects from varying streambed topography and induced hydrodynamic exchange and carbon processing What are the implications of our study? Streams and rivers are increasingly recognized to contribute to global carbon fluxes, but the underlying mechanisms remain obscure Figure S1Descriptive statistics of depth and velocity across the flow heterogeneity gradient.(0.02 MB PDF)Click here for additional data file.Figure S2Van Krevelen diagrams of CHONS molecular compositions.(0.14 MB PDF)Click here for additional data file.Figure S3Relationships of beta-diversity with diversity of DOC resource use and bulk DOC uptake.(0.02 MB PDF)Click here for additional data file.Figure S4Alternative metavariable path diagrams calculated from Mantel statistics.(0.03 MB PDF)Click here for additional data file.Table S1Characterization of the hydrodynamic conditions over the control streambed and the bedforms of the landscapes increasing in flow heterogeneity.(0.04 MB PDF)Click here for additional data file.Table S2Water-related environmental background conditions  measured at the outlet of mesocosms and in the header tank.(0.01 MB PDF)Click here for additional data file.Table S3Metavariable dissimilarity (distance) matrices and underlying variables.(0.02 MB PDF)Click here for additional data file.Table S4Results of hierarchical partitioning analysis of DOC compound-specific characteristics as predictors for mass transfer to the streambed.(0.01 MB PDF)Click here for additional data file.Table S5Selected multiple linear regression models using DOC compound-specific characteristics as predictors for mass transfer to the streambed.(0.01 MB PDF)Click here for additional data file.Table S6Results of flume level (gamma) biodiversity partitioning into independent orthogonal components alpha and beta, or richness and evenness.(0.02 MB PDF)Click here for additional data file.Table S7Associations between metavariable dissimilarity matrices as expressed by Mantel statistics.(0.02 MB PDF)Click here for additional data file.Text S1Method Details(0.11 MB PDF)Click here for additional data file."}
+{"text": "Reactivity of the monoclonal antibody 791T/36 with secondary malignant deposits has been investigated in frozen sections of 74 human liver biopsy specimens. There was no reactivity with hepatocytes but in some instances binding to fibrous tissues and in one case to portal tract lymphocytes was observed. Sections from 9 biopsy specimens contained malignant deposits. In seven of these 791T/36 bound either to malignant cells or to pseudoacinar contents . Two undifferentiated tumours  showed no antibody binding. The histological pattern of reactivity previously reported with primary tumours appears to be similar in secondary deposits. A wider range of tumours than recognised hitherto binds 791T/36. Whether the binding to fibrous tissue seen in some instances is sufficient to cause diagnostic uncertainty when 791T/36 is used for scanning requires further investigation."}
+{"text": "Reverse transfection microarrays were described recently as a high throughputmethod for studying gene function. We have investigated the use of this technology fordetermining the subcellular localization of proteins. Genes encoding 16 proteins witha variety of functions were placed in Gateway expression constructs with 3\u2032 or 5\u2032 greenfluorescent protein (GFP) tags. These were then packaged in transfection reagent andspotted robotically onto a glass slide to form a reverse transfection array. HEK293Tcells were grown over the surface of the array until confluent and GFP fluorescencevisualized by confocal microscopy. All C-terminal fusion proteins localized to cellularcompartments in accordance with previous studies and/or bioinformatic predictions.However, less than half of the N-terminal fusion proteins localized correctly. Of thosethat were not in concordance with the C-terminal tagged proteins, half did not exhibitexpression and the remainder had differing subcellular localizations to the C-terminalfusion protein. This data indicates that N-terminal tagging with GFP adversely affectsthe protein localization in reverse transfection assays, whereas tagging with GFP atthe C-terminal is generally better in preserving the localization of the native protein.We discuss these results in the context of developing high-throughput subcellularlocalization assays based on the reverse transfection array technology."}
+{"text": "Here we present a novel promising microbial diagnostic method that combines the sensitivity of Nucleic Acid Sequence Based Amplification (NASBA) with the high information content of microarray technology for the detection of bacterial tmRNA molecules. The NASBA protocol was modified to include aminoallyl-UTP (aaUTP) molecules that were incorporated into nascent RNA during the NASBA reaction. Post-amplification labeling with fluorescent dye was carried out subsequently and tmRNA hybridization signal intensities were measured using microarray technology. Significant optimization of the labeled NASBA protocol was required to maintain the required sensitivity of the reactions.Two different aaUTP salts were evaluated and optimum final concentrations were identified for both. The final 2 mM concentration of aaUTP Li-salt in NASBA reaction resulted in highest microarray signals overall, being twice as high as the strongest signals with 1 mM aaUTP Na-salt.We have successfully demonstrated efficient combination of NASBA amplification technology with microarray based hybridization detection. The method is applicative for many different areas of microbial diagnostics including environmental monitoring, bio threat detection, industrial process monitoring and clinical microbiology. In this paper we present a molecular diagnostics method that combines isothermal amplification of target tmRNA molecule with microarray-based detection. Nucleic Acid Sequence Based Amplification (NASBA) is a sensitive isothermal RNA amplification technology  that offgnostics ,14. AminS. pneumoniae tmRNA molecules was verified by observing only one peak of predicted size (307 nucleotides) nucleic acid on RNA 6000 chip electropherogram. Respective microarray signal intensities of labeled NASBA products are shown on Fig. Addition of aaUTP to NASBA mix resulted in a concentration-dependent effect on the reaction performance. Concentrations of up to 0,5 mM for sodium salt and 1 mM for lithium salt did not influence NASBA efficiency as seen from the amount of RNA produced Fig. , whereasThe aim of this work was to improve and expand the potential of a combined NASBA-microarray approach by developing a new optimized protocol suitable for further possible use in microbial diagnostics. All together, we have introduced a new method suitable for high-speed parallel detection of RNA targets. NASBA technology, widely used in various microbiology laboratories all over the world, is for the first time combined with microarray based RNA detection technology using simple one-step NASBA product labeling method. Previous methods described so far for NASBA amplicon detection have used additional enzymatic steps after the amplification and secondary labeled probes ,5. In ouIn general we have presented here a new optimized protocol for highly potential microarray based detection of NASBA amplified RNA products. Our method is suitable for further possible diagnostic applications where rapid identification of various RNA molecules from bacteria or different microorganisms is needed. The combination of NASBA with microarray detection is particularly advantageous in settings where different bacterial species may be present  or in clinical settings where it is necessary to identify one particular infection causing species from a panel of potential pathogens.Streptococcus pneumoniae strain ATCC 33400  was grown in Brain Heart Infusion Broth . Total RNA was purified from overnight cultures using RiboPure Yeast Kit . Although the RiboPure Yeast kit is not originally intended for RNA extraction from bacteria, high quality bacterial total RNA was obtained without making any modifications to manufacturer's instructions.S. pneumoniae total RNA. Conventional NASBA, in which the T7 promoter is included in the reverse primer, generates an antisense RNA product [NASBA primer pair Table  was desi product . In orde product . NASBA r2CO3 and incubated for one hour with 3 nmoles of amino reactive Cy3-N-hydroxysuccinimide ester dye  dissolved in 0,5 \u03bcl DMSO . Excess dye was quenched by addition of 3,5 \u03bcl 4 M hydroxylamine solution . Labeled RNA was purified with NucleoSpin kit and quantified using Bioanalyzer 2100 platform with RNA 6000 Nano Chip  according to the manufacturers manual.Following amplification, NASBA products were purified with NucleoSpin RNA Clean-Up kit  and vacuum dried. Labeling of the RNA product was carried out using protocol published by 't Hoen and colleagues with some modifications . The RNAS. pneumoniae tmRNA sequence . Probes were ordered from Metabion  and spotted onto SAL-1 Ultra microarray slides by Asper Biotech .The custom made microarray contained 97 probes, covering whole S. pneumoniae specific microarray in an automated HS-400 hybridization station  at 34\u00b0C. Complete hybridization protocol is shown in Table One third of the labeled NASBA product was resuspended in 80 \u03bcl of microarray hybridization buffer and hybridized for four hours on the Slides were scanned using Affymetrix 428 scanner  \u03bb = 532 nm. Raw signal intensity data was analyzed with Genorama software (Asper Biotech). Fixed concentration of short fluorescent oligonucleotide control sequences ('spikes'), complementary to the control oligonucleotides on microarray, were added to the final 80 \u03bcl hybridization solution for normalization purposes. At first step all signals from all microarrays, obtained from dilution series experiment, were rescaled by equating the average of spike-specific signals. Secondly, to compare data from 97 different probes on single microarray, all individual signal intensities were divided with the corresponding probe specific average signal intensity calculated over all microarrays in one replicate experiment. Average over probe-wise normalized signal intensities  were then calculated for each dilution series point (for each single microarray). Finally, considering replicate experiments (at least three), confidence intervals (\u00b1 one SD) were calculated for each average dilution series point (for every different aaUTP concentration).OS carried out the NASBA and microarray experiments, conducted statistical analysis and drafted the manuscript. BG carried out the microbiological experiments and RNA extraction and helped to draft the manuscript. SP participated in NASBA and microarray experiments and helped to draft the manuscript. KT participated in NASBA and microarray experiments. PP designed the microarray and helped to draft and review the manuscript. LK helped designing microarray and helped with data analysis. MR participated in design and coordination of making a microarray and helped conduct data analysis. MM conceived of the study and participated in its design and coordinated microbiological experiments. AK conceived of the study, participated in its design, coordinated NASBA and microarray experiments and helped to draft the manuscript. All authors read and approved the final manuscript.Microarray probes used in experiment. Table showing all the 97 microarray probes (covering whole S. pneumoniae tmRNA sequence) and their characteristics.Click here for file"}
+{"text": "Authors describe the incremental value of hybrid SPECT-CT in upstaging disease and changing the management strategy of a case of renal cell carcinoma Bone scintigraphy is less sensitive for detection of osteolytic lesions. We describe the utility of hybrid modality SPECT-CT in demonstrating the osteolytic lesion on morphological (CT) component of SPECT-CT associated with focal subtle tracer uptake.\u20103We report the case of a 47-year-old male patient who presented with abdominal pain, lower urinary symptoms and hematuria for three months. He was diagnosed as a case of renal cell carcinoma and subjected to radical nephrectomy. The patient also underwent a whole body bone scan for a metastatic workup. A planar whole body bone scan along with a hybrid single photon emission computed tomography (SPECT) / Computed Tomography (CT) imaging was performed. The planar imaging showed an area of mildly increased tracer uptake in the second lumbar vertebra . Subsequ"}
+{"text": "Plasmodium falciparum mitochondria and is the focus of a drug discovery programme. A miniaturised assay for recombinant PfNDH2 with robust assay performance measures was generated for the high throughput screening (HTS) of a focused library of 17,000 drug-like compounds. A quantitative structure-activity relationship has been developed around one of the chemical templates derived from the HTS hits. Lead molecules developed to date show selective inhibitory activity against PfNDH2 versus P. falciparum bc1 or dihydroorotate dehydrogenase (DHODH). Potent enzyme inhibition is accompanied by in vitro parasite kill of multidrug-resistant strains in the low nM range and clearance of parasites from in vivo P. berghei models. Lead molecules also display excellent in vitro therapeutic indices against human cell lines and bovine bc1. Initial metabolic studies in human liver microsomes and hepatocytes indicate favourable pharmacology. These data support the further development of this new candidate drug targeting a novel parasite component.NADH:quinone oxidoreductase (PfNDH2) represents a metabolic choke point in the respiratory chain of"}
+{"text": "Tumour growth depends on neovascularisation and tumour cell proliferation. Factor VIII-related antigen (F-VIII RA) localises to vascular endothelium. Expression of proliferating cell nuclear antigen (PCNA) is correlated with cell proliferation. We investigated the correlation between the expression of these antigens and prognosis in gastric carcinoma. A total of 108 specimens resected from patients with gastric carcinoma were investigated by staining with monoclonal antibodies against F-VIII RA and PCNA. Microvessel count  and PCNA labelling index  were determined. The results showed that prognosis was significantly worse in patients who had a tumour with a high MVC (16 or greater) or a high PCNA LI (42% or greater) than in those patients who had a tumour with a low MVC (less than 16) or a low PCNA LI (less than 42%). Furthermore, MVC was significantly associated with the risk of hepatic recurrence. In conclusion, both MVC and PCNA LI may be good prognostic indicators in patients with gastric carcinoma."}
+{"text": "We describe a patient with an implanted pacemaker for impaired AV conduction who presented with  an incessant tachycardia. EP study showed that the tachycardia was atrioventricular nodal reentrant tachycardia (AVNRT) with repeated spontaneous initiation because of poor or absent antegrade fast pathway conduction. Slow pathway ablation was successful in terminating the tachycardia and making it non-inducible. During a follow-up visit in the pacemaker clinic, a 45-year-old male complained of persistent palpitations for the past 2 months. He had undergone implantation of a permanent single chamber pacemaker with a ventricular lead 18 years back for trifascicular block with intermittent complete heart block and had subsequently undergone pulse generator replacement twice. His heart rate in the clinic was 130 bpm. Echocardiogram showed normal LV function without any abnormalities. He was not on any drugs. Electrocardiogram showed a broad complex tachycardia with a right bundle branch block (RBBB) morphology, 1:1 ventriculo-atrial (VA) association and a short RP interval. An electrophysiology study was planned in view of the persistent tachycardia.In the electrophysiology lab, he had tachycardia at the beginning of the procedure. The tachycardia could be easily terminated with ventricular overdrive pacing, and on termination of the tachycardia he was found to have sinus rhythm with a PR interval of 380 ms and broad QRS of RBBB morphology. However, tachycardia would always reinitiate spontaneously after a few beats of sinus rhythm . During Intracardiac electrograms during tachycardia showed 1:1 VA association with VA interval of 95 ms and central atrial activation. RV overdrive pacing at a cycle length (CL) slightly shorter than the tachycardia CL showed a ventricle-atrium-ventricle (VAV) response on termination of pacing with post pacing interval 216 ms longer than the tachycardia cycle length and VA interval was 150 ms longer than stimulus-atrial (SA) interval, all consistent with typical slow-fast atrioventricular nodal reentrant tachycardia (AVNRT) .Due to the incessant nature of the tachycardia, mapping had to be performed in tachycardia in the region of the slow pathway guided by fluoroscopy and electrograms. Ablation near the os of the coronary sinus was accompained by junctional beats. Post ablation, patient remained in sinus rhythm. AH and HV intervals were 228 ms and 50 ms respectively. Atrial programmed stimulation showed no dual pathway physiology and tachycardia could not be induced with atrial premature stimuli or burst pacing.AVNRT usually presents as a paroxysmal form of tachycardia with each episode lasting for a short period of time. We could find only one report of incessant presentation of AVNRT . In pati"}
+{"text": "IL-4 production was increased by the pretreatment whereas synthesis ofIFN-\u03b3 was diminished. Addition of DEX in the second activation suppressed all cytokineproduction. In brief, the transient presence of glucocorticoids in the culture induces a change in the pattern ofcytokine production but the continuous presence causes inhibition of cytokine synthesis. Further studies in whichIL-4 was used together with DEX showed that the cytokine potentiated the effect of the hormone.Purified rat CD4            The data here presented suggest that glucocorticoids and the neuroendocrine system may be expectedto have long-term immunological effects as well as short-lived immunosuppressive ones. High concentration ofglucocorticoids suppress cytokine production but when steroids return to basal levels the immune response isdirected in a way that favors Th2-type reactions. Possible implications regarding the immune response to pathogensand autoantigens are discussed."}
+{"text": "Giant ascending aortic aneurysm formation following aortic valve replacement is rare. A 28-year-old man who underwent aortic valve replacement with a prosthetic valve for aortic regurgitation secondary to congenital bicuspid aortic valve about 10 years ago was diagnosed with a giant ascending aortic aneurysm about 16\u2009cm in diameter in follow-up. The aneurysm was resected leaving the functional old mechanical prosthesis in place and implanted a 34-mm Hemashield woven graft, associated with the left and right coronary artery button implantation. Histological findings of the aortic aneurysm wall showed cystic medial necrosis. The postoperative course was uneventful and postoperative examination demonstrated good surgical results. Patients with bicuspid aortic valve are at increased risk for aortic complications and that aortic valve replacement does not prevent progressive aortic dilatation , 2. In tA 28-year-old man with severe aortic regurgitation underwent aortic valve replacement with a mechanical prosthetic valve about 10 years ago. At the time of this operation the ascending aorta was slightly dilated and measured as 3.4\u2009cm. An ascending aortic aneurysm was suspected with chest X-ray in routine follow-up of the patient who had not been controlled until that time . EchocarAortic complications occurring after aortic valve replacement (AVR) include aortic dissection, ascending aortic aneurysm, aortic root aneurysm, and pseudoaneurysm \u20134. To ouThe presented case had been operated before for severe aortic regurgitation secondary to congenital bicuspid aortic valve. Bicuspid aortic valve (BAV) is one of the most common congenital disorders involving the heart valves, with a prevalence ranging from 1% to 2% of the entire population , 5 demonBased on the law of Laplace, wall tension increases as the radius of an aneurysm increases (tension = pressure \u00d7 radius). It is therefore intuitive that larger aneurysms have a greater risk of rupture. Coady et al.  have wriWe believe that the patients with congenital BAV should be followed regularly in terms of aortic dilatation and aneurysm formation even if their aortic valve is replaced. The surgical management of aortic aneurysm should be done in order to decrease the morbidity and mortality in those patients before the diameter of aneurysm not exceeding relatively larger sizes."}
+{"text": "Scattering of shorter-wavelength visible light limits thefluorescence imaging depth of thick specimens such as wholeorgans. In this study, we report the use of four newly synthesizednear-infrared and far-red fluorescence probesto image tumor cells in the subpleural vasculature of the intactrat lungs. Transpelural imaging of tumor cells labeled withlong-wavelength probes and expressing green fluorescent protein was done in the intact ratlung after perfusate administration or intravenous injection. Ourresults show that the average optimum imaging depth for thelong-wavelength probes is higher (27.8 \u00b1 0.7\u2009\u03bcm) than for GFP , corresponding to a40% increase in the volume of tissue accessible forhigh-resolution imaging. The maximum depth of cell visualizationwas significantly improved with the novel dyes  compared with GFP . Stable binding of the long-wavelengthvital dyes to the plasma membrane also permitted in vivo trackingof injected tumor cells in the pulmonary vasculature. These probesoffer a significant improvement in the imaging quality of in situbiological processes in the deeper regions of intact lungs."}
+{"text": "UK CropNet currently provides a range of databases (and database-mining tools) to the plant community that are all freely accessible through our website (http://ukcrop.net/). Recent upgrades have meant that we can now expand the range of available facilities (e.g. addition of new databases) whilst also strengthening and improving access to existing services (e.g. providing a BLAST search facility against sequences in our databases). This article will briefly outline these and other new developments in our service."}
+{"text": "Gene expression similarity measuring methods were developed and applied to search rapidly growing public microarray databases. However, current expression similarity measuring methods need to be improved to accurately measure similarity between gene expression profiles from different platforms or different experiments.We devised new gene expression similarity measuring method based on pathway information. In short, newly devised method measure similarity between gene expression profiles after converting them into pathway based expression profiles. To evaluate pathway based gene expression similarity measuring method, we conducted cell type classification test. Pathway based similarity measuring method shows higher classification accuracy. Especially, pathway based methods outperform at most 50% and 10% over conventional gene expression similarity method when search databases are limited to cross-platform profiles and cross-experiment profiles.The pathway based gene expression similarity measuring method outperforms commonly used similarity measuring methods. Considering the fact that public microarray database is consist of gene expression profiles of various experiments with various type of platform, pathway based gene expression similarity measuring method could be successfully applied for searching large public microarray databases. As microarray experiment has been widely used for various field of biology, public microarray databases have been rapidly growing each year. Currently, the two largest microarray databases, GEO  and ArraIn accordance with this expensive collection of large scale gene expression databases, database searching methods have been developed to make the database easily accessible and practically useful. Since the microarray data is deposited in public microarray database as unit of experiment which is consist of several individual gene expression profiles, search methods also have evolved into two way, experiment dataset level search and individual gene expression profile level search.Most of experiment dataset level search methods are depend on dataset annotation by authors of dataset. Atul B. et al. has been tried to classify the gene expression experiment dataset in GEO (GEO series) by annotating each GEO dataset with medical language terms such as UMLS and SNOMED -5 and toAlong the attempts to search large public microarray databases at experiment dataset level, individual gene expression profile level search method has also been conceptualized and developed . GEST 99 is the Here we try to improve similar gene expression profile search. For this purpose, we devised a pathway based gene expression similarity measuring method. Our pathway based methods outperform conventional method especially for cross-platform and cross-experiment profile search.We used set of gene expression profiles curated by CellMontage group . Each geFor the classification procedure, we first selected cell types with which at least two different platform types are associated. For each selected cell type, we select at most two gene expression profiles from each platform in the same experiment. After the selection procedure, total 442 gene expression profiles of 40 different cell types from 54 different experiment with 23 different platform types were remained  method. Another method compares common pathway set between two comparing pathway expression profiles converted from gene expression profiles. To measure the similarity between gene or pathway expression profiles, we used Spearman rank correlation test. Spearman rank correlation coefficient between profile X and Y is given byi = xi-yi, i = 1, ..., n and xi, yi = rank of ith gene or pathway in each profile X and Y. Spearman rank correlation coefficient ranges from -1 to 1, where similarity is maximum at 1 and minimum at -1.where dTo evaluate the performance of similarity measuring methods, we conducted cell type classification using nearest neighbor classifier. For each of 40 query gene expression profiles, the similarities to all of 402 gene expression profiles in search database were calculated. Then the profile with highest Spearman rank correlation coefficient was predicted to have the same cell type to query profile. Predicted profile was considered as correct prediction if its cell type is the same as that of query sample. If there is no same cell type profile in search database for a query profile, the search for the given query profile is not counted in classification accuracy assessment. Accuracy of classification is calculated by number of correct predictions divided by number of predictions.Similar profile search from the profiles of different platform or different experiment is harder than search from the profiles of the same platform or the same experiment . To evalWe conducted cell type classification using two different similarity measuring methods and access the performances with overall, cross-platform and cross-experiment search databases.Barplot shown in figure We next calculated average similarity score of top scoring hit for correct and incorrect classification cases Table . AverageWe analyzed further to figure out the reason for low classification accuracy of cross-experiment search. More specifically, our question is why cross-experiment searches show lower classification accuracy than that of cross-platform searches even though the similarity scores for top hits are higher than that of cross-platform searches. To answer this question, we divided cross-experiment search database more specifically into cross-experiment with the same platform profiles and cross-experiment with different platform profiles and conducted cell type classification with those two search databases. Table Reduced analytical dimension of pathway expression profiles from gene expression profiles might also contribute improved classification accuracy by pathway based methods. Not all genes in gene expression profile are converted to pathway expression profile for the incompleteness of current pathway information ,17. In cWe first attempted to use pathway information for gene expression similarity measurement. As previously developed pathway based gene expression analysis methods were successfully improve intact gene expression based analysis methods -23, pathConsequently, expression variations of multiple genes are summarized by a robust pathway expression, which represents the activity of the functional unit rather than a component of the unit, thus the pathway based methods result with higher classification accuracy, which demonstrates again that pathway level expression is more robust than individual gene level expression and pathway based similarity scoring methods could be successfully improve similar gene expression profile search.We demonstrated that our new gene expression similarity measuring method improved the precision of similar gene expression profile search when it's applied to cell type classification. We showed pathway expression profiling based similarity measuring method outperformed conventional gene expression profile based similarity measuring method over at most 50% for cross-platform profile search and 10% for cross-experiment profile search. At the same time, the classification accuracy shows that the methods still need to be improved, especially for searching similar profiles across different experiment. We believe that our research shed new light on similar gene expression profile search over rapidly growing large microarray databases by showing that integrating gene expression profile with external data such as pathway could improve search accuracy.CGSEP: Common Gene Set Expression Profile; PEPA: Pathway Expression Profile for All Gene set; PEPC: Pathway Expression Profile for Common gene set.The authors declare that they have no competing interests.CK designed whole research process, implemented all required methods for the research, analyzed results, drafted and revised the manuscript. JHW devised similarity scoring algorithm with CK and revised the manuscript. WSO and KTN helped the conceptualization of the research process. All authors read and approved the final manuscript.BMC Bioinformatics Volume 10 Supplement 15, 2009: Eighth International Conference on Bioinformatics (InCoB2009): Bioinformatics, available online at http://www.biomedcentral.com/1471-2105/10?issue=S15.Other papers from the meeting have been published as part of Dataset detail for cell type classification. All 442 gene expression profiles used for cell type classification are listed with detailed information. Each gene expression profile is annotated with three original GEO accession id, sample id(GSM), experiment id(GSE) and platform id(GPL), and cell type.Click here for file"}
+{"text": "In the process of tumour progression genetic instability is the basis for the evolution of tumour cell clones with various genotypic and phenotypic characteristics causing heterogeneity. Renal cell carcinoma has a long prediagnostic growth period, which increases the probability of clonal evolution. We have studied 200 consecutive renal cell carcinomas, addressing the interrelationship between intratumour heterogeneity and clinicopathological factors. DNA ploidy patterns were analysed in multiple samples from each tumour using flow cytometry and compared with clinical stage, tumour invasion, metastatic rate and survival. Eighty-five of 192 evaluable tumours (44%) were homogeneous concerning DNA ploidy . Among 107 heterogeneous tumours a majority (79%) contained aneuploid as well as diploid cell clones. Homogeneously diploid tumours had a lower incidence of local tumour spread compared with tumours with aneuploid cell clones (P < or = 0.001), but the frequency of distant metastasis at time of diagnosis was similar. The presence of aneuploidy in at least one sample from a tumour was a significant adverse prognostic factor (P < 0.001), whereas the degree of heterogeneity had no influence on survival. The frequent heterogeneity demonstrated indicates that multiple samples must be investigated to evaluate properly the malignant character of renal cell carcinoma."}
+{"text": "A healthy 13-year-old boy who had spent the first 4.5 years of his life in an orphanage in Thailand before adoption by an American couple became ill with subacute sclerosing panencephalitis and died several months later. The boy had most likely contracted wild-type measles in Thailand. Measles complications are a risk in international adoptions."}
+{"text": "Daniorerio.The vertebrate genome contains a predicted 50 000 100 000 genes, many of unknownfunction. The recent development of morpholino-based gene knock-down technologyin zebrafish has opened the door to the genome-wide assignment of function basedon sequence in a model vertebrate. This review describes technical aspects ofmorpholino use for functional genomics applications, including the potential formultigene targeting and known methodological limitations. The result ofsuccessful gene inactivation by this agent is proposed to yield embryos with a\u2018morphant\u2019 phenotypic designation. The establishment of a morphant databaseopens the door to true functional genomics using the vertebrate,"}
+{"text": "PAF mediated lymphatic constriction was not altered by the intra-arterial infusion of phentolamine but was blocked by the intra-arterial infusion of the PAF receptor antagonist WEB 2170. These data indicate that in addition to PAF's effects on microvascular permeability, this agent may also impact the ability of the lymphatics to transport fluid through alterations in lymphatic smooth muscle tone. PAF mediated lymphatic constriction is not mediated by \u03b1-receptors but rather through PAF receptor mediated mechanism.Platelet activating factor (PAF) is a potent inflammatory lipid. In this study we assessed the ability of PAF to impact lymphatic vessel function by altering prenodal lymphatic resistance. Intralymphatic PAF (7.47 \u00d7 10"}
+{"text": "The authors report on 182 cases of intrathoracic metastases  observed as first single recurrences in the course of the follow-up of patients treated for primary breast cancer. ITM were detected on standard two-views chest X-ray (CXR) at regular follow-up visits and in absence of subjective symptoms (102 A cases) or in the interval between two consecutive planned controls because of the onset of subjective symptoms (80 S cases). The average disease-free interval since primary treatment was significantly shorter in A with respect to S cases  as a consequence of the early detection achieved by CXR survey. On the contrary, prognosis was not influenced by ITM early diagnosis as the 10-year survival since primary treatment did not differ significantly between A or S cases . Results were confirmed on multivariate (Cox's) analysis, adjusting for potential confounders such as age or nodal status. Periodic CXR survey looks a very questionable policy as it does not seem to have any favourable impact on prognosis. Its routine use in breast cancer patients should thus be carefully reconsidered."}
+{"text": "The fish medaka is the first vertebrate capable of full spermatogenesis in vitro from self-renewing spermatogonial stem cells to motile test-tube sperm. Precise staging and molecular dissection of this process has been hampered by the lack of suitable molecular markers.We have generated a normalized medaka testis cDNA library and obtained 7040 high quality sequences representing 3641 unique gene clusters. Among these, 1197 unique clusters are homologous to known genes, and 2444 appear to be novel genes. Ontology analysis shows that the 1197 gene products are implicated in diverse molecular and cellular processes. These genes include markers for all major types of testicular somatic and germ cells. Furthermore, markers were identified for major spermatogenic stages ranging from spermatogonial stem cell self-renewal to meiosis entry, progression and completion. Intriguingly, the medaka testis expresses at least 13 homologs of the 33 mouse X-chromosomal genes that are enriched in the testis. More importantly, we show that key components of several signaling pathways known to be important for testicular function in mammals are well represented in the medaka testicular EST collection.Medaka exhibits a considerable similarity in testicular gene expression to mammals. The medaka testicular EST collection we obtained has wide range coverage and will not only consolidate our knowledge on the comparative analysis of known genes' functions in the testis but also provide a rich resource to dissect molecular events and mechanism of spermatogenesis in vivo and in vitro in medaka as an excellent vertebrate model. The testis is the male gonad where spermatogenesis takes place throughout adult life to continuously supply sperm for the next generation. Defects in testicular structure and function lead to testicular tumors and male infertility. In mammals, the adult testis consists of male germ cells and three major somatic cell types Much is known about the cell biology of spermatogenic germ cell development, which proceeds through three major stages: mitotic phase of proliferation and differentiation, meiosis and postmeiotic spermiogenesis This study aimed to establish a medaka testicular EST collection. For this, we generated a normalized cDNA library from the adult medaka testis and sequenced 7040 random EST clones. Comparative sequence analysis revealed a total of 3641 unique gene clusters.The expression levels of each individual genes in a genome can vary considerably in different cells, tissues or organs, and can even be very different in the same tissue or organ at different developmental stages or physiological conditions. The magnitude of difference can range from a few to as much as thousand folds. When RNA samples from an organism or an organ or a tissue are directly used for cDNA library construction, the differences among different genes in expression levels will normally be reflected in such libraries. If such a library is used for EST sequencing project, the problem of high redundancy will be brought in synaptonemal complex protein 3  gene and kallikreini gene (Leydig cell marker) was represented by six and two EST clones, respectively, in the 747 unnormalized EST collection whereas no corresponding clones was found in our 7040 EST clones. synaptonemal complex protein 1 gene  was represented by three EST clones in the 747 unnormalized ESTs and was represented by only one clone in our EST set. From the mathematic view, all these facts demonstrate the effectiveness of normalization in our library.A total of 8736 clones from the normalized cDNA library was sequenced, generating 7040 high quality (7033 having reads \u2265200 bp read each) EST sequences (EMBO Accession numbers FM165707\u2013FM172746). These 7040 sequences were subjected to clustering analysis using CLUSTAL W (1.83) Multiple Sequence Alignments program and 3641 clusters were obtained . Overallhttp://www.ncbi.nlm.nih.gov/UniGene/; dated at February 28th, 2008) ftp://ftp.ncbi.nih.gov/repository/UniGene/Oryzias_latipes/). The longest sequences in each of our EST clusters were retrieved and used to blast search against the NCBI medaka Unigene database, with the aim to assess the representation of our library in the public database. Unexpectedly, only a small fraction of our 3641 unique clusters  exhibit a match in the NCBI medaka UniGene database , and 2058 clusters were found to have their corresponding hits with high confidence in the non-redundant database   and S3.The 1197 genes (550 Unigenes and genes corresponding to 647 clusters) with known putative molecular function were combined and subjected to ontology analysis based on molecular and cellular functions. As expected, genes encoding for metabolic enzymes  form the major group in our EST set and in total 162 out of 1197 (\u223c14%) genes were recorded . A totalIt would be interesting to compare medaka testis-enriched genes with other vertebrates through genomic analysis. For example, are the genes conserved among the vertebrates? Is there any synteny relationship among these conserved genes? Are these genes alternatively spliced from annotated genes? Are there genes completely new without any annotated protein domains? However, these bioinformatic analyses rely on the availability of full length cDNA. This is mainly because cross-species comparison is normally performed on the amino acid sequence level but not at the nucleotide sequence level (because of the high variation of nucleotide sequences for ortholog genes between species during evolution). Use the amino acid sequences derived from full length cDNA will permit the identification of true conserved or novel genes. Then the in situ hybridization method can be used to prove if the novel gene is enriched in the testis. For this purpose, we designed a python program to retrieve information for the 1034 unigenes listed in Blimp1, Bmi1, YY1 etc) and receptors, ligands and signaling molecules  in testis , germ cell markers , pre-meiosis markers , meiosis regulator&structural protein , and postmeiosis marker (Msap and Rsh)   [29].pum1 (germ cell marker) and rad51 (meiosis marker), were examined via in situ hybridization in medaka testicular sections. The pum1 gene is expressed weakly in Spermatogonia at the periphery, but highly in primary spermotocytes and moderately in secondary spermatocytes  to the medaka EST collection and these new EST clusters/unigenes will be invaluable in assisting gene annotation once the medaka genome sequencing is completed. The wide range coverage of genes involved in diverse cellular activities and large number of novel sequences in our EST collection will not only consolidate our knowledge on known genes in testis st and 2nd stranded cDNA was synthesized using cDNA synthesis system . Oligo-(dT)20-V  was used as primer for the 1st strand cDNA synthesis. Two primers LLR1A (5\u2032-gagatattagaattctactc) and LLR1B (complementary strand 5\u2032-gagtagaattctaatat-3\u2032) nd round PCR. Two more rounds of normalization were performed and the final PCR products were digested with EcoRI and ligated to pre-digested pBluescript SK+ vector for library construction. Colony picking and bacteria culturing are as described previously All procedures conducted with medaka fish are adhered to animal care guidelines  as outlined by the National Advisory Committee For Laboratory Animal Research in Singapore. Total RNA was extracted from pooled testes of adult medaka fish, using the Tri-Reagent according to the manufacturer's protocol . Total RNA was used for mRNA purification using mRNA purification kit . Both the 1Pasmid DNA was prepared in 96-well format using the conventional alkaline/SDS lysis method using robotics Biomek FX (Beckman) followed by ethanol precipitation http://www.mrc-lmb.cam.ac.uk/pubseq/manual/pregap4_unix_toc.html). In total 7040 ESTs (7033 with reads >200 bp) were obtained after editing (Table1) and clustering using Tigr-Assembler (http://www.tigr.org/software/assembler) identified a total of 3641 unique clusters  containing 17,307 unique clusters (released on February 2008). Sequences are considered identical if the blast E value is less than e\u221250ftp://ftp.ncbi.nlm.nih.gov/blast/db/nr). Only blast E value<e\u22128 were considered significant .The longest EST sequence in each of the 3641 unique clusters were retrieved and used as queries for BLASTN searches against the section Medaka UniGene Click here for additional data file.Table S2List of 1034 unique medaka testis EST clusters having hits in the medaka unigene database.(0.26 MB XLS)Click here for additional data file.Table S3List of 2057 unique medaka testis EST clusters having hit in the NCBI non-redundant database.(0.42 MB XLS)Click here for additional data file.Table S4Summary of ontology analysis of 1197 genes with known molecular/biochemical putative function(0.21 MB XLS)Click here for additional data file.Table S5List of 48 unigenes which have mRNA sequences in the unigene database.(0.02 MB XLS)Click here for additional data file."}
+{"text": "Nuclear expression of TS in human tissue in vivo has not been characterised and its clinicopathological correlates in malignancy are unknown. 52 cases of primary colorectal carcinoma (CRC) and 24 cases of matched metastatic carcinoma were studied immunohistochemically using the monoclonal antibody TS106. The degree of nuclear TS immunostaining correlated closely with levels of TS mRNA expression amongst 10 CRCs studied. Strong nuclear immunostaining was seen in normal basal crypt colonocytes and germinal centre cells, and in a varying proportion of adenocarcinoma cells. Amongst the primary carcinomas, higher TS nuclear expression was associated with prominent extracellular mucin production and right-sided location. Higher TS nuclear expression also showed a significant association with poorer response to protracted venous infusional 5FU therapy. There was no clear association between TS nuclear expression and Ki67 or p53 expression assessed immunohistochemically. There was a strong positive correlation between TS nuclear expression in primary and metastatic CRC but the latter generally showed higher expression than matched primary tumour tissue. These findings confirm the nuclear expression of TS protein in human cells in vivo and provide new insight into how such expression may relate to the behaviour of CRCs. \u00a9 2001 Cancer Research Campaign"}
+{"text": "The cytotoxic and cytostatic responses of peripheral blood lymphocytes from eight cancer patients and splenocytes from four patients activated with rIL2 and a combination of rIL2 and rTNF-alpha were tested against two tumour cell lines. The cytotoxic response of rIL2-activated lymphocytes did not exceed the natural killer cytotoxicity values in all patients tested. In fact the killing capacity of some PBL deteriorated after rIL2 activation. The combined use of rIL2 and rTNF-alpha reversed this detrimental effect and enhanced the cytotoxic capacity of all PBL tested. In instances where high levels of killing were already achieved by rIL2 alone additional rTNF-alpha did not induce a significant change. This indicates that the role of rTNF-alpha may be to promote the response to rIL2 of PBL which react suboptimally to this lymphokine. rTNF-alpha did not only enhance cytotoxic capacity but also conferred cytostatic capacity to rIL2-activated LAK cells which were cytotoxic but unable to inhibit the growth of the surviving target cells. Natural killer cell selected K562 target cells which were less susceptible to killing by untreated lymphocytes than the parent K562 tumour cell line were killed more aggressively by rIL2 + rTNF-alpha LAK cells than by rIL2-LAK cells. No phenotypic differences were detected in these two cultures of LAK cells which indicates that the increased cytotoxic and cytostatic capacity of rIL2 + rTNF-alpha-LAK cells may be due to a higher state of activation of these cells or due to their capacity to recognise a broader spectrum of targets than rIL2-LAK cells."}
+{"text": "Pericarditis as a differential diagnosis of the \"Brugada-type Electrocardiographic Pattern Induced by Electrocution\" reported by us   raised bHowever the early repolarisation pattern and non specific ST-T changes as a part of transient electrical injury of myocardium would be a better explanation for the ECG changes noted. The ST-T changes in right sided chest leads obviously simulates Brugada type pattern.The electrocution can result in non-specific electrocardiographic changes and varied ST-T changes mimicking pericarditis, early repolarisation, Brugada type pattern, myocardial infarction etc. However these changes needs to be correlated with the clinical background before the final diagnosis is made since majority of these changes are due to electrical injury of heart."}
+{"text": "A 44 year old man presented with recurrent symptomatic palpitations,  always appearing during physical stress each with a similiar extent and never during resting periods. He also had fatigue and moderate dyspnoea during the episodes. The past medical history of the patient did not reveal any significant diseases. Findings of the attending physician including 12 lead ECG and echocardiography did not show any abnormality. As there was no electrocardiographic documentation of the episode, a 12-lead Holter evaluation was done.When the patient returned one week later, he reported of a typical episode of palpitations. The corresponding extract of the Holter ECG is shown in In synopsis of the findings we saw the indication for an invasive electrophysiology study due to a documented paroxysmal narrow complex tachycardia with alternating R-R intervals coming along with symptomatic palpitations.An octapolar catheter was placed in the coronary sinus with distal and proximal pair of electrodes configured as CS 1-2 and CS 7-8 respectively. Dual atrioventricular conduction properties of the AV node were verified with programmed atrial stimulation with premature coupling of one extrastimulus (\u00ab 500 S3 \u00bb) showing a typical AH-jump. No retrograde ventriculoatrial conduction was observed in our patient.Under basal conditions no tachycardia was inducable, so we decided to use an orciprenaline infusion to simulate physical strain as the tachycardia of our patient always appeared under these conditions. Finally, during orciprenaline infusion and atrial pacing via CS 7-8 with premature coupling of one extrastimulus (\u00ab 400 S3 \u00bb), a narrow complex tachycardia was induced  is a rare manifestation of dual atrioventricular nodal pathways. Two electrophysiological characteristics are basic requirements for a double ventricular depolarisation due to a dual AV node and simultaneous absence of the inducibility of a typical AV-nodal reentry tachycardia: [In conclusion, we have induced the clinical tachycardia of our patient. The patient underwent successful slow pathway modification with complete disapperance of symptoms and electrocardiographic manifestations of 1 : 2 atrioventricular conduction."}
+{"text": "Clostridium difficile toxin alters colonic tissue levels of vasoactive intestinal peptide (VIP) at the expense of changes in colonic motility in the isolated perfused rabbit left colon. Colonic inflammation was induced by the intracolonic administration of 10\u22128 M C. difflcile toxin. Strain gauge transducers were sewn onto the serosal surface of the colon to evaluate colonic motility. C. difflcile administration produced histologic changes consistent with epithelial damage. This was associated with an increased production of prostaglandin E2 and thromboxane B2. Tissue levels of VIP but not substance P were significantly reduced. This was associated with an increased number of contractions per minute and an average force of each colonic contraction. These results suggest that tissue levels of VIP are suppressed by C. difflcile and may participate in colonic dysmotility during active inflammation.We investigated whether"}
+{"text": "Normal monkey tissues were found to contain an antigen which crossreacts immunologically with the carcinoembryonic antigen (CEA) of the human digestive tract. The monkey antigen reacted with complete or partial identity to the normal crossreacting antigen (NCA) in humans when tested in immunodiffusion against anti-CEA or anti-NCA. Extracts of monkey tissues inhibited in radioimmunoassays measuring human NCA. It is possible that monkey foetuses and colonic tumours contain CEA."}
+{"text": "Forty-six patients who were treated with cisplatin or carboplatin for ovarian cancer developed resistant disease (no change in measurable disease or progressive disease) and 'crossed over' to the other platinum compound. Three patients (6.5%) responded to this second treatment but these patients had no survival advantage compared to the non-responders. One responder had progressive disease on cisplatin before crossing over to carboplatin."}
+{"text": "A multistate outbreak of Escherichia coli O157:H7 infections occurred in the United States in June and July 1997. Two concurrent outbreaks were investigated through independent case-control studies in Michigan and Virginia and by subtyping isolates with pulsed-field gel electrophoresis (PFGE). Isolates from 85 persons were indistinguishable by PFGE. Alfalfa sprouts were the only exposure associated with E. coli O157:H7 infection in both Michigan and Virginia. Seeds used for sprouting were traced back to one common lot harvested in Idaho. New subtyping tools such as PFGE used in this investigation are essential to link isolated infections to a single outbreak."}
+{"text": "A randomized trial comparing routine follow-up with a treatment regimen aimed at increasing specific anti-tumour immunity has been carried out in 95 patients after total surgical excision of lung cancer . Treatment consisted of inoculation with an autologous irradiated suspension of tumour cells combined with a small dose of C. parvum given intradermally during convalescence. Although treatment was associated with virtually no side effects, there has been no apparent benefit and input to the trial has now stopped."}
+{"text": "Sir,Toxoplasma gondii (an intracellular coccidian parasite) is the most common cause of protozoon infections in humans and is highly prevalent in the adult population in the world and demonstrates various clinical manifestations throughout the world.[Mycobacterium tuberculosis antigen were negative. His chest X-ray and electrocardiography were normal. A repeat contrast MRI after 9 months showed the persistence of all the lesions and the patient was referred for a biopsy of the lesions. The patient underwent right frontal craniotomy and excision of the right frontal lesion. During surgery, there was well-defined firm, thick-walled lesion containing thick yellowish material. Histopathological examination of the specimen showed thick wall abscess and necrotic tissue with inflammatory cells in the center, features suggestive of toxoplasma cerebral abscess [3541111he world.\u20133 A 25-yhe world.. All the abscess . Further abscess 34 Severebscess 35 occasionbscess 358 The mosbscess 359 Althougbscess 35 As in thbscess 35 On imagibscess 3511 Howevescess 354 As in thess 35411 However,s 3541111 Spectross 3541111 Presumpts 3541111\u201316 As ins 3541111 The treas 3541111"}
+{"text": "The present study characterised p53 mutations in 44 hepatocellular carcinomas (HCCs) from Chinese patients residing in a high-incidence area. Twelve point mutations (27%) were detected in tumour tissues using single-strand conformation polymorphism analysis followed by direct DNA sequencing. Remarkably, no mutations were observed at codon 249. This is in contrast to HCCs from other high HCC incidence areas with endemic aflatoxin exposures, in which codon 249 is a mutational hot spot. It is therefore suggested that risk factors other than dietary exposure to aflatoxin may contribute to the high HCC incidence in Singapore."}
+{"text": "Soft tissue sarcomas comprise a heterogeneous group of aggressive tumors that have a relatively poor prognosis. Althoughconventional therapeutic regimens can effectively cytoreduce the overall tumor mass, they fail to consistently achieve acurative outcome. Alternative gene-based approaches that counteract the underlying neoplastic process by eliminatingthe clonal aberrations that potentiate malignant behavior have been proposed. As compared to the accumulation of genealterations associated with epithelial carcinomas, sarcomas are frequently characterized by the unique presence of a singlechromosomal translocation in each histological subtype. Similar to the Philadelphia chromosome associated with CML,these clonal abnormalities result in the fusion of two independent unrelated genes to generate a unique chimeric proteinthat displays aberrant activity believed to initiate cellular transformation. Secondary gene mutations may provide an additionalgrowth advantage that further contributes to malignant progression. The recent clinical success of the tyrosine kinaseinhibitor, STI571, suggests that therapeutic approaches specifically directed against essential survival factors in sarcoma cellsmay be effective. This review summarizes published approaches targeting a specific molecular mechanism associated withsarcomagenesis. The strategy and significance of published translational studies in six distinct areas are presented. Theseinclude: (1) the disruption of chimeric transcription factor activity; (2) inhibition of growth stimulatory post-translationalmodifications; (3) restoration of tumor suppressor function; (4) interference with angiogenesis; (5) induction of apoptoticpathways; and (6) introduction of toxic gene products. The potential for improving outcomes in sarcoma patients and theconceptual obstacles to be overcome are discussed."}
+{"text": "Hereditary non-polyposis colorectal cancer (HNPCC) is linked to an inherited defect in the DNA mismatch repair system. DNA from HNPCC tumours shows microsatellite instability (MSI). It has been reported that HNPCC patients have a better prognosis than patients with sporadic colorectal cancer. We examined whether the presence of MSI in a series of unselected colorectal tumours carries prognostic information. In a series of 181 unselected colorectal tumours, 22 tumours (12%) showed MSI. Survival analysis at 5\u201310 years follow-up showed no statistically significant difference in prognosis between MSI-positive and -negative tumours. Our results suggest that the MSI phenotype as such is not an independent prognostic factor. \u00a9 1999 Cancer Research Campaign"}
+{"text": "The incidence of nodal metastasis in early gastric carcinoma (EGC) is 10-20%. However, the optimal nodal dissection for early gastric carcinoma has not been established. A retrospective study was conducted in 392 consecutive patients who underwent potentially curative distal gastrectomy for EGC between 1962 and 1990. Of these 295 patients treated after September 1972 were prospectively entered into an extensive lymphadenectomy protocol. These patients were compared with 97 patients with simple gastrectomy in respect of the causes of death after surgery and the 10 year disease-specific survival rate. The incidence of nodal metastasis in early gastric carcinoma patients was 13.0%. Operative mortality from extensive lymphadenectomy was almost the same as from simple gastrectomy (2.0% and 2.1% respectively). Extensive lymphadenectomy provided a significantly higher 10 year survival rate than limited lymph node dissection . Among patients with nodal metastasis, the survival rate following extensive lymphadenectomy was significantly higher than that after simple gastrectomy . Among patients without nodal metastasis, there was no difference between the two groups in the survival rate . Multivariate analysis using the Cox proportional hazards model disclosed two significant independent prognostic factors on disease-specific survival, the nodal involvement  and the extent of lymph node dissection . Extensive nodel dissection appears to prevent recurrence and to improve the cancer-specific survival in EGC patients with nodal metastasis."}
+{"text": "We report a rare case of obstructive jaundice caused by a tuberculous abscess in the head of pancreas,mimicking carcinoma. The case was successfully treated by pylorus-preserving proximal pancreatoduodenectomyand antituberculous drugs."}
+{"text": "The thymic stromal cells alone induced positiveselection of functional CD4-CD8+ cells whose kinetics and efficiency were enhanced bynominal peptide. Fibroblasts expressing the selecting MHC alone did not induce positiveselection; however, together with nonselecting stroma and nominal peptide, there was inefficientpositive. These results suggest multiple signaling in positive selection with selection events ableto occur on multiple-cell types. The ease with which this model can be manipulated shouldgreatly facilitate the resolution of the mechanisms of positive selection in normal andpathological states.Presented here is a cell-suspension model for positive selection using thymocytes from"}
+{"text": "A long-finned pilot whale with morbilliviral disease was stranded in New Jersey. An immunohistochemical stain demonstrated morbilliviral antigen. Reverse transcriptase-polymerase chain reaction for morbillivirus P and N genes was positive. Novel sequences most closely related to, but distinct from, those of dolphin and porpoise morbilliviruses suggest that this virus may represent a third member of the cetacean morbillivirus group."}
+{"text": "Acute inflammatory polyradiculoneuropathy secondary to chemotherapy for leukemia has been described in the pediatric literature. However, the reports are rare and have been mainly from intrathecal methotrexate in pediatric acute lymphoblastic leukemia patients who developed demyelinating polyradiculoneuropathy.A case report is presented of an unfortunate 53 year old Hispanic woman with acute myelogenous leukemia who developed profound weakness with cranial nerve palsies following both intravenous and intrathecal chemotherapy.This is an interesting and unusual case of predominantly axonal ascending sensory motor polyradiculoneuropathy with cranial nerve involvement in an adult patient with acute myelogenous leukemia following intravenous Cytosine arabinoside and intrathecal methotrexate. Polyradiculoneuropathies and ascending motor paraplegia have been described in pediatric leukemia patients undergoing chemotherapy. These rare reports have focused mainly on demyelinating polyradiculoneuropathies and/or myelopathies secondary to intrathecal methotrexate in children with acute lymphoblastic leukemia (ALL) . A case The patient was a 53 year old Hispanic woman who originally presented at the end May in 2007 with complaints of shoulder tightness and weakness in the neck and shoulders for approximately 3 weeks duration along with shortness of breath. She presented to a local community hospital where examination revealed an ill-appearing pale woman with tachypnia. Subsequent investigations showed thrombocytopenia with prominent leukocytosis and numerous blasts on peripheral smear plus disseminated intravascular coagulation with subsequent diagnosis of acute myelogenous leukemia  with hypoactive reflexes (0/4). Extra ocular muscles were intact without dysconjugate gaze, and the pupils were briskly reactive and symmetric.A lumbar puncture did not reveal any increased protein  or abnormal cells , however there were oligoclonal bands  and an elevated myelin basic protein . Cerebrospinal fluid cytology was negative for any malignant cells. An electromyogram and nerve conduction study showed absent sensory nerve action potentials and absent compound motor action potentials with diffuse denervation in all four extremities.The presumptive diagnosis was Guillain-Barr\u00e9 syndrome (GBS), and intravenous immunoglobulin (IVIG) was considered but felt to be contraindicated secondary to her newly diagnosed AML and stroke. She was therefore given 4 sessions of plasmapharesis which was held on the fifth session because of blood pressure fluctuations.Over the next ten days or so she did not improve neurologically, and in fact went on to develop right ptosis with a dysreactive pupil and outward eye deviation thought to be a third cranial nerve (CN 3) palsy, and a few days later bilateral facial weakness. A repeat lumbar puncture (about 2 weeks after the last one) again did not reveal any increased protein  or abnormal white blood cells (white blood cells were 0/cmm and red blood cells were 1/cmm) and the cerebrospinal fluid cytology was negative for any malignant cells.A sensory-motor neuropathy panel, myasthenia gravis panel, and a Lambert-Eaton myasthenic panel both were negative for any abnormal antibodies (Quest Diagnostics).A combined muscle and nerve biopsy was performed. The sural nerve showed peripheral neuropathy with prominent evidence of axonal degeneration with digestion chambers and secondary dropout of myelinated fibers which was moderately severe  ranges from 0.6 to 2.4 cases per 100,000 population per year .Although the most common neurotoxic effects of intravenous ARA-C involve the central nervous system, the association of ARA-C and polyneuropathy has also been reported with both intravenous ,5 and inPredominantly sensory peripheral neuropathy is seen with low dose ARA-C, whereas sensorimotor neuropathy occurs after high-dose therapy. Symptoms can start from hours to 2\u20133 weeks after initiation of therapy ,9-11 andAlthough central nervous system involvement is the most common neurotoxicity associated with intrathecal methotrexate therapy ,14,15, tWerner  reportedIt should also be mentioned that GBS can be associated with leukemia alone. Vembu and colleagues  reportedThe patient presented developed a third cranial nerve palsy which then progressed to a bilateral facial nerve palsy. At first it was felt that this may be a vasculitis with multifocal involvement. However, given the setting of her motor quadriplegia, respiratory failure along with the vasculitis-negative sural nerve biopsy results it was most likely a manifestation of AIDP or a GBS-like syndrome. Facial paresis, usually bilateral, is found in at least one half of patients  and otheAlthough there have been occasional pediatric case reports, this is an interesting case of ascending sensory motor polyradiculoneuropathy with cranial nerve involvement in an adult patient with AML following intravenous ARA-C and intrathecal methotrexate. The polyradiculoneuropathy appears to have been secondary to predominant axonal loss rather than demyelination as reported in most other studies.The author declares that he has no competing interests.RAR wrote the entire manuscript.Written informed consent was obtained from the patients' husband for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal."}
+{"text": "We observed growing tumour vessels in vivo to study the relationship between blood flow and vascular enlargement. Mammary adenocarcinoma was implanted into Fisher-344 rat with dorsal skin-fold transparent chambers. Vascular growth was observed and recorded on videotape through a microscope for 6 h. Vascular networks were photographed and traced every 30 min to identify changes over time. Tumour sections were stained with Masson's trichrome and anti-Factor VIII-related antigen. Tumour growth was rapid enough for differences to be seen each hour. Vessels with a high blood flow showed an increase in diameter within a few hours and new branches formed from these vessels. In contrast, vessels without an increase in blood flow showed no change in diameter. Vessels within the interstitium surrounding the tumour were lined by endothelium that was positive for anti-Factor VIII-related antigen staining. Vessels in the tumour had extremely rare endothelial cells detectable by Masson's trichrome or anti-Factor VIII-related antigen staining. In conclusion, increased blood flow may cause vascular enlargement and some primitive vessels seem to lack endothelium."}
+{"text": "Plasmodium falciparum involved sequestration of parasitized red blood cells and immunopathological responses. Among immune factors, IgG autoantibodies to brain antigens are increased in P. falciparum infected patients and correlate with disease severity in African children. Nevertheless, their role in the pathophysiology of cerebral malaria (CM) is not fully defined. We extended our analysis to an Indian population with genetic backgrounds and endemic and environmental status different from Africa to determine if these autoantibodies could be either a biomarker or a risk factor of developing CM.The main processes in the pathogenesis of cerebral malaria caused by P. falciparum infected patients manifesting mild malaria (MM), severe non-cerebral malaria (SM), or CM and in control subjects from Gondia, a malaria epidemic site in central India using quantitative immunoprinting and multivariate statistical analyses. We identified beta tubulin III (TBB3) as a novel discriminant brain antigen in the prevalence of CM. In addition, circulating IgG from CM patients highly react with recombinant TBB3. Overall, correspondence analyses based on singular value decomposition show a strong correlation between IgG anti-TBB3 and elevated concentration of cluster-II cytokine  previously demonstrated to be a predictor of CM in the same population.We investigated the significance of these self-reactive antibodies in clinically well-defined groups of P. falciparum infection and plasma cytokine patterns with clinical outcome of malaria. They also provide significant insight into the immune mechanisms associated to CM by the identification of TBB3 as a new disease-specific marker and potential therapeutic target.Collectively, these findings validate the relationship between antibody response to brain induced by"}
+{"text": "We report a patient who underwent radiofrequency ablation of the distal insertion of an atrio-fascicular accessory pathway with decremental properties because of inability to map a suitable potential alongside the tricuspid annulus. Small, discrete potentials resembling those of Purkinje fiber were found at right ventricular apex. All these potentials showed early activation during tachycardia preceding the QRS onset of various degree. Pace mapping helped to localize the presumed main distal insertion of the atrio-fascicular accessory pathway in a region where damage of the His-purkinje system may ensue. This case report describes catheter ablation of an atriofascicular accessory pathway by targeting its distal (ventricular) insertion site. Atrio-fascicular accessory pathways (AP) with decremental properties (i.e. Mahaim fibers) are associated with uncommon types of wide QRS complex tachycardia -5. In maA 44 years old male with structurally normal heart was referred to our institution because of long standing episodes of palpitation. Despite a history of sustained episodes of palpitation no evidence of arrhythmia was previously documented. The standard 12 leads EKG showed no baseline abnormality. The presence of structural heart disease was excluded by physical examination and trans thoracic echocardiography.After written informed consent was obtained an invasive EP study was performed in un-sedated, drug free state. One quadripolar and two decapolar diagnostic catheters were inserted through the right femoral and left subclavian veins and positioned respectively in the his bundle (HB) region, coronary sinus (CS) and  along the lateral wall of the right atrium. During the study the decapolar catheter located in the right atrium was moved to the right ventricular apex in order to record right bundle branch (RBB) potentials. During incremental atrial pacing, a progressive lengthening of the atrio-ventricular (A-V) interval was noted as well as progressive widening of the QRS and proportional shortening of the His-ventricular (H-V) interval.  A wide complex tachycardia exhibiting left bundle branch block (LBBB) morphology and superior axis was induced during pacing at 240 milliseconds (msec) from the high right atrium. The appearance of LBBB morphology was invariably associated with the progressive shortening of the HV interval up to the merging of the His potential with the local ventricular electrogram. After a stable RBB potential recording was obtained it was shown an inversion of the physiologic HB\u2013RBB activation sequence during tachycardia, the HB resulting activated retrogradely. This tachycardia was characterized by an A:V ratio of 1:1 and a concentric retrograde atrial activation pattern . Programmed atrial stimulation at different drive cycles (600-400 msec.) with double and triple extrastimuli successfully initiated tachycardia at coupling interval of less than 300 msec. The arrhythmia onset was always preceded by the occurrence of LBBB aberration of the last paced beat. During the recording session tachycardia cycle length (TCL) varied from 290 msec to 340 msec. These TCL variations were associated to proportional prolongations of V-A interval and QRS duration while the atrial retrograde activation sequence remained unmodified. Despite TCL lengthening and VA prolongation the HA interval remained constant. Atrial pacing at cycle length shorter than the TCL up to 240 msec successfully entrained the tachycardia without obtaining sinus rhythm restoration after pacing interruption. Rapid atrial pacing during sinus rhythm also initiated a self-limiting typical counterclockwise atrial flutter with 2:1 A-V pre-excited response. Ventricular pacing from the parahissian region at a cycle length just shorter than TCL invariably interrupted the tachycardia after His bundle capture was obtained. The retrograde atrial activation in the His bundle trace always preceded the others and the atrial activation sequence remained unmodified during the entire recording session even in the presence of  TCL changes, this behavior was consistent with true antidromic AV reciprocating tachycardia using the Mahaim fascicle as antegrade limb. V-A prolongation without H-A modification excluded the involvement of a septal concealed accessory pathway as retrograde limb and also ruled out an atrioventriclar nodal reentrant tachycardia with a Mahaim fascicle participation as an innocent \"bystander\". We may speculate that this behavior probably reflected paroxysmal prolongation of the conduction time or block thorough the RBB next to the insertion of the Mahaim fiber.The ablation procedure was performed using a 7 F 4 mm ablation catheter . A careful and complete tricuspid ring mapping was performed in order to record a discrete potential resembling that recorded on His region, the so called Mahaim potential (MP). We failed to identify a discrete potential alongside the entire annulus so we decided to target the ventricular insertion. Given the superior axis of the arrhythmia we deliberately started from the right ventricular apex. Small, discrete potentials resembling those of Purkinje fiber were found near the right ventricular apex, these potentials showed various degrees of early activation during tachycardia and all preceded the His bundle activation. We delivered RF at a site with the apparently most negative local potential-QRS interval but we failed to terminate the arrhythmia. In order to reduce the number of unnecessary RF pulses we decided to perform pace mapping in a region where different sites with early local ventricular activation could be recorded. Pace mapping performed from the recording site of a small potential (SP), presumably the distal RBB, located 35 msec before the tachycardia QRS onset and 40 msec before the HB retrograde activation showed a QRS morphology identical to that observed during tachycardia. ,3.During sinus rhythm, pacing from this site was also followed by tachycardia initiation and of note the stim-QRS interval resembled the SP-QRS interval during tachycardia. This behavior was consistent with the antegrade limb distal insertion of the macroreentrant circuit. A single pulse of RF  interrupted the tachycardia after less than 3 sec, the RF delivery was then continued for 60 seconds in order to achieve a more complete lesion. At the end of the procedure the arrhythmia was no longer inducible, incremental atrial pacing demonstrated normal AV conduction and an incomplete RBB block was evident. Patient was followed up for one year and there were no recurrences of tachycardia.Recently unsuccessfull tricuspid annulus mapping for Mahaim discrete potential has been reported to be up to nearly 50 % . When th"}
+{"text": "Mice have been compeletly protected against the lethal effects of repeated injections of methotrexate by 5-methyltetrahydrofolic acid. Methotrexate-resistant cells probably owe their resistance to their high content of this substance.2. Daily small doses were much more effective than fewer but larger doses.3. The reduced efficiency found in counteracting high dosages of methotrexate may be due to interference with folate transport across cell walls.4. 5-Methyltetrahydrofolic acid and citrovorum factor did not differ greatly in their ability to inhibit methotre toxicity. It is suggested that the pharmaceutical effects of citrovorum factor are due to its conversion to 5-methyltetrahydrofolic acid."}
+{"text": "This article describes the chemical aminoacylation of the yeast phenylalanine suppressor tRNA with a series of amino acids bearing fluorinated side chains via the hybrid dinucleotide pdCpA and ligation to the corresponding truncated tRNA species. Aminoacyl-tRNAs can be used to synthesize biologically relevant proteins which contain fluorinated amino acids at specific sites by means of a cell-free translation system. Such engineered proteins are expected to contribute to our understanding of discrete fluorines\u2019 interaction with canonical amino acids in a native protein environment and to enable the design of fluorinated proteins with arbitrary desired properties. Over the past two decades, the interest in engineering proteins containing site-specific synthetic amino acids with novel functionalities has grown considerably. The utility of chemically aminoacylated suppressor transfer RNAs (tRNAs) combined with cell-free translation systems in producing proteins that contain non-canonical amino acids was reported independently from each other by Schultz and Chamberlin \u20132. TheirN\u03b1-protected amino acids were used to chemically aminoacylate the dinucleotide pCpA. Subsequent enzymatic ligation to truncated tRNAs  yielded the desired AA-tRNAs . Th. Thn-butThe efficient chemical and enzymatic synthesis of three novel fluorinated aminoacyl-pdCpAs and Abu-pdCpA and their corresponding charged tRNAs is reported. These aminoacyl-tRNAs can be used for site-specific protein mutagenesis in a cell-free protein synthesis system and will enable a systematic investigation of the structural and dynamic behavior of fluorine within a native protein environment.Supporting information features detailed information on experimental procedures and compound characterization.File 1Experimental procedures and compound characterization"}
+{"text": "Fifty-three biopsies from the oral mucosa in 51 Indian villagers with oral submucous fibrosis have been studied for epithelial changes. A marked atrophy of the epithelium was found in 71.7%; the atrophic epithelium showed no rete ridges. The normally unkeratinized buccal mucosa revealed either ortho- or parakeratosis or hyperortho- or hyperparakeratosis in 48.0%. In one patient the histologic examination disclosed a squamous cell carcinoma. In 22.6% an epithelial atypia was found. The histologic features in these atypias are compared with those seen in leukoplakias from the same survey. The possible precancerous nature of submucous fibrosis is discussed."}
+{"text": "Vesicoureteric complications present early after transplantation and contribute to patient morbidity, graft loss and mortality. Ureteral stenting provides a decrease in ureteroneocystostomy anastomotic complications following renal transplantation. There should be prophylactic stent insertion with endoscopic removal at a designated time post transplantation. With the addition of antibiotic prophylaxis post transplantation, ureteric stenting does not increase the rate of urinary tact infections. There is no significant increase in cost for stenting during transplantation in comparison to management of major ureteric complications. Routine stenting causes significant cost-saving per year and prevents anastomotic complications. It is wise to stent the transplant ureter routinely. Kidney transplantation is the treatment of choice for end-stage kidney disease. Ureteroneocystostomy anastomotic leakage and/or strictures complicate 3\u20139% of all renal transplants.\u20133 These We would like to address the following three categories:Initially, ureterovesical anastomosis was done using a transvesical Leadbetter-Politano approach which is presently superceded by the extravesical ureteroneocystostomy (Lich-Gregoir) approach.\u201316 RefinConventional native ureteric repairs over stents are widely accepted to have a better outcome. In addit26In all randomized and quasi-randomized controlled trials looking at the use of double-J stents to prevent urological complications, the incidence of MUCs ranged between 0 and 5% in stented patients (median 1.0%) and between 0 and 17.3% (median 7.0 %) in the non-stented patients .5\u201311] A A11] A tThe most significant theoretical complication in the use of a stent is an increase in the number and severity of urinary tract infections (UTIs). Other possible complications include persistent hematuria, bladder discomfort, stent migration, breakage, encrustation and complications during removal. Most centers have adopted a policy of prophylactic stent insertion with endoscopic removal at a designated time post transplantation in an effort to reduce the rate of MUCs. UTIs, inThe maximum reported non-infectious complications were irritative symptoms 5.6%, breakageIn another study it has been suggested that ureteral stasis may cause tubuloepithelial injury and slow down the decrease in creatinine levels. They concluded that Double J Stent (DJS) did not increase UTIs but provided a smooth decline in creatinine levels, which may reduce the question of acute rejection.The incremental inpatient hospital costs associated with a urinary complication during the first 12 months following renal transplantation were 145% of the cost of renal transplantation without this complication. Notably, this value does not include inpatient hospital indirect costs, any expenses generated on an outpatient basis or elsewhere, or any inpatient or outpatient professional costs. Thus, the actual incremental cost associated with a urinary anastomotic complication following renal transplantation is significantly higher than this value. There isP <0.0001).[P = 0.02).[A recent meta-analysis evaluated five prospective, randomized, controlled clinical trials of routine stenting following renal transplantation and indicated that the collective urinary complication rate following routine stenting was 1.5% compared to 9% without stenting .The review of the literature appears to tilt the balance heavily in favor of routine prophylactic stenting in renal transplant recipients. Transplant units currently using antibiotic regime as prophylaxis for pneumocystis carnii should not notice an excess of stent-related infections. The use of an appropriate size of stent and early removal at two weeks prevents morbidity and stent-related complications. It is wise and cost-effective to stent the ureteroneocystostomy after transplantation."}
+{"text": "Pulmonary edema after device closure of atrial septal defect (ASD) is a rare complication. We present illustrative images of a case of pulmonary edema after device closure of ASD in a 53 year old adult. Older patients undergoing ASD closure can benefit from their left atrial and left ventricular end diastolic pressures measurement before and after temporary balloon occlusion of ASD. These images illustrate the development of pulmonary edema after catheter closure of atrial septal defect (ASD) in a 53-year-old gentleman. He presented with shortness of breath and easy fatigability since six months. He was normotensive and non-diabetic with no history of effort angina. The chest X-ray obtained before the procedure  showed cEighteen hours after device closure the patient developed breathing difficulty and orthopnea. Clinical examination showed tachypnea and basal crepitation. Skiagram of chest in postero-anterior view showed features of evolving pulmonary edema  which eset al.[et al. reported pulmonary edema in a 78-year-old male. Our patient was relatively younger (53 years) without any coronary artery disease and normal systemic pressure.ASD is a common form of congenital heart disease accounting for approximately 10% of all congenital cardiac defects.[et al. reportedIn older patients, an impaired diastolic ventricular function due to reduced ventricular compliance is observed more frequently although this is occasionally also seen in childhood. RestrictOlder patients undergoing ASD closure in the catheterization laboratory should perhaps have their left atrial, LVEDP measured before and after temporary balloon occlusion and after defect is closed with a device."}
+{"text": "Geminiviridae) are small single-stranded (ss) DNA viruses infecting plants. Their virion morphology is unique in the known viral world \u2013 two incomplete T = 1 icosahedra are joined together to form twinned particles. Geminiviruses utilize a rolling-circle mode to replicate their genomes. A limited sequence similarity between the three conserved motifs of the rolling-circle replication initiation proteins (RCR Reps) of geminiviruses and plasmids of Gram-positive bacteria allowed Koonin and Ilyina to propose that geminiviruses descend from bacterial replicons.Geminiviruses (family Satellite tobacco necrosis virus was found to be the best template for homology-based structural modeling of the geminiviral capsid protein. Good stereochemical quality of the generated models indicates that the geminiviral capsid protein shares the same structural fold, the viral jelly-roll, with the vast majority of icosahedral plant-infecting ssRNA viruses.Phylogenetic and clustering analyses of various RCR Reps suggest that Rep proteins of geminiviruses share a most recent common ancestor with Reps encoded on plasmids of phytoplasmas, parasitic wall-less bacteria replicating both in plant and insect cells and therefore occupying a common ecological niche with geminiviruses. Capsid protein of We propose a plasmid-to-virus transition scenario, where a phytoplasmal plasmid acquired a capsid-coding gene from a plant RNA virus to give rise to the ancestor of geminiviruses. The origin(s) of viruses is a longstanding but yet unresolved question in biology. Several hypotheses were put forward in efforts to understand this enigma (reviewed in ). AccordCircoviridae family bear only two genes , which has been previously observed to be similar to Reps of circoviruses . The pairwise distances between the nanoviral and other Reps were considerably larger than distances between any other pair of sequences (data not shown). Examination of the sequence alignment [see Additional file The 40 sequences were aligned. The alignment was manually verified and edited [see Additional file N. tabacum [B. catenulatum DSM 16992 on the ML tree was different from that on the Bayesian tree.Maximum-likelihood (ML) and Bayesian trees were inferred using PhyML  and MrBa tabacum ) form a YP_001586272] and pUB110 [GenBank:CAA27141], the two plasmids whose Reps were found to be the closest to geminiviral Reps , 69.1% had corresponding amino acids in at least one of the four geminiviral CP sequences   Fig. . Given tMicroviridae and Parvoviridae families  was previously shown to be more similar to Reps of various circoviruses than it is to Reps from other bacterial plasmids and viruses /[LM]T) [YN]XHX [HQ]XYXXKXGXXXXGK [ST]XDD. The residues shown in square brackets are alternatives; X \u2013 any amino acid; numbers in parentheses denote the allowed distance between corresponding motifs; slash sign indicates alternation of the dipeptides in the second and third positions in the pattern. The non-redundant protein sequences and environmental protein sequences from BLAST database were downloaded (07.02.2009) from NCBI FTP site and searched for sequences exactly matching the derived pattern without paying attention to the sequences surrounding the conserved motifs . Using this approach sequences missed by BLAST searches are expected to be found. 1072 protein sequences were initially extracted. In order to avoid redundancy, the original dataset was subsequently filtered to leave only sequences with less than 70% identity. As a result, a dataset containing 43 protein sequences was obtained. Of these two sequences were false-positive \u2013 a 799 amino acid-long hypothetical protein [GenBank:XP_001614627] from Plasmodium vivax SaI-1 and a 440 amino acid-long hypothetical TrmE domain protein GOS_1133298 [GenBank:EDE42344] from marine metagenome project, which were not included in the further analysis. The resultant dataset (41 sequences) was used to create a multiple sequence alignment using CLUSTALW [ABD67440] was found to be considerably longer (469 aa) than the rest of the sequences. The protein was found to be a fusion of RCR Rep and geminiviral transcriptional activator AC2 and was therefore removed from the alignment. The 40 sequences were realigned and following manual examination and editing the subsequent alignment [see Additional file 6 generations and trees were sampled every 100 generations. To construct the consensus tree, the first 25% of the trees were discarded as \"burnin\".Koonin and Ilyina 1992) found that geminiviral rolling-circle replication (RCR) initiation proteins (Rep) are related to certain bacterial Reps . In ordeCLUSTALW . One gem992 found100)YXXKX,200GXXXXMultiple sequence alignment [see Additional file BioInfoBank MetaServer  was usedMK conceived the project, collected, analyzed and interpreted the data, and drafted the manuscript. JJR collected and analyzed the data, and revised the manuscript. DHB interpreted the data and revised the manuscript. All authors read and approved the final manuscript.Multiple sequence alignment of 40 RCR Rep proteins. Figure shows a multiple sequence alignment which has been used to calculate the phylogenetic trees.Click here for fileBayesian consensus tree of the RCR Rep proteins. Figure shows the Bayesian consensus tree which has been calculated using the same dataset as for the Maximum likelihood tree shown in Figure Click here for file"}
+{"text": "At the moment only early detection of lung cancer offers a good prognosis for the patients. Conventional white light endoscopy is mostly insufficient for early diagnosis. Therefore wedeveloped a system of fluorescence diagnosis using 5-aminolaevulinic acid (ALA)exogeneously applied. As precursor of the heme synthesis it is metabolized to protoporphyrinIX \u2013  a red fluorescent substance. Therefore protoporphyrin IX accumulates in tumorous andpremalignant tissue, and can be directly visualized by fluorescence bronchoscopy. Excitationwith blue light (380\u2013435 nm) causes a red fluorescence, which can be detected after filteringmost of the blue component with the naked eye or a camera system. After earlier work withlaser systems and cold light sources we now use the system D-Light AF for the fluorescencediagnosis using ALA-induced protoporphyrin IX fluorescence."}
+{"text": "Among gastric cancer patients, the Rhesus D-negative phenotype correlated with increased tumour recurrence  and reduced overall survival time  and was identified in multivariate analysis as the most important independent prognostic marker in the R0 patient group ."}
+{"text": "Biliary complications continue to be a major cause of morbidity after split-liver transplantation (SLT). In this report we describe an uncommon late biliary complication. One year after SLT the patient showed an intrahepatic bile dicy dilatation with severe cholangitis episodes. The segmentary bile duct of hepatic segment VI-VII draining in the left duct was unidentified and tied at the time of the in situ split-liver procedure. We perform a permanent obliteration of the dilated intrahepatic ducts by a percutaneous embolization using an n-butyl cyanoacrylate (NABC). The management of biliary complications after SLT requires a multidisciplinary approach. The use of NBCA in obliteration of a dilated bile duct seems to be a safe procedure with good results providing a less invasive option than hepatic resection and decreasing the morbidity associated with chronic external biliary drainage. Further studies are needed to determine whether this approach is effective and safe and whether it could reduce hospital stay and cost. Split-liver transplantation (SLT) is an attractive alternative procedure to expand the donor pool in patients waiting for liver transplantation. Paramount to the success of SLT is a careful donor and recipient selection. The standard split-liver procedure for a child and an adult , by splitting segment II-III for pediatric recipient and segment I-IV-V-VI-VII-VIII for an adult, is an accepted surgical option with good results both for the adult and for pediatric recipient .Biliary complications continue to be the major cause of morbidity after SLT with a reported high incidence ranging between 10% and 32% [As a consequence of bile duct anatomic variations, SLT requires a precise knowledge of the liver anatomy , 4. The In this report we describe an uncommon late biliary complication that occurred after SLT and was successfully treated by a multidisciplinary approach. A 63-year-old male with hepatitis C-related cirrhosis was referred for liver transplantation to our institution. We performed a conventional A/P SLT with in situ technique providing the left lateral segment for a child (segments II-III) and leaving the right lobe graft (segment I-IV-V-VI-VII-VIII) for an adult recipient. The celiac trunk was left on the left graft while the right hepatic artery remained on the right graft. The common hepatic bile duct was left on the right graft. The patient was transplanted using the piggy-back technique without a veno-venous bypass. The biliary tract was reconstructed performing a duct-to-duct anastomosis using a T-tube by our standard technique previously described .A cholangiography through the T-tube was performed on postoperative day 14, and the T-tube was clamped before patient discharge. Three months after A/PSLT the T-tube was removed after a cholangiography with normal findings. One year after transplant the patient showed abnormal liver function tests, hyperbilirubinemia, leukocytosis, and elevated g-glutamyl transpeptidase (GGT), and mild elevation in alanine transaminase (ALT). The patient underwent a doppler ultrasound that showed (a patent hepatic artery) an intrahepatic bile duct dilatation and an anastomotic biliary stricture. These findings were confirmed by a magnetic resonance cholangiography (MRC). The anastomotic stricture was treated by stenting the main biliary duct during an endoscopic retrograde cholangiopancreatoghaphy (ERCP) without any evidence of intrahepatic biliary dilatation. After this procedure the patient was submitted to a percutaneous transhepatic cholangiography (PTC) showing a complete obstruction of segments VI and VII biliary branches near the duct-to-duct biliary anastomosis . A percuWe supposed that the segmentary bile duct branch of posterior segments VI and VII draining in the left bile duct was unidentified and tied at the time of the in situ split-liver procedure during the parenchymal transection. A primary biliary reconstruction by biliary repair or biliodigestive anastomosis was considered at high risk because of the presence of postsurgical adhesions sand due to fibrotic tissue replacing the parenchymal transected area. A liver resection of the dilated segments VI and VII was considered at high risk of leaving an inadequate liver mass. We decided to perform a permanent intraoperative obliteration of the dilated intrahepatic ducts by a percutaneous embolization using a nonresorbable agent. With a fluoroscopic guidance through the transhepatic access we positioned a 5-French polyethylene catheter inside the ducts, preliminary flushed by a nonionic dextrose solution. We then injected the tissue adhesive agent n-butyl cyanoacrylate  mixed with ionized oil  for opacization in a ratio of 1:5. This solution completely filled the biliary duct, and the occlusion was totally accomplished in a few seconds .During the first 3 days after the chemical bile duct embolization, the patient had a low fever with a slightly abnormal liver function test. A computed tomography (CT) scan performed 6 months later showed no sign of hepatic abscesses, and the bile duct dilatation was completely occupied by the NBCA-Lipiodol mixture. One year after the procedure patient showed normal liver function tests without no episodes of cholangitis.The management of biliary complications after liver transplantation requires a multidisciplinary approach.Chemical bile duct embolization treatment could represent a valuable solution to treat uncommon biliary complications. These tissue adhesive glues are low-viscosity liquid monomers that undergo rapid polymerization and solidification when they come into contact with organic fluids such as bile. NBCA is a permanent liquid embolic material that produces long-term occlusion in vessels of various size through an inflammatory tissue response resulting in vessel thrombosis or tissue atrophy.Little is known about the use of cyanoacrylate compounds, and unlike European countries the use of Glubran has not been approved by the Food and Drug Administration yet. Other authors have described the efficacy of biliary duct ablation by NBCA in patients with persistent postsurgical bile leaks after lobectomy or cholecystectomy. Vu et al. treated six patients with persistent postsurgical bile leaks as a complication after hepatic lobectomy or cholecistectomy using NBCA glue for the obliteration of isolated segmental bile ducts in four cases . EndoscoThe percutaneous interventional technique represents an effective valuable approach to reduce mortality and morbidity in the treatment of biliary complications after liver transplantation.The use of NBCA in obliteration of a dilated bile duct seems to be a safe procedure with good results providing a less invasive option than hepatic resection above all in high-risk patients with posttransplant bile duct injuries, decreasing the morbidity associated with chronic external biliary drainage.Futher studies are needed to determine whether this approach is effective and safe and whether it could reduce hospital stay and costs."}
+{"text": "The NKactivity of PBL was detected by a cytotoxic test using3H-uridine human erythromyeloblast K562 cells. AutologousIFN-\u03b1 and IFN-\u03b3 did not augment NK activity of PBL fromhealthy donors in vitro, whereas in samples from MSpatients the IFNs strongly stimulated NK cell cytotoxic function.This stimulation suggests the existence of an inhibitor ofregulatory IFN action, that is produced in healthy donorssimultaneously with IFN in response to IFN induction, but which islacking in commercial IFN preparations. The factor-containingsupernatants from healthy donors reduced the stimulatory action ofautologous IFNs in patients with MS almost until complete blockade.Because this inhibitor was absent in patients with MS, deficiency ofan inhibitor of IFN regulatory action in MS could open the way totreatment of this compartment of the immune system.The"}
+{"text": "Sera from Balb/c mice bearing Moloney leukaemia block complement dependent antibody mediated cytotoxicity of an antiserum prepared in rats against syngeneic Moloney virus induced lymphomata when either spleen cells from mice bearing Moloney leukaemia (M) or an in vitro line of Moloney virus transformed cells (MSC) are used as targets. This antiserum has been shown to recognize p30, the major internal virion protein, as a cytotoxic target on these cells. Viral particles were identified by electron microscopic examination of pelleted material obtained from leukaemic sera after high speed centrifugation. However, removal of virus did not affect the capacity of the leukaemic sera to absorb cytotoxicity of rat ILR-3 for MSC targets, and only depressed somewhat its ability to absorb activity of the same antisera against M targets. Virus-free leukaemic sera also blocks complement dependent antibody mediated cytotoxicity of an antiserum prepared in goats against the gs3 determinant of p30. This indicates that the material in leukaemic sera responsible for the in vitro block of antibody mediated cytotoxicity was p30. A lesser degree of block was observed with sera obtained from normal Balb/c mice, but the nature of material responsible is as yet undefined."}
+{"text": "When multiple synchronous lung tumours are identified, discrimination of multicentric lung cancers from intrapulmonary metastases by clinical findings is often difficult. We used genetic alterations in p53 gene as a discrimination marker of double primary lung cancers from single lung cancer with intrapulmonary metastasis. Twenty of 861 patients with primary lung cancer who underwent lung resection were selected as subjects because they showed synchronous double solid tumours of the same histological type in the unilateral lung without distant metastases. In addition, they had been diagnosed as lung carcinoma with intrapulmonary metastasis by clinical and histological findings. DNAs were extracted from paraffin-embedded tissue of paired tumours from these 20 patients. Exons 5\u20139 of the p53 gene were examined for genetic alterations in the tumours by polymerase chain reaction, single-strand conformation polymorphism analysis and subsequent DNA sequencing analysis. Three different patterns in the distribution of p53 mutations in double lung tumours were observed: [A] mutation in only one of the tumours (four cases), [B] different mutations in the tumours (two cases), and [C] same mutation in both tumours (one case). The cases of [A] or [B] patterns could be classified as double primary lung cancers, while the case of the [C] pattern was suggested to be lung cancer with intrapulmonary metastasis. These results suggested that the multicentric cancers were more frequent than the intrapulmonary metastatic cancers in double cancer cases. \u00a9 1999 Cancer Research Campaign"}
+{"text": "The R\u00edo Tinto (RT) is distinguished from other acid mine drainage systems by its natural and ancient origins. Microbial life from all three domains flourishes in this ecosystem, but bacteria dominate metabolic processes that perpetuate environmental extremes. While the patchy geochemistry of the RT likely influences the dynamics of bacterial populations, demonstrating which environmental variables shape microbial diversity and unveiling the mechanisms underlying observed patterns, remain major challenges in microbial ecology whose answers rely upon detailed assessments of community structures coupled with fine-scale measurements of physico-chemical parameters.By using high-throughput environmental tag sequencing we achieved saturation of richness estimators for the first time in the RT. We found that environmental factors dictate the distribution of the most abundant taxa in this system, but stochastic niche differentiation processes, such as mutation and dispersal, also contribute to observed diversity patterns.We predict that studies providing clues to the evolutionary and ecological processes underlying microbial distributions will reconcile the ongoing debate between the Baas Becking vs. Hubbell community assembly hypotheses. Geological and geochemical studies show the R\u00edo Tinto to be an acidic river situated at the core of the largest Pyritic Belt on Earth  whose chet al.Vibrio spp., these clusters constituted individuals different at the genomic level but whose divergence should be neutral (i.e. with no selective advantage) because of the small spatial scale in which they coexisted Clustering sequences into operational taxonomic units (OTUs) is the first step in a molecular study exploring ecological diversity. Microbiologists traditionally use a 97% similarity cut-off value to form OTUs that delineate microbial species Acidithiobacillus ferrooxidans and Leptospirillum ferrooxidans and other relatively less abundant ribotypes similarity among samples through the use of multivariate methods that compare samples based on taxon composition and relative abundance. It is important to note that taxonomic description is not required for assessment of either of these measures.In order to generate accurate estimates of diversity, our sampling scheme consisted of a replicated sampling design and large area of coverage of the stations observed microbial richness among samples at the same sampling effort overall species richness and compare alpha diversity of communities provided they reach an asymptote et al. have suggested a new set of statistical approaches to calculate microbial richness from parametric models Each method for estimating richness and comparing alpha diversity between samples has advantages and drawbacks To evaluate relationships among samples based on shared OTU relative abundance, we present results using the Morisita-Horn pairwise similarity coefficient. This index is widely used because it is less influenced by species richness and sample size than other (dis)similarity measures of quantitative data et al.A. ferrooxidans and L. ferrooxidans obtain their energy from pyrite (FeS2) and the oxidized metabolites can in turn be mineralized by heterotrophic microbes like Acidiphilium spp., Ferromicrobium or sulfate reducers. Ferric iron buffers the pH at or below pH 3. In our study, of the 22 environmental parameters measured, seven best explained the variation in the data  (see Amils dox) see . We useddox) see . Monte Cdox) see . OTUs thdox) see  and 5. Fdox) see . We infeet al.Stochastic vs. deterministic community assembly hypotheses are being tested in parallel to explain the distributional patterns of organisms in natural environments Candidatus captivus acidiprotistaeglobal dispersion of ecotypes better adapted to certain environmental conditions, which prevail over less adapted units that emerge locally. Pommier et al. (2007) and Ramette et al. (2007) have suggested a similar pattern of global deterministic ecotype adaptation On the other hand, the presence of endemic ecotypes that correlate with particular environmental factors seem to contradict Baas Becking's ideas on global bacterial distribution Seasonal sampling that integrates bacterial, archaeal and eukaryal components of the microbial community is the necessary next step to understanding whether interaction of all trophic levels in the RT confirm or reject our scenario of the global distribution of adapted ecotypes.Our study included three stations in the RT that have distinct physico-chemical parameters and biology We added Cell Lysis Solution from the Puregene\u00ae DNA extraction kit  directly to the sterivex filter using a 3cc. syringe, sealed the filter, and placed it into a liquid nitrogen dry shipper . We extracted total DNA within one week of collection using the Puregene Bacteria DNA purification procedure with the following modifications. We added lysozyme (67 \u00b5L of 50 mg/mL solution) and proteinase K (10 \u00b5L at 20 mg/mL) consecutively directly to the sterivex filters and incubated these enzymes with agitation as indicated in the protocol. We then transferred incubated samples to three 2-mL microfuge tubes to proceed with the protein precipitation step. Nucleic acid precipitation occurred in 1 volume of isopropanol. Finally we resuspended DNA pellets in 30 \u00b5L Puregene\u00a9 DNA Hydration Solution per sample and stored them at \u221220\u00b0C until further processing.For each sample both filtered and unfiltered 15 mL water aliquots were analyzed using Total Reflection X-ray Fluorescence (TXRF) at the Universidad Aut\u00f3noma de Madrid  to determine the concentration of 22 chemical elements in the water samples examined. Given filtered vs. unfiltered geochemistries were not significantly different, we report results with unfiltered samples.in situ in the river at the time of water collection. These two parameters varied with time of day as the sun rose and heated the river so they were not included in our analyses.We measured redox potential and pH (using a Crison 506 pH/Eh meter) and conductivity (using a Orion-122 conductivity-meter) at the time of water collection from 15 mL aliquots. Oxygen concentration and water temperature were measured using an Orion-810 oxymeter http://www.ncbi.nlm.nih.gov/GeneBank) and RDPQuery SARST-V6 produces sequences of large concatemers of PCR-amplified ribosomal sequence tags (RSTs) from homologous V6 hypervariable regions. We performed amplification and purification of the V6 region of bacteria following We first compared diversity between samples by representing relative abundances of OTUs in a rank/abundance plot. We then tested whether the data fit one of four statistical models of species abundance distributions: the geometric series, log normal, log series, or broken stick models. We transformed total abundance data into 0/1 matrices as input into the program EstimateS We also used EstimateS to calculate Morisita-Horn, and the newly developed Chao-Jaccard and Chao-S\u00f8rensen abundance based beta similarity estimators We can consider our samples as real (independent) replicates of the studied sites because repetitive sampling was done independently from one sample to the next and the biological system under consideration is dynamic . This assumption not only validates ANOSIM analysis We used CCA as a constrained ordination direct gradient analysis method to relate RSTs grouped into OTUs to the environmental variables measured. We used CANOCO 4.5 Text S1Environmental tag sequencing methods facilitate comprehensive microbial ecology and biogeography studies.(0.05 MB DOC)Click here for additional data file."}
+{"text": "In 1997, an outbreak of human tularemia associated with hare-hunting in central Spain affected 585 patients. We describe the identification of Francisella tularensis biovar palaearctica in a second outbreak of ulceroglandular tularemia associated with crayfish (Procambarus clarkii) fishing in a contaminated freshwater stream distant from the hare-associated outbreak. The second outbreak occurred 1 year after the first."}
+{"text": "We speculate that multiple pleural metastasis may disturb the normalrepair mechanism of the lung tissue and cause prolonged persistent air leaks.A rare case of bilateral pneumothorax in a 54-year-old woman with advanced breast cancerassociated with lung and pleural metastases is presented. The patient was admitted to ourhospital complaining of unexpected severe dyspnea. A chest X-ray showed bilateral pneumothoraxassociated with multiple lung metastases and pleural effusions, followed byimmediate pleural drainage. Although air leak and effusions of the right lung were wellcontrolled by the conservative management, massive air leaks of the left lung had continuedfor 40 days. Because of patient's poor general status a surgical closure of the leaking sitewas selected using video-assisted thoracoscopic surgery techniques. Thoracoscopy revealeda ruptured bulla in the lower lobe (S"}
+{"text": "Lambda tomography (LT) is to reconstruct a gradient-like image ofan object only from local projection data. It is potentially animportant technology for medical X-ray computed tomography (CT) ata reduced radiation dose. In this paper, we prove the firstgeneral formula for exact and efficient fan-beam LT from datacollected along any smooth curve based on even and odd dataextensions. As a result, an LT image can be reconstructed withoutinvolving any data extension. This implies that structures outsidea scanning trajectory do not affect the exact reconstruction ofpoints inside the trajectory even if the data may be measuredthrough the outside features. The algorithm is simulated in acollinear coordinate system. The results support our theoreticalanalysis."}
+{"text": "Fifteen patients with acute myelogenous leukaemia were studied to determine if their remission blood leucocytes could be stimulated into taking up [3H] thymidine after in vitro culture with their own cryo-preserved irradiated AML leukaemia cells. In 6/15 patients it was possible to show autologous recognition and equal recognition of their stored leukaemia cells, even when they had previously been maintained in in vitro proliferative cultures in liquid suspension and undergoing myeloid maturation for one week. After in vitro proliferative culture, 4 populations of leukaemia cells produced material in the supernatant media between 3 and 7 days capable of inducing [3H] thymidine uptake in autologous  and allogeneic  AML remission lymphocytes, but not in normal donor lymphocytes. The relevance of these observations to tumour-associated AML antigen is discussed."}
+{"text": "Methylmercury compounds were kept intact without decomposition or losses by evaporation. Quantitative recoveries of total mercury were achieved with a two-step microwave attack using a combination of HNO3 and H202 solutions as extractant. The whole pretreatment procedure only takes 15 min, which can be further shortened by an automated robust operation with an open focused system. These analytical procedures were validated by the analysis of environmental certified reference materials. The results confirm that the open focused microwave technique is a promising tool for solid sample preparation in analytical and environmental chemistry.This paper describes rapid, simple microwave-assisted leaching/ digestion procedures for total and mercury species determination in sediment samples and biomaterials. An open focused microwavesystem allowed the sample preparation time to be dramatically reduced to only 24 min when a power of 40-80 W was applied. Quantitative leaching of methylmercury from sediments by HNO"}
+{"text": "LM985 has been shown previously to hydrolyse to flavone acetic acid (LM975) in mouse plasma and to produce significant anti-tumour effects in transplantable mouse colon tumours (MAC). It has undergone Phase I clinical trials and dose limiting toxicity was acute reversible hypotension. Substantially higher doses of LM975 can be given clinically without dose limiting toxicity. We have investigated the activity of LM975 against a panel of MAC tumours and also the in vitro cytotoxicity of both LM985 and LM975 in two cell lines derived from MAC tumours. LM985 is considerably more cytotoxic than LM975 in vitro but increased length of exposure to LM975 results in improved activity. Single in vivo injection of LM975 showed no activity against the ascitic tumour MAC 15A, moderate activity against the s.c. poorly differentiated tumour MAC 13 and produced a significant growth delay in the well differentiated MAC 26. These latter responses were considerably enhanced by repeated injection 7 days later. Pharmacokinetic studies in mice following i.p. injection of LM985 demonstrated rapid degradation of LM985 to LM975 in the peritoneum. Length of exposure as well as drug concentration appear important factors in determining anti-tumour responses."}
+{"text": "The effects of butyrate and retinoic acid in combination with catecholamines or histamine on the HN-1 human head and neck squamous carcinoma cell line were investigated analysing cell proliferation, placental alkaline phosphatase (PLAP) activity, and relative cytokeratin content. Butyrate inhibited cell proliferation in agar, whereas retinoic acid induced a small inhibitory effect. Butyrate enhanced PLAP activity in a time related manner in contrast to retinoic acid, which had no significant effect. However, retinoic acid inhibited the efficacy of butyrate to induce PLAP activity. A synergistic enhancement of PLAP activity was demonstrated after treatment of butyrate pretreated cells with catecholamines or histamine. The beta-adrenergic antagonist propranolol partly inhibited the aforementioned enhancement of PLAP activity, whereas the alpha-adrenergic antagonist phentolamine further enhanced PLAP activity. Indirect labeling of keratins with a polyclonal antibody showed that cytokeratin content was enhanced by butyrate but not by retinoic acid. Further analysis of cytokeratin content using four monoclonal antibodies showed that labeling of cytokeratins (5 + 8) was increased by butyrate. PLAP activity could be modulated by a concerted action of either butyrate plus retinoic acid or butyrate plus catecholamines or histamine, indicating a possible role for PLAP in tumour cell proliferation."}
+{"text": "Potential anti-cancer agents have classically undergone clinical assessment in Phase I, II and III trials. This paper examines the role of these trials and pre-clinical studies in the light of improving cancer chemotherapy. Many patients must now be treated with standard therapy before investigational drugs can be ethically used. The introduction of combined modality trials will require a very prolonged follow-up to demonstrate improved survival and recognize late onset of chronic toxicity."}
+{"text": "Arthropods are infected by a wide diversity of maternally transmitted microbes. Some of these manipulate host reproduction to facilitate population invasion and persistence. Such parasites transmit vertically on an ecological timescale, but rare horizontal transmission events have permitted colonisation of new species. Here we report the first systematic investigation into the influence of the phylogenetic distance between arthropod species on the potential for reproductive parasite interspecific transfer.We employed a well characterised reproductive parasite, a coccinellid beetle male-killer, and artificially injected the bacterium into a series of novel species. Genetic distances between native and novel hosts were ascertained by sequencing sections of the 16S and 12S mitochondrial rDNA genes. The bacterium colonised host tissues and transmitted vertically in all cases tested. However, whilst transmission efficiency was perfect within the native genus, this was reduced following some transfers of greater phylogenetic distance. The bacterium's ability to distort offspring sex ratios in novel hosts was negatively correlated with the genetic distance of transfers. Male-killing occurred with full penetrance following within-genus transfers; but whilst sex ratio distortion generally occurred, it was incomplete in more distantly related species.This study indicates that the natural interspecific transmission of reproductive parasites might be constrained by their ability to tolerate the physiology or genetics of novel hosts. Our data suggest that horizontal transfers are more likely between closely related species. Successful bacterial transfer across large phylogenetic distances may require rapid adaptive evolution in the new species. This finding has applied relevance regarding selection of suitable bacteria to manipulate insect pest and vector populations by symbiont gene-drive systems. Reproductive parasites represent a diverse assemblage of maternally inherited microorganisms that induce aberrations in their hosts' reproductive biology in order to proliferate within arthropod populations. Their vertical transmission route greatly limits opportunities for interspecific transfer. However, phylogenies of hosts and parasites are generally not congruent, indicating that interspecific horizontal transfer events characterise the evolutionary history of these selfish genetic elements .Wolbachia is the best known, a variety of other microbial taxa has also evolved to manipulate arthropod reproduction, including microsporidia, gamma proteobacteria and members of the genera Cardinium, Rickettsia and Spiroplasma  \u2013 [AM779613]). We discarded the data from the 3' region of the 16S fragment which spanned the 5' end of the ND1 gene and the leucine tRNA and combined the remaining sequence from the two rDNA genes. A sequence alignment was constructed using CLUSTALW and manually edited, then a tree was constructed using the neighbour joining method in MEGA version 4.0 [A. bipunctata were calculated in MEGA using the parameter options above. Correlations of the species means for bacterial transmission rate and offspring sex ratio with genetic distance were determined non-parametrically using Spearman rank tests due to non-normality of dependent variables.For phylogenetic analysis we investigated two conserved sections from the 3' ends of the 16S and 12S mitochondrial ribosomal subunits of all host species. These were amplified using primer pairs N1-J-12585 \u2013 LR-N-13398 (16S) and SR-J-14233 \u2013 SR-N-14588 (12S) AM7798 \u2013 [AM77sion 4.0 ). RobustMCT collected insect samples from the field, performed injections and conducted molecular work. MCT and MENM collaboratively designed the study, reared ladybirds in the laboratory and interpreted the results. MCT drafted the paper. Both authors read and approved the final manuscript."}
+{"text": "A panel of doxorubicin-resistant sublines of the human small-cell lung carcinoma cell line GLC4 displays decreasing DNA topoisomerase II alpha  mRNA levels with increasing resistance. In the present study we describe how this decrease may be regulated. No significant differences in TopoII alpha mRNA stability or gene arrangement were found, using mRNA slot-blotting and Southern blotting, in the most resistant cell line compared with the parental cell line. To investigate if TopoII alpha gene copy loss contributed to the mRNA decrease, fluorescence in situ hybridisation using a TopoII alpha-specific probe was performed. During doxorubicin resistance development, the composition of the population in each cell line shifted with increasing resistance, from a population in which most cells contain three TopoII alpha gene copies (GLC4) to a population in which most cells contain only two copies. A partial revertant of the most resistant cell line displayed a shift back to the original situation. We conclude that the TopoII alpha gene copy number decrease per cell line is in good agreement with the decreased TopoII alpha mRNA and protein levels, and TopoII activity levels in these cell lines which were described previously."}
+{"text": "Of the 2 patients with left-sided portal hypertension, one died after splenectomy and one rebled 6 months after left colectomy. This study suggests that extrahepatic portal hypertension is a series complication after liver transplantation that could be prevented by meticulous portal anastomosis and closure of portal tributaries or portasystemic shunts to improve the  portal venous flow. However, any ligation has to be performed under ultrasound guidance to avoid inadventent venous ligations.This study reports our experience of 8 cases of extrahepatic portal hypertension after 273 orthotopic liver transplantations in 244 adult patients over a 10- year period. The main clinical feature was ascites, and the life-threatening complication was variceal bleeding. Extrahepatic portal hypertension was caused by portal vein stenosis in 6 patients, and left-sided portal hypertension in 2 patients after inadventent ligation of portal venous tributaries or portasystemic shunts. All patients with portal vein stenosis had complete relief of portal hypertension after percutaneous transhepatic venoplasty ("}
+{"text": "The predicted folded structures of these twenty H/ACA snoRNA-like miRNA precursors reveal molecules which resemble the structures of known box H/ACA snoRNAs. The genomic regions surrounding these predicted snoRNA-like miRNAs are often similar to regions around snoRNA retroposons, including the presence of transposable elements, target site duplications and poly (A) tails. We further show that the precursors of five H/ACA snoRNA-like miRNAs  bind to dyskerin, a specific protein component of functional box H/ACA small nucleolar ribonucleoprotein complexes suggesting that these molecules have retained some H/ACA snoRNA functionality. The detection of small RNA molecules that share features of miRNAs and snoRNAs suggest that these classes of RNA may have an evolutionary relationship.MicroRNAs (miRNAs) and small nucleolar RNAs (snoRNAs) are two classes of small non-coding regulatory RNAs, which have been much investigated in recent years. While their respective functions in the cell are distinct, they share interesting genomic similarities, and recent sequencing projects have identified processed forms of snoRNAs that resemble miRNAs. Here, we investigate a possible evolutionary relationship between miRNAs and box H/ACA snoRNAs. A comparison of the genomic locations of reported miRNAs and snoRNAs reveals an overlap of specific members of these classes. To test the hypothesis that some miRNAs might have evolved from snoRNA encoding genomic regions, reported miRNA-encoding regions were scanned for the presence of box H/ACA snoRNA features. Twenty miRNA precursors show significant similarity to H/ACA snoRNAs as predicted by snoGPS. These include molecules predicted to target known ribosomal RNA pseudouridylation sites  The major functions known for RNA were long believed to be either messenger RNAs, which function as intermediates between genes and proteins, or ribosomal RNAs and transfer RNAs which carry out the translation process. In recent years, however, newly discovered classes of small RNAs have been shown to play important cellular roles. These include microRNAs (miRNAs), which can regulate the production of specific proteins, and small nucleolar RNAs (snoRNAs), which recognise and chemically modify specific sequences in ribosomal RNA. Although miRNAs and snoRNAs are currently believed to be generated by different cellular pathways and to function in different cellular compartments, members of these two types of small RNAs display numerous genomic similarities, and a small number of snoRNAs have been shown to encode miRNAs in several organisms. Here we systematically investigate a possible evolutionary relationship between snoRNAs and miRNAs. Using computational analysis, we identify twenty genomic regions encoding miRNAs with highly significant similarity to snoRNAs, both on the level of their surrounding genomic context as well as their predicted folded structure. A subset of these miRNAs display functional snoRNA characteristics, strengthening the possibility that these miRNA molecules might have evolved from snoRNAs. Small nucleolar RNAs (snoRNAs) and microRNAs (miRNAs) are two classes of abundant non-coding regulatory RNAs that carry out fundamental cellular activities but that have only been comprehensively investigated in recent years. SnoRNAs are small RNA molecules of approximately 60\u2013300 nucleotides in length which generally serve as guides for the catalytic modification of selected ribosomal RNA nucleotides MiRNAs are \u223c18\u201324 nucleotide-long RNAs that are processed out of \u223c70 nucleotide-long hairpin structures  Many members of the snoRNA and miRNA classes are well conserved throughout evolution Recent reports have also described some miRNAs as being derived from TEs, suggesting a possible mechanism for the rapid generation of miRNAs and their corresponding target sites. In the first such report, Smalheiser and Torvik identified six miRNAs that are derived from TEs A recent report investigating the small RNAs present in human cells has demonstrated the existence of specific small RNA fragments derived from larger known non-coding RNA molecules A comparison between the genomic positions of reported miRNA genes from miRbase In addition to these known miRNAs encoded in box H/ACA snoRNAs, ten small fragments matching exactly to portions of eleven box H/ACA snoRNAs have been detected Apart from HBI-100, all box H/ACA snoRNAs from The UCSC Genome Browser mammalian conservation track shows that for all snoRNAs listed in The box H/ACA snoRNA/miRNA relationship described above was further investigated by studying all known miRNAs to determine whether they might be encoded within genomic regions predicted to harbour H/ACA snoRNAs. Indeed, if some miRNAs have evolved from H/ACA snoRNA encoding regions, they might still display snoRNA features. The mammalian version of the snoGPS program predicts pseudouridylation guides in human, mouse and rat genomes by scoring weakly conserved primary and secondary structure motifs using a deterministic search algorithm In order to investigate whether the number of snoGPS predicted hits above a certain threshold was significant, we used snoGPS to scan 100 sets of 676 randomly generated sequences of same length distribution as the miRNAs under study, as described in the 148 distinct extended miRNA molecules were predicted to encode at least one hit above a score of 35.0, which is the threshold that is \u2018typically\u2019 used when predicting new candidate snoRNAs by snoGPS-C The position of the predicted H/ACA snoRNA was compared to the position of the miRNA hairpin, taking coordinates downloaded from the UCSC Table Browser as described in the SnoGPS predicts guide sequences and corresponding rRNA pseudouridylation sites within snoRNAs. For all the best snoGPS hits with scores above 40 listed in The miRNAs reported in miRbase have not all been validated to the same extent. While the mature forms of some of the miRNAs have only been identified with a very small number of sequence reads, others have been identified by larger numbers of reads, display characteristic miRNA signatures . While the H box is located between the two hairpins, the ACA box is located at the 3\u2032 end of the molecule. One or both of the hairpins contain bulges, allowing base-pairing with the target RNA, in complex pseudo-knot structures. In order to better characterise the predicted snoRNAs encoding miRNAs and visualise the position of the mature miRNA within these molecules, all predicted snoRNA sequences were folded using RNAstructure http://www.repeatmasker.org). Sixteen of the twenty miRNAs originally considered have repeat elements either overlapping the predicted snoRNA encoding the miRNA or within 400 nucleotides. The position of the repeat elements with respect to the position of the miRNA and predicted snoRNA is shown in Because numerous snoRNAs and miRNAs have been described as being derived from TEs, all extended miRNA molecules predicted to have box H/ACA snoRNA features surrounding them from  were furin silico predictions that some miRNA precursors sufficiently resemble box H/ACA snoRNAs to be bound by dyskerin.To explore further potential snoRNA-like features of these miRNA precursors and to investigate whether they have retained some H/ACA snoRNA functionality, we tested whether they can bind dyskerin, a protein component of the functional box H/ACA snoRNPs. Dyskerin serves as the pseudouridine synthase Two of the dyskerin-bound miRNA precursors were further characterised by fractionated northern analysis to investigate where the predicted snoRNAs and smaller fragments localise in the cell. As shown in Numerous miRNAs have been previously shown to be repeat-derived Due to the inherent similarity between miRNAs and snoRNAs, such a relationship is easy to overlook as once a region is categorized as belonging to one molecular class, it is often no longer considered when searching for other types of molecules. The human genome has been scanned previously for the presence of box H/ACA snoRNAs using mammalian snoGPS Although no significant sequence similarity is detected between predicted snoRNA molecules encoding miRNAs and the known snoRNAs that target the same pseudouridylation sites, it is interesting to note that three snoRNAs  share their target pseudouridylation sites with eight of the predicted snoRNAs encoding miRNAs . This siin silico data presented here support these ideas. We tested the predictions by experimentally showing that the precursors of five of the predicted snoRNA-like miRNAs, mir-664, mir-151, mir-605, mir-215 and mir-140, interact with dyskerin, a protein component of functional H/ACA snoRNPs. While a lack of interaction to dyskerin could not rule out an evolutionary relationship between these miRNAs and snoRNAs as the miRNAs might have evolved sufficiently to no longer interact with functional protein components of snoRNPs, the detection of such an interaction considerably reinforces such claims. These results show that the snoRNA-like miRNA precursors sufficiently resemble box H/ACA snoRNAs to bind dyskerin, strengthening the possibility of an evolutionary relationship between these molecules. Further experiments will be necessary to investigate whether these molecules also retain the capability of targeting rRNA in vivo. It will also be necessary to experimentally test whether the remaining fifteen predicted snoRNA-like miRNA precursors also display aspects of H/ACA snoRNA functionality. The fact that three of these molecules  display the sequence AGA instead of the canonical ACA box could indicate that they have evolved sufficiently to no longer retain H/ACA snoRNA functionality. We do note that while identifying molecules that display both miRNA and snoRNA functionality supports our evolutionary hypothesis, we also expect to find a larger number of molecules that display features of both molecules but do not represent completely prototypical examples.This redundancy in rRNA complementarity may suggest some box H/ACA snoRNAs and snoRTs are not under as much selective pressure to avoid mutations. We hypothesize that some of these snoRNA encoding regions might be in the process of evolving from functional snoRNAs to miRNA-like precursors. This process might be facilitated by the fact that box H/ACA snoRNAs have a structure (2 hairpins) that is probably favourable to the formation of miRNAs. The Saccharomyces cerevisiae has snoRNAs but no reported miRNAs, consistent with a relationship where primordial snoRNAs may have given rise to certain classes of miRNAs. This idea is supported by a recent article by Saraiya and Wang reporting that the primitive parasitic protozoan Giardia lamblia, which does not have RNA interference capabilities but has miRNA processing machinery, uses box C/D snoRNAs as miRNA precursors Arabidopsis and Schizosaccharomyces pombe generate small RNAs , which are associated with argonaute proteins GiardiaIt is interesting to note that In addition to investigating whether some of the H/ACA snoRNA-like miRNA precursors display functional H/ACA snoRNA capability by binding to dyskerin , we haveWhile all the miRNAs characterised in A recent large-scale study defining an expression atlas for mammalian miRNAs, by Landgraf and colleagues, classifies known miRNAs into four different groups: prototypical, repeat-derived, repeat-clustered and unclassified http://www.repeatmasker.org). MiRNA and box H/ACA snoRNA genes as well as repeat-elements and sequence features were visualised with the UCSC Genome Browser The genomic positions, sequences and flanking regions of human miRNA genes and box H/ACA snoRNA genes were downloaded from the UCSC Table Browser 676 distinct human miRNA encoding regions (including the miRNA hairpins and 175 flanking nucleotides on either side) were scanned for the presence of box H/ACA snoRNAs using a locally-installed copy of the snoGPS program RNA secondary structures were predicted using RNAstructure 4.5 YFP-Dyskerin and HeLaGFP stable cell lines. Purified nuclei were resuspended in RIPA buffer to solubilise proteins. Fluorescence proteins were immunoprecipitated using GFP binder (ChromoTek) covalently coupled to NHS-activated Sepharose 4 Fast Flow beads  using the SuperScript one-step RT-PCR kit (Invitrogen). To decide linearity of cycles, we performed real time PCR using the Superscript III Platinum SYBR Green one-step qRT-PCR Kit (Invitrogen) and Rotor-Gene RG-3000 system (Corbett Research). The same amount of RNA for input and immunoprecipitated RNA (IP) was used as templates for RT-PCR reactions. Each experiment was repeated three times independently.Immunoprecipitations were prepared as previously described 32P 5\u2032 end-labelled oligoribonucleotide probes specific for the following RNA species; . High sensitivity RNA blots were prepared as previously described HeLa cell extracts were fractionated using sucrose gradients, as previously described Figure S1Mammalian conservation of box H/ACA snoRNAs that encode experimentally detected smaller fragments(1.63 MB PDF)Click here for additional data file.Figure S2Predicted secondary structures of H/ACA snoRNA-like miRNA precursors(0.07 MB PDF)Click here for additional data file.Figure S3Repeat elements in proximity of H/ACA snoRNA-like miRNA genomic regions(3.58 MB PDF)Click here for additional data file.Figure S4Sequence elements surrounding selected miRNAs(0.03 MB PDF)Click here for additional data file.Figure S5Northern blot showing the subcellular localization of H/ACA snoRNA-like miRNA precursors (same as (0.31 MB PDF)Click here for additional data file."}
+{"text": "The secreted MIA protein is strongly expressed by advanced primary and metastatic melanomas but not in normal melanocytes. Previous studies have shown that MIA serum levels correlate with clinical tumour progression in melanoma patients. To provide direct evidence that MIA plays a role in metastasis of malignant melanomas, A-mel 3 hamster melanoma cells were transfected with sense- and antisense rhMIA cDNA and analysed subsequently for changes in their tumorigenic and metastatic potential. Enforced expression of MIA in A-mel 3 cells significantly increased their metastatic potential without affecting primary tumour growth, cell proliferation or apoptosis rate in hamsters, compared with control or antisense transfected cells. Additionally, MIA overexpressing transfectants showed a higher rate of both tumour cell invasion and extravasation. Cells transfected with MIA antisense generally exerted an opposite response. The above changes in function attributed to the expression of MIA may underlie the contribution of MIA to the malignant phenotype. \u00a9 2000 Cancer Research Campaign"}
+{"text": "Herpes viruses by constructing a graph alignment, which is based jointly on the similarity of their protein interaction networks and on sequence similarity. This hybrid method provides functional associations between proteins of the two organisms that cannot be obtained from sequence or interaction data alone.Sequence alignment is a prolific basis of functional annotation, but remains a challenging problem in the 'twilight zone' of high sequence divergence or short gene length. Here we demonstrate how information on gene interactions can help to resolve ambiguous sequence alignments. We compare two distant We find proteins where interaction similarity and sequence similarity are individually weak, but together provide significant evidence of orthology. There are also proteins with high interaction similarity but without any detectable sequence similarity, providing evidence of functional association beyond sequence homology. The functional predictions derived from our alignment are consistent with genomic position and gene expression data.Our approach shows that evolutionary conservation is a powerful filter to make protein interaction data informative about functional similarities between the interacting proteins, and it establishes graph alignment as a powerful tool for the comparative analysis of data from highly diverged species. With the advent of genome-wide functional data, cross-species comparisons are no longer limited to sequence information. A classic extension of sequence alignment is structural alignment, which has been used to compare evolutionary distant RNAs  and protvaricella-zoster virus (VZV), causing chicken pox and shingles, and the Kaposi's sarcoma-associated herpesvirus (KSHV), responsible for cancer of the connective tissue. The two viruses have diverged approximately 200 million years ago. Their sequence dynamics is characterised by a high rate of point mutations  and a hulations ). As a rgraph alignment establishes a mapping between genes of two species ; ORF 23: [GenBank: NP 572075.1]; ORF 41: [GenBank: NP 572094.1]; ORF 29b: [GenBank: NP 572081.1]. VZV ORFs: ORF25: VOCs ID 59436; ORF65: 59475; ORF39: 59450; ORF60: 59470; ORF42: 59453.Supplementary Text. The Supplementary Text [Additional file Click here for fileSupplementary Animation. The Supplementary Animation [Additional file Click here for file"}
+{"text": "To administer medication in high concentration:for severe inflammationfor treating infectionat the end of an operationfor dilating the pupil.local anaesthetic dropssterile 2 ml syringeprescribed medicationsterile 21G needlesterile 25G needleeye padtapebandageclean cotton wool or gauze swabs.Remember!This procedure can be very distressing for the patient and needs to be explained sensitively to ensure maximum cooperation.Position the patient lying comfortably with his/her head supported on a pillow.Reassure the patient that adequate anaesthetic drops will be instilled before the injection is given.Instill anaesthetic drops at five-minute intervals over half an hour - a minimum of six drops.Away from the patient's view, draw up the prescribed medication using the 21G needle  may be given for pain relief."}
+{"text": "Significant correlations betweenBOM and operation time and blood loss were found(p<0.01). Conclusions Bilirubin appears to act as anantioxidant for invasive surgery in humans. UrinaryBOM could be a reliable marker for the degree ofsurgical stress.Background Bilirubin has been recognized as an antioxidant.The purpose of this study was to examinewhether bilirubin would act as an antioxidant forsurgical stress in humans. Materials and MethodsSerum bilirubin and urinary bilirubin oxidativemetabolites (BOM) were measured in 96 patientswho underwent surgery. The antioxidant activityof bilirubin was assessed using BOM measuredby enzyme-linked immunosorbent assay with ananti-bilirubin monoclonal antibody. Results Serumbilirubin levels increased after surgery in all 96patients ("}
+{"text": "Multislice computed tomography (MSCT) scanners offer newperspectives for cardiac kinetics evaluation with 4D dynamicsequences of high contrast and spatiotemporal resolutions. A newmethod is proposed for cardiac motion extraction in multislice CT.Based on a 4D hierarchical surface-volume matching process, itprovides the detection of the heart left cavities along theacquired sequence and the estimation of their 3D surface velocityfields. A Markov random field model is defined to find, accordingto topological descriptors, the best correspondences between a 3Dmesh describing the left endocardium at one time and the 3Dacquired volume at the following time. The global optimization ofthe correspondences is realized with a multiresolution process.Results obtained on simulated and real data show the capabilitiesto extract clinically relevant global and local motion parametersand highlight new perspectives in cardiac computed tomographyimaging."}
+{"text": "Survival from colorectal cancer has been analysed in relation to marital status in a nationwide Danish study of 9596 patients with complete follow-up of 22-26 years. After exclusion of 2294 patients with missing information adjusted five-year survival among married patients was significantly longer ."}
+{"text": "We have measured the serum concentration of the acute phase reactant, C-reactive protein (CRP), in 20 patients with histologically proven small cell lung cancer undergoing their first pulse of induction cytotoxic chemotherapy. Baseline CRP concentrations were raised in 16 of 20 patients . CRP levels more than doubled in 11 of 20 patients during induction chemotherapy. This acute phase reaction was seen in seven of the 10 chemosensitive patients, but was not observed in any of the five non-responding patients. Five patients were non-evaluable for chemoresponse. These data indicate that there is a previously undescribed quantifiable acute phase response during chemotherapy for small cell lung cancer which has potential for predicting chemoresponse."}
+{"text": "A 45-year-old alcoholic male patient presented with hypovolemic shock and intense anemia (Hemoglobin 04.7 g/dl), and was operated on. A bleeding retroperitoneal varix located near the right colon was responsible for the clinical picture and was sutured. After operation the patient developed haemodynamic instability and pneumonia a situation which was reverted with intensive medical therapy. The patient is now doing well."}
+{"text": "Lymph node pathologic status is the most important prognostic factor in vulvar cancer; however, complete inguinofemoral node dissection is associated with significant morbidity. Lymphoscintigraphy associated with gamma-probe guided surgery reliably detects sentinel nodes in melanoma and breast cancer patients. This study evaluates the feasibility of the surgical identification of sentinel groin nodes using lymphoscintigraphy and a gamma-detecting probe in patients with early vulvar cancer. Technetium-99m-labelled colloid human albumin was administered perilesionally in 37 patients with invasive epidermoid vulvar cancer (T1\u2013T2) and lymphoscintigraphy performed the day before surgery. An intraoperative gamma-detecting probe was used to identify sentinel nodes during surgery. A complete inguinofemoral node dissection was then performed. Sentinel nodes were submitted separately to pathologic evaluation. A total of 55 groins were dissected in 37 patients. Localization of the SN was successful in all cases. Eight cases had positive nodes: in all the sentinel node as positive; the sentinel node was the only positive node in five cases. Twenty-nine patients showed negative sentinel nodes: all of them were negative for lymph node metastases. Lymphoscintigraphy and sentinel-node biopsy under gamma-detecting probe guidance proved to be an easy and reliable method for the detection of sentinel node in early vulvar cancer. This technique may represent a true advance in the direction of less aggressive treatments in patients with vulvar cancer. \u00a9 2000 Cancer Research Campaign"}
+{"text": "Natural killing (NK) by lymphocytes from normal individuals against primary and established ovarian carcinoma cell lines was tested in short-term chromium release assays. Two established cell lines and 5/6 primary cell lines tested showed significant susceptibility to NK. Primary cell lines are, in general, less sensitive to NK than long-term cultured target cells. A common NK recognition determinant on ovarian carcinoma cells and on the erythroleukaemic K562 cells was demonstrated by cold target inhibition assays. The recognition structure was also present on an ovarian cell line resistant to NK but not on the insensitive leukaemic cell line, SB. The activity against ovarian carcinoma cells was associated with the presence of large granular lymphocytes (LGL) previously shown to be the major effector cells against K562 targets. In fractions obtained by Percoll gradient centrifugation of lymphocytes, only fractions with a high content of LGL demonstrated good NK activity. LGL mediated NK against both non-adherent K562 and the adherent ovarian carcinoma target cells independent of monocytes."}
+{"text": "Total upper body drainage via left superior vena cava into coronary sinus (i.e. absent right superior vena cava) is a rare anomaly and distorts the anatomy of coronary sinus and triangle of Koch. Herewith we are reporting the first report of ablation in a patient with superior vena cava draining into coronary sinus totally. This patient with atrioventricular nodal re-entrant tachycardia, baseline left bundle branch block, transient complete heart block during electrophysiological study and total upper body venous drainage into coronary sinus had successful slow pathway ablation using anatomical approach. Anatomical approach to atrioventricular nodal re-entrant tachycardia (AVNRT) ablation based on the triangle of Koch is the standard technique now, with a success rate close to 99%. Anatomy of the coronary sinus is important to guide anatomy guided ablation. Left superior vena cava (LSVC) draining into coronary sinus is not an uncommon anomaly that enlarges the coronary sinus . The enlA 49 years old female presented with history of recurrent palpitations for last 10 years. During last year, she had 5 episodes of palpitations which required hospitalizations. The tachyardia was repeatedly terminated by intravenous adenosine and verapamil. She was nondiabetic and nonhypertensive. General physical and cardiovascular examination were normal. Her baseline electrocardiogram (ECG) showed left bundle branch block with normal PR interval. The electrocardiogram  of tachycardia revealed similar morphology, with the heart rate of 210 beats/min. . Her traThe approach for the ablation of slow pathway in patients with anomalous drainage of superior vena cava into coronary sinus is not clear because of distorted triangle of Koch due to dilated coronary sinus -5. This"}
+{"text": "Lymphocytes obtained from hilar and bronchial lymph nodes from 23 patients undergoing radical surgery for carcinoma of the bronchus were fused with established rat or mouse myeloma lines. 62% of the resultant hybrids were found to be secreting human Ig detected by a sensitive staphylococcal Protein A-coupled SRBC assay. Immunoglobulins synthesized by such hybrids were internally labelled with 3H-lysine and their antibody activity against a variety of membrane preparations determined. Nine monoclonal antibodies were found which bound to molecules on lung-cancer membranes and not on normal lung membranes from the same patient."}
+{"text": "Mice were exposed to plutonium dioxide (PuO2) aerosols 2 weeks before or after urethan injection. Both exposures reduced the number and size of adenomas. The incidence of arrested metaphases showed no consistently significant differences between plutonium-exposed and mock-exposed animals. The results are discussed in relation to recent electron microscopic evidence of degenerative changes in the type II epithelial cells of the mouse lung following PuO2 inhalation. It is concluded that damage at the cellular level may account for the observed reduction in growth of pulmonary adenomas in mice whose lungs contained plutonium particles."}
+{"text": "Methotrexate (MTX) is a folate antagonist widely used both as an anticancer drug and as an immunosupressant. Administration of an 8-day methotrexate and folinic acid regime may be associated with pleuritic chest pain and pneumonitis. We have reviewed the toxicity seen in 168 consecutive patients treated with low-dose MTX for persistent trophoblastic disease. Twenty-five per cent of patients developed serosal symptoms, pleurisy was the commonest complaint. The majority of patients had mild to moderate symptoms which were controlled with simple analgesia and did not necessitate a change in treatment; 11.9% had severe symptoms which necessitated a change in treatment. One patient developed a pericardial effusion and a second patient developed severe reversible peritoneal irritation. The possible aetiology and pathophysiology of methotrexate-induced serosal toxicity is discussed. \u00a9 1999 Cancer Research Campaign"}
+{"text": "Its ability to suppress DNA synthesis contributes little to the inhibition of cell cycling.Bleomycin inhibits cell division in HeLa S-3 and other mammalian epithelial cell lines. Its effect on suspension cultured cells is far greater than on monolayer cells; this was found to be due partly to the absence of divalent ions. Other mammalian epithelial lines in suspension culture are very sensitive but fibroblastic cells (BHK 21/C13/DWS-3) grown under identical conditions are relatively insensitive. This study has established that bleomycin is a powerful anti-mitotic agent during the G"}
+{"text": "The plus/minus symbol appears incorrectly as an upside-down Latin capital letter A in the Results subsection \"Depth-sampling reveals multiple copy RXLR effectors are prevalent,\" as well as in a number of other instances highlighted throughout the article."}
+{"text": "These studies were undertaken to assess the relative expression and autocrine activation of the epidermal growth factor receptor (EGFR) in normal and transformed prostatic epithelial cells and to determine whether EGFR activation plays a functional role in androgen-stimulated growth of prostate cancer cells in vitro. EGFR expression was determined by Western blot analysis and ELISA immunoassays. Immunoprecipitation of radiophosphorylated EGFR and evaluation of tyrosine phosphorylation was used to assess EGFR activation. The human androgen-independent prostate cancer cell lines PC3 and DU145 exhibited higher levels of EGFR expression and autocrine phosphorylation than normal human prostatic epithelial cells or the human androgen-responsive prostate cancer cell line LNCaP. PC3 and DU145 cells also showed higher levels of autonomous growth under serum-free defined conditions. Normal prostatic epithelial cells expressed EGFR but did not exhibit detectable levels of EGFR phosphorylation when cultured in the absence of exogenous EGF. Addition of EGF stimulated EGFR phosphorylation and induced proliferation of normal cells. LNCaP cells exhibited autocrine phosphorylation of EGFR but did not undergo significant proliferation when cultured in the absence of exogenous growth factors. A biphasic growth curve was observed when LNCaP cells were cultured with dihydrotestosterone (DHT). Maximum proliferation occurred at 1 nM DHT with regression of the growth response at DHT concentrations greater than 1 nM. However, neither EGFR expression nor phosphorylation was altered in LNCaP cells after androgen stimulation. In addition, DHT-stimulated growth of LNCaP cells was not inhibited by anti-EGFR. These studies show that autocrine activation of EGFR is a common feature of prostatic carcinoma cells in contrast to normal epithelial cells. However, EGFR activation does not appear to play a functional role in androgen-stimulated growth of LNCaP cells in vitro."}
+{"text": "An 18-year-old male patient presented with chronic nonspecific pain of three months located at his left proximal tibia. The patient was admitted to our department for plain X-ray, computed tomography and magnetic resonance imaging examination. Plain X-ray and computed tomography revealed a geographic lytic lesion at the medial aspect of the proximal tibia. Biopsy of the lesion showed telangiectatic osteosarcoma. Image findings of all modalities are presented. Telangiectatic osteosarcoma is an uncommon histopathologic subtype that represents 2.5 -12% of all osteosarcomas . These histologic features are the cause of telangiectatic osteosarcoma often having been described as showing non-specific bone lysis on radiographs and simulating aneurysmal bone cyst. The soft tissue counterpart of telangiectatic osteosarcoma is uncommon in young patients and usually affects adults older than 50 years . It presThe knowledge of radiologic findings of telangiectatic osteosarcoma is important as its often much less aggressive appearance may lead to underdiagnosis of this lesion and delay in therapeutic management of the patient."}
+{"text": "We report the first case of endocarditis caused by a Gordonia species genetically related to G. sputi but exhibiting some atypical biochemical features in a 31-year-old woman with a central venous catheter. This unusual pathogen may be a new cause of opportunistic infections in patients with severe underlying diseases."}
+{"text": "A 75 year old lady presented with acute central retinal artery occlusion and contralateral cotton wool spots.General physical examination and investigations led to a diagnosis of CREST syndrome; however, association of central retinal artery occlusion with CREST syndrome is not well known. While diabetes, systemic hypertension, carotid atherosclerosis and cardiac pathology are common causes of CRAO it is always important to rule out giant cell arteritis.This case highlights that inflammatory causes of central retinal artery occlusion other than giant cell arteritis should also be considered as a possibility to spare unnecessary use of excessive systemic corticosteroids. We present an unusual case of acute central retinal artery occlusion and cotton wool spots as the presenting feature in a patient subsequently diagnosed with systemic sclerosis, in particular with features of CREST syndrome.A 75-year old Caucasian lady presented with acute onset of painless visual loss in her left eye, which she noted on waking up that morning. She denied any associated headaches, jaw claudication or any clinical symptoms suggestive of temporal arteritis. Past ophthalmic history was not significant apart from one episode of transient visual loss in the left eye of about 5 minutes duration with zigzag lines three months earlier. This was accompanied by spontaneously resolving short-duration headache. The general practitioner diagnosed an episode of migraine with no further investigations or recurrence. She had treated essential hypertension and suffered especially in cold weather with Raynaud's phenomenon for 20 years; this had worsened in severity in the last few months.On examination visual acuity of 20/20 in the right and CF (counting fingers at 0.5 m) was noted in the left eye with a left relative afferent pupillary defect. Anterior segment examination was unremarkable with normal intraocular pressures. Dilated fundal examination showed a cherry-red spot in the left foveal area. No visible arteriolar embolus was noted Fig . Apart fFurther investigations revealed a positive ANA's at 8.1 U (0\u20131.0 reference range) with a positive anti-centromere antibody and a negative anti-Scl-70 and anti-ds DNA antibody. X-rays of the hands did not reveal any significant calcinosis or erosions. Barium swallow was unremarkable but echocardiography showed mild concentric hypertrophy of ventricular walls consistent with long-standing systemic hypertension.Mild non-flow limiting plaque was also detected on coronary angiography. Her pulmonary hypertension was attributed to her cardiac status with atrial fibrillation and systemic hypertension rather than connective tissue disorder related. Carotid duplex scans revealed minor calcific plaques with no significant stenosis in either carotid arterial system. She remains under joint rheumatology and ophthalmology review on immunosuppression with methotrexate 10 mg per week, prednisolone 7.5 mg daily and anti-platelet therapy with no further visual symptoms after 12 months of follow up.Various authors -5 have nCREST syndrome can be quite variable and may or may not show all the features in a single patient at one time point. Our case highlights the importance of thorough clinical examination including review of systems and appropriate referral as the appearance of her hands, telangiectasias & presence of Raynaud's phenomenon lead to well-directed investigations and subsequent clinical diagnosis. While temporal arteritis was a reasonable diagnosis to entertain initially, we stopped the oral steroids immediately with unremarkable blood and angiogram results. The patient was thus saved a significant systemic corticosteroid load with avoidance of possible adverse effects including scleroderma renal crisis which may be seen in scleroderma patients treated with high dose steroids.The presence of cotton wool spots in her right eye strongly suggested an inflammatory cause for CRAO and although microvasculopathy is a more consistent feature of the systemic sclerosis spectrum, macrovascular disease has been reported. It should be noted that in general CRAO is rarely caused by inflammation with atherosclerotic disease being the usual aetiology -7. In ouIn a review  listing Ophthalmologists should be aware of this unusual association between central retinal artery occlusion and CREST syndrome. While the prognosis for central retinal artery occlusion is extremely guarded, systemic workup to rule out life threatening co-morbid conditions remains the cornerstone of management.CREST: ; CRAO: ; ESR: Erythrocyte sedimentation rate; CRP: C Reactive Protein; ANA: (Anti-Nuclear antibodies); Anti-ds: (Anti-double strand).The authors declare that they have no competing interests.MR analyzed and reviewed the literature and drafted the case report. TM and BJB provided valuable input to the manuscript. All authors read and approved the final manuscript.Written informed consent was obtained from the patient for the publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal."}
+{"text": "P=0.119).The authors have performed this study to explore the effectiveness of neoadjuvant androgen suppression in patients of localized prostate cancer treated with high-intensity focused ultrasound (HIFU). From January 1999 to January 2005, they had treated 250 patients with HIFU. One hundred and fifty-four patients received neoadjuvant hormonal therapy and 96 were not treated with androgen suppression. Treatment failure was defined by presence of prostate cancer on biopsy taken six months after HIFU. In this unrandomized trial, the authors found a slightly lower treatment failure rate in patients who received neoadjuvant androgen suppression (31% vs. 34%), but this was not statistically significant (Use of neoadjuvant/concurrent hormonal therapy for localized prostate cancer treated by radical radiotherapy is currently getting studied in many trials. Initial results have been encouraging with significant benefit in the relapse-free /PSA-free interval in these patients. There ha"}
+{"text": "Pulmonary tumor thromoembolism is well described in literature especially in patients known to have cancer. We are presenting this report of a patient presenting with Acute Cor-pulmonale secondary to Occult Gastric carcinoma causing pulmonary tumor embolism. This is an unusual presentation of occult neoplasm. Pulmonary tumor embolism is an important but \u2018uncommon\u2019 cause of dyspnea in patients with cancer. It is \u2018uncommon\u2019 as it is under-recognized! Autopsy reports show that up to 26% of patients who die with cancer have tumor cells in their pulmonary vasculature. By this article we aim to increase the awareness of this condition, thereby leading to appropriate management.A 77-year-old Caucasian male who was admitted in the surgical ward with complaints of abdominal pain and altered bowel habits of 3-week duration was referred to the medical team due to increasing dyspnea. He had sustained an injury to knee 4 weeks back and had been taking regular codeine and paracetamol tablets for pain. His abdomen X-ray had shown fecal loading, rigid sigmoidoscopy was normal and the provisional diagnosis was constipation secondary to codeine. He gave a history of gradually progressive dyspnea over 2 weeks. There was no other significant past medical history. On examination he had features of right-sided heart failure with pulmonary hypertension. Arterial blood gases showed hypoxia. ECG showed S1Q3T3 pattern. The diagnosis of pulmonary embolism was made and he was started on full-dose low- \u2018molecular weight\u2019 Heparin. Echocardiogram showed dilated right ventricle with impaired function and right ventricular systolic pressure >80 mmHg. CT pulmonary angiogram showed no evidence of pulmonary embolism but did show multiple lymph node enlargement. Patient had cardiac arrest and resuscitation attempts were unsuccessful.Postmortem showed multiple lymph node enlargements inside mediastinum and abdomen, malignant-looking ulcer in stomach and tumor infiltration throughout small bowel mesentery. Microscopy of gastric ulcer revealed adenocarcinoma.Right ventricle did not show any features of hypertrophy.Macroscopically, lungs were edematous but pulmonary arteries showed no evidence of pulmonary embolism. Microscopy of pulmonary parenchyma showed pulmonary hypertensive changes and extensive tumor thromboemboli involving pulmonary microvasculature.Final diagnosis: Widespread carcinamatosis due to carcinoma stomach.Acute cor pulmonale due to pulmonary tumor thromboembolism.The entity of pulmonary tumor thromboembolism has been described as early as in 1897 (Schmidt).The most common presenting complaint is dyspnea. Other feThe incidence of pulmonary tumor thromboembolism is between 3 and 26% in patients with cancer, but therThe pulmonary arteries are grossly normal but microscopy reveals fibrocellular intimal proliferation with smooth muscle colonization of luminal neoplastic lesions and associated microthrombi. This cauHypoxemia with normal chest radiograph is the common finding. Ventilation perfusion scanning characteristically shows multiple subsegmental mismatched defects. CT pulmonary angiography, which is emerging as the investigation of choice in pulmonary embolism, is not a helpful test in this case. Pulmonary angiography, which is the gold standard to diagnose pulmonary embolism, has poor sensitivity and specificity. Right heThe median survival of these patients reported in literature is 3 days. Thrombol"}
+{"text": "Ventricular tachycardia (VT) occurring late after myocardial infarction is often due to reentry circuit in the peri-infarct zone. The circuit is usually located in the sub-endocardium, though subepicardial substrates are known. Activation mapping during VT to identify target regions for ablation can be difficult if VT is non inducible or poorly tolerated. In the latter, a substrate based approach of mapping during sinus rhythm in conjunction with pace mapping helps to define the reentry circuit and select target sites for ablation in majority of patients with hemodynamically unstable VT. Percutaneous epicardial catheter ablation has been attempted as an approach where ablation by a conventional endocardial access has been unsuccessful. We report a case of post myocardial infarction scar VT which could be successfully ablated with a substrate based approach from the epicardial aspect. A 62 year old male presented with recurrent ventricular tachycardia (VT). He had suffered an inferior wall myocardial infarction with resultant mild left ventricular (LV) dysfunction (LV ejection fraction 40%) and had an ICD implanted 3 years back. The patient was now hospitalised with recurrent appropriate ICD shocks. He was loaded upfront with intravenous amiodarone followed by oral amiodarone and beta blockers. However, VT continued to recur resulting in frequent ICD shocks despite maximal tolerated drug therapy.Patient was taken up for radiofrequency ablation. An initial endocardial approach was used using electro-anatomic mapping system (EAM) . The equipment used for recording was an EP-TRACER . An endocardial voltage map of the LV was created using a Navistar catheter under EAM guidance by a retrograde transfemoral approach. While mapping, a sustained monomorphic VT was induced with a LBBB, superior axis morphology, QS complexes in V1-V6; tachycardia cycle length (TCL) of 318 msec . The endThe pericardial space was exposed using a percutaneous subxiphoid approach. Pericardial puncture was performed with a 17-gauge epidural needle. The puncture was performed at the left lower edge of the xiphoid, at a 45 degree angle toward the left scapula. Two milliliters of contrast was injected via the needle to delineate the heart silhouette to confirm intra-pericardial location. A standard 8F sheath mounted over a guidewire was then introduced into the pericardium through a small incision. An externally irrigated RF catheter  was then introduced through the sheath and carefully pushed into the pericardial space. The catheter was constantly irrigated with saline (1 mL/min flow rate). Programmed electrical stimulation (PES) from the epicardium failed to induce the VT. Following isoprenaline infusion VT could be induced on PES. However the VT was hemodynamically unstable and had to be promptly terminated.A substrate based voltage map of the LV epicardium in sinus rhythm was constructed which revealed presence of scar (defined by voltages < 0.5 mV) in posterobasal LV. Multiple areas of low voltage fractionated activity in the peri-scar area associated with late diastolic potentials (LDP) during sinus rhythm could be identified . These aA review EP study was performed 24 hours later which did not induce any tachycardia on PES with isoprenaline. Oral amiodarone was stopped and the patient was discharged on beta blockers. Patient remained symptom free and at a follow up of three months, the ICD did not reveal  any new tachyarrhythmia by telemetry.Catheter ablation has an increasingly important role in controlling ventricular tachycardia (VT) episodes in patients with structural heart disease who have implanted cardioverter defibrillators. Substrate for reentrant VT is often subendocardial and is accessible for catheter ablation by a transvenous approach. However, epicardial ablation is required for 10-30% of postinfarct VTs, and for more than 30% of VTs due to nonischemic cardiomyopathy [The substrate for postinfarction VT is well characterized. Surviving muscle bundles commonly located in the subendocardium but also in the mid myocardium and epicardium, traverse the borders and penetrate the deeper scar . The locCiccasio et al  used sinPercutaneous, pericardial instrumentation via subxiphiod approach permits characterization and imaging of the epicardial substrate in a fashion similar to that for the endocardium. A substrate based ablation reduces or eliminates the need for mapping during prolonged periods of tachycardia and extends the potential benefits of ablation to the large majority of VTs that are hemodynamically unstable."}
+{"text": "Background: Although maternal infections with coxsackievirus during pregnancy are relatively common, fetal infections are quite rare. Coxsackievirus infection in utero has been associated with myocarditis, but has not been proven a teratogen.Case: A patient whose fetus had structural cardiac anomalies and hydrops was found to have an intrauterine infection with Coxsackie B-1 virus, proven by virus isolation from the amniotic fluid. This infection led to increasing intrauterine hydrops and subsequent neonatal death. Conclusion: This interesting association of intrauterine infection with Coxsackie B virus and structural cardiac anomalies in the fetus warrants further investigation."}
+{"text": "A promising new treatment for glioma involves Auger electron emitters such as 125I or 123I conjugated to deoxyuridine (IUdR). However, the presence in tumour deposits of non-proliferating cells with clonogenic potential poses a major limitation to this cycle-specific therapy. We have used multicellular tumour spheroids derived from the human glioma cell line UVW to study [125I]IUdR-targeted radiotherapy in aggregates containing cells in different proliferative states. Autoradiographic identification of labelled cells indicated that nuclear incorporation of [125I]IUdR decreased markedly with increasing size of spheroid. IUdR incorporation was maximal in the surface layer of cells and decreased with depth within spheroids. Radiopharmaceutical uptake corresponded closely to the regions of cell cycling as indicated by staining for the nuclear antigen Ki67. The uptake of drug was enhanced by increasing the duration of incubation from 52 h to 104 h. These observations suggest that significant sparing of non-cycling malignant cells would result from treatment delivered as a single injection of radiolabelled IUdR. To achieve maximal therapeutic effect. IUdR should be administered by multiple injections, by slow release from biodegradable implants or by slow-pump delivery."}
+{"text": "Biventricular (BiV) is extensively used in the treatment of congestive heart failure but so far no recommendations for optimized programming of atrioventricular-delay (AVD) settings have been proposed. Can AVD optimization be performed using a simple formula based on non-invasive doppler-echocardiography?25 patients (ejection fraction 30\u00b18%) received BiV ICDs. Doppler-echocardiographic evaluation of diastolic and systolic flow was performed for different AVDs (30ms to 150ms) and different stimulation sites (left ventricular (LV), right ventricular and BiV). The optimal atrioventricular delay was calculated applying a simple formula based on systolic and diastolic mechanical delays determined during doppler-echocardiography.The mean optimal AVD was calculated to be 112\u00b129ms (50 to 180ms) for BiV, 95\u00b130ms (65 to 150ms) for LV and 75\u00b128ms (40 to 125ms) for right ventricular pacing with wide interindividual variations. Compared to suboptimal AVDs diastolic optimization improved preejection and ejection intervals independent to pacing site. Optimization of the AVD significantly increased ejection time during BiV pacing . Compared to LV or right ventricular pacing BiV pacing produced the shortest mean pre-ejection and longest ejection intervals as parameters of improved systolic ventricular contractile synchrony. Diastolic filling times were longest during BiV pacing compared to LV or RV pacing.Individual programming of BiV pacing devices increases hemodynamic benefit when implementing the inter-individually widely varying electromechanical delays. Optimization applying a simple formula not only improves diastolic ventricular filling but also increases systolic functional parameters. Systolic resynchronization using biventricular (BiV) pacing has evolved as an established add-on therapeutic option in patients with symptomatic congestive heart failure. When pacing the left ventricle via the coronary sinus the contraction pattern of the interventricular septum and the contraction sequence of both ventricles is improved. This therapy has proven to increase systolic function (dP/dt) and cardiac function -5.In patients with left ventricular pump failure conventional dual chamber pacemakers have been shown to alter hemodynamics in regard to the programmed atrioventricular delay (AVD). A long AVD leads to atrial contraction too early for optimal ventricular filling . On the other hand a short AVD may lead to atrial contraction after closure of the atrioventricular valve (due to systolic increase of ventricular pressure) -10.Different methods have been proposed to determine the most favorable  AVD aiming at either optimizing systolic or diastolic cardiac function. Diastolic optimization of the AVD aims at restoring the atrial kick by coincidental timing of the end the left atrial systole and the mitral valve closure ,6,11-17.We studied the feasibility and efficacy of AVD optimization adapting a modification of a formula for optimal AVD programming in patients under biventricular stimulation with intrinsic atrioventricular conduction and left ventricular insufficiency. The effects on non-invasively determined parameters of cardiac systolic and diastolic function     were assessed. 25 consecutive patients were included after implantation of biventricular implantable defibrillators (ICD) (Medtronic InSync\u2122 ICD) for chronic heart failure class II to IV in between 1999 and 2001. All patients gave informed consent; the protocol was evaluated by the institutional ethics review board.In all patients a standard ECG (12-lead) and Doppler-echocardiographic studies were performed 30 days after implantation. Different AVDs were programmed  for the 3 programmable stimulation sites . Fusion beats were excluded on the basis of QRS morphology. For each programming mitral- and tricuspid-valve and aortic valve Doppler-echocardiograms were performed using our Hewlett Packard Sonos 5500 echocardiography system with continuous display of ECG at a paper speed of 100mm/sec. Measurements were performed after a resting period of 1 minute in intrinsic rhythm. Prior to each measurement an adapting period of 1 minute was established. 3 consecutive atrioventricular and aortic valve flow profiles were analyzed and different time intervals were measured see  and the Mitral valve diastolic filling time: Measure of diastolic left ventricular filling.Tricuspid valve diastolic filling time:Measure of diastolic right ventricular filling.Pre-ejection time:Indicating the intra- and interventricular conduction and contraction synchrony.Ejection time:Measure of left ventricular ejection.As a next step the AVD producing the most favorable diastolic left ventricular inflow  was calculated applying a simple formula see : Two steLong AVD pacing (150 to 200ms) to determine the atrial electromechanical delay:The atrial electromechanical delay constitutes the time interval in between the right atrial sensed electrical impulse to the end of the active mitral valve flow. This includes the interatrial conduction time and the electromechanical coupling of the left atrium. This interval is intraindividually fixed and has a wide interindividual variation.Short AVD pacing (30ms as the shortest programmable AVD) to determine the isovolumic contraction time:The isovolumic contraction time is the time interval in between the ventricular electrical stimulation and the closure of the mitral valve due to the left ventricular systolic pressure increase. This interval can be measured when the atrial contraction is attenuated by the ventricular systole as documented in Doppler-echocardiography. This interval is intraindividually fixed and includes the conduction time from the pacing electrode to the left ventricle, the electromechanical coupling of the left ventricle and the duration from the beginning of the left ventricular systole to increasing intraventricular pressure above atrial pressure.Calculation of the optimal AVD when subtracting the atrial electromechanical delay and the isovolumic contraction time .When the calculated optimal AVD was different from the before programmed AVDs measurements were performed after optimized programming.In each patient, measurements during optimized pacing  were compared to the mean of the three AVDs  (= control) excluding the optimal AVD .The means of the 3 consecutive measurements were calculated and the optimal AVD was calculated for each patients. Non-categorical variables of the different pacing site groups  and different AVDs  were compared using Student t-test. Treatment effects within the groups (optimized pacing versus control settings) were assessed by ANOVA analysis. A significant difference was proposed when p < 0.05.25 patients with a mean ejection fraction pre-implant of 30%  and mean end diastolic diameter (echocardiography) of 66mm (\u00b1 7) were analyzed. Mean age was 65 (\u00b110)years, 22 had left bundle branch block morphology whereas 3 had right bundle branch block morphology and mean intrinsic QRS width was 191 . Position of the LV pacing lead was posterolateral in 16 (64%), lateral in 6 (24%) and anterior in 3 (12%).All patients were in sinus rhythm . Mean QRS width was significantly shortened during BiV pacing to 162ms (\u00b1 23) (p = 0.02), significantly longer during LV-pacing (238ms \u00b135) (p = 0.001) and significantly longer during right ventricular pacing (231ms \u00b139) (p = 0.006).Heart rate did not significantly differ intraindividually (\u00b1 5 bpm) during any of the Doppler-echo studies. A consistent finding was the consecutive shortening of the diastolic filling times  when prolonging the programmed AVD see . LV paciLongest mean ejection period resulted during BiV pacing compared to the monoventricular pacing modes independent to the programmed AVD. LV pacing seems to produce a longer ejection time compared to right ventricular pacing except at the shortest programmed AVD (30ms) see .1 of the 25 patients (4%) had no atrial contraction documented during transthoracic Doppler-echo. This patient was conclusively not eligible for optimization of the AVD. 24 of the 25 underwent Doppler-echocardiographic AVD optimization. The optimal AVD during BiV pacing was found to range in between 50ms to 180ms with a mean of 112ms (\u00b1 30). When correlating the optimal AVD to the intrinsic PQ-interval  it was found to translate into 23% to 80%, indicating a shortening of the PQ-interval in between 20% to 77% to gain optimized BiV pacing. The optimal AVD during LV pacing was found to be 95ms (\u00b1 30) (p = 0.95 vs. BiV) (65ms to 150ms) and during right ventricular pacing was significantly shorter compared to BiV pacing at 75ms (\u00b1 28) (p = 0.003) (40ms to 125ms) see .BiV optimized pacing produced the most favorable systolic and diastolic functional Doppler parameter compared to LV and right ventricular pacing see . StatistAVD optimization compared to control settings during BiV pacing significantly increased ejection time from 266ms (\u00b1 30) to 279ms (\u00b1 25) (p = 0.03) correlating with an improved systolic ejection see . The preDuring LV-pacing AVD optimization increased ejection time from 266ms (\u00b1 30) to 268ms (\u00b1 33) (p = 0.96) and pre-ejection time was shortened from 177ms (\u00b1 31) to 166ms (\u00b1 35) (p = 0.32) see . DiastolDuring optimized right ventricular pacing ejection period stayed constant at 263ms (\u00b1 35)  but pre-ejection time was shortened from 189ms (\u00b1 27) to 182ms (\u00b1 25) (p = 0.32) see . DiastolThere is still controversy about the effects of different programmings of the AVD in patients with pacing devices for chronic heart failure. Studies have emphasized the influence of the optimal pacing site in patients treated with biventricular pacing and there seems to be a beneficial effect of different AVD programmings modulating systolic ventricular function ,16,23.This study demonstrates improved systolic and diastolic function after non-invasive diastolic optimization on patients with implanted biventricular pacing devices. The optimal AVD was determined using a simple formula derived from findings in patients with complete heart block and is based on Doppler-echocardiographically measured electromechanical time intervals. Applying calculated optimal AVD programming diastolic filling is optimized and systolic function is improved. Improvements in systolic function may be due to a leftward shift in the Frank-Starling curve initiated by improved diastolic function. Although, optimizing the AVD may not lead to chronic increase in systolic function. Only a single report exists indicating functional improvement in biventricular pacing patients due to AVD optimization more than one month after optimization .Different studies have evaluated the effects of different AVD optimization strategies. In most cases, the optimal AVD was determined by echocardiographic parameters of systolic function (e.g. left ventricular outflow). A recent study on 215 patients undergoing cardiac resynchronization therapy indicated the usefulness and safety of AVD optimization using Doppler mitral inflow data . ControvWe documented beneficial effects on systolic functional Doppler parameters indicating improved ventricular ejection and beneficial effects on intra- and interventricular electrical synchronization when coincidentally timing the end of the left atrial contraction and the beginning of the left ventricular systole. The optimal AVD can easily and non-invasively be calculated using a formula integrating two time intervals measured during long AVD and short AVD pacing. This formula was proposed by Ritter et al. in 1995 for patients with complete AV-block to resynchronize left atrial and ventricular systole enabling optimal ventricular filling and pre-load. However this formula has not yet been validated invasively -22. In oApplying the calculated optimal AV-delay not only led to optimized timing of the atrial contraction just prior to the left ventricular systole but also produced changes in systolic functional Doppler parameters. During BiV pacing non-invasive diastolic AVD optimization significantly increased ejection time (5% increment compared to control settings). This implements significantly improved left ventricular systolic function only by modulating the AVD settings. Even though the correlation between ejection time and ejection volume is weak it is a measure of systolic ejection function indicating increased contractile function. Also AVD optimization led to shorter pre-ejection times documenting improved intra- and interventricular synchronicity. These findings are consistent with the documented changes of systolic function by Kindermann et al. when tailoring diastolic flow ,21. The 22It seems possible to improve the beneficial effect of electric resynchronization therapy by careful and Doppler-echo guided individual programming of biventricular pacing devices. Even though, no guidelines for programming parameters for AVD optimization are available ,16,24-28It is well known that the effect of pacing therapies for chronic heart failure depend on selection of the pacing site. Whereas right ventricular pacing was shown to have controversial effects on left ventricular performance left ventricular based pacing seems to have beneficial effects on systolic function due to electrical resynchronization of the left ventricular contraction pattern ,16,18-23As indicated in our study not only the filling volume but the preload which can be increased by optimal timing of the left atrial contraction and its contribution to ventricular filling is crucial for left ventricular performance. During optimized pacing the diastolic filling time is shorter than during short AV-delay pacing but correct timing of the left atrial contraction leads to optimized ventricular filling and readjusted mitral valve Doppler flow. These considerations explain the shorter diastolic filling times during optimized pacing compared to the suboptimal AVD programmings but still improved cardiac function during AVD optimization ,18-22,28This study is limited by the small number of patients included making it impossible to determine any variables leading to changes in optimal AV-delay settings like LV-electrode position, cardiac disease or ejection.As control the mean of AVD settings of 80ms, 100ms and 150ms were calculated and compared to optimized AVD pacing. This artificially constructed control setting is usually close to the range of the optimal AVD and therefore differences in between AVD settings may be marginal. On the other hand this control may resemble manufacturer's AVD settings implemented in the BiV pacing devices and therefore the analysis indicates the incremental benefit of AVD optimization compared to baseline settings.We did not perform any invasive hemodynamic studies to validate the applied formula for AV-delay optimization. Even though the documented improvements in Doppler echocardiographic functional parameters indicate hemodynamic benefit this has not been clinically tested. In addition, no comparative study to other methods of AVD optimization was performed. It remains unclear, whether the proposed formula leads to the highest benefits or if other strategies (e.g. tailoring systolic Doppler-echo parameters) may further increase hemodynamics.Especially in the latest pacing devices for biventricular resynchronization not only atrioventricular delay but also interventricular delays are programmable. Therefore there is a definitive need for guidelines or recommendations how to program different parameters of diastolic and systolic synchronization in these devices.Individual programming in patients under biventricular stimulation can increase the benefit of the resynchronization therapy when implementing the differences in electromechanical delays. Optimization of the AVD integrating these individual intervals can easily and non-invasively be performed using Doppler echocardiography applying a simple formula. Optimized pacing cannot only improve diastolic but also optimize systolic functional Doppler parameters."}
+{"text": "Immunoreactive collagenase has been demonstrated in 5/14 specimens of cutaneous secondary melanomas. In contrast, very little enzyme was seen in 10 specimens of normal human skin. All specimens were fixed within minutes of excision. These findings support the hypothesis that collagenase facilitates connective-tissue breakdown which is associated with tumour invasiveness and metastatic spread."}
+{"text": "Dear Editor,A 70-year-old lady was seen in the retina clinic following a referral for suspected bilateral occult choroidal neovascular membranes (CNV). Her symptoms included intermittent blurred vision. Best corrected visual acuity was 20/60 in the right and 20/30 in her left eye. Fundus examination revealed a central area of cystoid macular edema surrounded by exudates and hemorrhages in her right eye and an area of serous pigment epithelial detatchment in the left eye. She had a healthy optic nerve with distinct disc margins . FluoresThere were no identifiable risk factors for NAION in her case apart from the age. Intraocular pressures were found to be normal during pre and post-treatment phase. One possible explanation can be a compromise in the vascular integrity of the optic nerve vessels as vascular endothelial growth factor (VEGF) participates in the maintenance of vascular systems in adults. To date,2"}
+{"text": "Human papillomavirus DNA was detected in cervical specimens from 366 sexually active young women with cytomorphologically normal cervices using the polymerase chain reaction. In 93% (25/27) of initially infected women, the same viral type was not detected upon re-examination four menstrual cycles later. These results suggest that the majority of HPV infections in young women are transient."}
+{"text": "Neural network breakdown is a key issue in neurodegenerative disease, but the mechanisms are poorly understood. Here we investigated patterns of brain atrophy produced by defined molecular lesions in the two common forms of genetically mediated frontotemporal lobar degeneration (FTLD). Nine patients with progranulin (GRN) mutations and eleven patients with microtubule-associated protein tau (MAPT) mutations had T1 MR brain imaging. Brain volumetry and grey and white matter voxel-based morphometry (VBM) were used to assess patterns of cross-sectional atrophy in the two groups. In a subset of patients with longitudinal MRI rates of whole-brain atrophy were derived using the brain-boundary-shift integral and a VBM-like analysis of voxel-wise longitudinal volume change was performed. The GRN mutation group showed asymmetrical atrophy whereas the MAPT group showed symmetrical atrophy. Brain volumes were smaller in the GRN group with a faster rate of whole-brain atrophy. VBM delineated a common anterior cingulate\u2013prefrontal\u2013insular pattern of atrophy in both disease groups. Additional disease-specific profiles of grey and white matter loss were identified on both cross-sectional and longitudinal imaging: GRN mutations were associated with asymmetrical inferior frontal, temporal and inferior parietal lobe grey matter atrophy and involvement of long intrahemispheric association white matter tracts, whereas MAPT mutations were associated with symmetrical anteromedial temporal lobe and orbitofrontal grey matter atrophy and fornix involvement. The findings suggest that the effects of GRN and MAPT mutations are expressed in partly overlapping but distinct anatomical networks that link specific molecular dysfunction with clinical phenotype. The role of neural networks in neurodegenerative disease has attracted much recent interest  age at baseline scan 53.5 (5.2)) and nine patients with a GRN mutation (mean (standard deviation) age at baseline scan 62.9 (6.1)) were included in the study: the MAPT mutation group comprised 8 patients with a 10\u00a0+\u00a016 mutation and single patients with 10\u00a0+\u00a014, S320F and G389R mutations; the GRN mutation group . T1-weighted volumetric brain images were obtained using an IR-prepared fast SPGR sequence  with a 24-cm field of view and 256\u00a0\u00d7\u00a0256 matrix to provide 124 contiguous 1.5-mm-thick slices in the coronal plane. We initially calculated whole-brain and hemisphere volumes in all patients. The brain region was created by segmenting the whole brain using a semi-automated technique in the MIDAS software package . For rathttp://www.fil.ion.ucl.ac.uk/spm) with default settings for all parameters. The images underwent an initial segmentation process in SPM5 which simultaneously estimated transformation parameters for warping grey matter (GM), white matter (WM) and cerebrospinal fluid (CSF) tissue probability maps (TPMs) onto the images. The native space GM and WM segments were then rigidly spatially normalised, using just the rotations and translations from the inverse of the TPM transformation, and resampled to 1.5\u00a0mm isotropic resolution. These \u201cimported\u201d images were then iteratively warped to an evolving estimate of their group-wise GM and WM average template using the DARTEL toolbox  at a 0.001 significance level. For disease group comparisons maps were generated uncorrected at a 0.001 significance level. Statistical parametric maps were displayed as overlays on a study-specific template, created by warping all native space whole-brain images to the final DARTEL template and calculating the average of the warped brain images. In order to visualise hemispheric asymmetries, we performed two VBM analyses: firstly with all images in their native space; and secondly, with native images flipped in the midsagittal plane within SPM5, such that the most severely affected cerebral hemisphere was on the same side in each patient. An image was selected for flipping if it had a hemispheric asymmetry index outside the control range and more severe right hemisphere atrophy : four images from the GRN group and three from the MAPT group met criteria for flipping.Voxel-based morphometry (VBM) was performed on the baseline images using SPM5 software  we performed non-linear registration of each follow-up image to its corresponding baseline using a multi-scale viscous fluid algorithm  with a NBaseline brain volumes were smaller in both disease groups compared to healthy controls and mean brain volume was significantly smaller in the GRN group compared to the MAPT group . Rates op\u00a0=\u00a00.07)  , Fig. 2APatterns of grey matter atrophy differed in the MAPT and GRN groups compared to healthy controls. The GRN group analysis on unflipped images showed an overall pattern of symmetrical brain atrophy including frontal, temporal and parietal lobes, cingulate cortex and thalamus. However, this result obscures any asymmetries in favour of left or right hemisphere at individual subject level: after flipping of images so that all patients had the most affected hemisphere in the same orientation the true asymmetry of GRN disease was apparent . The mosIn the GRN group compared to controls, the white matter VBM analysis showed most significant involvement of intrahemispheric long association tracts including inferior longitudinal fasciculus, superior longitudinal fasciculus, inferior fronto-occipital fasciculus and cingulum. There was additional involvement of the corpus callosum and brainstem tracts, particularly in the pons . In the Comparing the two mutation groups directly in the flipped VBM analysis  revealedDifferential patterns of longitudinal volume loss in the two mutation groups were similar to those seen in the cross-sectional VBM analysis . The GRNUsing convergent imaging techniques, we have shown that GRN and MAPT mutations are associated with distinct profiles of neuronal loss affecting distributed cortical areas and their white matter connections. GRN mutations are associated with asymmetric atrophy of frontal, insular, cingulate, parietal and temporal areas linked by intrahemispheric long association tracts, while MAPT mutations are associated with more restricted but bi-hemispheric atrophy of anteromedial temporal and orbitofrontal areas linked via the fornices and uncinate fasciculi. Disease evolution is more rapid in GRN- than MAPT-associated FTLD, as predicted from the more distributed cerebral damage associated with GRN mutations. Moreover, the degree of asymmetry increases over time in the GRN- (but not the MAPT) associated cases: in conjunction with the evidence presented here for asymmetric longitudinal intrahemispheric volume loss, this increasing asymmetry implies that the pathological process in GRN-associated FTLD is focused within the maximally affected hemisphere. The profiles of grey matter involvement demonstrated here help to integrate previous evidence concerning anatomical signatures and disease evolution in GRN and MAPT mutation cases. In particular, our findings suggest an anatomical substrate for the shorter disease duration  and greaWhite matter involvement in FTLD has been little studied but long association tracts including the anterior cingulum and superior longitudinal fasciculus have been implicated . A diffuNeural network dysfunction has been proposed to underpin phenotypic features of neurodegenerative disease including FTLD , and in A crucial unsolved question concerns the mechanisms whereby different molecular lesions may produce strikingly dissimilar patterns of neural network breakdown. There are three interrelated pathophysiological issues here: firstly, how one mutation produces asymmetrical cerebral damage and another more symmetrical damage; secondly, how these distinctive patterns of atrophy are maintained or amplified as the disease evolves; and finally, how phenotypic variation arises such that a particular mutation may selectively damage different cerebral hemispheres even between members of the same family . The varThe concept of large-scale neural network breakdown linked to specific molecular lesions may be relevant to the pathogenenesis of a number of neurodegenerative pathologies. Specific mutations within a general category of genetically mediated neurodegeneration (such as GRN or MAPT-associated FTLD) may mediate more fine-grained profiles of brain damage, as suggested by recent evidence within the MAPT spectrum . The sma"}
+{"text": "We are reporting an extremely prolonged sinus arrest documented by Holter monitoring. A 77-year-old woman was admitted to the geriatric unit at our institution. She complained of recurrent episodes of a sudden loss of consciousness at rest followed by 'seizures' lasting several minutes with complete spontaneous recovery after a few seconds. The patient had suffered multiple episodes in the previous weeks. She had a moderate degree of senile dementia and was not taken any medication. A blood analysis was unremarkable and the ECG showed normal sinus rhythm at 60 bpm with normal PR interval and QRS length. An echocardiogram revelead no significant cardiac structural abnormalities. Twenty-four hours ECG Holter recording was performed and the patient presented a syncopal episode while she was sitting on the armchair. Patient recovered completely after the episode. Holter examination revealed predominant sinus bradycardia (mean of 50 bpm) with no significant atrial or ventricular arrhythmia. At 19:34 pm, when she presented the syncopal attack, a gradual slowing of the sinus beats was observed followed by a sudden drop of ventricular activity due to extremely prolonged sinus arrest (2 minutes and 18 seconds) with two escape beats in between. The episode was terminated by 4 idioventricular beats followed by an accelerated junctional rhythm. Although a malignant vasovagal syncope can not be ruled out, lack of significant heart rate acceleration before ventricular asystole was in favour of sinus node dysfunction. A permanent pacemaker was implanted and no recurrences of syncopal episodes occurred during a year follow-up."}
+{"text": "Method. We performed a two-stage vascularized ipsilateral fibular            graft transfer for segmental tibial defect following excision of malignant bone tumours.            Results. We report 10 patients who had this procedure with an average            follow-up of 116 months.The graft was transposed medialy on its vascular pedicle by            two-stage surgery. Full weight bearing was achieved in six patients at 8\u201343 months            postoperatively, but every patient had a significant complication.            Discussion. The use of this method in isolation is not recommended             for reconstruction of the tibia following tumour excision."}
+{"text": "The population pharmacokinetics of51Cr-EDTA were analysed using NONMEM to evaluate the influence of each covariate. The formulae derived were then validated using a further 38 patients and compared with those obtained using existing formulae51Cr-EDTA clearance (GFR) was positively related to Dubois surface area, negatively related to age, and inversely related to serum creatinine (SCr). Females had lower51Cr-EDTA clearance than males. The enzymatic method of SCr assay gave more reliable results than the Jaffe colorimetric method. A measure of creatine kinase significantly improved the estimation of GFR. The new formula produced estimates of GFR which were less biased (Mean Prediction Error = \u20133%) and more precise (Mean Absolute Prediction Error = 12%) than Cockcroft and Gault (\u20138% and 16%) or Jelliffe (\u201315% and 19%) estimates. The formulae developed here can be used to provide reliable estimates of GFR, particularly in regard to targeted dosing of carboplatin. \u00a9 2001 Cancer Research Campaign http://www.bjcancer.comThe frequent need to obtain an estimate of renal function in cancer patients, not least for targeting carboplatin dose, has led to a number of approaches to estimate glomerular filtration rate (GFR). This study aimed to develop a simple and reliable method to estimate GFR using readily-available patient characteristics. Data from 62 patients with estimates of"}
+{"text": "Background: A concomitant infection with human immunodeficiency virus (HIV) may alter the natural history of other infections. Several reports indicate that syphilis may behave more aggressively when HIV infection is present.Case: A woman presented with a rash involving her hands and feet and progressive loss of the vision in her right eye. Her serologic tests for syphilis and HIV infection were positive. A diagnosis of neurosyphilis was confirmed by an analysis of cerebrospinal fluid (CSF). She was treated with high-dose intravenous (IV) penicillin. Her skin lesions resolved, but her vision did not improve.Conclusion: The incidence of HIV infection among women is rising. A patient with HIV and syphilis may develop neurosyphilis in a much shorter time than a patient without HIV infection."}
+{"text": "Vascular endothelial growth factor (VEGF) plays a critical role in normal development as well as retinal vasculature disease. During retinal vascularization, VEGF is most strongly expressed by not yet vascularized retinal astrocytes, but also by retinal astrocytes within the developing vascular plexus, suggesting a role for retinal astrocyte-derived VEGF in angiogenesis and vessel network maturation. To test the role of astrocyte-derived VEGF, we used Cre-lox technology in mice to delete VEGF in retinal astrocytes during development. Surprisingly, this only had a minor impact on retinal vasculature development, with only small decreases in plexus spreading, endothelial cell proliferation and survival observed. In contrast, astrocyte VEGF deletion had more pronounced effects on hyperoxia-induced vaso-obliteration and led to the regression of smooth muscle cell-coated radial arteries and veins, which are usually resistant to the vessel-collapsing effects of hyperoxia. These results suggest that VEGF production from retinal astrocytes is relatively dispensable during development, but performs vessel stabilizing functions in the retinal vasculature and might be relevant for retinopathy of prematurity in humans. Retinal astrocytes play an important role in the development of the mammalian retinal vasculature. They invade the retina from the optic nerve head as a proliferating population of cells and spread across the inner surface of the retina, creating a template for the developing retinal vasculature which follows in their wake Vegf mRNA in the not yet vascularized peripheral portion of the retina Vegf mRNA stabilization Numerous studies have shown that during retinal vascularization retinal astrocytes produce high levels of Vegf mRNA near arteries and consequently for the formation of so-called capillary free spaces along arteries Apart from driving angiogenesis, VEGF may also influence vessel remodelling, stabilization and differentiation during vascular plexus maturation. The stability of vessels plays an important role in the pathogenesis of retinopathy of prematurity (ROP), where exposure of premature infants to therapeutic hyperoxia can cause vaso-obliteration in the developing retinal vasculature It has been shown that VEGF secreted from pericytes can also contribute to vessel stabilization However, it is less clear to which degree retinal astrocytes and pericytes contribute to vessel stabilization and how important VEGF secretion from these cells is during the critical period of network maturation in the first 2\u20133 weeks after birth. We therefore investigated the role of astrocyte-derived VEGF in retinal vascular development by genetically abolishing VEGF expression using the Cre-lox system. Surprisingly, this only had a minor impact on the physiological development of the retinal vasculature. However, under hyperoxic conditions deletion of astrocyte-derived VEGF led to a pronounced destabilization of the retinal vasculature.Vegf mRNA is expressed by retinal astrocytes, retinal ganglion cells and cells in the inner nuclear layer  promoter (Gfap-Cre mice) In the developing retina ar layer  [7], [28 hypoxic . To testGfap-Cre allele into a homozygous background containing loxP sites flanking exon 3 of the Vegfa gene (Vegfc/c mice) Gfap-Cre allele was compared against littermates without the transgene. Cre recombinase activity in Gfap-Cre positive animals was confirmed by PCR of genomic DNA isolated from the retina with primers spanning a 2.1kb region across exon 3, which demonstrated deletion of a 1.3kb region in the Vegfa gene with the appearance of an additional shorter band of 800bp in Cre-positive animals  has been linked to sprouting angiogenesis at the leading edge of the expanding vascular plexus. We therefore assessed whether the absence of VEGF in astrocytes affected the morphology of angiogenic sprouts at the leading edged of the growing vascular plexus, but found no noticeable differences . To furtdeletion , confirmdeletion .Vegf mRNA, the in situ hybridization signal was still detectable within the vascular plexus, particularly along veins  Hif1ac/c) All animals were handled in accordance with the UK Animals (Scientific Procedures) Act 1986. The project was approved by the UK Home Office and the UCL Institute of Ophthalmology Ethics Sub-Committee . Transgenic mice expressing Cre recombinase under the control of promoter segment from the human CAG GCT TCG GTG GGG TGT GA and reverse GAG CAG GGA TAG GTG GTG GAG ATA. To assess VEGF isoforms reverse-transcribed cDNA obtained from P5 retinas was amplified using Taq polymerase (Promega). The VEGF isoform primer sequences were: forward GAA GTC CCA TGA AGT GAT CCA G and reverse TCA CCG CCT TGG CTT GTC A, as described previously To confirm Cre recombinase activity genomic DNA was isolated from P5 retinas and amplified by PCR using Megamix (Cambio Ltd.) containing 2% DMSO with the following primers: forward Retinal whole mount preparations were dissected from whole eyes after brief fixation in 2% (w/v) paraformaldehyde (PFA) in phosphate-buffered salt solution (PBS) and then processed for wholemount immunohistochemistry or in situ hybridization as previously described Network morphology of the retinal vasculature was analyzed in retinal whole mount preparations from 6 P5 and 5 P10 conditional VEGF litters and in 5 P5 conditional HIF1\u03b1 litters. We also analyzed 5 further litters after hyperoxia exposure for 5 days at P12 and 5 litters after 1 day of hyperoxia at P8. The surface area of the developing vascular network, width of capillary free spaces and vascular depleted areas in hyperoxia-exposed animals were measured using ImageJ. BrdU positive cells and artery side branches were counted by hand over fixed distances from the retinal centre. Intact and degenerating radial arteries and veins were counted by hand in each retina. Measurements were averaged for control and mutant animals in each litter and normalized against the control values. Statistical analysis was then performed across values obtained from each litter."}
+{"text": "Eight children treated between 1977 and 1983 with the UK Children's Cancer Study Group's non-Hodgkin lymphoma (NHL) and T-cell protocols have developed second malignancies within 7 years of commencing treatment. Five developed acute non-lymphoblastic leukaemia and a sixth died from infection while pancytopenic with a pre-leukaemic marrow. The other malignancies were cerebral astrocytoma and an undifferentiated low grade sarcoma. These eight children were included among 261 children studied in the first UKCCSG NHL and T-cell trials giving an actuarial incidence of 7.8% second malignancy at 7 years. Six had received adjuvant radiotherapy which may have contributed to the high incidence of second malignancy."}
+{"text": "A significant correlation  was found between the extent of residual DNA dsbs and clonogenicity for all 11 fibroblast strains. The parameter showing the highest correlation with fibroblast cell killing (D-) for the nine normal fibroblasts alone was the ratio of initial/residual DNA dsb dose\u2013response slope . A significant correlation  with clonogenic radiosensitivity was also found for all 11 cell strains when using the ratio of initial/residual DNA dsb damage at a single dose of 180 Gy. This study shows that fibroblast radiosensitivity measured using the neutral comet assay correlates with clonogenic radiation survival parameters, and therefore may have potential value in predictive testing of normal tissue radiosensitivity. \u00a9 1999 Cancer Research CampaignA study was made of the neutral comet assay as a potential method for measuring normal cell radiosensitivity. Eleven fibroblast strains were studied comprising nine derived from vaginal biopsies from pretreatment cervical cancer patients and two strains from radiosensitive individuals. DNA double strand break (dsbs) dose\u2013response curves for both initial and residual (20-h repair time) damage were obtained over the dose range 0\u2013240 Gy, with slopes varying 3.2 and 8-fold respectively. Clonogenic cell survival parameters were available for all the cell strains following both high- and low-dose rate irradiation. There were no correlations between the dose\u2013response slope of the initial level of DNA dsbs and parameters that mainly describe the initial portion of clonogenic radiation survival curves (SF"}
+{"text": "L -lactate and L -deprenyl prevented bystander factor associated cell kill. The lactate analogue, oxamate, was less effective. Data from experiments where media harvested from the different cell lines was exchanged suggest that signal production and cellular response may involve different mechanisms. The effects on exposed cells were transmitted to progeny which also showed excessive levels of cell death for several generations. The results suggest that energy/REDOX metabolism may be involved in the expression of a radiation induced bystander response. Given the aberrant energy metabolism in tumour cells, this may have implications for dose escalation in radiotherapy. \u00a9 2000 Cancer Research CampaignThese experiments were done to determine if interference with energy metabolism and REDOX biochemistry during low LET radiation exposure would alter the ability of medium harvested from the irradiated cells to induce a bystander effect in unirradiated cells. Human keratinocyte cells and CHO-K1 mutant cell lines were irradiated using cobalt 60. Clonogenic assays were used to determine the reproductive death of the cells exposed to direct irradiation or medium from irradiated cells. The persistence in progeny was also examined. Use of apoptosis inhibitors or medium from the LDH or G6PD null cell lines, reduced or prevented the bystander effect. Transfection with G6PD recovered the effect. Treatment with anti-oxidant substances,"}
+{"text": "Attempts were made to induce tumour-specific immunity in syngeneic mice by treatment with x-irradiated  tumour or surgical excision of developing subcutaneous tumour grafts. Resistance was evoked against 6 tumours and this was relatively weak. With the remaining tumours, no resistance against the immunizing tumour could be demonstrated, even though the transplantation tests were made highly sensitive by the use of inocula of as few as 2 \u00d7 103 cells in pre-irradiated (400 rad) hosts. Sera from mice immunized against each of the tumours were tested against viable cells of the immunizing tumour by indirect immunofluorescence. In no instance did tumour antisera give a convincing reaction with tumour cells although alloantisera raised by hyperimmunization of H-2 identical and H-2 different donors with osteosarcomata consistently gave strongly positive reactions. The results are interpreted as illustrating the weak tumour specific antigenicity of radiation-induced murine osteosarcomata. The possibility that antigenic deficiency is a consequence of immunosurveillance in this tumour system is discussed.The immunogenicities of 15 murine osteosarcomata induced with a bone seeking radioisotope ("}
+{"text": "Here we model SNARE-mediated adhesion kinetics in SNARE-reconstituted GUV-GUV or GUV-supported bilayer experiments. Adhesion involves many SNAREs whose complexation pulls apposing membranes into contact. The contact region is a tightly bound rapidly expanding patch whose growth velocity SNARE proteins are conserved components of the core fusion machinery driving diverse membrane adhesion and fusion processes in the cell. In many cases micron-sized membranes adhere over large areas before fusion. Reconstituted  In cells the controlled delivery of materials packaged by membrane-bound organelles and vesicles is achieved by membrane fusion. SNARE proteins are involved in most intracellular eukaryotic fusion processes trans complex assembly was blocked in PC12 It has been postulated that SNAREs are dual adhesion-fusion agents. Subsequent to bringing membranes into intimate contact, it has been proposed that SNAREs trigger fusion in vitro studies Identifying and quantifying the role played by SNAREs is challenging because the complex cellular fusion machinery involves many components. A substantial body of in vitro mechanisms. Typical measured fusion times greatly exceed the \u223c1 ms required for synaptic vesicle fusion in vitro, SNAP25 was not required in vitro fusion events may result from the small sub-population of vesicles rendered inherently unstable by particularly high curvature and SNARE\u2236lipid ratios SUV studies have contributed significantly to current understanding of SNARE function. Nonetheless questions remain as to the cellular relevance of in vitro studies have used \u223c50-nm SUVs, appropriate to processes such as synaptic transmission where 50-nm vesicles fuse with the presynaptic plasma membrane \u223c1 ms after Ca2+ stimulation Most giant unilamellar vesicles (GUVs). Studies have begun to realize the potential of SNARE-reconstituted GUVs as model in vitro systems which may reveal mechanisms of adhesion and fusion of micron-scale membrane compartments. Bacia et al To mimic large membrane cellular fusion systems it is natural to turn to In this paper we develop a model of SNARE-mediated adhesion kinetics in controlled SNARE-reconstituted GUV-GUV or GUV-SBL systems. We discuss experiments where such adhesion kinetics could be followed and GUV membrane tension and SNARE surface densities precisely controlled . Surface adhesion by other biosticker systems was observed to progress by growth of tightly bound patches, including GUV-substrate adhesion mobileimmobilized on a substrate. Thus different mathematical models are necessary to describe SNARE adhesion. Mobile complexes may exert 2D osmotic pressure tending to enlarge a patch. De Gennes, Puech, and Brochard-Wyart uniform complex density in the patch they predicted growth velocity v increases as the 3/2 power of receptor and sticker density. In this paper we explicitly calculate SNARE density profiles and show that in fast growing patches the complex density is in fact severely depleted at the boundary. Osmotic pressure and growth rate are thus diminished and a different power law results. Using properties taken from the literature we find typical SNARE systems belong to this fast growth regime.Since SNAREs and their complexes are apparently In our model the origin of adhesion patch growth is that the initial tension-dependent mean membrane separation in the GUV-GUV or GUV-SBL contact zone  normallyin vitro systems.In the Discussion the possible relevance of these results to cellular fusion pathways is addressed. Tight SNARE adhesion is preceded by loose binding by tethering factors. Given typical tether sizes  For simplicity the symmetric case is assumed: both vesicles have equal numbers of SNAREs per unit area in their respective membranes, ct area  .The first SNARE complex assembles at time xes form . The pat\u03b3, SNARE diffusivities and the complexation rate constant Our interest is steady state patch growth where the velocity To calculate Patch growth is driven by the 2D osmotic pressure In steady state the outward osmotic pressure is balanced by dissipative drag forces owth see . These dAs fluid is not expected to significantly penetrate the patch, dissipation occurs primarily in a narrow band along its boundary. The coefficient nce  see , yieldinSince a patch grows within contact zone of area ss than   patch grTo obtain the patch velocity For simplicity we assume the two SNARE types have equal diffusivities ties see . Irreverx, and the far field boundary conditions are in effect at x is distance from the boundary, and similarly We seek equations governing the steady state densities. In the region close to the patch boundary densities will change substantially as a function of position. Provided the patch radius is much larger than the size of this region, the situation becomes approximately 1D in the direction orthogonal to the patch boundary, Each of eqs. 5 consists of a convective term proportional to In this subsection we use scaling analysis to solve eqs. 4\u20137 for the steady state patch velocity The regime boundaries are defined by two critical densitiesNote the intermediate regime exists because we assume SNARE diffusivity exceeds that of the complex  will be presented which confirm the scaling results.Initially both adhering vesicles have uniform SNARE density, Slow regime,regime, . We defiFast regime,regime, . Since tIntermediate regime,regime, . This reIn the following subsection the scaling solutions will be evaluated using realistic parameter values taken from or inferred from the literature, listed in d values of C in eq. 1. We found in vitro values. The range represents a two-decade SNARE density window to test GUV adhesion kinetics. For comparison, in cells the SNARE density presumably depends on organelle or vesicle type. A report of synaptic vesicle composition suggests (i) Micropipette control allows direct regulation of GUV tension over a large range of values, shown in 2/s.Bacia et al report values A key parameter is the diffusivity  a point  the diff a point . It is pgiven overlap of two cognate SNAREs and the SNARE reach The rate constant Patch drag coefficient, . The model of ref. Using the parameter values of in vitro SNARE density range  The universal curve onto which the numerically obtained data collapses is in very close agreement with our earlier scaling predictions, eq. 8. The predicted power laws in each regime are clearly obeyed.Though adhesion is our main concern in this paper, we briefly consider a very simple model of fusion whose results articulate how adhesion and fusion may be coupled. Past theoretical work on fusion has focused mainly on protein-free membranes. Energy barriers to access intermediate high-curvature membrane structures on the pathway to fusion were calculated independently of all others. Only one such event can occur, assuming fusion results in immediate and irreversible conversion of the adhered vesicles into a single vesicle.Here we invoke the simplest imaginable model for SNARE-induced GUV fusion: each SNARE complex in the patch can trigger fusion with a certain probability per unit time, What is the delay before fusion occurs? This depends on the mean fusion time t. For constant velocity Adhesion kinetics analyzed in previous subsections determine the number of SNARE complexes t isAssuming each SNARE complex triggers fusion independently from all others in the mean time This is the product of factors The distribution of fusion times is thusInserting the particular form This distribution of fusion times road see . It follin vitro range Click here for additional data file.Figure S11crit and velocity scaled by v1crit\u200a=\u200a\u03b53/2\u03bb3/4v0. (B) As for (A), but for intermediate and fast regimes. Densities and velocities scaled, respectively, by \u03932crit and v2crit\u200a=\u200a\u03b5-3/2\u03bb3/4v0. Numerical results confirm the asymptotic solutions with relative errors in the velocity peaking at the critical densities (106% in (A) and 54% in (B)) and approaching zero far from the critical densities in each regime.Collapse of scaled SNARE-mediated adhesion data onto a single universal patch growth law. Same as (0.64 MB TIF)Click here for additional data file."}
+{"text": "We have utilized the blast cell assay of Buick et al. (1977) to grow and subsequently cytogenetically analyze cultured colony forming cells (CFUs) from patients with acute and chronic myelogenous leukaemia . Cytogenetic analysis of CFUs was successful in 30/36 cases (83%), a success rate similar to direct harvesting techniques. Identical clonal chromosomal abnormalities demonstrated by direct techniques were also observed in CFUs from AML and CML. Removal of T-precursor cells by E-rosetting prior to plating did not eliminate growth of karyotypically normal cells. The combination of morphologic and cytogenetic studies performed clearly established that the assay system supports the growth of leukaemic progenitors. Although both karyotypically normal and abnormal leukaemic colonies grew in this assay, growth of leukaemic colonies was much more likely if the plated cells were karyotypically abnormal (P = 0.010). Leukaemic colony growth was also more frequent if the tritiated thymidine labelling index (LI%) of plated cells was greater than or equal to 5% (P = 0.018). Leukaemic colonies were most likely (P = 0.018) to have been derived from plated cells with both abnormal karyotype and high LI% . Cytogenetic analyses from cultured cells revealed only those karyotypic features found in the uncultured cells . However, in most cases, the greatly enhanced number and quality of mitotic figures allowed for more detailed banding analysis."}
+{"text": "In 101 breast cancer patients, measurement of oestrogen receptor status in multiple biopsies across a tumour reveals a highly significant difference in the proportion of patients remaining either disease-free (P less than 0.04) or alive (P less than 0.005), when those with uniformly receptor positive (++) primary tumours are matched with clinically comparable patients whose tumours were homogeneously receptor negative (--). Mean follow-up time was 85 months. The prognostic value of this discriminant is particularly striking in the 53 patients with involved nodes at presentation. Of these, 13 were (++) and seven remain alive of whom six are disease-free, whereas 24 of the 29 (--) patients are dead. These results further suggest that receptor assay on a single homogenate gives less clinical information than do assays on multiple biopsies across the tumour. For patients with involved nodes, clinical management may best be decided after determination of 'macroheterogeneity'."}
+{"text": "In a prospective randomised study 68 patients with limited small cell bronchogenic carcinoma were assigned to induction treatment with combined alternating non-cross-resistant chemotherapy plus split course radiotherapy without (NM) or with (M) subsequent maintenance therapy. Induction chemotherapy consisted of cisplatinum and VP16213q. 3 weeks followed by cyclophosphamide, vincristine and methotrexate (CVM)q. 4 weeks. Three courses of this 7-week chemotherapy programme were given. Radiotherapy to the primary lesion of 25 Gy in 13 fractions was given after each of the first and second courses of chemotherapy. Those in complete remission following the induction phase received prophylactic cranial irradiation. Those assigned to maintenance received a further six cycles of CVM after induction. The overall survival of patients randomised to maintenance therapy was significantly inferior to that of those randomised to no maintenance therapy . Among patients achieving a complete remission of disease on induction therapy those receiving maintenance also showed a trend towards inferior survival . Deaths in each group of patients were predominantly due to tumour progression. The results do not support the use of maintenance chemotherapy after the use of intensive combined therapy induction programmes in the management of limited small cell bronchogenic carcinoma."}
+{"text": "Caenorhabditis elegans, several nematode species are unable to mount an RNAi response when exposed to exogenous double stranded RNA (dsRNA). These include the satellite model organisms Pristionchus pacificus and Oscheius tipulae. Available data also suggest that the RNAi pathway targeting exogenous dsRNA may not be fully functional in some animal parasitic nematodes. The genus Panagrolaimus contains bacterial feeding nematodes which occupy a diversity of niches ranging from polar, temperate and semi-arid soils to terrestrial mosses. Thus many Panagrolaimus species are adapted to tolerate freezing and desiccation and are excellent systems to study the molecular basis of environmental stress tolerance. We investigated whether Panagrolaimus is susceptible to RNAi to determine whether this nematode could be used in large scale RNAi studies in functional genomics.Gene silencing by RNA interference (RNAi) is a powerful tool for functional genomics. Although RNAi was first described in Panagrolaimus sp. PS1159 and Panagrolaimus superbus. Both nematode species displayed embryonic lethal RNAi phenotypes following ingestion of Escherichia coli expressing dsRNA for the C. elegans embryonic lethal genes Ce-lmn-1 and Ce-ran-4. Embryonic lethal RNAi phenotypes were also obtained in both species upon ingestion of dsRNA for the Panagrolaimus genes ef1b and rps-2. Single nematode RT-PCR showed that a significant reduction in mRNA transcript levels occurred for the target ef1b and rps-2 genes in RNAi treated Panagrolaimus sp. 1159 nematodes. Visible RNAi phenotypes were also observed when P. superbus was exposed to dsRNA for structural genes encoding contractile proteins. All RNAi phenotypes were highly penetrant, particularly in P. superbus.We studied two species: Panagrolaimus is amenable to RNAi by feeding will allow the development of high throughput methods of RNAi screening for P. superbus. This greatly enhances the utility of this nematode as a model system for the study of the molecular biology of anhydrobiosis and cryobiosis and as a possible satellite model nematode for comparative and functional genomics. Our data also identify another nematode infraorder which is amenable to RNAi and provide additional information on the diversity of RNAi phenotypes in nematodes.This demonstration that  Caenorhabditis elegans  was constructed using 18S small subunit rRNA gene sequences.  Bootstrap values  are placed next to the nodes.Click here for file"}
+{"text": "A low-mol.-wt compound isolated from rat Walker 256 carcinoma and found to induce neovascularization in vivo was tested on cultures of cow brain-derived endothelial cells (CBEC) growing on plastic and collagen substrates. This factor had a mitogenic effect on CBEC cultured on native collagen gels and for this reason has been called \"endothelial-cell-stimulating angiogenesis factor\" (ESAF). CBEC growing on plastic culture dishes or denatured collagen films were not stimulated by ESAF. The mitogenic effect of ESAF was equally apparent when added to cells already attached to the native collagen substrate or when the collagen substrate was pre-incubated with ESAF before plating the cells. A floating collagen gel pre-incubated with ESAF in cultures of CBEC growing on plastic dishes did not stimulate cell growth. Our data indicate that the substrate influences cell behaviour and that CBEC only respond to ESAF when growing on a native collagen substrate."}
+{"text": "The possibility of using tirapazamine (SR 4233) to identify hypoxic cells in multicell spheroids and murine tumours was examined by measuring tirapazamine-induced DNA damage to individual cells from multicell spheroids and SCCVII murine tumours. Fluorescence microscopy and image analysis were used to measure the extent of migration of DNA from individual cells embedded in agarose and exposed to an electric field. Using both the alkaline and neutral versions of the comet assay, at least 20 times more single-strand breaks were observed in cells from fully anoxic than fully oxic Chinese hamster V79 spheroids exposed to 30 microM tirapazamine, and about 10 times more single- than double-strand breaks were observed. Cells from spheroids containing about 50% radiobiologically hypoxic cells showed a pattern of tirapazamine breaks which translated to approximately 30% well-oxygenated in SCCVII tumors growing in C3H mice was also demonstrated. Cells close to tumour blood vessels showed less DNA damage by 20 mg kg-1 tirapazamine than cells distant from blood vessels. Rejoining of single-strand breaks was exponential, with a half-time of about 1 h under aerobic conditions, but rejoining half-time increased to 2 h for cells allowed to repair under anoxic conditions. While tirapazamine damage to DNA measured using the comet assay cannot provide a direct measure of hypoxic fraction, the degree of heterogeneity in DNA damage can be used to estimate the range and distribution of individual cell oxygen contents within spheroids and tumours."}
+{"text": "Post biopsy arterio-venous fistula in renal transplant range in incidence from 15-16%. Spontaneous resolution of 75% A-V fistulas is seen within four weeks. We report a patient with post biopsy arterio-venous fistula who had developed unexplained hypertension with no definite feature of rejection on biopsy. Doppler application revealed an arterio-venous fistula which showed spontaneous resolution in six weeks. In renal transplants post biopsy fistulas are well known. Most resolve spontaneously only few which are large need intervention. We report a case in whom we had done renal biopsy and who developed post biopsy AV fistula which we documented on color Doppler. He was followed for 6 weeks after which we noticed a spontaneous resolution. Most of the post biopsy AV fistula need follow up and are likely to resolve after some period.We evaluated a 46-year-old male, who had received live donor renal transplant one year ago, for a recent onset of hypertension. We performed three renal biopsies over a period of three months with no evidence of chronic transplant rejection. The patient was referred to the Radiology department for ultrasonography (USG) Doppler of the transplant. We performed a color Doppler study of the transplant kidney, which revealed an arteriovenous (AV) fistula in the lower pole involving lobar vessels with markedly increased peak systolic velocity PSV; >170 cm/s), end diastolic velocity  and a reduced resistive index (RI = 0.45). Arterialization of the venous waveform was evident along with perivascular random color assignment [Figs. 70 cm/s, The incidence of post-biopsy renal transplant AV fistulas range from 15% to 16%.138In most cases, color and duplex Doppler USG easily demonstrate AV fistulas besides other obvious vascular and nonvascular complications and requires invasive procedures such as renal angiography."}
+{"text": "Two AKR sublines appear atypical in possessing theta C3H. One of these two sublines - AKR/FuA - is notably resistant to lymphomata and is also characterized by reduced levels of the group specific murine leukaemia viral (MuLV) antigen. This suggested a possible association between theta status tumour susceptibility and viral content. Results here show no reduction in viral antigen titres in the other theta C3H tumour susceptible subline AKR/Cum, thus eliminating the possible association of theta status with the extent of MuLV replication."}
+{"text": "Mechanisms for improving photodynamic therapy (PDT) were investigated in the murine RIF1 tumour using meso-tetrahydroxyphenylchlorin (m-THPC) or bacteriochlorin a (BCA) as photosensitisers and comparing these results with Photofrin-mediated PDT. The 86Rb extraction technique was used to measure changes in perfusion at various times after interstitial PDT. Non-curative combinations of light doses with m-THPC and BCA PDT markedly decreased vascular perfusion. This decrease was more pronounced for both new photosensitisers than for Photofrin. Comparison of tumour perfusion after PDT with tumour response revealed an inverse correlation for all three photosensitisers, but the relationship was less clear for m-THPC and BCA. In vivo/in vitro experiments were performed after Photofrin or m-THPC PDT in order to assess direct tumour kill (immediate plating) vs indirect vascular effects (delayed plating). For both photosensitisers, there was little direct cell killing but clonogenic survival decreased as the interval between treatment and excision increased. When m-THPC PDT was combined with mitomycin C (MMC), light doses could be decreased by a factor of 2 for equal tumour effects. Lower light and m-THPC doses could be used compared with Photofrin PDT in combination with MMC. BCA PDT with MMC did not result in a greater tumour response compared with BCA PDT alone. Reduction in both light and photosensitiser does for effective PDT regimes in combination with MMC offers substantial clinical advantages, since both treatment time and skin photosensitisation will be reduced."}
+{"text": "The data describe a rational design and scale-up of LED-based photobioreactors for producing value-added algal biomass while removing waste CO2 from flu gases from power plants. The dataset were created from growth rate experiments for biomass production including direct biomass productivity data, PBR size and setup parameters, medium composition as well as indirect energy cost and overhead in Iceland. A complete economic analysis is formed through a cost breakdown as well as PBR scalability predictions.The data presented in this article are related to the research article entitled \u201cSugar-stimulated CO The key data are from the design parameters of LED-based photobioreactor systems as well as the experimentally derived biomass productivity data . As show22 level (mixed with air), LED illumination (different spectra and intensities), temperature and pH in the medium. Artificial light supplied to the PBRs was based on LEDs consisting of narrow spectrum of red light, blue light or combined red and blue light A bubble column LED-based PBR system was tested and used for economic analysis of mass production. The PBR systems are setup with controllable key parameters including input COC. vulgaris  achieved in a previous study A fast-growing algal strain"}
+{"text": "The idea that positive-sense RNA (+RNA) viruses may be to some extent taxonomically unified arose when unexpected similarities between animal and plant virus genomes were discovered (reviewed in reference The question thus arises, whether the membrane association of the polymerase was a primordial characteristic of viruses in branches 2 and 3, which may have facilitated virus replication in early eukaryotic cells possessing internal membranes. The phylogeny of RdRps cannot answer this question, since the membrane-binding sites in viral replicases reside outside the conserved core RdRp domain . Further"}
+{"text": "In 2013 RheinMain University launched its bachelor\u2019s degree program Health Care Economics requiring each student to participate in a mandatory two-month nursing internship. A preliminary risk assessment revealed serious risks for both students and patients and had to be addressed by appropriate measures such as mandatory systematic safety training for each student.A short-term educational intervention named \u201cSurvival-Day\u201d was designed to minimize risks related to nursing internships of students. This intervention consists of six 45-min-units with theoretical input (2\u2009units) and hands-on training (4\u2009units) imparting basic knowledge and skills in CPR, hand hygiene and handling of masks and protective gowns, prevention of needle stick injuries, fire protection and firefighting. Performance of CPR was assessed using computerized manikins. Acceptance, necessity and usability were assessed anonymously by standardized written questionnaires after completion of nursing internships.462 students have completed the Survival-Day until January 2019. CPR performance showed acceptable adherence rates to guideline recommendations . The majority of students performed aseptic health care activities (66%), treated patients with multi-resistant pathogens (62%) and disposed sharp instruments such as blood-contaminated needles (76%). According to students\u2019 self-reports about these hazardous activities, less than 50% of these students received adequate safety training at nursing facilities. However, no sentinel events such as needle stick injuries or students becoming second victim have been reported.Our study reveals severe discrepancies between legal obligation of nursing facilities to ensure safety instructions for nursing interns and initial training as perceived by this group. Mandatory initial training before conduction of hazardous tasks was mainly covered by our short-term educational intervention . Regarding responsibility for their students a preliminary safety instruction program like the Survival-Day should be considered for all educational institutions sending students to nursing internships unless mandatory and sufficient safety trainings for nursing interns can be guaranteed by nursing facilities. Since 2013 RheinMain University of Applied Sciences has offered a bachelor\u2019s program in Health Care Economics (BHCE). This includes a mandatory two-month nursing internship in order to gain detailed and realistic knowledge and understanding of patient care, regarded to be crucial for sustainable professional success. The RheinMain University has formal contracts with nursing facilities defining common aspects of nursing internships, which are not specific for the health care sector. Due to greatly varying standards and capacities in these nursing facilities regarding initial trainings for interns, a general contractual agreement ensuring standardized training by all nursing facilities is not realistic.Because of this lack of adequate training nursing internships can be categorized as danger-prone activities with relevant risks for the safety of patients and students \u20138. FurthUndoubtedly, infectious hazards belong to the most important dangers in the area of health care \u201324. HoweThe Survival-Day was invented to close gaps in knowledge and skills in order to empower non-nursing BHCE students to safely fulfill assigned tasks during their mandatory nursing internship since we hypothesized that induction training at nursing facilities might be inadequate due to lack of time due to staff shortage. Results of acceptance, necessity and usability of this training program will be presented in this paper.The intervention consists of six 45-min teaching units as shown in Table\u00a0Completion of learning objectives for firefighting, prevention of needle stick injuries, handling of protective gowns and masks and hand hygiene were assessed by teaching staff until sufficient performance was achieved during the intervention. Overall acceptance and recommendation rate were assessed for evaluation of the first event in January 2015 prior to nursing internships by using the German school grade system (1\u2009=\u2009very good to 6\u2009=\u2009unsatisfactory). Acceptance of this short-term intervention and on-site instructions at nursing facilities were assessed. Therefore, all students who finished their nursing internship between July 2017 and September 2018 were asked to complete a standardized content-validated questionnaire also using the German school grade system.All questionnaires were completely anonymized to ensure standards of data protection. Anonymized use of data for scientific reasons was declared in all questionnaires. Descriptive analysis was done using Microsoft Excel\u00a9 2016.Since the initial intervention in January 2014 a total number of 462 non-nursing BHCE students have participated in this educational intervention, as shown in Table\u00a0n\u00a0=\u2009346) compared to similar educational interventions [Performance rates of in-hospital BLS showed an overall acceptable ERC BLS scores . Overall acceptance of the initial session in January 2015 was very good with a mean score of 1.9 (median 2) and recommendation rate of 94%. Overall acceptance remained high after 2017 with mean grade 2.3 (median 2) compared to very mixed results for initial trainings at nursing facilities with mean grade 3.5 (median 3). Remarkably 24% of all students rated initial training at nursing sites to be deficient (grade 5) or unsatisfactory (grade 6). According to students\u2019 feedback concerning initial training at nursing facilities 54% of all students only received a rudimental initial training, while 30% reported to have had no initial training all. Detailed aspects of non-nursing students\u2019 tasks at nursing sites as shown in Table\u00a0As presumed by our previous risk assessment tasks with extraordinary damage potential like detection of medical emergencies and assistance during CPR  as well as firefighting  were quite rare but did occur.Among all 402 non-nursing BHCE students successfully completing nursing internships until January 2019 no case of needle stick injury, second victim phenomenon or other serious harm of patients or students has been reported so far.Health care workers are exposed to numerous potential hazards , 28\u201336. Since students are free to choose any nursing facility in Germany or comparable to German nursing standards, assessment of students\u2019 perceptions can be regarded as representative and evaluation of self-effectiveness can be regarded reasonable under the given circumstances. Quantification of risks for rare events like assistance during CPR or firefighting on a ward seemed to be adequate since these rare events occurred in this comparably small group of students with expected frequencies.It should be assumed that deficits in initial training during nursing internships will also affect students in other educational settings such as nursing internships for high-school students or future medical students. To our knowledge there is no other preventive educational intervention like \u201cSurvival-Day\u201d in any high-school or medical school in Germany.We implemented a short-term intervention that was widely accepted and regarded more helpful by non-nursing BHCE students preparing for their tasks at nursing internship than their received initial training at nursing facilities.One fourth of all BHCE students reported inadequate initial training at nursing facilities in general. Also more than half of all students were exposed to hazardous activities without preliminary safety training at nursing facilities supporting our primary hypothesis of inadequate initial training of nursing interns. This justifies the need of our curricular safety training Survival-Day in order ensure necessary safety training to keep non-nursing students as well as patients free from avoidable harm that otherwise could be caused.As long as mandatory safety trainings for all non-nursing interns are not implemented at nursing facilities, educational institutions, sending students to nursing internships should implement short-term educational interventions like the Survival-Day @ Wiesbaden Business School to ensure minimum standards of occupational and patient safety during nursing internships."}
+{"text": "Mycoplasma phocirhinis strain 852T was examined for determinants of tropism or virulence. It encodes multiple orthologs of an immunosuppressor that may predispose susceptibility to infection or influence outcomes of intercurrent diseases in marine mammals.The genome of  Mycoplasma phocirhinis strain 852T was examined for determinants of tropism or virulence. It encodes multiple orthologs of an immunosuppressor that may predispose susceptibility to infection or influence outcomes of intercurrent diseases in marine mammals.The genome of  Mycoplasma phocirhinis was first isolated from the respiratory tracts and hearts from harbor seals (Phoca vitulina L.) that died along the adjacent North and Baltic seacoasts during a mass mortality event in 1988  using an Easy-DNA genomic DNA purification kit . Libraries were constructed using the NEBNext UltraTMII DNA library prep kit  and dual-index NEBNext multiplex oligos  for Illumina MiSeq 2 \u00d7 150-bp paired-end sequencing. Trimming, adapter removal, and quality filtering with NxTrim v0.4.3  that have about 60% amino acid sequence similarity to mycoplasmal protein M, which binds the light chain of host IgG to block antigen-specific binding (M. phocirhinis to evade host defenses or modulate intercurrent distemper or influenza in seals. Although adherence and cytotoxicity of M. phocirhinis to epithelial cells has been demonstrated in a tracheal explant model (M. phocirhinis 852T genome sequence and annotation have been deposited in GenBank as BioProject PRJNA505803. The raw data are available in NCBI's Sequence Read Archive as SRX5310557.The"}
+{"text": "Introduction. The multifocal lumbar pathology including disc herniation and stenosis in the spinal canal or foramen has been considered the most difficult to approach surgically. It often requires mandatory dual approaches and/or fusion techniques. Traditional percutaneous endoscopic lumbar transforaminal and interlaminar approach has been focused on unifocal disc herniation. However, the development of endoscopic spinal instruments and surgical technique has broadened surgical indication and therapeutic boundary in endoscopic spine surgery. Cases Presentation. The authors present outcomes of four patients with multilumbar pathology including highly inferior migrated disc combined with lateral recess stenosis, multifocal disc herniation, bilateral disc herniations in spinal canal and foraminal disc herniation combined with central canal stenosis. They were successfully treated by percutaneous uniportal full endoscopic approach with single incision. Conclusion. Percutaneous endoscopic spine surgery is a safe and effective tool to figure out multilumbar pathology in a minimal invasive way. Traditional percutaneous endoscopic lumbar transforaminal and interlaminar approach has been focused on unifocal disc herniation \u20135. HowevThe multifocal lumbar pathology including disc herniation and stenosis in the spinal canal or foramen has been considered the most difficult to approach surgically. It often requires mandatory dual approaches and/or fusion techniques. Endoscopic surgical techniques may reduce the need for these more invasive methods. A uniportal full endoscopic approach with single incision can satisfactorily resolve these challenging cases. Here we present outcomes of four patients with multipathologies in the lumbar spine who were successfully managed with a single endoscopic approach.A 60-year-old woman suffered from left gluteal, thigh, and calf pain along the L5 dermatome for two months. Manual muscle test for the left great-toe dorsiflexion and the ankle dorsiflexion showed grades III and IV, respectively. She also suffered from neurogenic intermittent claudication symptom (50 m). Magnetic resonance (MR) images demonstrated disc extrusion and downmigrated disc herniation combined with spinal canal and lateral recess stenosis at L4\u20135 level . AlthougA 50-year-old woman visited the clinic because of severe right-leg radiating pain along the L2 and L3 dermatome. She has a history of fusion surgery five years ago. MR images revealed intracanal and extraforaminal multifocal soft disc herniation at the L3-4 level . AlthougA 58-year-old woman presented with acute onset left-leg radiating pain. She also had constant right-leg radiating leg pain for one year. Bilateral straight leg raise test was positive. MR images showed L5\u2013S1 bilateral herniated disc . DespiteA 77-year-old woman presented with complaints of radicular pain in the right gluteal region and anterolateral aspect of her thigh and leg for three months. She was also suffering from neurogenic claudication symptom. She could not walk more than 50 meters continuously. MR images of the lumbar spine revealed extraforaminal disc combined with central canal stenosis on L4-5 . A plainSpinal disease is the natural aging process. Such degenerative change induces lumbar spinal disease which has a variable spectrum ranging from simple disc herniation to severe degenerative spondylosis such as listhesis, stenosis, and kyphoscoliotic deformity. Among those diseases, a simple single lumbar pathology could be mostly figured out by a single therapeutic modality and approach. However, multifocal or combined different type of pathology in the lumbar spine would need more invasive surgical methods such as two staged dual approaches or fusion technique in order to solve such different and complex combined pathologies.We presented outcomes of four patients with multilumbar pathology who were successfully treated by a single endoscopic approach. If endoscopy was not used, more invasive treatments would have been needed for these cases.Endoscopic operations such as arthroscopy and laparoscopy are becoming standard operations nowadays. Lumbar spinal diseases ranging from simple contained disc to complicated cases such as highly migrated disc herniation and other pathology combined with bony degeneration to produce foraminal and canal stenosis can now be treated with full-endoscopic surgery using various accesses and techniques \u201313. ManyThe lens located on the tip of the tube-shaped endoscope to see the operative field can be referred to as the \u201coperative eye\u201d. The \u201coperative eye\u201d can be placed very close to the operative target directly passing anatomical structures in endoscopic spine surgery. Unlike traditional bare-eye or microscopic surgery, it is not necessary to destroy much of normal structures to access the target pathology and secure operative corridor to see the operative field. In the first case, traditional laminotomy techniques could be used for lateral recess decompression with removal of the highly inferior migrated disc herniation. However, these surgical options could not avoid injury to posterior segmental structures by dissection of the paravertebral muscle and the partial removal of the lamina and facet joint. Target oriented direct accessibility in endoscopic surgery mentioned above helped us minimize the operative iatrogenic injury and save normal segmental spinal structures in current cases. It led to good clinical outcome such as patient's fast recovery and early return to regular activity despite their multilumbar pathology.Operative instruments used in endoscopic spine surgery are relatively small compared to near anatomical spinal structures. The \u201coperative eye\u201d on the tip of such a small endoscope can navigate around the target with minimal pivoting movement of the endoscope via an initial single skin portal. Moreover, recent development of the endoscopic drill system has expanded surgical boundary where the endoscope could not previously approach or move around. Such characteristics of endoscopic spinal surgery provided probing and small sized working spot, enabling authors to explore a relatively large operative field and manage two different distant targets simultaneously in current cases. The second and third cases showed navigability of the spinal endoscope that helped us treat the multilumbar pathology successfully.Variability of endoscopic surgical angle is another distinct feature of spinal endoscope regarding surgical success in current series. Only a slight withdrawal of endoscope after the initial approach can give surgeons the opportunity to reapproach, change the working trajectory, and manipulate structures around different surgical targets without needing another skin incision or different secondary surgical corridor as shown in the second and third cases. The optical angle of a spinal endoscope is 15-20 degrees. With rotation or tilting of the endoscope, an endoscopic operative angle can provide a more variable surgical view and working trajectory. It helps the surgeon reach farther targets that could not be reached by microscope. It also helps surgeons explore hidden areas easily without destroying normal anatomical structures needed to be removed to observe the target with traditional surgical methods. The fourth case was a good example of endoscopic surgery which was performed by a precise, targeted approach via the least invasive surgical route using the endoscopic angled and long-distance visibility. Instead of using dual approach for both spinal canal decompression and removal of extraforaminal disc herniation or the fusion method with wide decompression, endoscopic contralateral approach was chosen. It achieved the same surgical goal. Optimized oblique sublaminoplasty for canal decompression and removal of far lateral disc from contralateral side were possible due to the long distance of the visibility, natural optical angle, and tilting maneuver of the spinal endoscope.In the current case series, satisfactory clinical results were acquired from all patients by using minimally invasive endoscopic procedure. However, percutaneous endoscopic spine surgery is not omnipotent. Although all cases in the current series were successfully resolved by a single endoscopic approach, these techniques cannot be applied to all forms of lumbar spinal diseases, especially for those with severe lumbar spinal stenosis with spondylolisthesis or instability. It should be performed carefully for selected patients. Percutaneous endoscopic spine surgery has a steep learning curve as previously reported by many authors , 16\u201319. Percutaneous endoscopic spine surgery is a safe and effective tool to resolve multilumbar pathology in a minimal invasive way. It can be an alternative to traditional surgical methods by minimizing iatrogenic injury to normal segmental structures and providing good clinical outcome to the patients."}
+{"text": "An approach for optimizing fuel particle reactivity involves the metallurgical process of pre-stressing. This study examined the effects of pre-stressing on aluminum (Al) particle ignition delay and burn times upon thermal ignition by laser heating. Pre-stressing was by annealing Al powder at 573 K and quenching ranged from slow  identified as pre-stressed (PS) Al to fast  identified as super quenched (SQ) Al. Synchrotron X-ray Diffraction (XRD) analysis quantified an order of magnitude which increased dilatational strain that resulted from PS Al and SQ Al compared to untreated (UN) Al powder. The results show PS Al particles exhibit reduced ignition delay times resulting from elevated strain that relaxes upon laser heating. SQ Al particles exhibit faster burn times resulting from delamination at the particle core-shell interface that reduces dilatational strain and promotes accelerated diffusion reactions. These results link the mechanical property of strain to reaction mechanisms associated with shell mechanics that explain ignition and burning behavior, and show pre-stressing has the potential to improve particle reactivity. For propulsion applications, ignition delay and burn times of Al particles are important to understand because reduced Al particle burn time and ignition delay can provide added energy to facilitate propellant surface burning regression or reduce particle agglomeration on the burning propellant surface [Aluminum (Al) is an important solid fuel for propulsion and pyrotechnic applications because of its high  were treated through an annealing and quenching process that is detailed elsewhere ,3 but suThe PS Al, SQ Al, and untreated Al (UN Al) powders were analyzed using Synchrotron XRD at the Advanced Light Source facility at Lawrence Berkeley National Laboratory on beamline 12.3.2. This beamline uses a micron focused synchrotron X-ray beam to determine dilatational strain and a white micro-beam technique ,17 to de2 laser focused down to a 200 \u00b5m spot size as shown in \u00ae script analyzed burn time and ignition delay data by tracking particle residence time and location of first light respectively, as shown in A 1-g powder sample of PS Al, SQ Al, or UN Al powder was loaded into the particle injector shown \u221215 J, while the energy required to heat the same particle to the melting temperature of alumina is approximately 1 \u00d7 10\u22127 J.Synchrotron XRD measurements in The SQ Al particles had the shortest burn times , with burn times for all particle treatments converging at 90% of the total particle population . Shorter2O3 passivation shell. Annealing and quenching the Al particles may alter the surface hydration layer and affect surface energy forces that promote agglomeration. It is assumed that after annealed and quenched particles were exposed to ambient conditions, they would naturally rehydrate. Visual inspection of the Al powders reveals no apparent differences in agglomeration behavior that would contribute to the behaviors observed in Aluminum particles inherently include a surface hydration layer surrounding the AlThe results presented in 2 laser beam. Pre-stressed Al particles quenched slowly (PS Al) exhibit reduced ignition delay times while pre-stressed particles quenched quickly (SQ Al) exhibit reduced burn times. Elevated strain energy may contribute to a reduction of energy needed to ignite the particles thereby leading to reduced ignition delay time. Shell-core delamination associated with SQ Al particles facilitates diffusion reactions thereby reducing burn times. Altering the mechanical properties of the shell-core particles alters their reaction mechanism. This study links reactive behavior with mechanistic understanding associated with the mechanical property of dilatational strain. Aluminum particles have been pre-stressed using two different quenching treatments that increase their dilatational strain. Quenching slowly elevates the particle strain and quenching quickly promotes delamination at the core-shell particle interface and reduces particle strain. Both quenching treatments produce Al particles at elevated strain compared with untreated Al. The mechanical alteration of the Al particles affects their ignition and burning behavior when subjected to a CO"}
+{"text": "Few studies have examined caregiver reactions to their loved ones receiving the results of an Amyloid PET scan which can be indicative of Alzheimer\u2019s disease. Therefore, we examine: 1) What are care partner\u2019s reactions to their loved one receiving negative or positive amyloid PET scan results?, and 2) To what extent are scan results and diagnostic category (dementia vs. mild cognitive impairment) associated with care partner depressive symptoms (PHQ-2) and anxiety (STAI-6)? Using data from 1,799 care partners in the CARE IDEAS study, we applied a sequential mixed-methods design and explored the reactions of 192 care partners who answered open-ended interview questions after learning about the Amyloid PET scan results. We first conducted qualitative content analysis of transcripts from open-ended questions to explore caregivers\u2019 emotional responses after their loved one received an Amyloid PET scan result. The qualitative data suggest that when the scan results fit care partner\u2019s expectations, i.e. positive scan when the patient has dementia and negative scan when the patient has mild impairment, care partners report satisfaction with this information and relief, rather than shock and frustration. Adjusted logistic regression models of survey responses support this finding; having dementia and a positive scan both increased the likelihood of care partners having high levels of anxiety, and a significant interaction indicated that a positive scan was associated with high anxiety among care partners of patients with mild cognitive impairment but not dementia. Only lower education and higher impairment in everyday cognitive function were associated with high depressive symptoms."}
+{"text": "An unexpected 18F-FDG uptake in left ventricule which mimicked either trombus or physiological papillary muscle was detected. Filling defect of intravenous contrast in CT images was also demonstrated in left ventricule cavity. Magnetic resonance imaging scan confirmed cardiac mass with metastatic features of malign melanoma in left ventricule.A 58-year old patient with a history of subungual malign melanoma was referred to our department for a"}
+{"text": "Sleep disturbances are core symptoms of posttraumatic stress disorder (PTSD), and recent studies also suggest a link between PTSD and cognitive impairment. There is some evidence of an association between sleep disturbances and cognitive abilities, such as memory, though few studies have focused on older adults and fewer still among those with mental health conditions. This study examined the association between subjective memory complaints and sleep  in older veterans with PTSD. Fifty-four veterans with PTSD  participated in the study. Sleep was assessed using the Pittsburgh Sleep Quality Inventory (PSQI) and the PSQI Addendum for PTSD (PSQI-A). Memory was assessed using the Frequency of Forgetting Scale (FOF) derived from the Memory Functioning Questionnaire. The relationship between sleep quality parameters and FOF were examined using bivariate correlations and independent samples t test. Over 60% of participants met military-specific criteria for poor sleep . Overall sleep quality on the PSQI-A was significantly associated with worse memory . Among specific sleep parameters , greater daytime dysfunction due to sleepiness was significantly associated with worse memory . Between-group analyses comparing memory complaints across participants classified as \u2018poor\u2019 versus \u2018good\u2019 sleepers on the PSQI-A approached significance (t(52)=1.93, p=.06). This study suggests that poor sleep may be a correlate of memory complaints among older adults with PTSD. Future studies are needed to determine whether poor sleep is an underlying factor in the link between PTSD and cognitive impairment."}
+{"text": "The experiment studies the effect of technical and social sources of complexity on effort required to complete abstracted design tasks. Parameter design tasks define a set of input design parameters and functional requirements modeled with a linear coupling matrix. Selecting design variables to meet all functional requirements within error limits completes a task. Technical complexity arises from the number and degree of coupling between design parameters. Social complexity arises from the number of designers involved in a task. The experiment includes 10 sessions with between 19 and 24 rounds of randomly generated parameter design tasks each having between two and six design variables and one, two, or three designers. Designers completed individual tasks in parallel during rounds. This article contains raw and post-processed data from 374 completed tasks ranging in effort from a few seconds for simple tasks to more than 15\u202fmin for complex ones. Specifications tableValue of the data\u2022Parameter design tasks are an important class of abstract engineering design problems for behavioral experiments because of their generalizability and reproducibility.\u2022This dataset provides a baseline of individual and small group performance on randomly generated fully decoupled and fully coupled tasks for cross-validation of future studies using parameter design tasks.\u2022Researchers may use this dataset to investigate temporal activities and search strategies within individual tasks to train computational design agents or explain the effectiveness of individual designers or design teams.1This dataset is included in supplementary data in multiple file formats. The session configuration data (raw/config.json) in JSON format describes details for each session. Key-value pairs in The designer data (raw/designers.csv) in comma-delimited CSV format describes demographic information collected from participants. Columns in The experiment configuration data (raw/session#/experiment#.json) in JSON format describes the conditions for experimental rounds. Key-value pairs in The experimental log data (raw/session#/session#.log) in comma-delimited text format describes actions taking place during a session. Columns in The post-processor script (post/processor.py) written in the Python language includes a main function to execute the script. The post-processor reads raw data and configuration files to build an in-memory model of a session with the following class hierarchy: PostProcessor composes Session composes Round composes Task composes Action. Each class provides helper functions for post-processing functions.The post-processor outputs task summary data (post/tasks.csv) in CSV format where each row describes results of a task during a design experiment. Columns in 22.1The study was conducted using an IRB approved protocol. It includes 30 graduate students in technical design-related fields such as aerospace and systems engineering. Participants were assigned to 90-min sessions in cohorts of three based on mutual availability. Sessions were conducted in university classrooms with the three designers and research administrator seated around a single table with computer displays positioned to restrict screen sharing.The study includes 19 (for sessions 1\u20133) or 24 (for sessions 4\u201310) rounds of tasks in partially randomized order to avoid coupled tasks with four variables in first ten rounds. Tasks vary the number of designers, number of design variables, and degree of coupling following the experimental conditions in 2.2Design tasks are based on previous work defining a class of randomly generated parameter design tasks for experimental study Designers work on a task by selecting values of design parameters between upper and lower bounds of 1 and \u2212 1 and observing the effect on functional requirements, attempting to reduce error below the threshold. Multi-actor tasks assign control over design parameters or visibility of functional requirements among multiple designers.2.3Participants interact with a graphical user interface illustrated in A distributed software layer based on the IEEE standard 1516 architecture for simulation interoperability communicates design changes between designer interfaces. A research administrator controls overall task progression from a separate console, which also logs actions. Any change to a design parameter immediately induces an update to show new functional requirements. A chime plays when all tasks are complete in a round, signaling the participants found an acceptable solution."}
+{"text": "A 57-year-old male with gastroesophageal reflux disease and esophageal stricture with dilation presented as a cardiac catheterization lab activation for anterolateral ST-segment elevation myocardial infarction. He had suffered an unwitnessed syncopal episode after severe substernal chest pain. Electrocardiogram (ECG) showed anterolateral ST-segment elevation. Markers of myocardial injury were negative. He subsequently had an unremarkable coronary angiogram, echocardiogram, and cardiac magnetic resonance imaging (MRI). He had another episode of crushing chest pain and palpitations during his hospital stay, which correlated with ST-segment elevation, followed by a slow run of ventricular arrhythmia that terminated after a dose of sublingual nitroglycerin. A diagnosis of accelerated idioventricular rhythm (AIVR) following coronary artery vasospasm (CAV) was made. This clinical vignette presents a unique presentation of AIVR following an episode of Prinzmetal\u2019s angina. Coronary artery vasospasm (CAV) is a constriction of coronary arteries and has been documented as a cause of myocardial injury, as well as fatal arrhythmia since the late 1950s . HoweverA 57-year-old Caucasian male was brought in by emergency medical services (EMS) with reports of severe substernal chest pain. The cardiac catheterization lab was activated for anterolateral ST-segment elevation noted on the electrocardiogram (ECG). He reported severe substernal chest pressure and belching followed by an unwitnessed syncopal\u00a0episode. He had several seconds of cardiopulmonary resuscitation performed by bystanders prior to electromyostimulation (EMS) arrival. His past medical history includes gastroesophageal reflux disease and esophageal stricture with dilation.The ECG on admission showed anterolateral ST-segment elevation Figure\u00a0. His vitStudies have found that the majority of arrhythmias associated with CAV were ventricular tachycardia, bigeminy, second and third degree atrioventricular (AV) block, and ventricular fibrillation\u00a0-4. AIVR Accelerated idioventricular rhythm is a slow (50-120 bpm) ventricular rhythm that consists of three or more consecutive monomorphic ventricular beats with gradual onset. It is usually a benign and self-terminating arrhythmia. It does not require specific anti-arrhythmic therapy unless in the presence of hemodynamic instability\u00a0. It has As part of the diagnostic approach to unexplained syncope, electrophysiological study (EPS) can be a useful tool. This was found to be most apparent in those subjects with concurrent structural heart disease\u00a0. There iDespite being an uncommon arrhythmia, the presence of AIVR after CAV should always be in the differentials to avoid unnecessary work up and treatment in the long run. Review of telemetry with correlation to symptomatic events can provide valuable insight into the etiology of arrhythmias and help in determining the correct diagnosis."}
+{"text": "OBJECTIVES/SPECIFIC AIMS: The long-term goal of this project is to develop a cost effective 3D printed multipurpose intravaginal ring (IVR) to prevent against unintended pregnancies and infectious diseases.Our goal is to develop a female-controlled method for prevention using innovative IVRs. METHODS/STUDY POPULATION: In vitro and in vivo characterization. RESULTS/ANTICIPATED RESULTS: Controlled and fine-tuned release kinetics 100% drug release from 3D printed IVRs compared with 10%\u201315% with traditional injection molded IVRs cost-effective engineering of multipurpose IVR with CLIP 3D printing technology. DISCUSSION/SIGNIFICANCE OF IMPACT: If successful, this project will revolutionize the engineering of IVRs and will have a global impact on human health. Not only we will help save millions of women around the world but also millions of children that are infected by their HIV-positive mothers through gestation or breast feeding."}
+{"text": "This study examined whether perceived neighborhood social disorder predicted depressive symptoms among non-married older women (N = 823) drawn from the 2016 Health and Retirement Study. It also tested the stress buffering effect of friends support. A negative binomial regression model showed that higher perceived neighborhood social disorder was associated with higher depressive symptoms. Presence of good friends in the same neighborhood and number of close friends were protective factors, but no stress buffering effect of friends support was identified. This study highlights the adverse effect of negative perceptions of the neighborhood social environment on non-married older women\u2019s depressive symptoms."}
+{"text": "Paenibacillus polymyxa isolates and control efficacy of P. polymyxa ShX301 for controlling Verticillium wilt of cotton, isolated in experimental fields at the Sanyuan Agricultural Experiment Station of North-West Agriculture and Forestry University, Sanyuan county, Shaanxi province, China. Ultrastructural characteristics of P. polymyxa isolates made using technique of transmission electron microscopy. A strain ShX301 has a broad-spectrum antifungal activity against V. dahliae and other plant pathogens and has been used for in vitro experiments for controlling this disease in greenhouse, \"Biocontrol potential of Paenibacillus polymyxa against Verticillium dahliae infecting cotton plants\" We present the data corresponding to the ultrastructural characteristics of  Specifications tableValue of the data\u2022Peanibacillus.Our data provide the evidence that hints the three-layered spore coat is possibly a common feature in genus \u2022P. polymyxa strain ShX301 has great potential using as biocontrol bacterium for controlling Verticillium wilt of cotton.Biocontrol assay showed that \u2022The data can be used for general analysis of bacterial identification and screening of biocontrol strains.1Paenibacillus polymyxa strain ShX301 was described P. motobuensis by Iida et al. P. polymyxa also shared the same characteristics with strain ShX301. The mature spores in the sporangia all had the three-layered spore coats in the four strains . The raw information related to disease incidence and severity contained in the 2For endospore observation, bacterial strains were grown on specific spore-forming medium  for two days at 25\u2009\u00b0C Gossypium hirsutum cv. Ejing-1) were used. The disease assessment was carried out 45 days after planting. Disease severity was assessed for each plant on a 0 to 4 rating scale Paenibacillus polymyxa against Verticillium dahliae infecting cotton plants.\" The seeds of a susceptible cotton ("}
+{"text": "Our data demonstrates that dietary protein restriction increases energy expenditure and improves glucose homeostasis, and that this effect is largely mediated by the metabolic hormone fibroblast growth factor 21(FGF21). Considering that the central nervous system (CNS) is acknowledged as a major regulator of both energy and glucose homeostasis, we have extended our studies to identify the tissue site mediating these FGF21-dependent effects via dietary protein restriction. In this study, mice with dysfunctional FGF21-signaling in either the CNS or adipose tissue were fed a control or low protein (LP)-diet to assess changes in body weight and metabolic endpoints. Our data show that LP diet increased energy expenditure and reduced body weight in control littermates, but these effects were lost in mice bearing CNS-specific deletion of Klb. These data highlight a liver to brain FGF21-signal as the first known neuroendocrine mechanism to explain the coordinated metabolic changes induced by dietary protein restriction."}
+{"text": "Understanding individual factors  associated with self-reported memory problems is important to refine identification of individuals at a higher risk of developing Alzheimer\u2019s disease (AD). Using multilevel modeling, we examined the association of family history of AD and personality traits with self-reported memory problems in older adults . Results showed that individuals with a family history of AD reported more frequent memory problems and greater one-year memory decline. Similar findings were reported for individuals with higher extraversion scores. Further, older adults with higher neuroticism scores reported greater one- and ten-year memory decline. Neuroticism was positively related to frequency of memory problems, but only among participants with a family history of AD. Findings suggest that higher neuroticism and lower extraversion may increase older adults\u2019 reports of memory problems. Family history of AD may further exacerbate this tendency."}
+{"text": "Stent placement in the cephalic arch is being used with increasing frequency. Late complications of bare metal and stent grafts in dialysis access, in particular stent migration, are often under-reported and can lead to compromise of future dialysis circuits.A 52-year-old man developed acute arm swelling 2\u2009days after creation of a left arm brachio-basilic arteriovenous graft. The axillary vein was found to be jailed by a previously deployed cephalic arch stent graft which had migrated into the subclavian vein. There was failure to cross through the fabric of the stent graft using conventional chronic total occlusion wires and techniques. A TruePath device was used successfully to cross through the fabric of migrated cephalic arch stent graft and recanalise the short subclavian-axillary vein occlusion.The adapted use of a drilling chronic total occlusion device to drill through the fabric of migrated stent graft was performed successfully to allow complete recanalisation of the occluded axillary vein. Stent-graft (SG) placement for cephalic arch stenosis in dysfunctional dialysis access is an option for patients, and a recent systematic review suggests that it may be more durable in the short term compared to angioplasty alone  initially created were abandoned. He underwent hemodialysis via a right brachiocephalic arteriovenous graft (AVG) but required multiple interventions to maintain patency. During a thrombolysis procedure, venoplasty of a cephalic arch occlusion resulted in a focal rupture for which conservative management with balloon tamponade was unsuccessful. An 8\u2009\u00d7\u200960\u2009mm Fluency SG  was deployed in the cephalic arch to manage the rupture. Following deployment, the SG showed no protrusion into the subclavian vein Fig.\u00a0. On a suA new left loop brachiobasilic AVG was created inadvertently and the patient developed left arm swelling 2\u2009days post-surgery. A graftogram showed complete occlusion of the axillary-subclavian vein from the migrated cephalic arch SG. Attempts to cross the axillary vein occlusion using 0.035\u2033 standard guide wires, 0.018\u2033 glide wires , a 0.014\u2033 Winn 200\u2009T  and 0.018\u2033 Victory 25\u2009g  CTO wires were all unsuccessful due to the inability to traverse the fabric of the Fluency SG , the peripheral end of the occluded SG was accessed Fig.\u00a0. Using aLeft arm swelling improved significantly over the 3\u2009days. Unfortunately, late infection of the AVG developed and was explanted 28\u2009days post intervention. New long-term AVG dialysis access was created in the left lower limb. Six months after left subclavian-axillary vein stenting, an opportune catheter angiogram via his left groin AVG demonstrated continued patency, and without recoil, of the stented segment Fig. .Cephalic arch stenosis affects up to 34% of dysfunctional brachiocephalic AVFs (Bennett et al. Conventional techniques of crossing the occlusion were unsuccessful due to the SG fabric preventing wire passage. Due to vascular anatomy and potential inadvertent subclavian artery injury, sharp recanalisation employing a straight needle was deemed high risk. Bench-testing using a demonstration unit of the TruePath device and Fluency SG demonstrated controlled and easy traversal of the drilling tip of the device through the SG fabric. TruePath is guidewire-mounted mechanical recanalization device with a rotating distal diamond tip designed for true-lumen crossing of peripheral arterial occlusions. We adapted the previously reported balloon puncture technique, for placement of dialysis access catheters in occluded internal jugular veins (Too et al. The case report demonstrates the successful novel use of the TruePath device to drill through the fabric of a migrated cephalic arch stent graft which had jailed the axillary vein outflow causing acute arm swelling due to compromise of the axillary vein outflow. Migration of cephalic arch stent grafts are under-reported and can compromise future dialysis access options. The use of the TruePath device facilitated recanalization of the occluded axillary vein. The device and techniques used in this case can be utilised in similar situations, where conventional techniques would pose high risk of arterial injury or likely be futile."}
+{"text": "Routine cancer screening is widely recognized as an effective strategy for reducing cancer mortality \u2013 the second leading cause of death in the U.S. Research shows cancer screening rates need to be improved, and men are less likely to uptake recommended screening than women. Cancer screening requires an array of tasks such as seeking up-to-date guidelines, making appointments, planning a hospital visit, and communicating with health care professionals in the complex health care systems. Importantly, modern health care systems are rapidly adopting technology such as web-based applications for information dissemination and communication with patients. This current study is designed to better understand the roles of problem-solving skills in the technology-rich environment (PSTRE) in two selected cancer screening behaviors among middle-aged and older men. We obtained nationally representative data with a sophisticated PSTRE assessment from the 2012/2014 Program for the International Assessment of Adult Competencies (PIAAC). Binary logistic regression models with survey weights were used to estimate the association between PSTRE scores (1 \u2013 500 points) and two cancer screening behaviors of men who meet the recommended guideline of age between 45 to 74 years old . Results showed that greater PSTRE scores were positively associated with prostate cancer screening . Improvement in PSTRE may promote the specific cancer screening behaviors. Our findings also inform future interventions that seek to improve cancer screening among a vulnerable section of older populations."}
+{"text": "We read with great interest the article by Yeh et al. about microcirculation in cardiogenic shock supported by venoarterial extracorporeal membrane oxygenation (VA ECMO) . We woulThe heterogeneity of cardiogenic shock (CS) etiologies and its complex pathophysiology requires the thorough study of selected populations, especially when studying microcirculation. The inflammatory component in CS pathophysiology has become increasingly acknowledged  and it mThe authors outlined the usefulness of early microcirculatory parameters in predicting 28-day mortality in CS shortly after VA ECMO implantation . They foFinally, as almost 50% of CS patients are known to die despite having restored cardiac output [ We thank Montero et al. for their comments regarding our article investigating the microcirculation in patients with VA-ECMO life support . First,"}
+{"text": "Blair, was originally published Online First without open access. After online publication Novartis Pharma AG requested that the article be Open Choice to make the article an open access publication. Post-publication open access was funded by Novartis Pharma AG. The article is forthwith distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (The original article has been update."}
+{"text": "Microbes modulate their metabolic and physiological mechanisms in response to changing environmental conditions. It is our interest toidentify small regulatory RNAs using microarray expression data (GSE26043) obtained from B. cereus ATCC 14579 in AgNO3 stress. Bydefinition, expression of transcripts from the Intergenic Regions (IGR) with >=2 fold under silver stress is predicted as novel small RNAs.Computational analysis of the IGR expression levels extracted from the available microarray data help in the identification of stressresponsive sRNAs with rare promoters  followed by terminator signals predicted using the sRNAscanner tool.We predicted 1512 sRNA specific regions on both positive and negative strands collectively. Thus, a non-redundant high scoring unique860 sRNAs with distinct promoter  and terminator signals are reported.These unique computationally predicted sRNA regions were verified with the highly expressing IGRs from the microarray data. It shouldbe noted that 14 sRNAs reported in earlier studies were also found in this dataset. This study has reported 71 additional sRNAs from thetranscriptome under metal stress response. Hence, we use global transcriptomics data for the identification of novel sRNAs in B. cereus. Wedescribed a general model using a procedure for the identification of small regulatory RNAs using microarray expression data withappropriate cross validation modules. It is found that some sRNAs reported in this study were found to have multiple rare promoters. Thisopens the possibility of sRNA activation under multiple stress condition. These sRNA data reported in this study should be characterizedfor their mRNA targets and molecular functional networks in future investigations. Microbes are often exposed to the changing environmentalconditions such as low temperature, oxidative stress and heavymetal stress, etc -6.To adOne such drastic environmental condition is heavy metal ionsexposure like Ag+, Cd2+, Hg2+, Co2+, Cu2+, Ni2+, Zn2+ thatcauses toxic effects in the microbial cell . To reduSmall untranslated regulatory RNAs are identified in all forms oflife. In eukaryotes it is referred as noncoding RNAs (ncRNAs) andprokaryotic counterparts are called as sRNAs . RecentlThe chromosomally encoded sRNA regulate the mRNA targets inresponse to the drastic environmental conditions like lowtemperature, heavy metal exposure, iron homeostasis, quorumsensing, outer membrane protein modification, etc. They functionas either positive or negative regulators of the gene expression.Several bioinformatics and experimental approaches have beendeveloped for genome wide identification of sRNAs. Informationon sRNAs was reported in BSRD database ; sRNAmapTranscriptional factors are the proteins bind at a particular site inthe upstream region of the gene, involve in the initiation oftranscription by enabling the binding of RNA polymerase. Sigmafactors are the exclusive regulators for transcription initiation inmicrobes. Based on the sequence analysis, major sigma factors areclassified into sigma 70 (S70), sigma 54 (S54) and extra cytoplasmicfunction (ECF) sigma factors -24 such The global expression profile [GSE26043] of the control and AgNO3exposed test samples at various time intervals were collected fromNCBI-GEO database. The expression data has 15000 oligo probesto monitor protein coding (10450) and Intergenic regions (4550) inboth sense and anti-sense directions. Details about the targetinggene/mRNA coordinates and respective probe information werecollected from the complete genome of B. cereus ATCC14579(NC_004722). We have created specific PERL script to calculate thecoordinates for empty IGRs from the above protein coding table.The normalized global expression pattern of coding and IGRs werealso collected from the above Affymetrix data. We have selectedthe IGR regions showing expression values >=2 fold comparedwith the control sample and proposing these regions to expressintergenic transcripts.Binding nucleotides along with their specific spacer regions ofvarious sigma factors were collected  and usedComplete genome sequence of the B. cereus ATCC 14579(NC_004722.fna) and corresponding coding region file(NC_004722.ptt) were retrieved from GenBank . RhoindeWe have overlapped the predicted sRNA locations with theintergenic region coordinates retrieved from the genomemicroarray by using the In-house developed awk script. If, any partof sRNA matches with the intergenic coordinates showingexpression in the microarray were confirmed as sRNA encodingIGR. Expression levels of these sRNA harboring IGRs at varioustime points were taken from the microarray data and presented inthe form of a heat maps .Bacterial sRNAs are novel regulators of gene expression involvedin diverse biological processes. A change in the environment oftencauses physiological stress and bacteria cope with that stress byaltering the expression of relevant genes and producing newproteins, which may allow the cell to repair damage or protect itselfin future. This stress-induced gene expression response is oftenmediated by proteins called sigma factors . Recent This study is aiming to identify novel stress responsive sRNAsusing virtual comparison of computational sRNA predictions withglobal transcriptome data collected under silver stress condition.The genome wide microarray experiment in B. cereus ATCC 14579was designed with custom designed oligo probes against CDS'sand IGR's to monitor their expression under various time intervals. It was We have constructed the promoter datasets for S24, S28, S32, S54and S70 using the PWM_create module given in sRNAscanner suite.We have applied these PWMs with their corresponding spacerregions in sRNAscanner to predict the intergenic sRNAs under predefinedparameters . Above sMost of the sRNAs were found to be regulated at high frequency bysRNA specific \u03c3 70 (567) followed by \u03c3 70 (506) and \u03c3 24 (183) than\u03c3 28, \u03c3 32 and \u03c3 54. Initially 567 sRNAs were predicted to betranscribed by sRNA specific \u03c370, among them 380 sRNAs werefound to be unique and it may play a major role in stress tolerance.Expression profiles of the 367 IGRs within the microarray data haveshown significant transcripts . Among tThe total number of unique sRNAs in predicted sequences for eachsigma factor of Bacillus spp. was shown in The present study clearly demonstrated the use of globaltranscriptomics data for the identification of novel sRNAs in B.cereus. This methodology may be applied in any model organismsupported with the microarray and genome data. Proposedmethodology also retained fourteen novel sRNAs reported inearlier studies, which clearly validated the reliability of the appliedmethod. Interestingly, few sRNAs reported in this study werefound to have multiple rare promoters and it opens the possibilityof sRNA activation under multiple stress condition. Remaining,sRNAs reported in this study may be functionally characterized fortheir mRNA targets and molecular functional networks."}
+{"text": "This review highlights the utilization of dendron-polymer conjugates as building blocks for the fabrication of nanosized drug delivery vehicles. The examples given provide an overview of the evolution of these delivery platforms, from simple micellar containers to smart stimuli- responsive drug delivery systems through their design at the macromolecular level. Variations in chemical composition and connectivity of the dendritic and polymeric segments provide a variety of self-assembled micellar nanostructures that embody desirable attributes of viable drug delivery systems. Recent decades have witnessed an increasing trend in the application of polymeric nanomaterials for cancer therapy ,2,3. WidAlthough the overall picture appears quite simplistic, there are several challenges in using micellar constructs as delivery platforms . When NPNanotherapeutic agents with an average size in the range of 10 to 200 nm can escape filtration through the kidneys, with a renal clearance cut off value around 5 nm. As a result, these NPs can stay in the blood stream circulating for prolonged periods of time. In this extra time frame, NPs have increased probability to extravasate to the tumor tissue leading to improved drug accumulation profiles . The ultNanotherapeutics can enhance a drug\u2019s efficacy profile during three phases; initially by interaction with the reticuloendothelial system (RES) agents while in systemic circulation; secondly during extravasation from the blood vessel towards tumor environment and finally upon uptake by target cells and release of the delivered agents. RES is a system composed of macrophages widespread in multiple organs and sites, such as lymph nodes, adipose tissue, and bone marrow, but the most essential ones are those located in the spleen and liver, since they have the greatest potential to alter the clearance profiles of NPs. The NP-corona complex formed after introduction to serum may induce recognition by macrophages and removal of these particles via phagocytic routes, as macrophages can detect the NPs coated by these serum proteins ,23. ThusThe concept of three-dimensional branched polymers like dendrimers, possessing an alternative macromolecular structure compared to linear polymers was first proposed by Flory in the early 1950s . Howevern type monomers  rather than the standard AB monomers which result in linear polymers. They are synthesized in an iterative manner, thereby allowing an excellent unimolecular molecular weight distribution as well as providing control over desired core and/or peripheral functionalization . De. De74]. Pasut and coworkers reported \u03b2-glutamic acid dendrons to introduce multiple bone targeting groups. A linear dendritic construct was prepared by conjugating a 5 kDa PEG polymer with an amino-bisphosphonate alendronate (ALN) modified generation 2 \u03b2-glutamic acid dendron, where PTX was attached to the other end of PEG through an ester group . The ALNN-vinylcaprolactam) . Ge. Ge85]. It must be noted that while oligonucleotide based materials have been used as a cargo, dendrimeric constructs composed of oligonucleotides have been synthesized. For example, Tomalia and coworkers used complementary DNA strands at focal points of dendrons to assemble dendrimers through self-assembly . Likewis\u22126 mol/L), their counterparts where the peripheral groups were removed to expose hydroxyl groups were soluble under similar conditions. The authors postulated the potential of these self-assembled aggregates for possible applications in drug delivery.As mentioned earlier, formation of micellar structures from diblock and triblock copolymers was reported by Fr\u00e9chet and coworkers in 1992 . A more w/w.This study was followed by a report by Nguyen and Hammond who reported the assembly of a ABA-type dendron-polymer-dendron conjugate composed of PAMAM dendrons as hydrophilic components and poly(propylene oxide) as the hydrophobic middle block . NotablySanyal and coworkers used an ABA type dendron-polymer-dendron conjugate with 10 kDa middle PEG segment connecting two identical polyester dendrons with generation 1\u20133. The dendron surfaces were further modified with combretastatin-A4 anti-angiogenic drug  91]. Si. Si91]. Nanostructured delivery agents can also be fabricated using a combination of diblock and triblock dendron-polymer conjugates. In a recent study, Sanyal and coworkers reported a modular micellar system for delivery of docetaxel. An AB type diblock dendron polymer conjugate was used to introduce targeting RGD (arginine-glycine-aspartic acid) peptides onto NP surface  92]. Th. Th92]. 50 values for primaquine and chloroquine were reported for assemblies formed using dendritic-linear-dendritic conjugates. Additionally, improved plasma circulation times and survival times were noted relative to free drugs in malaria infected mice.Although a majority of studies to date have focused on the delivery of anti-cancer drugs, these dendritic conjugates can also be utilized as delivery platforms for drugs against different diseases such as malaria. To overcome the high drug resistance of malaria parasites, provide improved cellular delivery of antimalarial drugs and achieve sustained drug release micellar assemblies were prepared using different Janus-like dendrons or ABA type dendritic-linear-dendritic conjugates . Enhancel-lactide) (PLA) based middle blocks, respectively. These polymers also yielded a mixture of unimolecular micelles and micellar aggregates in aqueous environment, which could be loaded with an anti-cancer drug, etoposide, with higher loading in the PCL-containing construct. Interestingly, the 32-arm PAMAM-PCL-PEG constructs exhibited lower drug loading for etoposide than the 16-arm counterpart, which authors suggest could be a result of higher PCL chain density in the star polymers obtained with the higher generation dendrimer . T. T107]. Dendronized polymers are another emerging class of macromolecular architecture that have been frequently utilized in recent years to obtain nanomaterials for drug delivery. These constructs comprise of dendrons conjugated as side chain residues along the backbone of a polymer. In a simple approach, amphiphilic constructs are obtained when hydrophilic synthetic or natural polymers are appended with dendrons that are either inherently hydrophobic or become so upon attachment of hydrophobic drug molecules.In a recent example, Gu and coworkers generated dendronized polymers composed of heparin backbone decorated with G2 lysine-based dendrons bearing DOX molecules  110]. A. A110]. The same group reported another dendronized copolymer composed of a 20 kDa dextran decorated with fluorinated G2 lysine dendrons as side chains conjugated to polymer backbone via acid-labile hydrazone linkers . DextranIn an alternative assembly strategy, Gu et al. used a G3 lysine dendron functionalized with DOX via hydrazone linkages appended with two mPEG tails at the dendron focal group . The denIn a subsequent study, the authors further modified this NP system by using a G2 lysine dendron and thickening their PEG corona by using four 2 kDa PEG tails . Additiol-lysine units thereby introducing an oxidation responsive disulfide linkage along the polymeric back bone. Thereafter, the backbone was further modified with G1 or G2 poly(l-lysine) dendrons with peripheral modifications with different hydrophobic or hydrophilic amino acids, thereby creating a combinatorial library of dendronized peptide polymers for siRNA delivery to NIH 3T3 cells.A conceptually different type of dendronized polymers was reported by Guan and coworkers . They emThe siRNA complexation with various dendronized polymers resulted in spherical NPs with diameters below 100 nm, which disintegrated upon treatment with glutathione (GSH) and released the siRNA. The in vitro transfection efficiency of NIH 3T3 cells with an anti-GFP siRNA demonstrated that polyplexes formed with the G2 construct containing 75 mol% histidine and 25 mol% tryptophan residue at dendron periphery at 80 primary amine/siRNA phosphate (N/P) ratio were able to provide improved GFP down regulation especially at lower serum conditions in comparison the lipofectamine. The effect of different amino acids at dendron periphery on the complex formation and transfection efficiency was evaluated.Dendritic polyglycerol (dOG) unit appended polymers are appealing building blocks with polyether internal cavities, biocompatibility similar to PEG and multiple hydroxyl groups enabling surface functionalization. Haag and coworkers conjugated polyglycerol dendrons modified with paclitaxel (PTX) through acetal linkages to hyaluronic acid (HA) to prepare HA-dOG-PTX-PM micelles. The HA shell serves as a protective natural polysaccharide layer, as well as enables active targeting of CD44 positive cancer cells  116]. T. T116]. The dendritic polyglycerol unit has also been used as side chain appendages in dendronized polymers. A hydrophobic polymer bearing glycerol dendrons as side chains self-assemble to generate micellar NPs . Haag an50 of 0.12 \u03bcM against 4T1 cells, compared to free DOX. Usually, in general, the free DOX is observed to possess more cytotoxicity in in vitro studies. Drug loaded micelles demonstrated 1.5 fold improved tumor growth inhibition relative to free DOX in BALB/c mice bearing 4T1 mammary tumors [A recent study from Imae and Chung and coworkers demonstrated that apart from using homopolymers components, diblock polymers where one of the block is dendronized can be used as building blocks for NPs effective for drug delivery. A linear polyelectrolyte block conjugated to a hydrophobic block with pendant dendrons assembled into micelles . DOX loay tumors .The brief survey of the abovementioned diverse polymeric structures that can be obtained through combination and dendrons and polymers, and are different than the classic AB and ABA type block copolymer systems, illustrate that variations in macromolecular architecture can yield novel NP based delivery vehicles.A diverse collection of nanosized aggregates can be obtained from macromolecular architectures derived from dendron-polymer conjugate based on simple combinations of dendritic and polymeric building blocks. Since their inception more than two decades ago, advances in synthetic polymer and dendrimer chemistry have witnessed the evolution of these dendron-polymer conjugate based nanosized aggregates as simple containers for therapeutic agents to smart drug delivery systems. The abovementioned examples provide a glimpse of how clever design of the discrete dendron-polymer conjugate yields through self-assembly a \u2018more than the sum\u2019 aggregate that brings novel attributes which qualifies these nanoparticles as viable drug delivery platforms. The confluence of organic chemistry and polymer science is enabling the design of dynamic constructs that are responsive to intrinsic and external cues to yield stimuli-responsive systems. Incorporation of bioactive motifs onto these nano-objects which would allow more specificity for triggered release will further advance these systems. To date, while the efficiency of most systems have been evaluated in vitro, a few examples in recent years have demonstrated through in vivo studies the promise that these self-assembled nanosized aggregates hold for shaping the future of nanotherapeutics. One of the challenges in the area of nanoparticle technology relates to large scale synthesis of the particles with homogenous properties such as size and polydispersity. For developing practical applications, it is important that delivery vehicles can be prepared in large amounts within certain specifications for preclinical and clinical test phases. To address such issues, may be new technologies such as continuous manufacturing techniques such as use of microfluidic flow systems can provide access to large amounts of homogenous nanoparticles. For a chemist, the flexibility in the chemical design of both dendritic and polymeric components, as well as the final dendron-polymer conjugates offers plenty of room for creativity to tailor effective drug delivery platforms."}
+{"text": "Eighteen-year-old restrained male driver involved in a flip over motor vehicle accident resulting in a seatbelt injury triad . The patient did well after the surgical resection of the sigmoid colon, repair of the rectus abdominis muscle and endovascular repair of the aorta. Our objective is to shed light on this potentially fatal injury.\u00a0 Seat-belt sign was described as a\u00a0linear ecchymosis of the abdominal wall following a motor vehicle accident in 1962 by Garrett and Braunstein . The incEighteen-year-old restrained driver was brought to our emergency room after a flip over motor vehicle accident with back seat passenger fatality. Immediate intubation was done for a Glasgow coma scale of five. Focused assessment with sonography for trauma was negative. Bleeding scalp laceration repaired and left femur fracture splinted. He was admitted to the intensive care unit (ICU) after a pan scan concerning for filling defects  within the infra-renal aorta extending into the bilateral common iliac artery Figure  and a smIn spite of aggressive resuscitation, four hours after ICU admission, the patient continued to be acidotic ( lactic acid 4.3 mMol/L), tachycardic ( 120-130 beats per minutes), hypotensive (systolic blood pressure in the eighties) with a stable hemoglobin\u00a0(12G/dl). The clinical picture was concerning for hallow viscous injury not apparent on initial computed tomographic (CT) scan as no other explanation for his worsening acidosis was\u00a0found. Abdomen exploration with resection of de-vascularized sigmoid colon segment, ABTHERA (open abdomen negative pressure therapy) application with a planned return to the operating room the next day for re-exploration, colostomy diversion and repair of transected rectus abdominis muscle  is a significant life-threatening injury that should be considered in patients with significant trauma mechanism. Early diagnosis with CT improve patient\u00a0outcomes. It may be associated with other organ injury and endovascular repair is a valuable minimally invasive option for critically ill patients."}
+{"text": "OBJECTIVES/SPECIFIC AIMS: To learn the edit distance costs of a symbolic univariate time series representation through a stochastic finite-state transducer to predict patient outcomes in intensive care units. METHODS/STUDY POPULATION: High frequency data of patients in intensive care units were used as a data set. The nearest neighbor method with edit distance costs (learned by the FST) were used to classify the patient status within an hour after 10 hours of data. Several experiments were developed to estimate the parameters that better fit the model regarding the prediction metrics. RESULTS/ANTICIPATED RESULTS: Different metrics were obtained for the several parameters. These metrics were metrics . DISCUSSION/SIGNIFICANCE OF IMPACT: Our best results are compared with published works, where most of the metrics  were improved."}
+{"text": "Thoracic endovascular aortic repair (TEVAR) is the therapeutic choice for type B aortic dissection. One of the most unfavored complications of this procedure is hemorrhage, which has a low incidence but high mortality. Renal hemorrhage (RH) after endovascular aortic repair has been rarely reported. We presented two cases of unexpected RH after TEVAR for complicated type B aortic dissection, and the potential causes, diagnosis and therapeutic management were discussed.A 67-year-old female developed hypotension and progressively decrease of hemoglobin within 5\u2009h after TEVAR for acute complicated type B dissection. Bedside ultrasonography and abdominal computed tomography angiography revealed a massive right perinephric hematoma. The right renal angiography detected multiple tortuous vascular branches with diffuse perinephric bleeding. The main trunk of right renal artery was embolized. The patient recovered uneventfully and presented with normal renal function 6\u2009months later. Another patient was a 69-year-old male who was admitted for endovascular repair of a chronic complicated type B aortic dissection. The patient presented with hemodynamic instability early after TEVAR. Bedside ultrasonography showed a giant left retroperitoneal hematoma. The abdominal angiography revealed two active bleeding sits located in the distal branches of left renal artery. A super-selective embolization of the two arteries was performed, however the patient developed abdominal compartment syndrome and died of multiple organ failure.Unexpected RH after endovascular repair of aortic dissection might be associated with iatrogenic and idiopathic factors. Close surveillance and clinician\u2019s awareness of this rare complication is crucial for accurate and prompt diagnosis. Renal angiography and subsequent selective embolization of bleeding vessels are effective interventions for treating this fatal condition.The online version of this article (10.1186/s12893-018-0440-1) contains supplementary material, which is available to authorized users. Thoracic endovascular aortic repair (TEVAR) is the therapeutic choice for type B aortic dissection \u20133. One oA 67-year-old female patient presented in the emergency department with persistent chest pain for 12\u2009h, followed by aggravating lower limbs numbness and oliguria, with a urine output of 40\u2009ml after onset. Computed tomography angiography (CTA) revealed an acute type B aortic dissection with a primary entry tear approximating to the left subclavian artery (LSA) and extending to the iliac arteries  was inserted into the aortic true lumen via the right femoral artery, and the angiography showed poor perfusion of the right kidney and bilateral iliac arteries  without any hemodialysis. The patient recovered uneventfully, and no signs of hemorrhage of the right kidney were detected by pre-discharge CTA 7\u2009days after TEVAR   and the second   thoracic stent grafts were accurately deployed without sacrificing LSA, and the entry tear was successfully occluded Additional file 2:The procedures of thoracic endovascular aortic repair and left renal embolization for the second patient. (MP4 11521 kb)"}
+{"text": "Multi-planar transverse, U-type, and vertical sacral fractures occur from high energy trauma or as pathologic fractures and often have associated neurologic and extremity injuries. Modern treatment algorithms fall into two broad categories: 1) percutaneous posterior pelvic fixation  or 2) lumbopelvic fixation. Posterior pelvic screw fixation is minimally invasive but typically requires restricted weight bearing until fracture union. In many cases, lumbopelvic fixation allows for a closed reduction and provides stability to allow full weight bearing immediately after surgery; however, this fixation is often removed in a second surgery after fracture healing. Lumbopelvic fixation was originally described as an open procedure, minimally invasive lumbopelvic fixation is a recent variation and has shown promising results with less morbidity. We present a case series of unstable U-type sacral fractures treated with minimally invasive lumbopelvic fixation with staged hardware removal to illustrate the advantages and complications associated with this new technique. Ten patients with U-type sacral fractures underwent minimally invasive lumbopelvic fixation from 2016 to 2019. Six patients underwent scheduled hardware removal an average of 3.5 (range 1.9-5.5) months after index surgery. Two patients did not undergo hardware removal due to short life expectancy and diagnosis of pathologic fractures. One patient was lost to follow-up. One patient had failed fracture reduction and went on to sacral malunion that required a late sacral extension osteotomy to restore her ability to stand upright. Final disposition of all nine patients with follow-up was normal standing upright posture and normal ambulation without assistive device. There were no late displacements on postoperative upright radiographs. Complex sacral fractures are a challenging injury that can be treated with percutaneous posterior pelvic or lumbopelvic fixation. Lumbopelvic fixation offers the advantages of closed reduction to restore pelvic incidence and immediate weight bearing but has greater surgical morbidity than percutaneous posterior pelvic fixation and often requires hardware removal. The morbidity of lumbopelvic fixation may be reduced with minimally invasive techniques. Minimally invasive lumbopelvic fixation is a treatment option to be considered for complex sacral fractures. U-shaped sacral fractures are uncommon injuries that cause dissociation between the lower sacrum/pelvis from the upper sacrum/lumbar spine. These fracture patterns can be difficult to interpret on plain radiographs and early reports without the benefit of advanced imaging reflect the difficulty in understanding the fracture lines within the sacrum . Denis eU-type sacral fractures are zone three injuries that consist of many fracture lines but fundamentally only two main fracture fragments . The supThe two types of operative fixation for complex sacral fractures are posterior pelvic fixation  and lumbopelvic/triangular fixation. Fluoroscopy and navigation allow the placement of posterior pelvic fixation percutaneously . LumbopeIn this series, we review the outcomes and complications of 10 patients who underwent minimally invasive lumbopelvic fixation to treat unstable U-type sacral fractures. We highlight the advantages and disadvantages of lumbopelvic fixation for the treatment of these complex injuries.MethodsTen patients with unstable U-type or vertical sacral fractures were treated with minimally invasive lumbopelvic fixation and fracture reduction Figure\u00a0-B. All pA lateral pelvis fluoroscopy image was checked to ensure that pelvic incidence had been restored. Fractures with excessive impaction or severe angulation can be difficult to reduce with this maneuver, however, every effort should be made to achieve a closed reduction since a sacral malunion requires a complex osteotomy for correction. Non-displaced fractures were instrumented in situ. Patients were mobilized immediately with no weight bearing restrictions. Radiographs were taken immediately post-op and at the 6-week post-op visit to assess maintained alignment Figure -B. HardwResultsTen patients underwent minimally invasive lumbopelvic fixation from 2016 to 2019. Eight patients had sacral fractures from high energy trauma, and two had pathologic sacral fractures from falls from standing height and did not undergo implant removal due to short life expectancy. One patient with polytrauma including complex neurologic injuries was lost to follow-up and did not have implant removal. Of the eight patients who had planned hardware removal, six underwent scheduled removal an average of 3.5 (range 1.9-5.5) months after index surgery. The hardware removals have been uncomplicated and performed as outpatient surgeries without extending the surgical incisions. One of the planned hardware removal patients was lost in follow-up. The one other planned hardware removal patient had a sacral malunion and required hardware revision and sacral osteotomy. All nine patients who have complete follow-up transitioned to full weight bearing immediately after surgery; final disposition of all patients was normal ambulation without assistive devices, restoration of upright posture, and a final fracture union with no late displacement. All patients with normal ability to ambulate had a restoration of their pelvic incidence to within two standard deviations of normal  allows in situ fixation of the fracture without a reduction maneuver, or may be performed in the prone position to exaggerate lordosis and achieve some fracture reduction. The disadvantages of percutaneous posterior pelvic fixation are the inability to directly manipulate the fracture fragments and insufficient stability for immediate weight bearing. Nork published his experience with a posterior pelvic fixation on 13 patients with unstable U-type sacral fractures where he used bracing and restricted each patient to a wheelchair after surgery for 8-12 weeks . PercutaOpen lumbopelvic fixation is associated with high rates of complications including infections, wound complications, dural tears, and pseudomeningocele that may be related to the soft tissue dissection needed to obtain adequate exposure . Our serTo reduce the sacral fracture and restore normal standing posture the surgeon must understand the relationship between the sacrum and the overall alignment of the spine. Dubousset described the state of balanced upright posture where the knees are fully extended, the hips are in a neutral position, and the pelvis with the rest of the spine are maintained upright within a narrow cone without active muscle contraction . If a maSpine surgeons now have a broader understanding of the concepts of sagittal balance and the \u201ccone of economy\u201d . PercutaThis series of patients illustrates the benefits and the complications of minimally invasive lumbopelvic fixation for complex sacral fractures. The advantages of lumbopelvic fixation include immediate full weight bearing. Lumbopelvic fixation can be used to maintain or to restore pelvic incidence. Our series is similar to previous reports that show minimally invasive lumbopelvic fixation for unstable sacral fracture is an option in treating these complex injuries. The minimally invasive technique is associated with lower wound complication rates compared to open lumbopelvic fixation and still allows for immediate full weight bearing -8. EveryWhen closed reduction and normal pelvic incidence was achieved, patients in this series had good clinical outcomes. When the pelvic incidence was not restored, as in our one patient, the clinical outcome was poor. If the surgeon carefully considers the restoration of pelvic incidence then minimally invasive closed reduction and lumbopelvic fixation is a viable treatment option for complex unstable sacral fractures."}
+{"text": "Infrarenal abdominal aortic dissections (IAAD) are exceedingly rare, accounting for 1-4% of all aortic dissections. The evidence is scarce on how to best manage IAAD when they become symptomatic. Two main interventional approaches exist, open surgery and the endovascular approach. Conventional stent-graft systems make it difficult to treat nonaneurysmal aortic disease due to limb competition in a narrow distal aorta. Thus, we present a novel use of the Endologix Anatomical Fixation 2 (AFX2) Abdominal Aortic Aneurysm (AAA) endograft system for the treatment of four patients with IAAD. We also highlight an individual case study that was treated with an alternative endovascular approach and the complications that followed. This was to highlight and compare our successful experience with Endologix AFX2 AAA endograft system. There were multiple benefits for choosing this stent-graft; however the main advantage is its suitability in the narrow distal aorta. Our aim was to highlight an alternative endovascular approach for the successful treatment of a rare, challenging, and potentially fatal pathology. Infrarenal abdominal aortic dissections (IAAD) are exceedingly rare with most aortic dissections originating in the ascending thoracic aorta. Infrarenal abdominal aortic dissections (IAADs) account for 1% to 4% of all aortic dissections . They caWe report the clinical features and novel use of the Endologix AFX2 AAA endograft system for the treatment of four patients who presented to our institution with IAADs. Special emphasis is placed on the clinical presentation of this rare entity and the endovascular treatment and complications experienced within our institution.BH is a 59-year-old male presented after a high-speed motor vehicle accident. Screening Computed-Tomography (CT) imaging was carried out to exclude any injuries, revealing a L3 fracture and infrarenal aortic dissection. Dedicated CT angiography revealed a 7cm dissection in the infrarenal abdominal aorta extending into the proximal left common iliac artery (CIA) . The patA 73-year-old male presented with an incidental finding of an IAAD extending to the left CIA on CT angiography . Due to The case is a 56-year-old male who underwent a CT angiogram as a work-up for prostate surgery. There is an incidental finding of a 3.2cm infrarenal abdominal aortic aneurysm (AAA) with dissection extending distally involving both common iliac arteries . Due to The case is a 70-year-old female with an infrarenal aortic dissection and an associated AAA which showed progression at surveillance. CT angiography showed a minor eccentric saccular aneurysm measuring 23mm involving the right anterolateral aspect, extending over a 9mm intimal flap . Due to A 71-year-old female presented with a pulsatile mass in her left groin causing significant discomfort. CT angiography showed a dissection involving the infrarenal abdominal aorta extending from the level of the inferior mesenteric artery into an aneurysmal left common iliac artery (CIA) measuring 29mm x 27mm. The patient was treated with a 24mm x 56mm Zenith\u00ae Spiral-Z\u00ae AAA Iliac Leg Graft  and deployed into the infrarenal aorta. Kissing iliac stents were deployed to exclude both the dissection at its distal point and the left CIA aneurysm. At 12-month follow-up CT angiography demonstrated exclusion of both the dissection and the left CIA aneurysm. However, CT angiography at 48-month follow-up demonstrated a type 2 endoleak with filling of the false lumen of the dissection in the infrarenal aorta with associated mild aneurysmal dilatation . The patInfrarenal aortic dissections are rare. The increasing use of CT scanning for further investigation of undifferentiated abdominal pain has begun to reveal this condition more frequently . The mosThe most common risk factors for spontaneous infrarenal aortic dissection are hypertension, hyperlipidaemia, and atherosclerosis and these factors were observed across all six patients. A dissection left untreated may result in the formation of an aneurysm that could ultimately rupture or lead to progressive stenosis leading to distal arterial insufficiency.Nonpenetrating injuries of the abdominal aorta are rare, with only between 0.01% and 0.07% resulting in aortic dissection . AlthougTherapeutic options in the case of chronic IAADs include close observation with regular follow-up, prosthetic replacement of the involved aorta, or open surgery . ConservEndologix AFX2 AAA endograft system  differs from the other approved EVAR systems in several ways. It features the only unibody main body component, in contrast to the usual two- or three-component modular design. The device is deployed directly onto the aortic bifurcation, providing secure anatomic fixation, eliminating main body graft migration, and essentially relining the distal aorta and common iliac arteries. The base component is then complemented by an aortic extension cuff that is available in either an infrarenal or suprarenal option that provides seal through radial force and the ability of the compliant expanded polytetrafluoroethylene (ePTFE) graft material to accommodate irregularities in the aortic wall .The prevalence of a narrow distal aorta (< 20 mm) associated with AAA may be as high as 65%; this was noted amongst our cohort with an average diameter of 17.8mm (range = 9.4mm \u2013 19.8mm). In these situations, relining the aortic bifurcation with the Endologix AFX2 AAA endograft sysytem is more appealing than trying to squeeze two limbs side-by-side within a narrow lumen. Relining the aorta provides the ability to more aggressively postdilate the bifurcation to ensure an adequate-flow lumen and lower limb occlusion rates .Finally, the main body device and aortic or iliac extensions are delivered through a single 17-Fr ID hydrophilic access sheath without the need for exchanges. The contralateral side is managed through a 7Fr sheath that is approved for standard percutaneous access and makes Endologix AFX2 AAA Endograft System the lowest profile system currently available . The sysAll patients treated with the Endologix AFX2 AAA endograft system had no complications perioperatively and had no evidence of endoleak on follow-up at 12 months. Our one patient treated with the Zenith\u00ae Spiral-Z\u00ae AAA Iliac Leg Graft  and kissing iliac covered stents which was deployed proximal to the origin of the dissection unfortunately developed a type 2 endoleak and persistent filling of the false lumen of the dissection with expansion of the luminal diameter. The reason for this treatment choice was that the Endologix AFX2 AAA endograft system was not available at our institution.Isolated infrarenal aortic dissections are a rare condition affecting both the young and elderly population. In those where aetiology is spontaneous, patients are often elderly with significant comorbidity. The use of the Endologix AFX2 AAA endograft System has been shown to be a safe and low-risk alternative to open aortic surgery in these populations."}
+{"text": "Ganoderma boninense is known to be the causal agent of basal stem rot (BSR) disease in oil palm (Elaeis guineensis). This disease causes rotting in the roots, basal and upper stem of oil palm. Infection causes progressive destruction of the basal tissues at the oil palm trunk and internal dry rotting, particularly at the intersection between the bole and trunk. Molecular responses of oil palm during infection are not well study although this information is crucial to strategize effective measures to control or eliminate BSR. Here we report three sets of transcriptome data from samples of near-rot section of basal stem tissue of oil palm tree infected with G. boninense (IPIT), healthy section of basal stem tissue of the same G. boninense infected palm (IPHT) and the healthy section of basal stem tissue of the healthy palm (HPHT). The raw reads were deposited into NCBI database and can be accessed via BioProject accession number PRJNA530030.To date,  The data sets were named as IPHT , IPIT  and HPHT .22.1G. boninense fruiting body attached at the basal stem and the palm does not exhibit stress-related symptoms phenotypically. All collected basal stem tissues were immediately submerged in liquid nitrogen and kept at \u221280\u00a0\u00b0C freezer until further processing for RNA extraction.A pair of healthy and infected clonal mature palm was selected from Serting Hilir field research station, Negeri Sembilan, Malaysia owned by Felda Agricultural Services Sdn Bhd. Briefly, the bark was marked according to the health status. The healthy section (IPHT) and near-rot section (IPIT) of infected oil palm were collected from the cross section of the basal stem. The cross section of healthy tissue section of healthy oil palm tree (HPHT) was also collected. The healthy palm was determined by healthy oil palm phenotype with no 2.2et\u00a0al., 2009 Total RNA of matured basal stem samples; IPHT, IPIT and HPHT were extracted using method from Saidi 2.3Messenger RNA isolation and cDNA synthesis were performed using TruSeq RNA Sample Preparation Kit  and SuperScript II Reverse Transcriptase  by following the manufacturers' protocol, respectively. The amount of synthesised cDNA was measured using Qubit 2.0 DNA Broad Range Assay . A minimum of 15 ng cDNA was fragmented using Covaris S220  to a targeted size of 200\u2013300bp. The fragmented cDNA was then end repaired, ligated to Illumina TruSeq adapters, and PCR-enriched using TruSeq RNA Sample Preparation Kit  by following the manufacturer's protocol. The final sequencing libraries were quantified using KAPA kit  on Agilent Stratagene Mx-3005p quantitative PCR  and sizes were confirmed using Agilent BioAnalyzer High Sensitivity DNA Chip . The resulting libraries were sequenced using an Illumina flow cell and 209 cycles on the Illumina HiSeq 2000 platform .2.4E. guineensis genome Ganoderma boninense genome The quality of RNA-seq raw data was assessed using FastQC"}
+{"text": "In recent years, Medicare Advantage (MA) plan enrollment has increased, a trend that is expected to continue. Many skilled nursing facilities (SNFs) rely on MA managed care insurer referrals to maintain their census in a market with high competition for post-acute care patients. This study used semi-structured interviews to describe the relationship between MA plans and SNFs from the perspective of key decision-makers in SNFs. Twenty-three interviews were conducted with key stakeholders from 11 Denver Metropolitan area SNFs. A combined purposive-snowball sampling approach was used to identify and recruit select staff from the participating facilities. Interviews focused on the relationship between MA plans and SNFs, including mechanisms of control, power dynamics, and preferences for MA versus Fee-for-Service (FFS) Medicare patients. Key findings included: 1) challenges SNF staff had navigating MA plans\u2019 case management processes, a key mechanism used by MA plans to influence the behavior of SNF decision-makers; 2) MA plans exercising power over beneficiaries\u2019 length of stay, potentially leading to early discharge and heightened risk for rehospitalization; 3) SNF preference for admitting Medicare FFS over MA patients due to higher rates of Medicare FFS reimbursement and greater control over patient care. SNFs are increasingly reliant on MA plans for patient referrals and revenue. The themes suggest that this growing reliance may place SNFs at odds with MA plans on how best to manage overall patient care. It is therefore important that future research investigate how MA plans\u2019 influence over care affects patient outcomes in SNFs and other post-acute settings."}
+{"text": "Juglans nigra L.) is not practical and timber breeders have historically utilized only open-pollinated half-sib families. An alternate approach called \u201cbreeding without breeding,\u201d consists of genotyping open-pollinated progeny using DNA markers to identify paternal parents and then constructing full-sib families. In 2014, we used 12 SSR markers to genotype 884 open-pollinated half-sib progeny harvested from two clonal orchards containing 206 trees, comprised of 52 elite timber selections. Seed was harvested in 2011 from each of two ramets of 23 clones, one upwind and one downwind, based on prevailing wind direction from the west\u2014southwest. One orchard was isolated from wild black walnut and composed of forward selections while the other orchard was adjacent to a natural forest containing mature black walnut composed of backward selections. Isolation significantly increased within-orchard pollination (85%) of the progeny from the isolated orchard compared to 42% from the non-isolated orchard. Neither prevailing wind direction nor seed tree position in the orchard affected paternity patterns or wild pollen contamination. Genetic diversity indices revealed that progeny from both orchards were in Hardy\u2013Weinberg equilibrium with very little inbreeding and no selfing. A significant level of inbreeding was present among the forward selected parents, but not the first generation (backward selected) parents. Some orchard clones failed to sire any progeny while other clones pollinated upwards of 20% of progeny.Artificial pollination of black walnut ( Juglans nigra L., is a valuable timber tree native to eastern North America that also provides mast and habitat for wildlife and watershed protection  d dFig 2E  progeny  and 5 of progeny . Three ograndis) .Unequal male reproductive success could lead to decreased genetic diversity and inbreeding which can lower survival and fecundity. Use of a mix of different pollen parents, or a \u201cpolymix,\u201d , 51 to pPhenological markers such as the timing of bud-break, female and male bloom times and bloom duration vary yearly depending on local temperatures and winter chilling. We found that the period of pollen shed lasted 25 to 30 days over three consecutive years in LO. In Missouri, bud break among 21 black walnut cultivars over four years varied from 26 to 47 days . Among-yBloom phenology , in general, was a poor predictor of mating pairs in LO. Paternal clones that shed pollen during the intermediate bloom period pollinated more seedlings compared to early and late blooming clones. Early and late trees, which rarely mated with each other, were both receptive to intermediate pollen and highlighted the importance of having surfeit receptive parents throughout the flowering period. We also noted early and late flowering clones were more receptive to wild pollen than intermediate clones. Knowing such dynamics would help improve the timing of supplemental pollen application, for example, by focusing on the early and late bloom period rather than the intermediate period.This is the first large-scale examination of molecular genotyping used to identify open-pollinated black walnut timber family paternity. Open-pollinated half-sib breeding of black walnut can be improved utilizing DNA SSR markers to identify pollen parents. We found that isolation from other black walnut led to 85% within-orchard pollination in contrast to 42% within-orchard pollination from our non-isolated orchard. Now that we have genotyped LO and VO in their entirety, we can determine the male parent of selections in other progeny tests derived from these two orchards. New black walnut timber seed orchards should consider having at least 40 parents and be isolated from other walnuts to create a \u201cpolymix-like\u201d open pollinated population.While VO had many more parents than LO, (37 versus 15 clones), VO parents showed a slight yet significant level of inbreeding while LO parents did not. The difference likely results from the fact that VO parents were forward selections from progeny harvested from a single grafted clone bank. In contrast, LO parents were primarily first generation backward selections. As  point ouSince most pollination occurred within 50 m, future orchards could be planted with single ramets of clones completely randomized to ensure all parents can cross pollinate. Given the practical difficulties of artificially pollinating black walnut in the field, and the expense and resources required to grow large grafted seed parents in a pollen-free greenhouse, \u201cbreeding without breeding\u201d using DNA markers, is an excellent and effective method for advancing black walnut timber breeding.S1 Table(XLSX)Click here for additional data file."}
+{"text": "Amomum subulatum Roxburg), is an ancient spice native to North-Eastern India and Southeast Asia, which belongs to the family Zingiberaceae under the order Scitaminae. Large cardamom is mostly affected by a viral disease termed Chirke caused by Large Cardamom Chirke Virus (LCCV). These disease has spread due to drastic changes in the ecosystem, inadequate rain in dry months and absence of good agricultural practices by the farmers resulting in aphid infestations. In the present study, using HiSeq\u2122 2000 RNA sequencing technology transcriptome sequencing was performed for both control (disease not expressed) and diseased large cardamom leaf tissues. RNA-seq generated 77260968 (7.72 GB) and 72239708 (7.22 GB) paired raw reads for large cardamom control and diseased samples respectively. The raw data were submitted to the NCBI SRA database under the accession numbers SRX2529373 and SRX2529372 and the assembled transcriptomes were submitted to TSA under the accession numbers GIAV01000000 and GIAW01000000 for the control and diseased samples respectively. The raw reads were quality trimmed and assembled de novo using TRINITY assembler which created 156822 (control) and 148953 (diseased) contigs with N50 values 2107 (control) and 2182 (diseased). The data were used to identify the significantly differentially expressed genes between control and diseased samples.Large cardamom ( The data files were deposited at NCBI SRA database under project accession no. PRJNA369131. Information generated from the raw data and that of assembly are provided in The dataset contains raw sequencing data obtained through transcriptome sequencing of leaf samples of large cardamom (22.1Amomum subulatum Roxburg). Large cardamom chirke virus (LCCV) was not expressed in one of the samples which served as the control whereas the disease was expressed in the other sample. Leaf tissues from both sets were collected followed by immediate freezing in liquid nitrogen.Transcriptome sequencing was carried out in leaf samples of large cardamom (2.2RNA extraction was done using a modified protocol of the RNeasy Plant Mini Kit (Qiagen) and CTAB method  RNA inte2.3De novo transcriptome assembly was performed using the Trinity [Raw reads were first quality checked using the FastQC  tool and Trinity  assemble Trinity  and the  Trinity  to produ Trinity .2.4https://www.ncbi.nlm.nih.gov/nuccore/?term=chirke) and found only 4 sequences for chirke . These were aligned to both infected and control sequences using BLAST+ [Virus genome sequences were fetched from NCBI (2.5A total of 156822 transcripts were generated from the control sample while 148953 were generated from the diseased. While converting the transcripts into peptides the control sample generated 76913 peptide sequences while the treatment generated 74060. The obtained peptides were clustered for non-redundancy which resulted in 30498 unique peptides being generated from control compared to the 29512 that were generated from the diseased ."}
+{"text": "She later developed local post-radiation retroperitoneal fibrosis with resulting ureteric stenosis. Serial oncological follow ups with Temporary glucose hypermetabolism in denervated muscle has been described in small patient groups. The exact mechanism of this hypermetabolism has not yet been elucidated. One proposed mechanism is the immunohistochemically proven increase of certain cellular membrane proteins  in response to denervation. Another theory links the rise in metabolism to widespread apoptosis \u2013 an energy-consuming process. Hypermetabolism due to denervation can be important in an oncological context, because unexpected FDG uptake increase in regional skeletal muscles might lead to false-positive diagnoses of cancer recurrence or metastases ["}
+{"text": "U test to compare obese Versus nonobese groups. RESULTS/ANTICIPATED RESULTS: Obese children have lower scores in measures of affect recognition than healthy weight children. They also showed higher median scores in both salivary and plasma IL-6 and TNF-\u03b1. DISCUSSION/SIGNIFICANCE OF IMPACT: Although no statistical differences were found among groups in either measurement, these preliminary data based on the initial recruitment suggest that children with higher body mass index may have difficulties in emotional processing. More data will be available after completing recruitment to determine if the association between obesity and affect recognition is significant and if it is mediated by inflammation.OBJECTIVES/SPECIFIC AIMS: Childhood obesity has become an issue of some concern worldwide. Some reviews and a recent study in adults have indicated that obesity-related inflammatory responses produce brain damage. However, studies exploring associations between inflammation and executive functions in children are overlooked. Therefore, the objective of this cross-sectional study is to determine whether difficulties in executive functions and emotional processing are associated with obesity and inflammation. METHODS/STUDY POPULATION: We have recruited 12 of a total of 60 children aged 6\u20138 years old. They have completed the NIH Toolbox Cognition Battery and the NEPSY II Affect Recognition tests. Samples of plasma and saliva were collected to quantify inflammatory biomarkers cytokines (IL-6 and TNF-\u03b1) assay by Luminex procedure. We performed descriptive analysis and Mann-Whitney"}
+{"text": "Giant retinal tear is usually challenging among retinal detachment with recurrent rate up to 45%. Here we presented a case of giant retinal tear being treated by microincision vitrectomy and retinal tacks fixation.A 53-year-old male presented to our hospital with blurred vision of his right eye for one week with floaters and obscured sensation over nasal visual field. Ocular examination showed a 120 degree giant tear with large inverted flap and retinal detachment of his right eye. The BCVA was only naming digit. Under the impression of giant retinal tear with retinal detachment, 23-gauge pars plana vitrectomy were performed using Constellation high speed vitrectomy system and Topcon non-contact wide angle viewing system. During surgery, the vitreous was removed and perfluorocarbon liquids (PFCL) was injected to help unfolding the large inverted retinal flap. Three retinal tacks were applied to help fixating the large inverted retinal flap. Then, fluid-gas exchange, endolaser photocoagulation and intraocular silicone oil tamponade were performed as well. Initial reattachment of his right retina was achieved and his best corrected visual acuity improved to 0.3 of his right eye postoperatively. There was no recurrent retinal detachment during follow up period of 19\u00a0months.Primary microincision vitrectomy using wide-angle viewing system with intraoperative perfluorocarbon liquids (PFCL) assistant, retinal tacks fixation and intraocular silicone oil tamponade appears to be safe and feasible for managing giant retinal tear with retinal detachment. Giant retinal tear (GRT) is usually challenging among retinal detachment with recurrent rate up to 45% . In ordeA 53-year-old male denied past medical and trauma history presented to our hospital with blurred vision of his right eye for one week with floaters and obscured sensation over nasal visual field. Ocular examination showed a 120 degree retinal tear (from 7 to 11 o\u2019clock) with large inverted rigid flap and retinal detachment from 6 to 12 o\u2019clock with macula-off in his right eye Fig.\u00a0. The graPrevious studies had reported that primary success rate for GRT treated by 20-gauge PPV using PFCL assistant without scleral buckling can achieve over 90% . AnotherAlthough our report has limitation of small case number and relatively short follow-up period, our findings indicate that MIVS is a safe, effective and feasible method for managing GRT. In addition, in cases with large, inverted and rigid retinal flap, retinal tacks for stabilizing retinal flap might be inevitable to prevent retinal redetachment."}
+{"text": "Percutaneous trans-splenic portal vein recanalization (PVR) has been reported for facilitation of transjugular intrahepatic portosystemic shunts (TIPS), however has not been applied to patients undergoing direct intrahepatic portosystemic shunt (DIPS). We report the utilization of trans-splenic-PVR with DIPS creation in a patient with chronic portal and hepatic vein occlusions undergoing liver transplantation evaluation.A 48-year-old male with decompensated alcoholic cirrhosis complicated by refractory ascites, hepatic encephalopathy, and variceal bleeding underwent CT that demonstrated chronic occlusion of the hepatic veins (HV), extrahepatic portal vein (PV), and superior mesenteric vein (SMV). Due to failed attempts at TIPS at outside institutions, interventional radiology was consulted for portal vein recanalization (PVR) with TIPS to treat the portal hypertension and ascites and also facilitate an end-to-end PV anastomosis at transplantation. After an initial hepatic venogram confirmed chronic HV occlusion, a DIPS with trans-splenic PVR was planned. The splenic vein was accessed under sonographic guidance using a micropuncture set and subsequently upsized to a 6 French sheath over a stiff guidewire. A splenic venogram via this access confirmed occlusion of the PV with drainage of the splenic vein (SV) through gastric varices. The thrombosed PV was then recanalized and angioplastied to restore PV flow via the transsplenic approach. A transjugular liver access kit with a modified 21-gauge needle was advanced into the IVC through the internal jugular vein (IJV) sheath and directed towards the target snare in PV. The needle was used to subsequently puncture the PV through the caudate lobe and facilitate placement of a wire into the SV. The initial portosystemic gradient (PSG) was 20\u2009mmHg. The IJV sheath was advanced through the hepatic parenchymal tract into the main-PV and a stent-graft was placed across the main PV and into the IVC. A portal venogram demonstrated brisk blood flow through the DIPS, resolution of varices and a PSG of 8\u2009mmHg. One month after the procedure, the patient had a significant reduction in ascites and MELD-NA score. Patient is currently listed and awaiting transplantation.In the setting of chronically occluded portal and hepatic veins, trans-splenic PVR DIPS may serve as an effective bridge to liver transplantation by facilitating an end to end portal vein anastomosis. The presence of hepatic vein (HV) occlusion poses challenges for patients with decompensated liver cirrhosis being considered for transjugular intrahepatic portosystemic shunts (TIPS). Such cases can be treated by recanalization of HVs with angioplasty and/or stenting prior to performing TIPS. Alternatively, direct intrahepatic portosystemic shunt (DIPS) creation from the IVC to portal vein can also be considered. DIPS has been shown in literature to have equivalent five-year survival rates and clinical outcomes to HV recanalization with TIPS in patients with Budd-Chiari syndrome . Prior studies have reported techniques for accessing the PV including fluoroscopic \u201cgun sight\u201d  interventional radiology was consulted for portal vein reconstruction in combination with TIPS to alleviate portal hypertension and ascites and to facilitate transplantation allowing direct portal- portal anastomosis. After a hepatic venogram confirmed chronic hepatic vein occlusion, a multidisciplinary discussion ensued during which time an attempt at DIPS with trans-splenic PVR was decided upon. The patient was scheduled for the procedure with interventional radiology under general anesthesia. Ultrasound guidance was used to allow two 10 French sheaths to be placed into the intra-hepatic IVC via the right internal jugular vein (IJV). A percutaneous trans-splenic access into the main splenic vein was subsequently obtained by puncturing a peripheral splenic venous branch with a micropuncture set  under sonographic guidance. The access was exchanged for a 6 Fr sheath over a stiff guidewire. A splenic venogram was performed, confirming chronic occlusion of the PV with primary drainage of the SV through gastric varices . After the PV was reconstructed, a snare was then placed into the main PV and used as a target for DIPS creation. A Roche-Uchida transjugular liver access kit with a modified 65-in. 21-gauge needle was advanced into the IVC through the sheath within the IJV and directed towards the PV. An intravascular echo probe was advanced into the IVC through the other IJV sheath and used for real time sonographic guidance of the needle puncture from the IVC to the snare in the reconstructed PV. The needle was then used to subsequently puncture the PV through the caudate lobe and facilitate placement of a wire into the SV , and distal superior mesenteric vein (SMV). ces Fig.\u00a0. Next, tig.\u00a0Fig.\u00a0. After tTrans-splenic PVR has been described as an effective method for restoring patency to chronically thrombosed PVs in patients with decompensated liver failure awaiting liver transplant. (Thornburg et al."}
+{"text": "Organotellurium and organoselenium compounds catalyze the oxidation of halide salts to hypohalous acids using H2O2. When sequestered into xerogel monoliths, the xerogel-chalcogenide combinations have demonstrated increased catalytic activity relative to the organochalcogen compound alone in solution for the oxidation of halide salts to hypohalous acids with H2O2. Diorganotellurides, diorganoselenides, and diorganodiselenides bearing triethoxysilane functionalities were sequestered into xerogel monoliths and their catalytic activity and longevity were investigated. The longevity of the catalyst-xerogel combinations was examined by isolating and recycling the catalyst-xerogel combination. It was found tellurium-containing catalyst 3 and selenium-containing catalyst 8 maintained their catalytic activity through three recycling trials and adding electron-donating substituents to catalyst 3 also increased the catalytic rate. The presence of organotellurium and organoselenium groups in the +4 oxidation state was determined by X-ray photoelectron spectroscopy.While H These catalysts will likely be based on telluride or seleninic acid functionality sequestered in xerogels tailored to direct the negatively charged halide ions to the active site."}
+{"text": "Thirty-nine years old patient presented to the emergency department with left-sided chest pain for four months and 4kg weight loss through the same period. Physical examination showed bulging of the left scapula which is tender to touch and decreased breath sounds on the left side. Chest X-ray done in ED showed opaque left hemithorax with rib resections. A CT was done showing a heterogeneous mass shadow with a solid and cystic component associated with linear calcifications causing a near total collapse of the left lung with shifting of the mediastinum to the right side. Similar findings were seen on an MRI. A PET-CT scan showed hypermetabolic complex mass occupying most of the left hemithorax infiltrating the back muscles bulging to the subcutaneous fat with Irregular thick active gastric mucosa as well and intense large colon activity. A biopsy of the lesion and immunohistochemical studies were done and showed malignant diffuse spindle cell neoplasm positive for CD56, CD99, Bcl2 CKAE1/AE3, H. Caldesmon and EMA. The patient was started on IFOS/DOX chemotherapy regimen and completed three cycles uneventfully."}
+{"text": "OBJECTIVES/SPECIFIC AIMS: Voiding postponement is common cause of LUT dysfunction in which children void infrequently with large volumes. This condition is modeled in mice that are subjected to social stress who show decreased voiding frequency and increased voided volumes along with increases in corticotropin-releasing hormone (CRH) expression in Barrington\u2019s nucleus (BN) . Optogenetics is a technique to selectively stimulate cells or neurons of interest via light activated channel receptors . Here we examined the effects of optogenetic manipulation of CRH BN neurons on the in vivo voiding phenotype and urodynamics in awake mice. We hypothesized that stimulating these neurons at higher frequencies (10\u201350 Hz) would lead to CRH-dependent alterations in voiding phenotype . RESULTS/ANTICIPATED RESULTS: Fiberoptic stimulation (470 nm at 25 and 50 Hz) produced a significant rise in the intermicturition interval, bladder capacities and increased void volumes. This effect was especially pronounced in females in whom bladder capacity and intermicturition interval more than doubled at 50 Hz stimulation. Fluoroscopic images confirmed complete bladder emptying with each void. The increased bladder capacity at higher frequencies (25 and 50 Hz) was CRH-dependent as injection of a CRH antagonist (NBI 30775) blocked the optogenetic effect. Control non-double mice showed no effects from optogenetic stimulation. DISCUSSION/SIGNIFICANCE OF IMPACT: Our results suggest that optogenetic stimulation of CRH-expressing neurons in BN at high frequency (25 and 50 Hz) inhibits micturition and recapitulates the voiding phenotype seen in socially stressed mice . Lower frequencies of optogenetic stimulation (2 and 10 Hz) had no effects on cystometry parameters or voiding phenotype. In addition, females had a greater response to optogenetic stimulation compared with males with larger bladder capacities and longer intermicturition intervals. The changes in voiding phenotype seen were CRH dependent as blockage of the CRH receptor prevented changes in cystometry parameters with optogenetic stimulation. Further elucidation of these and other neural subpopulations in BN are warranted to understand micturition and how it may be manipulated in disease states such as voiding postponement and acute urinary retention."}
+{"text": "Virtually complete nitrification of the available ammonium in soil and nitrification activity in the forest floor are important factors predisposing forests in the San Bernardino Mountains of southern California to nitrogen (N) saturation. As a result, inorganic N in the soil solution is dominated by nitrate. High nitrification rates also generate elevated nitric oxide (NO) emissions from soil. High-base cation saturation of these soils means that soil calcium depletion or effects associated with soil acidification are not an immediate risk for forest health as has been postulated for mesic forests in the eastern U.S. Physiological disturbance  of ozone-sensitive ponderosa pine trees exposed to high N deposition and high ozone levels appear to be the greater threat to forest sustainability. However, N deposition appears to offset the aboveground growth depression effects of ozone exposure. High nitrification activity reported for many western ecosystems suggests that with chronic N inputs these systems are prone to N saturation and hydrologic and gaseous losses of N. High runoff during the winter wet season in California forests under a Mediterranean climate may further predispose these watersheds to high nitrate leachate losses. After 4 years of N fertilization at a severely N saturated site in the San Bernardino Mountains, bole growth unexpectedly increased. Reduced C allocation below- ground at this site, presumably in response to ozone or N or both pollutants, may enhance the bole growth response to added N."}
+{"text": "In the final publication of \u201cA micro X-ray computed tomography dataset of South African hermit crabs (Crustacea: Decapoda: Anomura: Paguroidea) containing scans of two rare specimens and three recently described species,\u201d by Jannes Landschoff et al., many copyediting errors were erroneously published. These errors have been corrected throughout the article to improve clarity. No substantial revisions have been made to the paper's research.The Publisher regrets this error."}
+{"text": "The recently published manuscript entitled \u201cEpigenetically Altered T CellsContribute to Lupus Flares\u201d summarizes recent advances in our understanding ofhow the environment alters the immune system to cause flares of systemic lupuserythematosus (SLE) in genetically predisposed people, and why it affects womenapproximately 9 times more often than men . SLEis The manuscript summarizes how in vitro studies on the epigenetic regulation ofgene expression in T lymphocytes can alter their function to cause lupus flares.Briefly, each nucleated cell in the human body contains approximately 3 meters of DNA,tightly packaged in the nucleus as chromatin, consisting of the DNA wrapped around acore of 8 histone proteins. The tightly packaged DNA is inaccessible to thetranscription factors, and the chromatin structure must be locally \u201copenedup\u201d to allow the relevant transcription factors to bind and allow mRNA synthesisto proceed. The cell promotes the condensation of DNA into a transcriptionallyrepressive configuration by methylating dC bases located in CpG pairs. This allows thebinding of methylcytosine binding proteins to the methylated regions, which then attractthe chromatin inactivation complex which promotes the condensation of the DNA into atightly packaged chromatin structure. However, the DNA methylation patterns must bereplicated accurately every time a cell divides, and it is at this point where DNAmethylation becomes sensitive to environmental influences. Inhibiting methylation of thenewly synthesized DNA strand allows expression of those genes previously suppressed byDNA methylation, and for which the cell expresses the necessary transcriptionfactors.+ T cells with thecovalent DNA methyltransferase inhibitor 5-azacytidine (5-azaC) converts antigenspecific CD4+ T cells into autoreactive cells which respond to self class IIMHC molecules on antigen presenting cells without added antigen, thus becomingautoreactive [+ murine T cells with 5-azacytidine (5-azaC) then injecting thetreated cells into syngeneic recipients. Mice receiving the treated, but not untreated Tcells developed lupus-like autoimmunity [+ T cells were found in lupuspatients, and the number of the epigenetically altered cells was directly proportionalto flare severity. In addition, the two drugs which cause drug-induced lupus mostfrequently, procainamide and hydralazine, were found to be DNA methylation inhibitors[+ T cells from patients with active lupus.Together the experiments indicate a mechanism by which environmental agents that causeinflammation can trigger lupus flares.Early studies demonstrated that treating CD4reactive . The pat"}
+{"text": "The subpleural arteriovenous shunts that are hallmarks of hepatopulmonary syndrome may cause stroke. A 76-year-old-woman was admitted for right hemiparesis. Her medical history included cirrhosis with portal hypertension known for 14 years. Her heart rhythm was regular, with a heart rate of 65 beats per minute. Brain MRI demonstrated an acute ischemic lesion in the left part of the pons. A brain cortical atrophic sequela was also seen in the right occipital lobe. Vascular arteriosclerosis and any cardiac cause of stroke were excluded by dedicated imaging. During the neurological revalidation, she developed a platypnea. SpO2 was <90%. Clinical examination demonstrated diffuse spider naevi predominantly on the abdominal wall. Chest CT angiography ruled out pulmonary embolism. MIP reconstructions in lung window showed dilated pulmonary vessels abutting the pleura on the non-dependent part of the right lung (Figure HPS is defined by a triad including liver disease regardless of type and severity, oxygenation impairment and intrapulmonary vascular dilatation resulting in right-to-left shunting . Contras"}
+{"text": "Dementia family caregivers are routinely enlisted as proxy assessors of care recipient quality of life (QOL). Proxy assessment is not ideal because proxy assessments differ systematically from self-assessments and the assessment process can elicit negative affect from family caregivers. Prompting adoption of the care recipient\u2019s perspective can enhance assessment congruence and may improve the emotional experience for assessors. This study explored family caregivers\u2019 cognitive and affective experiences during QOL proxy assessments made from both their own and care recipients\u2019 perspectives. Thirty-six dementia family caregivers were recruited from senior service agencies. Subjects completed the Quality of Life-Alzheimer Disease (QOL-AD), Caregiver Version using standard instructions to assess QOL across thirteen domains of their care recipient\u2019s life without specifying the perspective to be used. Subjects were next asked to repeat the QOL-AD with instructions to adopt the perspective of their care recipient, as they imagined it to be. Subjects were then interviewed about what they thought and felt during each proxy assessment experience. Content analysis indicated that spontaneous perspective shifts and response shifts frequently occurred. Most subjects (91.7%) reported changed thinking for one or more QOL-AD domains when they were prompted to switch perspectives. Over half (61.12%) reported changed affect when switching perspectives and 90.9% of those experiencing changed affect reported affective improvement. Little or no affective change was reported by 38.89%. Findings suggest awareness of perspective can enhance clinical interpretation of proxy assessed QOL and can inform clinical response to dementia family caregivers who experience negative emotions while proxy reporting QOL."}
+{"text": "Management of cerebrospinal fluid (CSF) leak during minimally invasive lumbar tubular microdiscectomy poses challenges unique to the surgical approach.\u00a0Primary repair can be limited via tubular retractor systems, and onlay graft and dural sealant are often the treatment of choice intraoperatively.\u00a0Postoperative persistent CSF leak may lead to intracranial hypotension (IH) and positional headaches.\u00a0Early epidural blood patch (EBP) efficacy in the treatment of spinal CSF leaks of both spontaneous and iatrogenic origin is well-established in numerous studies. However, there is no consensus on treatment of persistent IH symptoms for patients undergoing lumbar tubular microdiscectomy. We describe the clinical courses of two patients who were treated with early EBP for IH symptoms following CSF leak during tubular microdiscectomy. Both patients underwent intraoperative repair with onlay autologous tissue graft followed by dural sealant after discectomy was completed without evidence of pseudomeningocele, but they developed postoperative positional headaches and presumed IH. Both patients received an early EBP with an immediate and complete resolution of positional headaches sparing them reoperation and/or lumbar drainage. EBP should be considered as a first-line treatment to treat postoperative IH symptoms without pseudomeningocele after iatrogenic CSF leak during tubular microdiscectomy. Tubular microdiscectomy has become a widespread method of treating lumbar disc herniation due to its minimally invasive approach and favorable benefit and risk profile . A rare Case 1A 34-year-old female presented with intractable left leg radiculopathy. She reported moderate pain in her lower back with pain and numbness radiating down the left S1 distribution. She had no motor weakness or altered bowel or bladder function. Magnetic resonance imaging (MRI) demonstrated L5-S1 disc herniation compressing the S1 nerve root (Figure Case 2A 49-year-old male presented with intractable and progressive pain in the lower back and left leg. Additionally, he had weakness of left plantar flexion. MRI revealed a large disc herniation at L5-S1 with compression of the left S1 nerve root Figure . The patThe use of transmuscular tubular retractor systems represents a safe and efficacious surgical approach for the treatment of lumbar disc herniation ,2,7. CSFIn our cases, the CSF leaks were intraoperatively sealed with autologous tissue and a dural sealant. However, both patients reported significant spinal headaches postoperatively indicative of IH. Although the precise diagnosis of IH requires a brain or spinal MRI, orthostatic headache is a classical symptom of IH . If imagThere are several complications associated with an EBP. For instance, paresthesia, neck ache, facial nerve palsy, and lumbovertebral syndrome have been reported after the procedure ,12. AddiWe present our cases to outline a paradigm of using EBP as management for postoperative IH symptoms in patients with iatrogenic CSF leak associated with tubular lumbar microdiscectomy and without pseudomeningocele. EBP is a well-documented treatment for CSF leaks of both spontaneous and iatrogenic etiologies. In a study of 30 patients with spontaneous CSF leak, a complete cure was obtained in 77% of patients after application of EBP . In anotWe have demonstrated that the efficacy of EBP extends to the treatment of the postoperative sequelae of CSF leak associated with tubular microdiscectomy. In the absence of other complications such as pseudomeningocele, the application of EBP complements well the minimally invasive methodology of tubular spinal surgery, which may obviate the need for more aggressive treatments for CSF leak such as lumbar drain and exploratory reoperation. Patients may benefit from future studies examining the success rate of intraoperative EBP, which may enable patients to avoid re-exploration, and consequently an extended hospital stay and increased risk of infection."}
+{"text": "A 14-year-old female patient was referred to our radiology department for evaluation of right hypoacousia. Unenhanced Computed Tomography (CT) of the temporal bones showed a 15 mm hypodense mass infiltrating the right cerebellopontine angle (CPA) and the internal auditory canal (IAC)  performed for better evaluation showed homogeneous high T1 signal of the lesion with signal drop on fat-saturated sequence, thus confirming the fatty composition of the mass  since CPA lipoma is considered a developmental disorder. Surgery should only be considered for symptomatic patients in whom conservative treatment has failed given that lipoma is a non-neoplasic slowly growing lesion closely related to nervous structures ."}
+{"text": "A wide range of neurosurgical implants, cranioplasty materials and catheters have been developed to treat a variety of intracranial disorders. Interpretation of postoperative imaging can be challenging and confounded by postoperative changes and implant-related complications. Review of recent literature suggested that there is a paucity of data on postoperative cranial implant-related complications.If not addressed appropriately in a timely manner, these complications may cause a delay in the patient\u2019s treatment with subsequent prolongation of hospital stay. It is therefore paramount for clinicians and radiologists to be aware of the appearance of these implant-related complications on imaging during postoperative surveillance. Various neurosurgical implants and catheters have been developed to treat a variety of intracranial pathologies. Interpretation of postoperative imaging can be challenging due to postoperative changes and implant-related complications. Postoperative complications can be divided according to the period of occurrence: Immediate (<6 hours), early (between 6\u201372 hours) or late (>72 hours) following surgery . In thisA burr hole is created in the skull for evacuation of subdural hemorrhage or stereotactic tumor biopsy. After surgery, the burr hole can be repaired by applying patient\u2019s autologous bone dust or titanium cover plates to prevent sinking of the overlying skin.Craniotomy is an operation for temporary removal of a bone flap to expose the underlying brain. Titanium CranioFix (Aesculap) plates are widely used to fix the bone flap to the cranium after craniotomy. Rarely, late complication may occur due to skin erosion overlying these plates. Patients with poorly vascularized or fragile skin are particularly vulnerable, risking infections such as meningitis and subdural empyema.Craniectomy is a similar surgical approach as craniotomy except that the skull flap is not replaced after surgery Figure . It is cThe material used for cranioplasty are either patient\u2019s autologous bone flap, titanium mesh Figures  and 4, cThe most commonly used acrylic resin is methylmethacrylate (MMA), which is prefabricated and created with computer-aided 3D CT data of the skull defect. Acrylic cranioplasty may appear radiolucent on CT and contain gas bubbles formed during exothermic polymerization hence, it should not be mistaken for infection Figure  and 3B. Immediate postoperative complications following cranioplasties are intracranial hemorrhages and infections Figure . StaphylThese are among the most common cranial implanted materials. Immediate postoperative complications are hemorrhages along the shunt tracks Figures  and 6A pEarly complications are mechanical dysfunctions from shunt obstruction or disconnection leading to hydrocephalus. Dysfunctions of programmable shunt valves may necessitate adjustment of the valve threshold. Over-shunting of the cerebrospinal fluid (CSF) may result in slit-like ventricles and intracranial hypotension Figure . By adjuDBS is inserted to treat medically intractable Parkinson disease. The tips of DBS electrodes are ideally positioned in the subthalamic nuclei. The electrodes are subsequently tunneled under the skin to the chest to be connected to a battery powered internal pulse generator (IPG) in a subcutaneous pouch Figure . IntermeThe most common hardware-related complications are infections (5.12%), electrode breakage 0.94%), lead migration or misplacement (1.6%), and stricture formation (1.9%), fracture or failure of the lead or other parts of the implant , IPG malfunctions (1.1%), and skin erosions (0.5%) [3%, lead mEndovascular detachable coils have been widely used for treatment of intracranial aneurysms while liquid agents (include N-butyl cyanoacrylate and Onyx) are being used for treatment of arteriovenous malformations. Artifacts from these embolization materials and clips may pose some challenges during postoperative surveillance.Postoperative imaging can be challenging and confounded by postoperative changes and implant-related complications. Awareness of these complications are paramount to clinicians and radiologists during postoperative surveillance."}
+{"text": "Fatty acid biosynthesis enzymes (Fab enzyme) are important targets for anti-malarial drug development. The present study describes thetoxicity screening of designed novel analogues which inhibit FabI enzyme regulation, a protein with multifunctional property. Newanalogues were prepared using ChemDraw Ultra 10 Software and converted into 3D PDB structure format for binding studies with FabI(PDB ID: 4IGE). Further Lipinski's rule of FIVE and ADMET profiling for toxicity prediction has been performed on the designedanalogues. The result shows that ISN-23 is potential analogue exhibiting inhibition at the active site of FabI enzyme with good bindingfeatures. Malaria is one of the most prominent tropical parasitic diseases Available drugs respond to three classes of compounds: (1) arylaminoalcohol compounds eg. quinine 2) antifolates dihydrofolatereductase inhibitors like pyrimethamine, and 3) Derivatives ofartemisinin. Artemisinin was first isolated in 1970 by Chinesescientists from Artemisia annua  antifola DerivatiThe anti-malarial effect of fatty acids has propelled towardsdeliberation in the past but the realization that fatty acidsthemselves might inhibit the fatty acid biosynthetic machinery ofthe parasite P. falciparum has only been presently examined to makestrategy towards combating of parasite. It is known that thatantimalarial property of n3 and n6 fatty acids which werepolyunsaturated in nature postulates the in-vitro invasion of intraerythrocytic forms of P. falciparum The structures of enzymes (FabI) involved in Plasmodium falciparumregulation was obtained from Protein Data Bank (PDB ID: 4IGE).Meta pocket 2.0 Finder was used for several separate procedures toperform active/ binding site prediction . To miniThe 2D-structure of Isoniazid and its 23 analogues were designedby using ACD lab software extension ChemDraw in MDL .molformat.The Lipinski rule of FIVE predicts the pharmacological, biologicaland ADME exercise of the particular compound and also predicting itspotentiality to an orally active drug in humans Using Pre ADMET online server Results show that Isoniazid drug inhibit the fabI enzyme regulationduring the erythrocytic phase of parasitic incubation. Hence, theactive site of FabI enzyme was predicted. Thus, different aminoacids residues of the enzymes were found out using meta-pocket2.0 Finder . The resVarious designed analogues or compounds are associated withknown anti-malarial drugs (isoniazid standard) by clocking FabIenzyme in the treatment of malaria caused by P. falciparum. Wedocument the predicted binding of 23 designed analogues with theFabI enzyme and show that ISN-23 analogue have the best bindingfeatures with FabI enzyme for further in vitro and in vivoconsideration.Authors declare no conflict of interest."}
+{"text": "Here we present a case of maternal-fetal hemorrhage characterized by intermittently reassuring fetal testing. Additional testing performed with ultrasound, including middle cerebral artery (MCA) doppler waveforms, confirmed fetal hemorrhage followed by emergent cesarean section. This report highlights the acute usage of MCA dopplers in obstetric decision making. The Newborn required transfusion but otherwise recovered well. MCA may be a useful tool for fetal assessment in Labor and Delivery units. Patient is a 32-year-old G1P0 at 33 weeks and 1 day gestation that was admitted to the hospital for further evaluation of decreased fetal movement for the two days. Pregnancy was uncomplicated prior to this admission. The patient was started on continuous fetal monitoring along with intravenous fluids. The patient was found to have alternating category II and III tracing . Given tFetal-maternal hemorrhage (FMH) is the presence of fetal blood cells in the maternal circulation prior to the time of delivery. Under normal circumstances, maternal and fetal circulations are kept separate from direct exchange by the placental membrane composed of syncytiotrophoblasts and cytotrophoblasts . GaseousMCA doppler ultrasonography is often used as a screening tool for chronic fetal anemia such as parvo B19 infection or twin anemia-polycythemia syndrome and is not routinely used on labor and delivery units . InpatieWhile fetal heart rate monitoring continues to be the initial assessment of fetal wellbeing, advanced supplemental ultrasonography may provide additional tools for clinical management of complex cases or extreme prematurity. In addition, a category III tracing is indicative of fetal acidemia. Ultrasonography offers a non-invasive method for assessing fetal well-being when compared to amniocentesis or cordocentesis . We unco"}
+{"text": "Accumulation of protein aggregates are a common pathology in many neurodegenerative disorders. This accumulation may be due to a function decline in the protein homeostasis network known to occur during the aging process. Small heat shock proteins are a class of molecular chaperones that assist in protein folding and ameliorates the degradation activity of the proteasome and autolysosome thereby decreasing disease-associated aggregates. Prior work in rodents and C. elegans has shown expression levels of the small heat shock protein 25 (HSP25) correlates with maximum lifespan potential. Increased levels of HSP25 extends lifespan in a transgenic C. elegans model. This lifespan extension is dependent on skn-1 with evidence suggesting an enrichment in several skn-1-related pathways, such as lysosomal genes. Concomitantly, proteasome activity declines while autolysosome activity increases. This observation might suggest a switch from proteasome degradation to autophagy as the main driver of protein degradation in C. elegans in this transgenic model. To investigate if a reduction of proteasome function and elevated lysosomal gene activation during aging and under proteotoxic stress are modulated by HSP25 we have crossed our HSP25-transgenic worm with an aggregating and non-aggregating tau worm model. This work will elucidate a possible mechanism that explains the change in the protein degradation response pathways potentially modulated by HSP25 during increased protein misfolding."}
+{"text": "A 39-year-old male ex-smoker gave a history of exertional chest pain ever since he suffered a respiratory tract infection. Clinical examination, electrocardiogram and echocardiography were normal and he was referred for a cardiac CT scan to assess coronary artery calcification and patency. The scan demonstrated incidental fistulae between the right internal mammary artery and the right coronary artery, and the left internal mammary artery and the left anterior descending artery. A 39-year-old male ex-smoker gave a history of exertional chest pain ever since he suffered a respiratory tract infection. Similar symptoms after a previous chest infection a few years ago had cleared spontaneously. He was reviewed in the respiratory clinic and found to have no lung disease and then referred to cardiology. Clinical examination, electrocardiogram, echocardiography and chest radiograph  were norCT scan with volume-rendered and axial curved maximum intensity projection techniques elegantly demonstrated the fistulous communication (white and blue block arrows) between the right internal mammary artery (white chevron) and mid-right coronary artery (thin white arrow) and left internal mammary artery (thin blue chevron) and mid left anterior descending artery (thin blue arrow) . The patSupplementary Video A). Coronary angiography confirmed patent coronary arteries and the presence of the fistulae (Supplementary Videos B and C).A subsequent stress cardiac MR scan demonstrated normal cardiac function and no inducible perfusion defects  or pulmonary circulation (coronary arteriovenous fistula).The patient\u2019s symptoms resolved spontaneously and it was felt that his fistulae were not of functional significance. He was reassured and discharged from regular review.Congenital coronary fistulae are rare and do not necessarily have functional significance. Common communications are to the cardiac chambers or pulmonary circulation.Fistulae involving the mammary arteries may be congenital or secondary to intervention.Informed consent to publish this case (including images and data) was obtained and is held on record."}
+{"text": "The present study is to highlight the challenges in managing cervical spine injuries in toddlers (less than 4\u2009years of age) without neurological deficit. Cases of unilateral cervical C4\u2013C5 facet dislocation in toddlers are very rare.A 3-year-old girl suffered cervical spine injury after a motor vehicle collision with unilateral C4\u2013C5 facet dislocation without neurological deficit. Magnetic resonance imaging (MRI) showed no spinal cord injury, Frankel grade E. Initial management was cervical spine protection. Definite treatment and complication were discussed with the patient\u2019s parents before closed reduction maneuver with minerva cast was applied under sedation. The patient showed no complication after closed reduction and the cervical spine had aligned well in radiographs. The minerva cast was removed at 8\u2009weeks, at which point neck muscle stretching rehabilitation program started. At one-year follow up, the child was asymptomatic, had full active cervical motion and good function. In radiographs, the cervical spine had normal alignment and was healed.Unilateral cervical facet dislocation in toddlers is very rare. Closed reduction maneuver and the minerva cast applied were optional in this case. The parents were highly satisfied with the effective treatment and outcome. Cervical spinal cord injury without radiographic abnormalities (SCIWORA) is more commonly seen in the pediatric age group than in adults. Incidences have been reported as 13\u201319% of spinal injuries in children . HoweverA 3-year-old girl suffered cervical spine injury after a motor vehicle collision while sitting in the car without wearing a seatbelt. ATLS protocol was performed on the patient at a local hospital and she was referred to the emergency department at author\u2019s hospital within 12\u2009h of the injury. The pediatric surgeon and our orthopedic team re-evaluated that the status of the patient showed head injury with alteration of consciousness, intubation, cervical spine protection with hard collar and first rib fracture without pneumohemothorax. The emergency radiographs x-ray and CT brain including cervical spine showed no intracerebral hemorrhage but the cervical spine suffered unilateral cervical C4\u2013C5 facet dislocation. Radiographic features showed anterior dislocation of the affected vertebral body less than the vertebral body in anterior posterior diameter, discordant rotation above and below involved level, facet within intervertebral foramen on oblique view, widening of the disk space and \u201cBat wing sign\u201d appearance of the overriding facet  which is a very rare condition. The most common causes of pediatric subaxial servical spine injury are motor vehicle accidents (50%) and sports-related activities (25%) [Knowledge of the anatomical characteristics of pediatric unilateral cervical facet dislocation is very important. Three studies , 9, 10 rIn our case, the purpose was to highlight the challenges in managing cervical spine injuries in toddlers without neurological deficit. The authors described the management of an acute pediatric unilateral facet dislocation by manual reduction and stabilization with minerva cast. The patient was asymptomatic, had full active cervical motion and good function. The cervical spine showed normal alignment and had healed in radiographs at one-year follow up. Unilateral cervical facet dislocation without neurological deficit in toddlers is very rare. The closed reduction maneuver and applied minerva cast is optional for treatment if successful manual reduction and stabilization with cervical orthosis has a good clinical outcome."}
+{"text": "Phaseolus vulgaris L.). This study evaluated the genetic diversity and symbiotic nitrogen fixation of bacteria nodulating common bean in soils of Western Kenya. The genetic diversity was determined using 16S rRNA gene partial sequences while BNF was estimated in a greenhouse experiment. The sequences of the native isolates were closely affiliated with members from the genera Pantoea, Klebsiella, Rhizobium, Enterobacter and Bacillus. These results show that apart from rhizobia, there are non-rhizobial strains in the nodules of common bean. The symbiotic efficiency (SE) of native isolates varied and exhibited comparable or superior BNF compared to the local commercial inoculants (CIAT 899 and Strain 446). Isolates  recorded equal or significantly higher SE (p < 0.05) compared to N supplemented treatments. The results demonstrate the presence of genetic diversity of native bacteria nodulating bean that are effective in N fixation. These elite bacterial strains should be exploited as candidates for the development of Phaseolus vulgaris inoculants.Biological nitrogen fixation (BNF) in legumes plays a critical role in improving soil fertility. Despite this vital role, there is limited information on the genetic diversity and BNF of bacteria nodulating common bean ( Phaseolus vulgaris) is one of the most important legumes in the human diet and serves as a significant source of proteins  and KSM-011 [KP137106]) had >99% sequence identity with members of the genus Enterobacter while the other remaining two (MMUST-001 [KP027686] and MMUST-007 [KP137109]) had >99% sequence similarity with members of the genus Pantoea. The isolates that belonged to the three genera  formed one major cluster supported with a bootstrap value of 100% (Klebsiella variicola strain ALK036 (KC456523) and Klebsiella sp. N28 (KP410798). Isolates (KSM-001 and KSM-011) had a 100% sequence similarity with Enterobacter hormaechei strain D40 [KM019812]. Two isolates (MMUST-001 and MMUST-007) formed a sub-cluster with Pantoea dispersa [KM019887] supported with a bootstrap value of 96%  formed a single sub-cluster supported with a bootstrap value of 99% and this sub-cluster was affiliated with strains of Rhizobium tropici. Five isolates  formed a sub-cluster (Rhizobium cluster) supported with a bootstrap value of 100% and was affiliated to strains belonging to Rhizobium leguminosarum  formed a major cluster with several species belonging to the genus Bacillus. This was supported by a bootstrap value of 100%. These two isolates were affiliated with Bacillus aryabhattai [MF109128] and Bacillus megaterium [KY31279] with \u226599% sequence identity. The evolutionary relationship estimated using matrix pairwise genetic distances for the 16S rRNA partial gene sequences indicated that the isolates were closely related (Bacillus (KSM 007[KP027678]) and Pantoea (MMUST 001[KP027686]). Similar evolutionary distances were observed between isolates (KSM 007[KP027678]) and (KSM 001[KP027682]).The PCR amplification of 16S rRNA genes of 25 selected isolates produced a single band of approximately 1500 bp. The sequences were deposited in the Genebank and assigned accessions numbers . Compari of 100% . Isolatee of 96% . A total related . The lonp < 0.05) effective in N fixation compared to the reference strains (CIAT 899 and Strain 446). Similarly, CIAT 899 recorded signifcantly lower SE (p < 0.05) compared to all the isolates from Kisumu county  and Klebsiella sp. Gad1 (KJ940119) and have previously been isolated from soil and nodules, respectively. Nodulation is considered as a confirmatory test for bacteria nodulating legumes (BNL). Several authors have demonstrated that no bacterial isolate can be regarded as BNL until its identity has been confirmed through plant infection test on an appropriate host crop  and MMUST-002 [KP027689]) and were considered bean nodulating bacteria. The two isolates that failed to initiate nodulation were closely affiliated with ost crop , 48. Noto be BNL . Failureo be BNL . Our resa g58 KM0887 and Ko be BNL .P. vulgaris in soils of Western Kenyan soils. The differences in the SDW and N content of the plants inoculated with different strains of native bacteria indicate their variation in symbiotic N fixation. The varaition in N fixation among genera has been attributed to the differences in the chromosal or plasmid borne symbiotic genes [All the five genera of the native bacteria were able to nodulate and fix N with ic genes . For exaPhaseolus vulgaris.The results of this study have demonstrated that soils across different regions in Western Kenya harbour diverse indegenous symbiotic bacteria that initiate nodulation in common bean apart from the rhizobia. These native bacterial isolates exhibited comparable or superior symbiotc N fixation characteristics compared to the locally available commercial inoculants for P. vulgaris. These elite isolates should be subjected to further investigations under different environmental conditions to optimize their N fixing potentials.Notably, it was established that most of the symbiotic strains recovered are not known to commonly nodulate"}
+{"text": "Plasmodium falciparum infections carrying plasmepsin 2 duplications (associated with piperaquine resistance) in 7/65 recurrent infections within 2 months after DHA/PPQ treatment. These findings raise concerns about the long-term efficacy of DHA/PPQ treatment in Africa.Dihydroartemisinin/piperaquine (DHA/PPQ) is increasingly deployed as an antimalaria drug in Africa. We report the detection in Mali of  Plasmodium falciparum to develop drug resistance, many antimalarial programs have recently included dihydroartemisinin/piperaquine (DHA/PPQ) as a second-line antimalarial drug. This decision is sensible, considering the recent reports of substantially decreased artemether/lumefantrine cure rates in some regions, signaling a potential focus of lumefantrine resistance  coding for the food vacuole enzyme plasmepsin II, which is speculated to be a major piperaquine target.DHA/PPQ has shown near-perfect efficacy levels in clinical trials conducted in Africa; the combination also has been proposed as a tool for intermittent preventive approaches  with the CFX96 Real-Time System (Bio-Rad) detection system. We executed all procedures in triplicate. We determined copy number by using a SYBR-green\u2013based quantitative PCR  in a protocol modified from the one previously described by Witkowski et al . In high-transmission areas, this long period of decreasing drug exposure is likely to progressively select less sensitive, potentially pfpm2 CNV\u2013carrying parasites. Parallel studies conducted in these areas have not detected substantial altered parasite clearance dynamics or K13 mutations associated with artemisinin-derivative therapy (pfpm2 duplications are emerging despite the efficacy of dihydroartemisinin. Further studies are urgently needed to clarify the clinical implications of piperaquine resistance and to monitor occurrence in other areas of high malaria transmission in Africa.Our results clearly show that piperaquine resistance\u2013associated"}
+{"text": "OBJECTIVES/SPECIFIC AIMS: Epidemiologic studies have found that the incidence of pancreatic cancer is greatest in countries that consume diets high in fat. The gastrointestinal peptide cholecystokinin (CCK) is released from the duodenum in response to dietary fat. CCK has also been shown to stimulate growth of pancreatic cancer through the CCK receptor that is over-expressed on pancreatic cancer cells. The aim of this investigation was to determine if dietary fat promotes growth of pancreatic cancer through the actions of CCK at its receptor. METHODS/STUDY POPULATION: The effects of dietary fat on growth of murine Panc02 pancreatic cancer xenografts were studied in 3 different systems with immune competent mice: (1) pharmacologic blockade with a CCK receptor antagonist, (2) genetic knockout of the CCK receptor by CRISPR, and (3) in genetically engineered mice lacking the CCK peptide (CCK-KO). After injection of 2\u00d7106 Panc02 cells subcutaneously, mice were fed either a high-fat diet or a control diet for 37\u201342 days. Tumor volumes and weights were measured and histology performed. RESULTS/ANTICIPATED RESULTS: Dietary fat significantly increased the size of pancreatic cancer xenografts and this effect was reversed by CCK receptor blockade. Receptor antagonist therapy also significantly reduced tumor-associated fibrosis and increased the influx of CD8+ lymphocytes in the micro-environment. Panc02 cancer cells lacking CCK receptors failed to respond exogenous administration of CCK in vitro and to dietary fat in vivo. Dietary fat did not stimulate Panc02 tumor growth in CCK-KO mice. DISCUSSION/SIGNIFICANCE OF IMPACT: The mechanism by which dietary fat stimulates growth of pancreatic cancer is by CCK and this effect is independent of obesity. This is a significant finding because of the potential beneficial effects of medications which can block the effects of CCK in populations at risk for pancreatic cancer consuming a high-fat diet."}
+{"text": "Mitochondrial Thioredoxin Reductase (TrxR2) is a rate limiting enzyme in the mitochondrial thioredoxin system which serves as one of the major mitochondrial ROS scavenging pathways. Txnrd2 is also a repressor of the ASK-1 oxidative stress induced apoptotic pathway. Our group previously identified a correlation with the expression of this protein and long-lived species and its overexpression prolonged lifespan in Drosophila. We have generated a TrxR2 transgenic (T-tg) mouse which has ubiquitously heighted (two-fold) TrxR2 expression. We found that overexpression of TrxR2 leads to enhanced mitochondrial metabolism and increased resistance to mitochondrial oxidative damage in MEFs (data not shown). We also found that female T-tg mice showed a leaner trend and reduced food consumption, with improved glucose tolerance but no difference in insulin sensitivity. These mice showed a lower Oxygen consumption and CO2 production with lower energy expenditure in individual metabolic cages. We further tested their exercise capacity where T-tg mice had a similar performance to control mice. These results suggest that TrxR2 overexpression can lead to some beneficial metabolic changes that need to be further understood. ."}
+{"text": "Multinucleate Giant Cell (GC) reaction is a biological response that occurs secondary to infection, an implanted foreign body, tissue injury, or inflammation. In rare instances GC reactions have been reported following tissue ablation. Multinucleate GC reactions and tumefactive fat necrosis both have the ability to mimic cancer recurrence or metastasis and can appear as enhancing masses. We discuss a case of a surgically resected retroperitoneal perinephric mass thought to be recurrent renal cell carcinoma (RCC) that was pathologically confirmed as tumefactive fat necrosis with multinucleate GC reaction 2 years following percutaneous cryoablation of a small renal mass. Multinucleate Giant Cell (GC) reaction is typically a biological response to infection, tissue injury, or inflammation and can be noted following implantation of biomaterials or medical devices . The GC A 60-year-old male had incidentally discovered bilateral renal masses identified on computed tomography (CT) imaging. Robotic assisted partial nephrectomy of the right renal lesion was completed on a 4-centimeter Furman Grade 2, pT1a clear cell RCC with negative surgical margins. Due to the posterior location of the 2-centimeter mass on the left kidney , the patCryoablation is a favorable nephron-sparing treatment for certain renal lesions secondary to its ability to treat small, complex lesions in a minimally invasive fashion . Our repThe cellular disturbances that occur during cryoablative therapy can contribute to the development of a multinucleate GC reaction due to tissue damage, necrosis, and creation of cellular debris which stimulates an immune response . A GC reAlso notable in our case was the presence of abundant fat necrosis. A study by Lokken et al. found that necrotic fat and inflammatory nodules have the ability to mimic tumor seeding or recurrence following cryoablation with delayed presentation in 2.7% of cases [The histological appearance of our patient's radiographic abnormality following partial nephrectomy and perinephric fat excision is characterized by extensive tumefactive fat necrosis and multinucleate GC reaction at the site of previous ablative therapy . As seenGC reactions have been noted to be enhanced on both contrast-enhanced CT and MRI thereby mimicking cancer recurrence  Figure . VariousOur report describes the delayed presentation of tumefactive fat necrosis and multinucleate GC reaction following cryoablation of clear cell RCC. This case demonstrates the importance of considering every possibility when presented with a patient that develops new perinephric abnormalities following ablation. This knowledge, combined with thorough evaluation, may aid in avoiding unnecessary invasive treatments for suspicious but nonmalignant lesions following ablation treatments."}
+{"text": "Following the publication of this article , the autBacillus group members than cultured phages. We speculate this pattern may reflect gene acquisition from host Firmicutes. Other authors have previously speculated that instances of strong homology observed between B. cereus phage MurNAc-LAA endolysins and host autolysins may reflect horizontal transfer between Bacillus phages and various B. cereus group hosts [30]. The molecular diversity of the BLP lysins and their homologs is exhibited primarily by the presence or absence of the C-terminal amidase_02C domain. Consistent with previous data on lysPBC4 [9] the N-terminal amidase_3 domain of the BLPs show greater conservation among their homologs than the C-terminal amidase_02C domain and linker re- gion that are absent in most phage endolysin homologs.\u201d\u201cFull-length sequences of the putative BLP endolysins display closer overall homology to"}
+{"text": "Toxoplasma gondii is a zoonotic intracellular parasite, able to infect any warm-blooded animal via ingestion of infective stages, either contained in tissue cysts or oocysts released into the environment. While immune responses during infection are well-studied, there is still limited knowledge about the very early infection events in the gut tissue after infection via the oral route. Here we briefly discuss differences in host-specific responses following infection with oocyst-derived sporozoites vs. tissue cyst-derived bradyzoites. A focus is given to innate intestinal defense mechanisms and early immune cell events that precede T. gondii's dissemination in the host. We propose stem cell-derived intestinal organoids as a model to study early events of natural host-pathogen interaction. These offer several advantages such as live cell imaging and transcriptomic profiling of the earliest invasion processes. We additionally highlight the necessity of an appropriate large animal model reflecting human infection more closely than conventional infection models, to study the roles of dendritic cells and macrophages during early infection. Toxoplasma gondii affects an estimated 25\u201330% of humans worldwide . Early in vivo situation and allow live cell imaging and transcriptomic profiling of the earliest invasion processes. Great advances in generation, cultivation and cell-type characterization of intestinal organoids (IOs) offer unique opportunities to observe these early events in different hosts with different T. gondii stages  and the savings on animal experiments once IOs have been established. They are also genetically tractable  are constantly renewed every 3\u20134 days . The vulnerability of T. gondii sporozoites  recognize the parasite through pattern recognition receptors on the cell surface, such as Toll-like receptors (TLRs), which activate secretion of pro-inflammatory cytokines that induce a subsequent Th1 response  DCs and M\u03a6s directly phagocytose free, opsonized parasites upon crossing the epithelial barrier. (2) Both cell types also phagocytose infected apoptotic IECs  cells and CD8+ T cells to begin secreting IFN-\u03b3, the primary mediator of resistance to T. gondii  and macrophages (M\u03a6s). Once the intestinal barrier is overcome by T. gondii has evolved a means to subvert this host defense mechanism  .ED provided parts of The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Plasmodium falciparum gametocytes can be determined microscopically but recent transcriptomics studies paved the way for the development of molecular methods that allow sex-ratio assessments at much lower gametocyte densities. These sex-specific gametocyte diagnostics were recently used to examine gametocyte dynamics in controlled and natural infections as well as the impact of different antimalarial drugs. It is currently unclear to what extent sex-specific gametocyte diagnostics obviate the need for mosquito feeding assays to formally assess transmission potential. Here, we review recent and historic assessments of gametocyte sex ratio in relation to host and parasite characteristics, treatment, and transmission potential.A mosquito needs to ingest at least one male and one female gametocyte to become infected with malaria. The sex of  P. falciparum gametocyte sex-specific targets and provided new insights in gametocyte biology.Recent RNA sequencing studies have uncovered a number of in vitro experiments, molecular tools for assessing gametocyte sex ratio are now increasingly available for use in natural P. falciparum infections.After decades when gametocyte sex-ratio research was restricted to nonhuman malarias or Evidence that gametocyte sex ratio is influenced by total gametocyte density and antimalarial treatment, and improves predictions of transmission potential, highlight the relevance of understanding the gametocyte sex ratio during natural infections.P. falciparum gametocyte marker Pfs25 is expressed predominantly by female gametocytes and has non-negligible levels of background expression in asexual parasites necessitates a re-evaluation of existing gametocyte data.The finding that the most widely used  We present the merits and limitations of molecular tools for quantifying gametocyte sex ratio and review evidence for a sex-specific effect of antimalarial drugs on circulating gametocytes and the implications for malaria transmission potential.Here, we summarize historic and recent estimates of gametocyte P. falciparum, the sex ratio of circulating gametocytes is mostly female biased Pf77 (PF3D7_0621400) and Pfg377 (PF3D7_1250100), both enriched in female gametocytes Pfg27  Box 1AP2-G2 in P. bergheiPuf family of translational repressors in P. falciparumP. falciparum, respectively Molecular mechanisms underlying the differentiation switch towards becoming male or female gametocytes remain largely unknown. Candidate genes that may be associated with sex-specific differentiation include the Proteomic and transcriptomic data reflect this, showing upregulation of genes involved in nucleic acid metabolism, DNA replication, and axoneme formation. Female gametocytes, on the other hand, contain many proteins and transcripts intended for longer term sustainment of postfertilization stages, including genes involved in protein biosynthesis, degradation, transport, and metabolic activity. Another important female gametocyte-specific mechanism is translational repression in which stored transcripts support cellular processes immediately after fertilization, when transcription is absent for multiple hours P. berghei, results in full developmental arrest during ookinete formation, although fertilization is successful. The first indication that translational repression is also active in P. falciparum was obtained through deletion of Puf2, which resulted in altered expression of genes known to be translationally repressed, such as Pfs25 and Pfs28P. falciparum female gametocytes Male gametocytes are terminally differentiated forms with one last task ahead; producing motile microgametes upon activation. Alt-text: Box 1In natural infections of PF3D7_06200 and PfPF3D7_06200 and Pfet al. reported the first molecular assay for an indirect detection of gametocyte sexes based on in situ hybridization using a Pf77 RNA probe that targeted female gametocytes Pfs25 (PF3D7_1031000) transcript, which was considered highly specific for mature gametocytes, using qRT-PCR Pfs25) has recently been shown to be expressed predominantly by female gametocytes Plasmodium chabaudi using targets that were previously described in a proteomics study in Plasmodium bergheiCG1 or PSOP1: PCHAS_0620900) RNA, and male gametocytes by the male gametocyte-specific gene 1 . Schneider and colleagues P. falciparum through quantification of a combination of female-enriched (Pfs25) and male-enriched (Pfs230p) transcripts. The higher limit of detection for male  compared to female gametocytes  in this assay, and the typical female bias in natural infections, may affect the sensitivity of sex ratio determination at low gametocyte densities. Recently, additional male gametocyte-enriched transcripts  were identified that improved the detection limit of male gametocytes to the level comparable with female gametocytes P. falciparum-infected individuals. Whilst it remains plausible that (nearly) all infections produce gametocytes Box 2Mature male and female gametocytes can be distinguished on the basis of light microscopy on Giemsa-stained thin smears Pfs25 expression in asexual blood-stage parasites is not completely absent Pf13 and Pf230p) Suitable targets for gametocyte diagnostics require high and stable expression of the gene in the stage and sex of interest. In P. falciparumP. bergheiPfs25 shows lower expression in male gametocytes compared to females, ranging from 35-fold lower as detected by RNAseq PfMGET) and female (CCp4) targets was recently proposed as a more scalable and robust approach to molecular gametocyte sex ratio assessments.Differential Alt-text: Box 2Gametocyte detection has been improved in the last decade with the introduction and wider use of molecular detection tools. Baker P. falciparum, the sex ratio changed from female biased to equal sexes over 13\u00a0days Recently, molecular methods to accurately sex gametocytes have been used to assess the first appearance of mature male and female gametocytes after experimental infections. Gametocyte appearance is estimated to occur 10\u00a0days post blood-stage inoculum Plasmodium gallinaceum and rodent malaria Plasmodium vinckei further suggest that the sex ratio in Plasmodium infections varies substantially during the course of an infection proportion of male gametocytes in P. vinckei and increases overall gametocyte density in P. gallinaceumP. chabaudiData from the avian parasite f)/2, and f is Wright\u2019s inbreeding coefficient P. chabaudi where genetic diversity was adjusted deliberately, sex ratio became more male-biased as the number of genotypes present increased Competition between parasites of different genotype can also affect sex ratio. Hamilton\u2019s theory of \u2018local mate competition\u2019 (LMC) The effect of sex ratio on transmission success may depend on total gametocyte density P. vivax malaria also reported a shorter lifespan of male P. vivax gametocytes in vitro. Longitudinal studies are needed to understand the dynamics of male and female gametocyte densities during natural infections and their impact on transmissibility.Differences in the longevity of male and female gametocytes can also contribute to sex ratio differences. Two studies have also hinted towards a shorter circulation time of male gametocytes upon clearance of the asexual progenitors Plasmodium can indeed alter sex ratio in response to environmental cues, an essential outstanding question is what governs sex allocation. Candidate genes that may be associated with sex-specific regulation (other than or in addition to AP2-G) include MAPK1 (PF3D7_1431500) as potential regulator of female gametocytogenesis, and MAPK2 (PF3D7_1113900) as possible regulator of male gametocytogenesis P. falciparum infections and early commitment to the sexual stage (and plausibly gametocyte sex), any response to environmental triggers must involve significant \u2018planning ahead' and cross-talk between potentially very low numbers of gametocytes or precursors. Even if environmental signals are as rapidly translated into elevated gametocyte conversion rates as recently shown for P. chabaudiP. falciparum to rapidly respond to environmental triggers is the bone marrow reservoir for gametocytes. It is conceivable that mature gametocytes may not all be immediately released upon completion of maturation but may be in part retained for release upon environmental stimuli.If -G transcripts Pfs16, PF14_0748) Plasmodium parasites or clones Our understanding of environmental factors that influence gametocyte sex ratio is incomplete. Moreover, some of the \u2018known\u2019 stimuli for overall investment in gametocyte production appear uncertain when assessed with current methodologies P. chabaudiP. falciparumP. falciparum parasites may respond to their proliferation state rather than directly to the presence of drugs. Drug pressure may thus lead to an initial increased investment in asexual proliferation  until survival is unlikely and a terminal investment in transmission occurs In vitro drug tests suggest that male gametocytes are more sensitive to a range of antimalarial drugs compared to female gametocytes, with impaired male gametocyte fitness (reduction in exflagellation) at drug concentrations that do not affect female gametocyte fitness (as measured by activation into gametes) Malaria parasites may alter their investment in asexual replication and transmission in response to drug pressure. Treatment with subcurative doses of antimalarial drugs has been shown to increase the rate of gametocytogenesis in the rodent malaria parasite mosquito feeding assays remain essential to predict transmission potential after treatment One important outstanding question is whether transmission potential is predictable after treatment based on gametocyte density and sex ratio, or whether P. falciparum to mosquitoes represents a developmental bottleneck in terms of parasite numbers; at the same time it is a very efficient process that may even increase in efficiency once transmission intensity declines Outstanding QuestionsWhat are the sensing mechanisms and stimuli that allow malaria parasites to adjust their sex ratio?Do male and female gametocytes differ in longevity or the duration of infectivity?What range of gametocyte sex ratio allows transmission under different conditions?Do different clones within the same infection vary in gametocyte sex ratio, and how does this affect their transmission?Do antimalarial drugs prevent transmission by means of gametocyte sterilization rather than gametocyte clearance?Can robust quantification of male and female gametocytes replace mosquito feeding assays?The transmission of"}
+{"text": "Formation of pancreatic pseudocyst is one of the well-known complication.While small pseudocyts are asymptomatic, large ones can become symptomatic and causeseveral complications including infection, rupture, bleeding, biliary complicationsand portal hypertension, Various interventions are available for the management of symptomatic pancreaticpseudocysts. Endoscopic ultrasound (EUS) guided cystogastrostomy is a choice fortreatment of large pseudocyts, witch bulge into gastric lumenFifty years old male was in reanimation clinic with the diagnosis of complicated andsevere acute pancreatitis due to gallstones for three months. His physicalexamination revealed a large sized mass extending from epigastric to left upperquadrant of abdomen. The contrast enhanced CT showed a cystic lesion with 150x100 mmdimensions in the tail and body of pancreas pushing the stomach . Thediagnostic upper gastrointestinal endoscopy revealed a bulge localized on largecurvature related to pancreatic pseudocyst. An endoscopic cystogastrostomy wasplanned. After detection of the area for cytogastrostomy in gastric lumen withstandard video-endoscope (Pentax EG 290 LK), it was marked by argon plasmacoagulation probe (30 watt); the gastric wall was opened step-by-step with the probe(60 watt) until pancreatic fluid drainage into stomach was seen. After aspiration ofpancreatic fluid (approximately 1500 ml), the gastric opening area enlarged by usingan ERCP sphincterotomy. Then a guide wire was inserted into the cyst with the C armfluoroscopy. Finally, 8.5 F pigtail plastic stent was placed into the cyst throughthe gastric lumen. The procedure was completed without any complication. ,,EUS guided cystogastrostomy is a safe method for management of pancreaticpseudocytsOur case has demonstrated that argon plasma coagulation without endoscopicultrasonography cytogastrostomy can be an option in handling large volume pancreaticpseudocyst during endoscopic cystogastrostomy."}
+{"text": "With age, peripheral nerves undergo demyelination along with overall decrease in peripheral nerve conduction velocity in both sensory and motor nerves. Loss of innervation in muscles is thought to be a major factor in causing age-related sarcopenia including a decrease in muscle function. Dietary restriction attenuates the detrimental effects of aging in mice. Reduction of mTOR signaling is hypothesized to have overlapping mechanisms with dietary restriction. Furthermore, inhibition of mTOR via rapamycin treatment is known to extend lifespan in mice as well as improve peripheral nerve myelination. Therefore, I hypothesized that reducing mTORC1 signaling in neurons would be able to ameliorate the deleterious effects of aging in peripheral nerves. An overall decrease in nerve conduction velocity was observed in both tail sensory and sural nerves with age (15 vs. 30 months). In neuronal mTORC1 KD animals, there was an age-related preservation of both sural and sciatic nerve conduction. Rapamycin treatment produced similar effects with a trend towards increased sciatic nerve conduction velocity in rapamycin-treated wild-type mice at 19 months. The preserve sciatic nerve conduction velocity could be partially explained by preserved myelination. Neuronal mTORC1 knockdown animals had more myelin in the sciatic nerve at 30 mo. as compared to age-matched controls. Overall, these data indicate that mTORC1 signaling plays a role in the age-related decline in peripheral nerve myelination as well as nerve conduction velocity. Future therapeutics could utilize rapamycin or other rapalogs to combat the decline in peripheral nerve function associated with age and other diseases as well."}
+{"text": "Longissimus dorsi muscle label-free quantitative proteomic reveals biological mechanisms associated with intramuscular fat deposition\u201d published in Journal of Proteomics Longissimus dorsi muscle from Nelore steers and identified differentially abundant proteins associated with the intramuscular fat (IMF) content. An integrated transcriptome-assisted label-free quantitative proteomic approach by High Definition Mass Spectrometry (HDMSE) was employed to identify and quantify the proteins. A functional enrichment analysis using the differentially abundant proteins list was performed to understand the biological processes involved in IMF deposition. Moreover, to explore and clarify the biological mechanisms that influence IMF content, the mRNA data for the same trait from Cesar and collaborators The proteomic data presented in this article are associated with the research article entitled \u201c Specifications TableValue of the data\u2022Bos indicus) Longissimus dorsi muscle promoted a better characterization of the protein profile of the samples.A customized protein database from RNA sequencing data of the Nelore  for intramuscular fat (IMF) content was compared Intramuscular fat (IMF), or marbling, is a relevant trait for the sensory attributes and nutritional values of beef. Individual differences of IMF content are notable and affect production systems. In this way, understanding of the biological mechanisms that regulate IMF deposition in beef cattle is essential to improve beef quality. The proteomic profile of 2Longissimus dorsi muscle samples from Nelore cattle at 24\u00b11 month of age were collected during the first-hour post-mortem. We selected 10 samples with higher (H) and 10 samples with lower (L) genomic estimated breeding values (GEBV) for intramuscular fat to carried out proteomic analysis  device. The MS spectra were acquired with Waters MassLynx v.4.1 software and processed using Progenesis QI for Proteomics (QIP) 2.0 software. For protein identification and quantification, the raw data were searched against a Nelore transcriptome database built from RNA-sequencing data from LD muscle. Proteins identified are shown in p-value <0.05 by ANOVA test from Progenesis software (The peptides samples were separated using nanoACQUITY UPLC 2D Technology system software .4p<0.05) between groups The list of the differentially abundant proteins ("}
+{"text": "OBJECTIVES/SPECIFIC AIMS: This study seeks to test the feasibility and effectiveness of a brief acceptance and commitment therapy (ACT) treatment for chronic pain patients in a primary care clinic METHODS/STUDY POPULATION: Primary care patients aged 18 years and older with at least 1 pain condition for 12 weeks or more in duration will be recruited. Patients will be randomized into (a) ACT intervention or (b) control group. Participants in the ACT arm will attend 1 individual visit with an integrated behavioral health provider, followed by 3 weekly ACT classes and a booster class 2 months later. Control group will receive enhanced primary care that includes patient education handouts informed by cognitive behavioral science. Data analysis will include 1-way analysis of covariance (ANCOVA), multiple regression with bootstrapping. RESULTS/ANTICIPATED RESULTS: The overall hypothesis is that brief ACT treatment reduces physical disability, improves functioning, and reduces medication misuse in chronic pain patients when delivered by an integrated behavioral health provider in primary care. In addition, it is anticipated that improvements in patient functioning will be mediated by patient change in pain acceptance and patient engagement in value-consistent behaviors. DISCUSSION/SIGNIFICANCE OF IMPACT: This pilot study will establish preliminary data about the effectiveness of addressing chronic pain in a generalizable integrated primary care setting. Data will help support a larger trial in the future. Findings have potential to transform the way chronic pain is currently managed in primary care settings, with results that could decrease disability and improve functioning among patients suffering from chronic pain."}
+{"text": "The Kessler 6 (K6) Psychological Distress Scale is a well-known screening instrument to screen for psychological distress of general population. While some studies  concluded that the K6 was appropriate for capturing psychological distress of diverse racial/ethnic groups, other studies  reported that it was less successful in screening for psychological distress of diverse racial/ethnic groups. Few studies conducted measurement equivalence test across older Asian immigrant subgroups. Using Multiple Group Analysis, this study examined whether parameters of the single factor model  is equivalent across the two Asian immigrants . Data were generated from the California Health Interview Survey. The configural model showed good fit . When all factor loadings were constrained, it indicated measurement non-invariance status between Chinese and Koran . Given findings of non-invariance on the full constrained model, the invariance test of each factor loading was performed additionally. It was focused on evaluating which items were similar or different across the two groups. The three items, \u2018hopeless,\u2019 \u2018restless,\u2019 and \u2018depress,\u2019 were significantly nonequivalent between the two groups. Clinicians/researchers should aware of the potential risk for misclassification when they try to screen for psychological distress in older Chinese or Korean immigrants. Professionals should pay attention to cross-cultural comparability when interpreting results from the K6."}
+{"text": "A 56-year-old female presented with a complaint of left flank pain for two weeks. Her past medical history was unremarkable. A left pelvic calcification was observed on abdominal X-ray . UltrasoOvarian MCT is a cystic or solid tumor  which accounts for 10-20% of all ovarian tumors , but theEarly diagnosis and treatment in terms of a conservative surgical approach is recommended. Ovarian MCT should be considered in the differential diagnosis of distal ureteric obstruction causing proximal hydroureteronephrosis in young female patients ."}
+{"text": "Left ventricular assist devices (LVAD) have become a common treatment option in advanced heart failure. Lack of aortic valve opening during left ventricular unloading is a common complication and associated with a worse outcome. Maintaining a minimum pulse pressure is an important goal during the early postoperative period after LVAD implantation since it is commonly seen as secure sign of aortic valve opening.We report a case of an LVAD-supported patient with early permanent closure of the aortic valve despite a pulse pressure\u2009>\u200915\u2009mmHg at all times following LVAD implantation. We demonstrate how careful assessment of the invasive arterial blood pressure curve can indicate aortic valve closure irrespective of pulsatile blood flow.A 69-year old male patient with terminal ischemic cardiomyopathy was referred for long-term mechanical circulatory support. Due to mild aortic regurgitation both an aortic bioprosthesis and a continuous-flow left ventricular assist device were implanted. Postoperative echocardiography documented a patent aortic bioprosthesis and an acceptable residual systolic left ventricular contractility. During invasive arterial blood pressure monitoring repetitive transient slight blood pressure decreases followed by slight blood pressure increases coincided with programmed LVAD flushing cycles. Permanent pulsatile flow with a pulse pressure of \u226515\u2009mmHg conveyed systolic opening of the aortic valve. Echocardiography, however, proved early permanent aortic valve closure. In retrospect, transformation of the automated LVAD flushing cycles into visible changes of the arterial blood pressure curve during invasive blood pressure monitoring is indicative of ejection of the complete cardiac output through LVAD itself, and therefore an early clinical sign of aortic valve closure.We present this interesting didactic case to highlight caveats during the early postoperative period after LVAD implantation. Moreover, this case demonstrates that careful and differentiated observation of the arterial blood pressure waveform provides crucial information in this unique and growing patient population of continuous-flow LVAD support. Mechanical circulatory support has advanced considerably within the past two decades , 2. As oA 69-year old diabetic male with ischemic heart disease, severely reduced ejection fraction and surgical revascularization with quadruple coronary artery bypass grafting in 1997 presented to his family physician with nausea and dyspnea for 24\u2009h in late August 2016. A subacute non-ST segment elevation myocardial infarction was diagnosed and partial thrombotic occlusion of the internal mammary bypass graft to the distal left anterior descending coronary artery was identified as culprit lesion. However, the remaining flow was reported to be TIMI grade 3. The venous bypass graft to the first diagonal branch was patent, whereas the remaining venous grafts to the intermediate and the posterior descending artery proved chronically occluded, as did all native coronary vessels. LV enddiastolic pressure (LVEDP) was severely increased (40\u2009mmHg) and LV ejection fraction was below 15%. In spite of increasing congestion of the spontaneously breathing patient the remaining coronary flow was judged sufficient, and a conservative medical management was adjudicated and therapeutic anticoagulation and dual antiplatelet therapy were initiated. After initial recompensation the patient experienced repetitive hemodynamically relevant ventricular tachycardia that could not be controlled with ICD- and medical therapy and was associated with the repetitive need for inotropic support (INTERMACS level 3) . ConsequWe present a case of continuous-flow LVAD support in a patient with ischemic cardiomyopathy. Even though systolic contractility of the unloaded LV was sufficient to generate pulsatile blood flow, 7\u00a0days after LVAD and bioprosthetic AV implantation, no more systolic AV opening could be documented. This finding was evident by transformation of LVAD flushing cycles into systemic BP changes during preserved pulse pressure\u2009\u2265\u200915\u2009mmHg as assessed by invasive arterial monitoring. The flushing cycle encompasses a reduction of the pump speed by 200\u2009rpm below the set speed for 2\u00a0seconds, followed by an increased pump speed to 200\u2009rpm above the set speed for 1\u00a0second before the pump returns to the programmed speed (Fig. In summary, the presence of pulsatile blood flow alone is insufficient proof of a patent aortic valve during continuous-flow LVAD support. Even in presence of remaining LV contractility, permanent AV closure may occur. However, transmission of LVAD flushing cycles and disappearance of the dicrotic notch in the arterial blood pressure waveform may hint toward AV closure early after continuous-flow LVAD implantation. Careful observation of the arterial blood pressure waveform during the early postoperative phase may provide highly relevant information on both cardiac function and valvular mechanics."}
+{"text": "Childhood misfortune encompasses a diverse set of negative early life experiences that have damaging effects on lifespan development. We extended this topic by examining how early life misfortunes predicted changes in measures of physical functioning (FUNC) and body mass index (BMI) in adulthood (ages 25-75). We used 3-wave data  from the Midlife Development in the U.S. study across 20 years. Unconditional latent growth curve models  suggested significant (p < .05) mean-level change and variability in change for FUNC  and BMI . Higher levels of childhood misfortune  significantly predicted worse FUNC  and higher BMIs  at baseline and steeper increases over time. Findings underscore the need to address adult health problems that emerge much earlier in life."}
+{"text": "Rapid disease progression and associated opportunistic infections contribute to high mortality rates among children aged <15 years with human immunodeficiency virus (HIV) infection  is also required to initiate ART for patients with newly diagnosed HIV infection. Lastly, community-based retention and adherence support are necessary to help maintain children with HIV infection on ART; patient tracking might help initiate ART for previously ineligible children or those lost to follow-up  guidelines have expanded the recommended criteria for life-saving antiretroviral therapy (ART) eligibility among children with human immunodeficiency virus (HIV) infection.All 20 sub-Saharan African countries included in this analysis adopted the 2013 WHO guidelines by 2015. In 2016, 13 of 20 countries adopted the 2016 guidelines to treat all children; however, approximately 56% of children aged <15 years with HIV infection in these countries were not receiving ART.Closing the ART coverage gap requires prompt adoption of WHO guidelines, and strengthening ART programs to identify children with HIV infection, link them to HIV treatment programs, and ensure their retention in care."}
+{"text": "SUB3915640.In the original article, there was an error. Readers were unable to access the 16S sequencing data submitted to the Short Read Archive (SRA) under the accession number MATERIALS AND METHODS, DNA Isolation and 16S rRNA Gene Sequencing:A correction has been made to PRJNA486651\u201d.\u201cTo avoid contamination, DNA isolation was performed using the cultured cells protocol supplied with the DNeasy Blood and Tissue Kit  in a laminar flow hood. The concentration of extracted DNA was determined through a Nanodrop ND-1000 spectrophotometer . The genomic DNA isolated from the clinical samples was amplified using primer sets specific for V4 regions . In order to evaluate contribution of extraneous DNA from reagents, extraction negative controls (no urine) and PCR negative controls (no template) were included. The resultant PCR products were purified by Qiaquick PCR purification kit . Finally, purified samples were normalized to equal DNA concentration and sequenced using the Illumina Miseq sequencer . The 16S rRNA gene sequences have been submitted to the Short Read Archive (SRA) under accession number The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."}
+{"text": "Sternal cleft is a rare congenital chest malformation with an incidence of <0.15% and is predominant in girls (A full-term newborn aged 42 days and weighing 3370 g with a superior sternal cleft was transferred to our clinic. There was no antenatal diagnosis. The patient was initially followed up in the pediatric intensive care unit due to respiratory distress without intubation. Computed tomography and three-dimensional reconstruction revealed a superior U-shaped sternal cleft with displacement of the medial ends of the clavicles . LaboratSternal cleft is a rare anomaly of the chest wall . Accordi"}
+{"text": "We demonstrate optically pumped telecom-band lasing in single InAs/InP nanowires at room temperature. Telecom-band single nanowire lasers made by the bottom-up vapor-liquid-solid approach, which is technologically important in optical fiber communication systems, still remain challenging. Here, we report telecom-band single nanowire lasers operating at room temperature based on multi-quantum-disk InP/InAs heterostructure nanowires. Transmission electron microscopy studies show that highly uniform multi-quantum-disk InP/InAs structure is grown in InP nanowires by self-catalyzed vapor-liquid-solid mode using indium particle catalysts. Optical excitation of individual nanowires yielded lasing in telecom band operating at room temperature. We show the tunability of laser wavelength range in telecom band by modulating the thickness of single InAs quantum disks through quantum confinement along the axial direction. The demonstration of telecom-band single nanowire lasers operating at room temperature is a major step forward in providing practical integrable coherent light sources for optoelectronics and data communication. The discovery and continued development of the laser have revolutionized both science and industry  multi-quantum-disk (MQD) heterostructure . An MQD From the point view of the synthesis approach, most nanowires have been synthesized by selective area epitaxy  system, where the InP/InAs nanowire was grown via indium particle\u2013catalyzed  VLS mode. We used InP (111)B as the substrate for vertically aligned nanowires on the substrate by epitaxial growth, as shown in the scanning electron microscopy (SEM) images . High-any direction remains coherent, while the lattice along the z direction is elongated in the InAs QDisk to relax strain energy. The compressively strained InAs QDisk is potentially expected to have several advantages, such as improved band imbalance and reduced threshold . These results indicate that the lasing is the longitudinal mode in the nanowire Fabry-P\u00e9rot cavity structure.To confirm the lasing mode, we calculated the mode spacing using \u0394\u03bb = \u03bb3, where N is the carrier density . We plotted the dependence of decay time on pump power (fig. S6A). With decreasing lifetime, the PL shows continuously increasing intensity. This indicates that the shortened lifetime is dominantly induced by stimulated emission. The decay evolution is a further indication of lasing behavior in the nanowire (We have further carried out time-resolved PL measurement at room temperature to clarify the evolution of PL decay process under increasing pump power  (43). AbAbove the lasing threshold, the lasing peak shows broadening line width and blue shift with increasing pump power (fig. S6B). The broadening peak above the threshold might be induced by temperature increase of the nanowire due to the heating effect by intense laser irradiation. The tiny blue shift (~1 nm) of the lasing peak might be due to the change of effective refractive index resulting from the high carrier concentration under intense laser irradiation. One more issue might be the blue shift of effective bandgap originated from quantum-confined stark effect due to screening effect by high carrier concentration, since the <111>-oriented MQD InP/InAs nanowire has strong spontaneous and piezoelectric polarizations  for a same nanowire. The nanowire shows reproducible lasing behavior even 1 week after the initial lasing measurement. In general, most nanowires showed stable lasing operation despite the surrounding air atmosphere and room temperature conditions.About the stability of nanowire lasing, we first conducted the lasing measurement at cryogenic temperatures . The lasing state was very stable and reproducible. This is attributed to the cryogenic temperature and vacuum environment. The heating effect induced by lasing pump could be effectively suppressed. We then performed the measurement at room temperature, and the surrounding atmosphere of nanowire samples was air. So the heat effect by laser irradiation may be serious and probably cause burning out of nanowires. However, later, we found that using the substrate with high thermal conductivity of a gold film was very helpful to suppress the heating effect. That is why we used gold film\u2013covered SiOThe tunability of laser wavelength in a broad range, e.g., the full telecom band (1.2 to 1.6 \u03bcm), is considerably important for the development of practical applications. The MQD heterostructure serving as the active region provides the ability to modulate the photon emission energy by tuning the thickness of the InAs QDisk in a broad range through quantum confinement . The thiThe spontaneous emission PL spectra show that the dominant peak is shifted up to the high-energy (short-wavelength) side with reducing thickness of single InAs QDisks , indicatWe have then observed the stimulation emission for a number of nanowires by increasing excitation power . For nan\u22122 per pulse. The value is about 10 times higher than those of GaAs nanowires (~0.2 mJ cm\u22122 per pulse) (\u22122 per pulse) , we consider our MQD InP/InAs nanowire as strained quantum wells with a vertical wire structure. The InP/InAs heterostructure interface exhibits coherent growth despite as high as 3.1% lattice mismatch. We calculated the strain in our MQD InP/InAs nanowires (see Supplementary Text)\u22121 in micro-Raman measurement  plane and a tensile strain along the perpendicular <111> direction. This high strain has also been verified by transverse optical phonon shift to the high energy side as large as 15 cmWe demonstrate optically pumped telecom-band single nanowire lasers operating at room temperature based on MQD InP/InAs heterostructure nanowires. Our work represents a new level of complexity in nanowire structures with working wavelength in telecom-band range by a gold-free CMOS-compatible synthesis approach .The morphology of the nanowires was analyzed using a scanning electron microscope  at an accelerating voltage of 5 to 15 kV. The cross-sectional samples used for the TEM measurements were prepared by using a focused ion beam  system. The STEM analysis was performed in a JEM2100F  equipped with a HAADF detector and an x-ray energy-dispersive spectrometer. The aberration-corrected STEM analysis was carried out in a JEM-ARM200F  equipped with a HAADF detector. The strain analysis of MQD nanowires was performed by GPA software  facet mirrors could be resulted at both ends of a nanowire and hence construct a Fabry-P\u00e9rot cavity because of the refractive index difference between the nanowire and the surrounding air.We mechanically dispersed nanowires onto a gold film\u2013covered SiOA mode-locked Ti:sapphire laser delivering several-picosecond pulses was used to pump a single nanowire. The pump wavelength was fixed at 800 nm with a repetition rate of 80 MHz. The pump laser spot with a circular shape was focused down to 2.0-\u03bcm diameter using 50\u00d7 lens with a numerical aperture of 0.42. The detection parts contain a visible near-infrared CCD (charge-coupled device) camera and a highly sensitive short-wave infrared InGaAs photodiode array CCD with a long-wave-pass filter (cutoff wavelength of 1100 nm) for the microscope image and the PL image, respectively. To measure the PL spectrum, we coupled the emission into the multimode fiber and directed it to a grating spectrometer with a cooled InGaAs array.With regard to the time-resolved PL measurement, we used a femtosecond Ti:sapphire laser (repetition rate of 80 MHz) as a pump laser, a superconducting nanowire single-photon detector, and a time-correlated single-photon counting module for our time-resolved PL ("}
+{"text": "Hemangiomas are benign tumors usually found in the lower extremity yet their surgical management on the location in the foot is rarely documented.We report a case of a plantar intramuscular hemangioma in 25-year-old patient with a history of percutaneous therapy. Patient had undergone intralesional sclerotherapy 3\u2009years prior to his admission with persistent pain on weight bearing activities.MRI demonstrated a multi lobulated lesion of the 1st IMS with a peripheral enhancement on gadolinium injection. The patient underwent elective surgery with complete excision and no functional impairment at the last follow-up 3\u2009years after surgery.Intramuscular hemangiomas are rare occurrences. Steroid injection and sclerotherapy are effective non-operative methods. Complete excision of isolated hemangioma lesions allows definite diagnosis with no recurrence. Intramuscular hemangiomas (IMH) are benign neoplasms accounting for less than 1% of all hemangiomas . Foot loThe patient is a 24-year-old male with no prior trauma who presented with a 7\u2009year history of forefoot pain placed on several over-the-counter drugs and other conservative treatments including percutaneous therapy. The patient recalled steroid injection and intralesional sclerotherapy three years prior to her admission with no relief. Physical examination demonstrated a firm mass on the plantar surface of the first intermetatarsal space (IMS) without motor nor sensory deficit. Vascular examination was unremarkable.Plain x-ray demonstrated a soft tissue widening of the 1st IMS with phleboliths Fig.\u00a0.Fig. 1PlThe patient underwent surgery after written and informed consent was obtained. A plantar longitudinal approach across the 1st interosseous metatarsal space was undertaken. After careful dissection, an intramuscular tumor taking up the interosseous muscles was excised. Fig.\u00a0. ImmediaIntramuscular hemangioma or angioma (IMH) is a benign vascular neoplasm of the skeletal muscle. It occurs in young adults before the third decade with a slight feminine predominance observed in most cases  .MalignaAlthough its pathogenesis still remains unclear, a congenital origin is often suggested  and a hiA palpable mass is found on physical examination at time of diagnosis in 98% of reported cases [Plantar intramuscular hemangiomas are seldom reported in literature. Wisniewski et al.  reportedPlain films may reveal phleboliths that are round lumps of calcifications primarily due to thrombosis within the lesion . MRI is Surgical excision is the mainstay treatment  as it alCompressive sclerotherapy, using a variety of products, radiotherapy and laser ablation have also been suggested as treatment options in large diffuse hemangiomas where excision is impractical. Uslu et al.  demonstrIMH are rare benign tumors that do not undergo spontaneous regression. Plantar IMH are nuisance to weight bearing activities and their management could cause a therapeutic dilemma. This case report demonstrates a unique presentation of intramuscular hemangioma due to its localization. The hemangioma was surgically excised with no recurrence or functional impairment of the foot."}
+{"text": "Inefficient Mg-induced p-type doping has been remained a major obstacle in the development of GaN-based electronic devices for solid-state lighting and power applications. This study reports comparative structural analysis of defects in GaN layers on freestanding GaN substrates where Mg incorporation is carried out via two approaches: ion implantation and epitaxial doping. Scanning transmission electron microscopy revealed the existence of pyramidal and line defects only in Mg-implanted sample whereas Mg-doped sample did not show presence of these defects which suggests that nature of defects depends upon incorporation method. From secondary ion mass spectrometry, a direct correspondence is observed between Mg concentrations and location and type of these defects. Our investigations suggest that these pyramidal and line defects are Mg-rich species and their formation may lead to reduced free hole densities which is still a major concern for p-GaN-based material and devices. As freestanding GaN substrates offer a platform for realization of p-n junction-based vertical devices, comparative structural investigation of defects originated due to different Mg incorporation processes in GaN layers on such substrates is likely to give more insight towards understanding Mg self-compensation mechanisms and then optimizing Mg doping and/or implantation process for the advancement of GaN-based device technology. Any increase in Mg atomic concentrations beyond 1019\u2009cm\u22123 lead to a decrease in the free hole concentration  direction pointing towards their head, their base on [0001] plane with six walls on  direction and two-line defects with features separated by few nanometers deeper in [0001] direction. Pyramidal domains are believed to be Mg"}
+{"text": "RTEL1 rs2297441  and rs3208008  were associated with PCa risk. These two risk single nucleotide polymorphisms (SNPs)  and another SNP PARP1 rs1136410  were also associated with leukocyte telomere length. These findings support that genetic determinants of telomere length may influence PCa risk.Telomere length measured in lymphocytes has been evaluated as a potential biomarker for prostate cancer (PCa) risk. Identifying genetic variants that affect telomere length and testing their association with disease could clarify any causal role. We therefore investigated associations between genetic variants in three telomere length-related genes and PCa risk in a case-control study. The influence of these variants on the leukocyte telomere lengths was then appraised by real-time PCR.  Telomeres are TTAGGG nucleotide repeats and a protein complex at chromosome ends that play an essential role in maintaining chromosomal stability. Due to the inability of DNA polymerase to fully extend 3' DNA ends, telomeres become gradually shorter with each cell division in the absence of telomerase activityTelomere length is influenced by inherited genetic factorsRTEL1, POT1 and PARP11) in relation to PCa risk in a case-control study. We also evaluated whether these genetic variants are associated with leukocyte telomere length to investigate a potential etiologic relationship.In the present study, we evaluated six potentially functional genetic variants from three telomere length-related genes (The study subjects were mostly from previously published case-control studyhttp://www.ncbi.nlm.nih.gov/) for potentially functional SNPs and SNPinfo (http://snpinfo.niehs.nih.gov/) to identify the candidate SNPs based on the following three criteria: (1) located at the regulatory or coding region of genes ; (2) the minor allele frequency (MAF) \u2265 5% in Chinese Han, Beijing descendants reported in HapMap; (3) affecting the activities of microRNA binding sites in the 3' UTR and transcription factor binding sites in the putative promoter region or changing the amino acid in the exons. All these six SNPs were genotyped by the TaqMan real-time PCR method as described previouslyWe searched the National Center for Biotechnology Information dbSNP database  and 95% confidence intervals (CIs) were calculated by univariable and multivariable unconditional logistic regression models to evaluate associations between the genotypes and risk of PCa without and with adjustment for confounding factors, respectively. Spearman rank correlation was used to investigate associations between telomere length and age. Telomere length was categorized into dichotomies based on the distribution. All statistical analyses were performed with SAS software .For all subjects, the \u03c7Table 1. Briefly, there were no statistical differences in the distributions of age and smoking status between two groups.The distributions of demographic characteristics of the subjects are shown in Table 2. The observed genotype frequencies of six SNPs in controls agreed with the Hardy-Weinberg equilibrium. Furthermore, the genotype distribution of RTEL1 rs2297441 and rs3208008 was significantly different between the cases and controls. In multivariate logistic regression analysis, RTEL1 rs2297441 and rs3208008 were associated with PCa risk. Compared with GG genotype, rs2297441 variant AA genotype was associated with an increased risk of PCa . Compared with AA genotype, rs3208008 variant AC/CC genotype was associated with an increased risk of PCa . However, no associations between the other four SNPs and PCa risk were observed.The genotype frequencies of six SNPs and their associations with PCa risk are summarized in P < 0.001). When participants were dichotomized according to the median telomere length value, significant differences in telomere length by genotype of RTEL1 rs2297441, RTEL1 rs3208008 and PARP1 rs1136410 were observed (Table 3). Compared with GG genotype, rs2297441 variant AA genotype was associated with shorter telomere length .To investigate whether the telomere length had prognostic significance, 426 patients were categorized into dichotomies based on their telomere length distribution . Telomere length was inversely associated with age -containing DNA helicase that is critical for facilitating telomere replication and maintaining the integrity of chromosome endsRTEL1 variants involved with genetic predispositions to cancers development. A principal component-adjusted GWAS study, comprising over 275 000 autosomal variants among 692 adult glioma cases and 3992 controls, identified two SNPs within intron 12 (rs6010620) and intron 17 (rs4809324) of RTEL1 that were significantly associated with glioma and astrocytoma predispositionRTEL1 geneRTEL1 rs41309931RTEL1 rs2738780, rs7261546 and rs6062299 were found to be associated with lung cancer development in Han Chinese populations in case-control studiesA number of GWASs and candidate gene studies have identified  RTEL1 variants associated with predisposition to cancers has confirmed the hypothesis that genetic factors underlying telomere length have an especially strong influence on cancer development. Definitive proof of such a role has emerged from the existence of genetic variants influencing both telomere length and cancer susceptibility. Nine common genetic variants have been identified that are associated with leukocyte telomere length at a level of genomewide significanceRTEL11 rs2297441 and rs3208008 risk alleles in the current study.The emergence ofRTEL1 is known to regulate telomere length, the precise function of RTEL1 variant genotypes in PCa development remains elusive. Our findings do not imply that telomere length acts directly on cancer risk and could reflect pleiotropic effects of telomere-length loci. It remains to be answered why another SNP PARP1 rs1136410 cause telomere shortening has no association with PCa risk. One potential explanation might be RTEL1 function as a tumour-suppressor geneEven though A large number of intrinsic and extrinsic factors, such as heredity, epigenetics, aging, stress, immune components, and hormones are all states have been previously associated with telomere shorteningRTEL11 rs2297441 and rs3208008). Our findings also suggest that candidate genes encoding proteins with known function in telomere biology variants contribute to telomere length associations. We expect that further replication and mechanistic studies will continue to provide insights into the etiology of PCa.In conclusion, here we present two novel candidates for PCa risk ("}
+{"text": "There has been an increasing trend for Congress and the Centers for Medicare and Medicaid Services (CMS) to add non-skilled services to coverage under Medicare Advantage and Medicaid inpatient hospital. At the same time there has been a 75% decline in home health aide visits, the only Medicare home health non-skilled service, as a percentage of all Medicare home health visits from 2000-2016. A literature review indicates no studies addressing the potential factors accounting from these seemingly contradictory trends. The present study is based on interviews of five Chief Executive Officers (CEOs), five Chief Financial Officers (CFOs), and eight Chief Nursing Officers (CNOs) from Medicare-certified home health agencies between October 2017-July 2018. Results indicated agreement among interviewees on three themes: the Medicare home health relies on a medical model which focuses on intermittent skilled care; the Medicare home health prospective payment system (PPS) exacerbated the focus on skilled care by rewarding higher reimbursement for skilled care based episodes; and a synergy has evolved of \u201cless is better\u201d regarding utilization of home health aide services and reimbursement. Policymakers are urged to consider adding coverage of non-skilled services under Medicare home health, similar to Medicare Advantage, by funding demonstration projects with appropriate changes in reimbursement."}
+{"text": "A 29-year-old man with no significant medical history presented to the emergency department with severe pain, swelling, and inability to move his right knee. He was injured when he extended his right knee to hit a tennis ball after running to the net. On examination, high-riding patellae were found on both the injured and non-injured sides. A lateral view radiograph showed patella alta in both knees . MagnetiPatellar tendon rupture is an uncommon clinical presentation that generally affects patients younger than 40 years who actively engage in sporting activities.What do we already know about this clinical entity?Patellar tendon rupture is an uncommon clinical presentation. Patellar tendon rupture occurring in a patient with patella alta is quite rare.What is the major impact of the image(s)?Diagnosis based on radiographs is difficult because the non-injured side also showed patella alta in this case.How might this improve emergency medicine practice?Emergency doctors should suspect patella tendon rupture from the clinical findings. Considering our case such as non-injured side also showing patella alta, magnetic resonance imaging is essential for diagnosis."}
+{"text": "A 74-year-old male with a history of metastatic prostate cancer presented to the emergency department with hypotension and shortness of breath. We assessed volume status using point-of-care ultrasound (POCUS) with a phased array probe in the subxiphoid orientation. This revealed a large inferior vena cava (IVC) thrombus extending from above the IVC bifurcation into the right atrium , Video. Venous thromboembolisms are estimated to occur in 0.1% of patients; 1.5% of patients hospitalized with deep vein thrombosis (DVT) were diagnosed with vena cava thrombosis, of whom 12% had a pulmonary embolism.5Recently, ultrasound has shown promise for quick identification of IVC thrombus.Once diagnosed, confirmation using CT imaging and admission to the hospital for anticoagulation and hemodynamic monitoring is recommended.3Our case highlights the use of POCUS to quickly identify etiologies of hypotensive and dyspneic patients. Further imaging should be obtained in IVC thrombosis patients to rule out PE or additional clots.What do we already know about this clinical entity?Inferior vena cava thrombosis is a rare, life-threatening condition that usually requires advanced imaging techniques to diagnose.What is the major impact of the image(s)?This image highlights the utility of the rapid ultrasound for shock and hypotension protocol for finding both obvious and less-obvious pathologies.How might this improve emergency medicine practice?Rapid diagnosis of undifferentiated hypotensive patients using point-of-care ultrasound expedites care and medical intervention.VideoRapid ultrasound for shock and hypotension protocol using the phased array probe in the subxiphoid orientation revealed a large thrombus situated in the inferior vena cava."}
+{"text": "Two cases of testicular metastases of a clear cell renal cell carcinoma sharing a very similar ultrasonographic pattern are reported. The observed pattern \u2013 masses containing multiple tiny cyst-like areas \u2013 is very similar to that of a previously described ovarian metastasis of clear cell renal parenchymal tumor and can be explained by histopathologic features. Despite the small number of cases, this ultrasonographic pattern of testicular mass may be specific for metastasis of clear cell renal cell carcinoma origin. Only few ultrasonographic descriptions of testicular metastases have been reported in the literature. In textbooks, their sonographic appearance is usually described as solid hypoechoic lesions indistinguishable from other types of tumor . The maj2A 69-year-old man without relevant medical history presented with a small lump in the right testis. Ultrasound examination revealed a solitary intra-testicular hyperechoic 12 mm tumor with heterogeneous appearance and with multiple small cystic-like areas Figure . On coloA 77-year-old man presented with painless swelling of the left hemiscrotum. He underwent a partial left nephrectomy for a CCRCC five years earlier and later developed pulmonary metastases. On physical examination, there was a firm left testicular mandarin-sized mass. Scrotal sonography showed a hyperechoic intra-testicular mass (diameter 47 mm) replacing almost the entire left testis. This heterogeneous mass contained multiple small anechoic cystic-like areas Figure  and was The testis is an uncommon site for metastases, with a reported prevalence ranging between 0.02%  and 0.063Since ultrasonography has shown a high sensitivity in tumor detection nearly 100%) and in discrimination of intratesticular from extratesticular localization 97\u201399%) 0% and in12, ultra7\u201399% 0% The features of the two cases of testicular metastases of CCRCC are almost similar to sonographic pattern of an ovarian metastasis of a renal clear cell carcinoma previously described in the literature . In all This sonographic pattern reflects the gross morphology and underlying histologic characteristics of CCRCC (primary tumor as well as their metastases) which can be considered as quite specific. CCRCC commonly presents as a well-circumscribed mass with a capsule or pseudocapsule. Typically, it is characterized by solid nests and hollow tubules composed of polygonal epithelial cells with clear and abundant cytoplasm. The transparency of the cytoplasm results from intra-cytoplasmic accumulation of droplets of glycogen and lipids, giving rise to the yellow coloration at macroscopic examination and probably to increased echogenicity due to multiple intra-cellular interfaces. The tumor may also show cystic areas when luminal spaces of the tubular structures dilate and become filled with fluid, necrotic material and red blood cells, explaining the cystic areas on ultrasonography. Cellular nests and tubules are separated by a delicate branching network of highly vascularized connective tissue.Based on this sonographical-pathological correlation, facing a testicular lesion with these characteristics in an elderly male should raise suspicion of a metastases of CCRCC.The authors declare that they have no competing interests."}
+{"text": "Intracardiac blood cysts (ICBC) are cardiac pseudoneoplasm commonly seen in infants below two months of age. ICBC typically resolve spontaneously; however, they can sometimes persist in adults and can cause detrimental consequences. A 47-year-old female presented to our facility with complaints of chest pain and was found to have an incidental subvalvular chordal mitral apparatus echolucent mass on transthoracic echocardiogram (TTE). A stress echocardiography was performed, which revealed transient left ventricle outflow tract (LVOT) obstruction in the absence of anginal symptoms. A cardiac magnetic resonance imaging (MRI) showed no evidence of increased mass enhancement confirming the diagnosis of a benign blood cyst of mitral apparatus. The cyst was treated conservatively with carvedilol to prevent worsening of exertional LVOT obstruction. A follow-up study done at six months showed stable exertional hemodynamics. There is no general consensus while managing ICBC. In asymptomatic, non-surgical patients stress echocardiography can offer valuable information by assessing the hemodynamic implications resulting from the cyst. Primary cardiac tumours (PCT) are rare, with an estimated incidence of less than 0.1% . IntracaA 47-year-old Caucasian female with a known medical history of essential hypertension being treated with labetalol came to the emergency department (ED) with complaints of non-exertional, intermittent (lasting one to two minutes), 3/10, left-sided chest pain which started three days ago. At the time of presentation, the patient was asymptomatic. She was afebrile with a blood pressure of 188/90 mmHg, heart rate of 73 beats per minute, respiratory rate of 16 per minute and normal oxygen saturation levels. Physical examination revealed a faint 1/6 systolic murmur which accentuated to 2/6 in intensity when she was made to go from crouching to standing. The remainder of the physical exam was unremarkable. The patient denied any pertinent family history. She was a former smoker and reported no allergies. Laboratory studies disclosed normal serum chemistry with normal troponin and brain natriuretic peptide (BNP) levels. Electrocardiogram (EKG) showed normal sinus rhythm with no ST-T wave changes. A chest radiograph identified borderline cardiomegaly with no evidence of infection or pulmonary vascular congestion.\u00a0A transthoracic echocardiogram (TTE) was pursued, which revealed normal left ventricular (LV) size and function. LVOT appeared normal without sub-valvular ridge or asymmetric septal hypertrophy. Mitral valve demonstrated normal-appearing leaflets; however, there was a large centrally echolucent sub-valvular chordal cyst greater than 1 cm in the largest diameter\u00a0Figure -3.\u00a0A cardiac magnetic resonance imaging (MRI) showed no evidence of increased enhancement confirming the diagnosis of a benign subvalvular blood cyst of the mitral apparatus. In light of asymptomatic nature of the condition, mild to moderate LVOT obstruction at peak exertion in a beta-blocker deprived state, a conservative strategy was opted after multidisciplinary discussion with cardiothoracic surgery. The patient was resumed on carvedilol and was advised to maintain adequate hydration to avoid worsening of LVOT obstruction due to dehydration. A surveillance stress echocardiogram done during six months follow-up visit showed stable exertional hemodynamics.ICBCs are diverticula resulting from invagination of atrial endothelium into atrioventricular valves. Histologically the cyst walls are made up of fibrous connective tissue either formed by mucous degeneration or calcification. Congenital ICBC often results from lacunar remanence created during the embryological development of atrioventricular valves. Disturbed blood flow can lead to enlargement of blood cysts which against the norm of spontaneous disappearance can persist into adulthood. Other theories such as hematoma formation, vessel ectasia or dilation, and abnormal development of cardiac mesothelial progenitor cells have also been postulated . AcquireThe clinical course of ICBC can vary depending on the location and size of the cyst. Majority of the adults are asymptomatic and are diagnosed incidentally. LVOT obstruction from ICBC can result in exertional dyspnea or syncope . IsolateIn our case, given the episodic nature of patient\u2019s symptoms a decision was made to perform an exercise stress echocardiogram to establish hemodynamic consequences from the mass. Though there have been previously reported cases of LVOT obstruction, to the best of our knowledge this is the first case in which ICBC was worked up with exercise stress echocardiography. Stress echocardiography is a non-invasive valuable tool which can help evoke underlying dynamic LVOT and ascertain the need for surgical removal. Due to the patient\u2019s reluctance to have surgical intervention and asymptomatic nature of her condition at maximal stress, the patient was treated conservatively with optimum medical management and surveillance echocardiogram.\u00a0Management of ICBC is controversial. Due to the lack of general consensus or guidelines, management varies based on the nature of the presenting symptoms and surgical appropriateness. Earlier recommendation by\u00a0Pa\u015fao\u011flu et al. was to resect all valvular cystic tumor to achieve a definitive diagnosis\u00a0,however,ICBCs are diverticula resulting from invagination of atrial endothelium into atrioventricular valves. The clinical course of ICBC varies depending on the degree of hemodynamic compromise. In symptomatic cases with dyspnea, stroke, and coronary artery embolism, surgical removal of the cyst in warranted. Exercise stress echocardiography offers an alternate approach to assess hemodynamic consequences from ICBC."}
+{"text": "There are many proposed classification systems for traumatic thoracolumbar fractures (TLF). More recently published are the AO Spine Classification System and the Thoraco-Lumbar Injury Classification System (TLICS). There has been a paucity of high-level evidence to link these classification system subtypes with clinical outcomes and/or management strategies. Previously, post-traumatic burst fractures or two column injuries identified on computed tomography (CT) scan have been deemed stable injuries. The addition of magnetic resonance imaging (MRI) evaluation for concomitant ligamentous injuries in cases of incomplete burst fractures has been widely debated without high-level evidence. In this report, we present a case of an incomplete burst fracture at L1, AO-A3, which did not receive an MRI and presented with delayed paraplegia four weeks later. Several classification systems have been proposed for traumatic thoracolumbar fractures (TLF). The more recently published systems include\u00a0the AO Spine Classification System and the Thoraco-Lumbar Injury Classification System (TLICS) -4. ThereA 28-year-old male was admitted after a motor vehicle collision (MVC) with low back pain and orthopedic fractures. The admission CT scan of his lumbar spine was read as a posterior superior endplate fracture at L1 extending to the posterior vertebral body, without posterior element displacement or disc space widening Figure . The disBurst fractures compromise the most commonly encountered TLF -14. The TLF are common injuries that occur after trauma. There are several classification systems that attempt to provide guidance for diagnostic and clinical management; however, there is little high-level evidence supporting these classification systems and their significance. In this case, a seemingly stable posterior vertebral body injury seen on CT was discovered to have significant ligamentous injury and instability after the MRI was obtained post mobilization. CT imaging alone may not be a completely reliable imaging modality to fully assess spinal integrity in cases of posterior vertebral body fractures. Patients with coinciding ligamentous injuries may present radiographically with only subtle findings on CT that can be easily missed with catastrophic neurologic consequences. Further outcome-based studies using these classification systems and imaging modalities should be performed in order to understand their significance in the management of patients with acute traumatic thoracolumbar fractures."}
+{"text": "Salmonella enterica subsp. enterica serotype Heidelberg isolates collected from several chicken- and turkey-associated farm environments in the Midwestern United States were analyzed using whole-genome sequencing.Thirty-one different  Salmonella enterica subsp. enterica serotype Heidelberg isolates collected from several chicken- and turkey-associated farm environments in the Midwestern United States were analyzed using whole-genome sequencing. Availability of these genome sequences may shed light on Salmonella adaptation to different farm environments.Thirty-one different  Salmonella is one of the leading causes of human foodborne gastroenteritis in North America, with public health costs of approximately $695 million annually in the United States (https://wwwn.cdc.gov/norsdashboard/). Salmonella enterica subsp. enterica serotype Heidelberg is the most common serotype isolated in all poultry breeder types and throughout all levels of the production chain in the United States and Canada  and another set specific to the Salmonella. Heidelberg serotype  and compared to a known Salmonella Heidelberg strain . Sequencing libraries were prepared using 1\u2009ng of genomic DNA with a Nextera XT DNA sample prep kit . PCR amplification was done in a Veriti 96-well thermal cycler machine  using Nextera XT Index 1 primers (N7XX) from the Nextera XT index kit (FC131\u20101001). Illumina paired-end sequencing was performed on a MiSeq platform using 2 \u00d7 250 paired-end sequencing chemistry. The raw data files were demultiplexed and converted to FASTQ files using Casava v.1.8.2. . Quality control of the raw reads was performed using FastQC . The reads were trimmed and assembled with BBDuk  and SPAdes , respectively. The coverages of the assembled genomes were evaluated with BBMap .Salmonella adaptation to different niches in poultry production  and NCBI GenBank (BioProject number PRJNA417775) and are listed in Draft genomic sequences have been deposited in the NCBI Sequence Read Archive (SRA accession number"}
+{"text": "Current approaches for pathway analyses focus on representing gene expression levels on graph representations of pathways and conducting pathway enrichment among differentially expressed genes. However, gene expression levels by themselves do not reflect the overall picture as non-coding factors play an important role to regulate gene expression. To incorporate these non-coding factors into pathway analyses and to systematically prioritize genes in a pathway we introduce a new software: Triangulation of Perturbation Origins and Identification of Non-Coding Targets. Triangulation of Perturbation Origins and Identification of Non-Coding Targets is a pathway analysis tool, implemented in Java that identifies the significance of a gene under a condition (e.g. a disease phenotype) by studying graph representations of pathways, analyzing upstream and downstream gene interactions and integrating non-coding regions that may be regulating gene expression levels.https://github.uconn.edu/ajt06004/TriPOINT under the GPL v3.0 license.The TriPOINT open source software is freely available at Bioinformatics online. Methods for pathway analysis over the years have fallen into three categories  and  gene inconsistent with their upstream targets and (ii) genes that are highly supported by their upstream associated genes, which can be useful for identifying enriched pathways. To assess the significance of each score, TriPOINT calculates permuted P-values. Permuted P-values are obtained by randomly reassigning gene expression values between genes from the expression values provided and recalculating scores based on the number of permutations to generate a null distribution.TriPOINT utilizes graph representations of pathways obtained from GRAPHITE  profiled by The Cancer Genome Atlas . Among these genes/pathways with negative triangulation scores, we identified ACVR1 and BMPR1A in the \u2018Signaling pathways regulating pluripotency of stem cells\u2019 KEGG pathway as among the top genes/pathways using these scoring criteria (triangulation scores. ACVR1 and BMPR1A have each been previously associated with breast cancer (We obtained 864 gene/pathway combinations with criteria . We alsoConflict of Interest: none declared.bty998_Supplementary_InformationClick here for additional data file."}
+{"text": "The current study investigates whether metal deposition onto an existing nanorod can be carried out using an ionic liquid, and the effect this has on catalytic performance. Platinum, gold, and silver nanoparticles were deposited onto CdSe@CdS (core@shell) nanorods from metal salts in an ionic liquid (1-butyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide) without additional surfactants or reducing agents. Photocatalytic dye degradation experiments showed that catalysts with platinum particles deposited using the ionic liquid out-performed similar materials synthesized using organic solvents and ligands. We concluded that metal particles can be deposited onto well-defined semiconductor nanorods using ionic liquids and metal salts without the need for additional reagents, and the deposited particles did not cause significant aggregation even when these materials were taken into organic media. It is possible that a broad range of metal/semiconductor heterostructured particles can be prepared using the methods reported here. Core@shell semiconductor nanorods with attached noble metal particles have been widely studied as photocatalysts, and any improvement on the synthesis of these materials has potential to impact a number of applications \u20134. DeposAnother widely investigated approach to nanoparticle synthesis uses ionic liquids as solvents for the synthesis of nanoparticles without the need for additional stabilizing surfactants \u201317. The 2 in the ionic liquid 1-butyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide ([bmim][Tf2N]) without needing to add any additional reagents. We also deposited platinum nanoparticle cocatalysts onto CdSe@CdS nanorods using a traditional organic system (toluene/triethylamine) as shown in 2N] for metal deposition was found to be applicable to other noble metals in addition to platinum. Gold and silver nanoparticles were also deposited onto CdSe@CdS nanorods without the need for additional surfactants or reducing agents.Herein, we demonstrate that an ionic liquid may be used to deposit nanoscopic noble metal particles onto a well-defined semiconductor nanorod substrate with diameters less than 10 nm. We found that photodeposition of platinum onto CdSe@CdS (core@shell) nanorods proceeded readily from Pt(acac)max = 509 nm)  2 without addition of triethylamine as a sacrificial reducing agent, followed by irradiation using a xenon arc lamp. Nanorod powders were difficult to disperse directly in [bmim][Tf2N], so the nanorods were dispersed in a small amount of chloroform prior to mixing with the ionic liquid. Complete evaporation of the chloroform then afforded well-dispersed nanorods in the ionic liquid. The mass of the nanorod powder, Pt(acac)2, and the ionic liquid were each measured prior to dispersing the nanorods in chloroform and combining with the ionic liquid; complete removal of the chloroform was confirmed by taking the mass of the nanorod dispersion in [bmim][Tf2N] after evaporation of the chloroform under reduced pressure.The obtained nanorods are capped with tightly bound phosphonic acid ligands bearing long hydrophobic alkyl chains. Rather than exchanging these ligands to allow these nanorods to be dispersed in polar media, platinum nanoparticles were deposited onto these CdSe@CdS nanorods in hydrophobic media based on the photochemical process reported by Alivisatos and coworkers , with th2N] . We chos tol-NR, , CdSe@Cd, IL-NR, , CdSe@Cd2N], the platinum decorated nanorods were extracted into toluene from the ionic liquid prior to purification by centrifugation. The final pellets obtained were dispersed in toluene for storage and subsequent experiments regardless of the solvent used for the platinum deposition reaction. TEM images of both products are shown in Platinum deposition under both solvent conditions initially afforded a mixture of platinum-decorated nanorods and additional platinum nanoparticles that were not attached to CdSe@CdS nanorods. For the platinum deposition conducted in toluene, the unattached platinum particles were removed by several dissolution and precipitation cycles using toluene and ethanol. For the platinum deposition conducted in [bmim][Tf2N] without needing to add a sacrificial reducing agent. The chemical species oxidized during platinum reduction and deposition onto these nanorods in [bmim][Tf2N] is not known at this time, though others have observed similar results. CoPt nanoparticles were previously formed in [bmim][Tf2N] using Pt(acac)2 and an ammonium bromide  or toluene/triethylamine.With two nearly identical samples in hand, we were able to compare the performance of two catalysts where the only notable difference was the synthetic history of the sample . We used2N] showed a measurably increased dye degradation rate compared to the sample prepared in toluene/triethylamine. Error bars corresponding to the standard deviation values of these experiments show that the obtained results are reproducible for these materials (2N] to rule out any possible effects from the ionic liquid itself (A known amount of the nanoparticle catalyst was combined with methylene blue and chloroform for photocatalytic dye degradation experiments , based oaterials . Note thd itself . AlthougThese heterostructured nanorod photocatalysts bleach methylene blue by donating electrons from platinum cocatalyst sites to the dye . Thus, t2N] without any additional surfactants or reducing agents to determine if this ionic liquid was generally useful for deposition of other metals (2N] as described above, AuCl3 dissolved in [bmim][Tf2N] was added, and the mixture was heated in a 50 \u00b0C water bath for 10 minutes. The nanorod product was then extracted into toluene and a TEM sample was prepared without further purification (2N] and AgNO3 at 50 \u00b0C (We then investigated reduction of gold and silver in the presence of CdSe@CdS nanorods using [bmim][Tfr metals . For golfication . We obseat 50 \u00b0C . Due to 2N] without the need for additional surfactants or reducing agents. These procedures resulted in heterostructured particles with similar morphology and elemental composition compared to particles synthesized using traditional organic solvents and ligands. The performance of the resulting materials with metal cocatalysts deposited in [bmim][Tf2N] showed only modest improvement over materials prepared in conventional solvents, which is attributed to the fact that the semiconductor nanorod substrate was still capped with insulating organic ligands in both samples. The methods reported herein could be used to achieve a multistep synthesis of metal-decorated core@shell particles using only ionic liquids to determine if the increased surface availability will benefit catalytic performance. This approach using an ionic liquid for deposition of metal particles onto semiconductor nanoparticles may enable greener synthetic approaches involving recycling the ionic liquid solvent, and the large liquid range of the ionic liquid also allows studying of photocatalysis over a broad range of temperatures.In conclusion, we have demonstrated that deposition of noble metal nanoparticles onto CdSe@CdS nanorods is possible using the ionic liquid [bmim][TfFile 1Synthetic procedures and raw data for methylene blue degradation experiments."}
+{"text": "Dear Editor,We all must have faced difficulty in inserting nasogastric tube (NGT) during general anesthesia (GA). Procedure seems to be very straightforward but has got consequences in terms of failure, which can cause bleeding and alteration in hemodynamic variables. The overall failure rate turned out to be around 50-60%."}
+{"text": "Human peripheral blood monocytes are isolated by flotation from a dense leukocyte-rich plasma (LRP) through two lower-density barriers prepared from OptiPrep\u2122. The separation from lymphocytes depends on the more rapid rate of flotation of the monocytes because of their slightly lower density and larger size. The method works optimally only with fresh (within 2 h of drawing) EDTA-anticoagulated blood."}
+{"text": "Prostate cancer (PCa) is the most frequently diagnosed among men malignant disease that remains poorly characterized at the molecular level. Advanced PCa is not curable, and the current treatment methods can only increase the life expectancy by several months. Identification of the genetic aberrations in tumor cells provides clues to understanding the mechanisms of PCa pathogenesis and the basis for developing new therapeutic approaches. Here we present data on somatic mutations, namely single nucleotide variations (SNVs), small insertions and deletions, detected in prostate tumor tissue obtained from Russian patients with PCa. Moreover, we provide a raw dataset on the whole exome and targeted DNA sequencing of tumor and non-tumor prostate tissue obtained from Russian patients with PCa and benign prostatic hyperplasia (BPH). This data is available at NCBI Sequence Read Archive under Accession No. PRJNA506922. DNA extracted from these samples was used to construct 61 whole exome and 25 targeted DNA libraries that were sequenced using Ion Proton platform. The corresponding raw sequencing data (reads in FASTQ format) was deposited at NCBI SRA database under project accession No. PRJNA506922.The data on whole exome sequencing of samples from PCa patients (50 matched samples from 25 patients) was analyzed to detect somatic mutations in prostate cancer tissue. Reads were mapped to the GRCh37 assembly of the human genome. Paired variant calling performed for matched samples allowed to filter germline mutations and detect somatic variants in tumor tissue. The information on identified somatic alterations is presented in VCF format in Moreover, variant annotation was performed using Variant Effect Predictor (VEP) which identifies genes and transcripts affected by genetic alterations and predicts their consequences on protein sequences .Fig.\u00a01SuIn addition, SIFT and PolyPhen algorithms were implemented to predict the effect of amino acid substitution caused by a variant on the structure and function of a protein . The VEP22.1All patients had signed an informed consent form. Tissue samples were obtained from 26 patients with PCa and 8 patients with BPH from City Clinical Hospital No. 50 via radical prostatectomy or TURP, respectively. All patients had not received specific therapy prior to sample collection. Clinical patient data including serum PSA level, Gleason grade, TNM clinical and pathological stage, extraprostatic extension, seminal vesicles and perineural invasion, surgical margins status is provided in 2.2Amplification of exonic regions was performed using Ion AmpliSeq Exome RDY Kit (Thermo Fisher Scientific). Considering the quality of FFPE-derived DNA the number of cycles in this amplification step was raised to 13\u201315 instead of 10 recommended by the manufacturer. Further steps of library preparation were carried out in accordance with the manufacturer's instructions.2.3GeneRead DNAseq Targeted Human Prostate Cancer Panel (Qiagen) was used for targeted enrichment of the extracted DNA. This amplification procedure was also modified as for exome libraries to account for DNA quality extracted from FFPE tissue samples. Number of PCR cycles was raised to 20\u201322 instead of 18 recommended for standard DNA samples. Subsequent library construction was performed using GeneRead Library Prep workflow (Qiagen) following the manufacturer's recommendations.2.4Quality of the constructed libraries was assessed by 2100 Bioanalyzer (Agilent Genomics) using Agilent High Sensitivity DNA Kit (Agilent Genomics). High-throughput sequencing was performed on Ion Proton platform using ION PI HI-Q Sequencing 200 Kit and Ion PI Chip Kit v2 (Thermo Fisher Scientific) following the recommendations of the manufacturer. Base calling was performed by Torrent Suite 5.0, fastqCreator v3.4.56313.2.5bwa mem tool from BWA package with the following non-default parameters: -c 250 -M 1)DP\u00a0>\u00a0102)QUAL >203)AF in normal sample <0.005 or AF in normal sample is at least three times less than AF in tumor sample.Reads were mapped to the human genome (GRCh37 assembly) with At least two callers should have called a mutation as a somatic to include it into the final somatic call set. The resulting lists of somatic variants were filtered according to the target regions of AmpliSeq Exome Kit provided by the manufacturer and off-target variants were excluded. The final sets for each individual were combined into a single multi-sample VCF file See . Variant"}
+{"text": "Several studies have demonstrated beneficial effects of views on aging (VoA) on health, while the reverse relationship is seldom in focus. Serious health events  are life-threatening and remind individuals of the finitude of life possibly changing their VoA. The present study investigates the effect of cardiovascular events (CVE) on longitudinal changes in VoA using pooled data of three waves of the German Ageing Survey . To account for alternative explanations, individuals without CVE were matched to the individuals with CVE (n = 202) using a propensity-score-matching approach. Individuals who experienced a CVE showed more adverse changes in three VoA indicators  than individuals without CVE. Results show that CVE can change how we view our own aging which in turn affects future health changes. Following a CVE people may benefit from promoting positive VoA."}
+{"text": "OBJECTIVES/SPECIFIC AIMS: The objective of this work is to determine the mechanistic consequences of BRCA1 mutants in inter-strand crosslink (ICL) repair. METHODS/STUDY POPULATION: Our lab uses Xenopus egg extracts to study ICL repair. These extracts can be depleted of endogenous BRCA1 by immunoprecipitation. The goal of this work is to rescue endogenous depletion with in vitro translated, wild type BRCA1. Once achieved, we can supplement the depleted extract with BRCA1 mutants to access their function in ICL repair. RESULTS/ANTICIPATED RESULTS: We hypothesize that the BRCT and RING domain mutations will abrogate ICL repair, while mutations in the coiled coil region will not affect repair. DISCUSSION/SIGNIFICANCE OF IMPACT: These findings will have an immense impact on the understanding of BRCA1 domains. Importantly these results will spur personalized therapy of BRCA1 mutants by showing which domains are sensitive to cross-linking agents."}
+{"text": "Providing care of older parents is a family obligation for children with Mexican cultural contexts . Nevertheless, little is known about how parents with Mexican cultural backgrounds believe about their family obligations. The current study conceptualized Mexican American older adults\u2019 sense of family obligation. Data was collected from 307 Mexican Americans  through an online survey. A 2-factor model: Expectation on children\u2019s caregiving (3-item) and Efforts to reduce children\u2019s burden (7-item) were identified as the best-fit model through EFA and CFA analyses . The component of efforts to reduce children\u2019s burden predicted participants\u2019 generativity assessed by the scale of McAdams and Aubin (1992). The findings suggest that Mexican American older adults expect their children to take care of them, as they feel obligated to reduce their children\u2019s caregiving burden. The function of the cultural value in intergenerational relations is discussed."}
+{"text": "Pseudoangiomatous stromal hyperplasia (PASH) is an uncommon benign proliferation of fibrous stroma, containing slitlike pseudovascular spaces lined by myofibroblasts. Less than 200 cases of PASH have been described in the English literature with the largest series including 40 cases. A 48-year-old woman with no particular past medical history, presented with a complaint of a slow, progressive, painless left breast mass. The patient underwent mammography which revealed a well delineated left breast nodule with microcalcifications classified BI-RADS 4. An excisional biopsy was performed on the mass to confirm the histological diagnosis. The specimen was a well-circumscribed whitish tumor measuring 3 x 3 cm with several microcysts (A). Histological examination revealed proliferation of fibrous stroma, with spindle cells and a network of slit-like empty clefts within acellular hyalinized stroma (B). The spindle cells were positive for CD34 and smooth muscle actin but were negative for Factor VIII. The final pathological diagnosis was nodular PASH. Postoperative course was uneventful and the patient is still being followed-up."}
+{"text": "This data article features supplementary figures and tables related to the article \u201cDifferential Multivariable risk prediction of appropriate shock vs. competing mortality \u2013 a prospective cohort study to estimate benefits from implantable cardioverter defibrillator therapy\u201d  [1]. The figures show the clinical study CONSORT graph  and the correlation scatter plot for risk scores of appropriate shock vs. mortality . The tables show the results for the univariate Cox regressions for prediction of mortality and appropriate shock. For further information, please see Bergau et al. (2018) [1]. The rationale, objectives and design of the study including statistical plan and sample size calculations have been published previously. In brief, the study enrolled a contemporary implantable cardioverter defibrillator cohort to test multiple carefully selected risk markers of clinical relevance for prediction of mortality and arrhythmias. The large majority of patients underwent non-invasive programmed ventricular stimulation via their implanted ICDs. Inducibility of sustained ventricular arrhythmia was defined as induction of a single monomorphic ventricular tachycardia lasting for 30 seconds or two polymorphic ventricular tachycardia/ventricular fibrillation episodes requiring cardioversion. A 24-h Holter monitoring was performed using standard devices. The primary endpoint was all-cause mortality. First appropriate implantable cardioverter defibrillator shock was selected as a key secondary endpoint. Cox regression analysis was implemented as described. Risk models for shock and mortality were developed using forward selection among a set of known potential risk factors  , Table 3"}
+{"text": "Advances in determining prion structure have been severely impeded by the difficulty in recovering relatively homogeneous prion particles from infected brain and definitively associating infectivity with the PrP assembly state. Recently, however, images of highly infectious ex vivo PrP rods that produce prion-strain specific disease phenotypes in mice have been obtained using cryo-electron microscopy and atomic force microscopy. These images have provided the most detailed description of ex vivo mammalian prions reported to date and have established that prions isolated from multiple strains have a common hierarchical structure. Misfolded PrP is assembled into 20 nm wide rods containing two fibers, each with double helical repeating substructure, separated by a characteristic central gap 8\u201310 nm in width. Irregularly structured material with adhesive properties distinct to that of the fibers is present within the central gap of the rod. Prions are clearly distinguishable from non-infectious recombinant PrP fibrils generated in vitro and from all other propagating protein structures so far described in other neurodegenerative diseases. The basic architecture of mammalian prions appears to be exceptional and fundamental to their lethal pathogenicity.Prions are lethal pathogens, which cause fatal neurodegenerative diseases in mammals. They are unique infectious agents and are composed of self-propagating multi-chain assemblies of misfolded host-encoded prion protein (PrP). Understanding prion structure is fundamental to understanding prion disease pathogenesis however to date, the high-resolution structure of authentic  Prion diseases are a closely related group of neurodegenerative conditions which affect both humans and animals. They include bovine spongiform encephalopathy (BSE) in cattle, scrapie in sheep and goats, chronic wasting disease (CWD) in deer and elk, and the human prion diseases, kuru, Creutzfeldt-Jakob disease (CJD), variant CJD (vCJD), fatal familial insomnia (FFI) and Gerstmann\u2013Str\u00e4ussler\u2013Scheinker disease  and Parkinson\u2019s disease where propagating assemblies of amyloid-\u03b2, tau and \u03b1-synuclein are being studied  with terms such as propagons and prionoids being proposed  is a highly conserved cell surface glycosylphosphatidylinositol (GPI)-anchored sialoglycoprotein with an ordered C-terminal domain containing three \u03b1-helices, a short anti-parallel \u03b2-sheet and a flexible disordered N-terminal domain . Such prototypical PrPSc comprises a small proportion of total disease-related PrP isoforms and while it is clearly an infectious structure its specific contribution to other aspects of disease pathogenesis remains unclear  may comprise the neurotoxic species, and that prototypical PrPSc and indeed prions per se may not themselves be highly neurotoxic  has been reported, specific-infectivities are generally too low for meaningful structural analysis  and that the morphology of the prion rods was incompatible with a uniform virus structure  formed by a double helical arrangement of two protofilaments , negative-stain electron tomography, cryo-EM and atomic force microscopy (AFM) have recently revealed a common three-dimensional architecture  cannot be applied with any certainty to the PrP rods  their basic architecture can now be compared with fibrillar assemblies of other proteins that propagate in other neurodegenerative diseases . Based uPrion-infected transgenic mice expressing mutant GPI-anchorless PrP replicate authentic prions (that are transmissible to wild-type mice) but they also develop intense PrP amyloid plaques in their brain which are not seen in the brain of prion-infected wild-type mice  would be expected to be capable of co-propagating both authentic prions (infectious PrP rods) and alternative transmissible PrP amyloid assemblies, patients with different PRNP stop mutations which produce C-terminally truncated PrP devoid of N-linked glycans (for example Y163X; Mead et al., Importantly, such co-propagation of infectious paired-fiber PrP rods and distinct single-fiber amyloid PrP assemblies may also be occurring in some inherited prion diseases in particular in patients with GSS disease phenotypes in which amyloid plaques are a prominent neuropathological feature (see Terry et al., Prion-infected brain contains multiple disease-related PrP assemblies. Infectious PrP rods comprise authentic prions that generate a lethal transmissible spongiform encephalopathy when inoculated into a susceptible host. Neurotoxicity accompanying the propagation of authentic prions is thought to involve the generation of a distinct toxic PrP species whose steady-state level may determine the rate of neurodegeneration. In some inherited prion diseases transmissible PrP amyloids only may be generated while in others transmissible PrP amyloids may variably co-propagate with authentic prions and act as a major modifier of clinicopathological phenotype. Studying the transmission properties of synthetic prion preparations is complex and experiments should be carefully designed and interpreted in order to differentiate between the generation of authentic lethal prions and transmissible PrP amyloids. At present, propagating fibrillar assemblies of proteins in other neurodegenerative diseases appear to have biological and structural properties that are more closely aligned with transmissible PrP amyloids rather than authentic lethal prions.CT and JW wrote the article.JW is a shareholder of D-Gen Limited, an academic spin-out company working in the field of prion disease diagnosis, decontamination, and therapeutics. The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "The present study considers how race combines with chronological age to shape kidney function among older adults. We analyzed cross-sectional data from a nationally representative study of older adults. Our measure of kidney function derived from the cystatin C-based estimated glomerular filtration rate. We use a pattern variable to divide White and Black respondents into four groups based on their age group membership: early midlife (age 52\u201359), late midlife (age 60\u201369), young old (age 70\u201379), and oldest old (80s+ years). Results from our ordinary least squares models reveal that Blacks and Whites in late midlife, young old, and oldest old exhibited poorer kidney function than Whites in early midlife. Our study uncovers evidence of race by age disparities in kidney function among older adults. Future longitudinal studies will provide further insight into how and why race combines with age to pattern kidney function over time."}
+{"text": "A 74-year-old female presented with a 6-month history of easy bruising as manifested by purpura after minor trauma to her face. Her physical examination was unremarkable except for the presence of pinch purpura scattered on her face . LaboratCutaneous manifestations are reported in 30%-40% of AL amyloidosis cases . The les"}
+{"text": "Twenty seven years old lady presented to the emergency department accompanied by family members with complaint of fluctuating consciousness and fever for the past three days. Upon further questioning the patient has been complaining of headache for two months, decreased appetite for the past month and had a travel history to Ethiopia five months ago. Family members were not sure about any history of weight loss, the patient took a one week course of antibiotics for tooth infection two weeks ago. Physical examination showed an ill looking, vitally stable lady on chest auscultation diffuse crackles heard bilaterally. Septic work up including CSF sample was ordered to rule-out meningitis chest X-ray was also ordered. Chest X-ray result showed a clinical image specious of miliary TB (A) and results were confirmed by a positive acid fast stain of the CSF. Patient was taken to isolation and proper management was started with a final diagnosis of TB meningitis. A follow-up MRI showed few hyper-intense foci in deep white matter of left frontal lobe (B)."}
+{"text": "Praziquantel represents the frontline chemotherapy used to treat schistosomiasis, a neglected tropical disease (NTD) caused by infection with macro-parasitic blood fluke schistosomes. While this drug is safe, its inability to kill all schistosome lifecycle stages within the human host often requires repeat treatments. This limitation, amongst others, has led to the search for novel anti-schistosome replacement or combinatorial chemotherapies. Here, we describe a repositioning strategy to assess the anthelmintic activity of epigenetic probes/inhibitors obtained from the Structural Genomics Consortium.Schistosoma mansoni schistosomula using the high-throughput Roboworm platform. At 10 \u03bcM, 14 of these 37 compounds (38%) negatively affected schistosomula motility and phenotype after 72 hours of continuous co-incubation. Subsequent dose-response titrations against schistosomula and adult worms revealed epigenetic probes targeting one reader (NVS-CECR2-1), one writer (LLY-507 and BAY-598) and one eraser (GSK-J4) to be particularly active. As LLY-507/BAY-598 (SMYD2 histone methyltransferase inhibitors) and GSK-J4 (a JMJD3 histone demethylase inhibitor) regulate an epigenetic process (protein methylation) known to be critical for schistosome development, further characterisation of these compounds/putative targets was performed. RNA interference (RNAi) of one putative LLY-507/BAY-598 S. mansoni target (Smp_000700) in adult worms replicated the compound-mediated motility and egg production defects. Furthermore, H3K36me2, a known product catalysed by SMYD2 activity, was also reduced by LLY-507 (25%), BAY-598 (23%) and siSmp_000700 (15%) treatment of adult worms. Oviposition and packaging of vitelline cells into in vitro laid eggs was also significantly affected by GSK-J4 (putative cell permeable prodrug inhibitor of Smp_034000), but not by the related structural analogue GSK-J1 (cell impermeable inhibitor).Thirty-seven epigenetic probes/inhibitors targeting histone readers, writers and erasers were initially screened against Collectively, these results provide further support for the development of next-generation drugs targeting schistosome epigenetic pathway components. In particular, the progression of histone methylation/demethylation modulators presents a tractable strategy for anti-schistosomal control. Schistosoma mansoni epigenetic processes, we performed anthelmintic screening of 37 epigenetic probes/epigenetic inhibitors obtained from the Structural Genomics Consortium (SGC). The results of these studies highlighted that schistosome protein methylation/demethylation processes are acutely vulnerable. In particular, compounds affecting schistosome SMYD  or JMJD (GSK-J4) homologues are especially active on schistosomula and adult worms during in vitro phenotypic drug screens. The active epigenetic probes identified here as well as their corresponding S. mansoni protein targets offers new starting points for the development of next-generation anti-schistosomals.Human schistosomiasis is caused by infection with parasitic blood fluke worms. Global control of this NTD is currently facilitated by administration of a single drug, praziquantel (PZQ). This mono-chemotherapeutic strategy of schistosomiasis control presents challenges as PZQ is not active against all human-dwelling schistosome lifecycle stages and the evolution of PZQ resistant parasites remains a threat. Therefore, new drugs to be used in combination with or in replacement of PZQ are urgently needed. Here, continuing our studies on  Amongst human infectious diseases caused by macro-parasitic organisms, schistosomiasis is the most significant in terms of its negative impact on both individual health and population-driven socio-economic outputs \u20133. The cOne recent approach applied to schistosome drug discovery is based on the concept of compound repositioning or repurposing, where new indications for existing drugs are sought . Two benS. mansoni) of thirty-four SGC-supplied EPs  and three EIs (compounds that do not display these specific epigenetic probe traits)  authors used such a small incubation time (20h) with cytotoxicity assays on the human cell line for calculating selectivity indexes. It's an issue since parasite assays were all performed with 72h incubation time. The authors should generate new data with 72h incubation or make a strong case justifying their choice for 20h since keeping the later should overestimated the selectivity/safety of compounds\"Reviewer's Responses to QuestionsKey Review Criteria Required for Acceptance?As you describe the new analyses required for acceptance, please consider the following:Methods-Are the objectives of the study clearly articulated with a clear testable hypothesis stated?-Is the study design appropriate to address the stated objectives?-Is the population clearly described and appropriate for the hypothesis being tested?-Is the sample size sufficient to ensure adequate power to address the hypothesis being tested?-Were correct statistical analysis used to support conclusions?-Are there concerns about ethical or regulatory requirements being met?Reviewer #1: -Are the objectives of the study clearly articulated with a clear testable hypothesis stated?Yes-Is the study design appropriate to address the stated objectives?Yes-Is the population clearly described and appropriate for the hypothesis being tested?NA-Is the sample size sufficient to ensure adequate power to address the hypothesis being tested?NA-Were correct statistical analysis used to support conclusions?Yes-Are there concerns about ethical or regulatory requirements being met?NAReviewer #2: Several minor details in the methods text could be clarified. - Line 149. What strain of Mus musculus?- Line 188. Schistosomules were cultured with compound at 37 degrees \u2013 were they also imaged at 37 or at room temperature?- Line 189. Reference 50  is mentioned regarding phenotype and motility. However, some details on this package could be clarified. Is this package publically available? What was the rational for the hit thresholds (dotted line figure 1A and 1B)?- For RNAi, what concetration of siRNA duplexes were used?- Line 263. How many worms sample input are used in this assay?Reviewer #3: Methods are appropriate for the study--------------------Results-Does the analysis presented match the analysis plan?-Are the results clearly and completely presented?-Are the figures  of sufficient quality for clarity?Reviewer #1: -Does the analysis presented match the analysis plan?Yes-Are the results clearly and completely presented?Mostly.-Are the figures  of sufficient quality for clarity?Yes.Reviewer #2: The results are clearly presented. As mentioned above in the methods, a description of the hit threshold scores shown in Figure 1A and 1B could be elaborated upon. Either on the legend, or in the text around line 361-364 when these cutoffs are mentioned.For table 2, add in either the table or the legend a description of the assay used to generate the IC50 data for adult males and females. Also, in the text around line 409 where these results are discussed.The structures of the chemicals shown in table 2 should be included. It may not be convenient to include them in the actual table 2, but perhaps a supplemental table or in text form . While this is not essential, I am interested in whether pharmacological or genetic inhibition of histone methylation effects mitotic activity of somatic neoblasts or germ tissues ? Is this the mechanism by which egg laying is arrested?Reviewer #3: Results match the analysis plan.--------------------Conclusions-Are the conclusions supported by the data presented?-Are the limitations of analysis clearly described?-Do the authors discuss how these data can be helpful to advance our understanding of the topic under study?-Is public health relevance addressed?Reviewer #1: -Are the conclusions supported by the data presented?Generally, yes.-Are the limitations of analysis clearly described?Mostly.-Do the authors discuss how these data can be helpful to advance our understanding of the topic under study?Yes.-Is public health relevance addressed?Yes.Reviewer #2: The conclusions are well supported by the data. Some discussion could elaborate the repurposing of epigenetic probes / inhibitor compounds. As mentioned in the introduction, praziquantel is not effective against juvenile life stages . Granted, ex vivo assays on these worms are more challenging \u2013 but is anything known about the expression of targets such as Smp_007000 across the schistosome life cycle? Given the effects on egg laying, it would be interesting whether these are differentially expressed in males and females or in the gonads (PMID: 27499125).Reviewer #3: Conclusions are appropriate.--------------------Editorial and Data Presentation Modifications?Use this section for editorial suggestions as well as relatively minor modifications of existing data that would enhance clarity. If the only modifications needed are minor and/or editorial, you may wish to recommend \u201cMinor Revision\u201d or \u201cAccept\u201d. Reviewer #1: (No Response)Reviewer #2: (No Response)Reviewer #3: minor revision--------------------Summary and General CommentsUse this section to provide overall comments, discuss strengths/weaknesses of the study, novelty, significance, general execution and scholarship. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. If requesting major revision, please articulate the new experiments that are needed.Reviewer #1: The authors describe the anti-schistosomal activities of compounds that are known modulators/inhibitors of human molecular targets involved in epigenetic processes. The deck of 37 compounds was obtained from the Structural Genomics Consortium and tested against schistosomula and adult schistosome lifecycle stages. The study combines several approaches to support/validate the main hits from the initial screenings: in silico modelling, RNAi-mediated functional genomics, enzyme assays and confocal microscopy. This is an important work with interesting findings to schistosomal drug discovery targeting epigenetic processes. Hence, it should be highly appreciated by the journal readership. I list below several minor points to be corrected but the only major point to be addressed is why authors used such a small incubation time (20h) with cytotoxicity assays on the human cell line for calculating selectivity indexes. It's an issue since parasite assays were all performed with 72h incubation time. The authors should generate new data with 72h incubation or make a strong case justifying their choice for 20h since keeping the later should overestimated the selectivity/safety of compounds.Minor points:- Methods:1- Compound acquisition, storage and handling: Please indicate where appropriate that compounds structures can be found at Table S12- Homology modelling and epi-drug docking: 2a - Provide  evidence for model validation and quality, having special attention to any issues involved in the proposed docking site.2b - Are all the EP/Eis know to be competitive with the substrates? if so, authors should state it earlier.- Results:Lines 311-313: Kd, Ki or IC50? the term potency may be misleading since it's usually expressed as an inverse proportional term. Then, higher potency may actually mean < 100nm.=\"\" lines=\"\" _348-3493a_=\"\" figure=\"\" 1=\"\" _legend3a_=\"\" please=\"\" indicate=\"\" if=\"\" dashes=\"\" crossing=\"\" vertical=\"\" connecting=\"\" each=\"\" replicate=\"\" mean=\"\" averages=\"\" or=\"\" medians.=\"\" line=\"\" _3853a_=\"\" _please2c_=\"\" complement=\"\" s1=\"\" by=\"\" including=\"\" chemical=\"\" structures=\"\" for=\"\" the=\"\" compounds.=\"\" _386-3873a_=\"\" authors=\"\" contend=\"\" fact=\"\" that=\"\" none=\"\" of=\"\" 386=\"\" these=\"\" chemotype=\"\" controls=\"\" demonstrated=\"\" anti-schistosomula=\"\" activity=\"\" suggests=\"\" specificity=\"\" hits=\"\" s.=\"\" mansoni=\"\" homologue=\"\" is=\"\" similar=\"\" to=\"\" found=\"\" original=\"\" human=\"\" target=\"\" but=\"\" other=\"\" interpretation=\"\" would=\"\" be=\"\" they=\"\" lack=\"\" proper=\"\" sar=\"\" targets.=\"\" it=\"\" should=\"\" discussed.=\"\" table=\"\" _23a_=\"\" all=\"\" ec50=\"\" and=\"\" cc50=\"\" accompanied=\"\" standard=\"\" errors=\"\" _9525_=\"\" confidence=\"\" intervals.=\"\" also=\"\" incubation=\"\" time=\"\" below=\"\" headings.=\"\" in=\"\" _footnote2c_=\"\" define=\"\" _22_accurate22_.=\"\" _413-4153a_=\"\" are=\"\" there=\"\" any=\"\" discussed=\"\" compounds=\"\" lly-507=\"\" _bay-5983f_=\"\" _4443a_=\"\" _22_strong22_=\"\" _22_close22_=\"\" _463-4783a_=\"\" make=\"\" their=\"\" conclusions=\"\" lighter=\"\" using=\"\" expressions=\"\" like=\"\" _22_is=\"\" predicted=\"\" _bind...22_=\"\" _22_predicted=\"\" interaction=\"\" may=\"\" _prevent...22_=\"\" _5233a_=\"\" clarify=\"\" why=\"\" gsk-j4=\"\" a=\"\" prodrug.=\"\" how=\"\" drug=\"\" _processed3f_=\"\" _typos3a_=\"\" _713a_=\"\" theat=\"\" threat=\"\" _1273a_=\"\" _22_cultured=\"\" _this22_=\"\" with=\"\" _4523a_=\"\" _22_ceb2_=\"\" _stands22_=\"\" _strands22_=\"\" reviewer=\"\" _23_23a_=\"\" this=\"\" study=\"\" screened=\"\" panel=\"\" known=\"\" epigenetic=\"\" against=\"\" schistosomules=\"\" then=\"\" proceeded=\"\" active=\"\" more=\"\" detail=\"\" on=\"\" adult=\"\" parasites=\"\" _e28093_=\"\" profiling=\"\" phenotypic=\"\" outcomes=\"\" such=\"\" as=\"\" motility=\"\" egg=\"\" _laying2c_=\"\" well=\"\" assaying=\"\" histone=\"\" methylation.=\"\" pharmacological=\"\" experiments=\"\" were=\"\" controlled=\"\" negative=\"\" further=\"\" validated=\"\" rnai=\"\" data=\"\" showing=\"\" knockdown=\"\" putative=\"\" methyltransferase=\"\" phenocopies=\"\" treatment.=\"\" convincing=\"\" controlled.=\"\" laying=\"\" phenotype=\"\" particular=\"\" _promising2c_=\"\" since=\"\" pathology=\"\" associated=\"\" disease=\"\" driven=\"\" parasite=\"\" eggs.=\"\" several=\"\" suggestions=\"\" clarification=\"\" methods=\"\" results=\"\" have=\"\" been=\"\" outlined.=\"\" _23_33a_=\"\" manuscript=\"\" written=\"\" will=\"\" interest=\"\" pntd=\"\" readers.=\"\" minor=\"\" revisions=\"\" suggested.=\"\" abstract=\"\" author=\"\" summary=\"\" _numerous2c_=\"\" undefined=\"\" abbreviations.=\"\" distracting=\"\" _confusing3a_=\"\" _482c_=\"\" _532c_=\"\" 76.=\"\" _general2c_=\"\" has=\"\" large=\"\" number=\"\" _abbreviations2c_=\"\" making=\"\" tedious=\"\" _read2c_=\"\" do=\"\" not=\"\" addressed.=\"\" 54=\"\" _1525_=\"\" something=\"\" indicated.=\"\" define.=\"\" at=\"\" places=\"\" _e2809c_cell=\"\" permeable=\"\" _prodruge2809d_=\"\" described.=\"\" _however2c_=\"\" _e2809c_worm=\"\" _permeablee2809d_=\"\" another=\"\" matter=\"\" general=\"\" poorly=\"\" understood.=\"\" from=\"\" overstated=\"\" absence=\"\" direct=\"\" enzymatic=\"\" evidence=\"\" inhibition.=\"\" was=\"\" done=\"\" indirectly=\"\" h3k36me2=\"\" levels=\"\" _studies2c_=\"\" which=\"\" better=\"\" support=\"\" inhibitor=\"\" _link2f_mechanism=\"\" action.=\"\" 311=\"\" 313=\"\" /> signs should be reversed.A general comment: the reality of therapy for schistosomiasis is that compounds need to be active after a single dose, where active means worm killing. Blocking motility or egg production after extended exposure to a compound will not be adequate for novel therapies. Did the compounds tested actually _kill_ the worms?--------------------PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.If you choose \u201cno\u201d, your identity will remain anonymous but your review may still be made public.Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.Reviewer #1: Yes: Floriano Paes Silva-JrReviewer #2: NoReviewer #3: No 28 Oct 2019AttachmentResponse to reviewers_Whatley and Padalino.docxSubmitted filename: Click here for additional data file. 30 Oct 2019Dear Prof. Hoffmann,We are pleased to inform you that your manuscript, \"The repositioning of epigenetic probes/inhibitors identifies new anti-schistosomal lead compounds and chemotherapeutic targets\", has been editorially accepted for publication at PLOS Neglected Tropical Diseases.Before your manuscript can be formally accepted and sent to production you will need to complete our formatting changes, which you will receive in a follow up email. Please note: your manuscript will not be scheduled for publication until you have made the required changes.IMPORTANT NOTES* Copyediting and Author Proofs: To ensure prompt publication, your manuscript will NOT be subject to detailed copyediting and you will NOT receive a typeset proof for review. The corresponding author will have one final opportunity to correct any errors when sent the requests mentioned above. Please review this version of your manuscript for any errors.plosntds@plos.org. If you need to know your paper's publication date for media purposes, you must coordinate with our press team, and your manuscript will remain under a strict press embargo until the publication date and time. PLOS NTDs may choose to issue a press release for your article. If there is anything that the journal should know, please get in touch.* If you or your institution will be preparing press materials for this manuscript, please inform our press team in advance at http://www.editorialmanager.com/pntd, log in, and click on the \"Update My Information\" link at the top of the page. Please update your user information to ensure an efficient production and billing process.*Now that your manuscript has been provisionally accepted, please log into EM and update your profile. Go to http://www.plosntds.org/static/latexGuidelines.action] in the meantime.*Note to LaTeX users only - Our staff will ask you to upload a TEX file in addition to the PDF before the paper can be sent to typesetting, so please carefully review our Latex Guidelines [Thank you again for supporting open-access publishing; we are looking forward to publishing your work in PLOS Neglected Tropical Diseases.Best regards,Philip T. LoVerdeGuest EditorPLOS Neglected Tropical DiseasesJennifer KeiserDeputy EditorPLOS Neglected Tropical Diseases***********************************************************The authors have satisfactorily addressed the concerns of the reviewers. 7 Nov 2019Dear Prof. Hoffmann,We are delighted to inform you that your manuscript, \"The repositioning of epigenetic probes/inhibitors identifies new anti-schistosomal lead compounds and chemotherapeutic targets,\" has been formally accepted for publication in PLOS Neglected Tropical Diseases.We have now passed your article onto the PLOS Production Department who will complete the rest of the publication process. All authors will receive a confirmation email upon publication.The corresponding author will soon be receiving a typeset proof for review, to ensure errors have not been introduced during production. Please review the PDF proof of your manuscript carefully, as this is the last chance to correct any scientific or type-setting errors. Please note that major changes, or those which affect the scientific understanding of the work, will likely cause delays to the publication date of your manuscript. Note: Proofs for Front Matter articles  are generated on a different schedule and may not be made available as quickly.Soon after your final files are uploaded, the early version of your manuscript will be published online unless you opted out of this process. The date of the early version will be your article's publication date. The final article will be published to the same URL, and all versions of the paper will be accessible to readers.Thank you again for supporting open-access publishing; we are looking forward to publishing your work in PLOS Neglected Tropical Diseases. Best regards,Serap AksoyEditor-in-ChiefPLOS Neglected Tropical DiseasesShaden KamhawiEditor-in-ChiefPLOS Neglected Tropical Diseases"}
+{"text": "Coronary artery aneurysm is a rare condition which constitutes a small proportion of coronary artery disease. Such condition mimicking an intra-cardiac mass is extremely rare and poorly understood.We present an unusual case of a 53-year-old female with decreased exercise tolerance and lower extremity edema for 3\u2009months. The echocardiography showed moderate tricuspid regurgitation and a right intra-ventricular mass below the tricuspid valve. No ventricular wall akinesia or ST segment change was found on echocardiography or electrocardiogram. Coronary computed tomographic angiography confirmed the diagnosis of intra-ventricular mass with feeding vessel originated from the right coronary artery. The patient was scheduled for tumor resection, and the mass turned out to be a thrombosed giant right coronary artery aneurysm. The patient received successful aneurysm resection and had an uneventful postoperative recovery. Unfortunately, a fistula between right coronary artery and right ventricle was detected on follow-up three months later by echocardiography.Coronary artery aneurysms presenting as intra-cardiac masses are extremely rare. Comprehensive preoperative evaluation is highly recommended because the surgical strategies for tumor and aneurysm are completely different. Aneurysm resection with bypass surgery is preferred rather than aneurysm repair. To our best knowledge, coronary artery aneurysms presenting as intra-ventricular masses have seldom been reported. Coronary artery aneurysm is a rare condition of coronary artery disease. It is defined as segmental coronary dilatation that exceeds the diameter of normal adjacent artery or the diameter of the largest artery by 1.5 times , with co9/L) and percentage (14.4%). Tumor markers were negative for malignancy. The transthoracic echocardiography (TTE) showed a cystic mass (3.5\u2009\u00d7\u20092.7\u2009cm) with hyperechoic external capsule locating below the tricuspid annulus  are of great necessity and importance for differential diagnosis between aneurysm and tumor. MRI is the most sensitive modality for characterizing the tumor tissue due to its excellent soft tissue contrast and variable manipulable parameters. In addition, coronary angiography is valuable to confirm diagnosis of coronary artery aneurysm and myocardial infarction, which is helpful for the surgical strategy.The management of coronary artery aneurysm includes medical intervention, stent insertion and surgical resection . IncidenWe experienced a rare case with a giant right coronary artery aneurysm mimicking a right intra-ventricular mass. MRI and coronary angiography are of great importance and value for preoperative diagnosis. We emphasize the necessity of comprehensive evaluation and accurate diagnosis before further treatment. For symptomatic patients with giant coronary artery aneurysms, aneurysm resection with bypass surgery is highly recommended."}
+{"text": "The regulation of ubiquitination status in the cell is controlled by ubiquitin ligases acting in tandem with deubiquitinating enzymes. Ubiquitination controls many key processes in the cell from division to death making its tight regulation key to optimal cell function. Activity based protein profiling has emerged as a powerful technique to study these important enzymes. With around 100 deubiquitinating enzymes and 600 ubiquitin ligases in the human genome targeting a subclass of these enzymes or even a single enzyme is a compelling strategy to unpick this complex system. In this review we will discuss different approaches adopted, including activity-based probes centered around ubiquitin-protein, ubiquitin-peptide and mutated ubiquitin scaffolds. We examine challenges faced and opportunities presented to increase specificity in activity-based protein profiling of the ubiquitin conjugation/deconjugation machinery. Also, the presence of a native isopeptide bond in the scissile position may affect probe stability in complex systems.A further example of this probe type was developed by the Chatrerjee laboratory in 2016 using a selenocystine ligation  to sequentially functionalize thiols at a single carbon center for profiling E1 enzyme activity (Stanley et al., 73-thioester was reacted with azidoaminoethane to afford Ub-azide. Alkyne functionalized acrylate and acrylamide were used to prepare two TDAE functionalized ubiquitin monomers. A single cysteine mutant of His-UBE2L3 was reacted with the monomers to form the E2-Ub conjugate probes (Elaborated TDAE probes aimed to specifically target the E3 ligase Parkin by incorporating ubiquitin into the probe (Pao et al., e probes . The trie probes  later sh75-NH2NH2 using native chemical ligation followed by Dha formation. The probes were tested against catalytic domains of NEDD4 and UBE3C, labeling both active sites. Probing HeLa cells saw enrichment of several E3 enzymes, with strong enrichment of NEDD4. This work demonstrates an alternative route to E2-Ub probes however the linker is three atoms longer than the native and the electrophilic trap is presented two and five atoms away from Ub and UBE2D2, respectively.Shi and co-workers (Xu et al., Several approaches have been taken to confer selectivity to activity-based probes for ubiquitin conjugation/deconjugation machinery . MutatioCertain conjugate probes are limited due to their hydrolysable linkers and despite several well-designed solutions, many of the probes also do not perfectly mimic the linker length or trap position of the wild-type substrate. There is therefore scope for optimisation of the probe design and implementation of new chemistry for the synthesis of novel probes. Furthermore, these probes are currently limited by their lack of cell permeability. Recent work demonstrated that incorporation of cleavable cell-penetrating peptides can help deliver monoubiquitin probes into a cell (Gui et al., JM and NT drafted and edited the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Posterior reversible encephalopathy syndrome (PRES) is a rare neurological disorder usually associated with specific medical conditions that cause a disturbance of the CNS homeostasis. It has seldom been reported to be a consequence of an iatrogenic intervention causing intracranial hypotension.We report the case of an individual 69-year-old male presenting with headache and blurred vision following cerebrospinal fluid (CSF) leak from resection of a sellar mass. The patient developed the condition following removal of the lumbar drain post-operatively. Magnetic Resonance Imaging showed bilateral occipital, parieto-occipital, and cerebellar T2 FLAIR hyper-intensities, suggesting a radiological diagnosis of posterior reversible encephalopathy syndrome (PRES). The patient\u2019s symptoms started to improve shortly afterwards and had completely resolved at 3\u2009months follow-up.The absence of severe hypertension and presence of an intraoperative CSF leak requiring placement of the lumbar drain suggests that decreased CSF volume and associated reactive hyperemia could have a role in the pathophysiology of the disease. Posterior reversible encephalopathy syndrome (PRES) originally described by Hinchey includes neurological abnormalities and associated characteristic findings on neuroimaging . PRES isOur patient is a 69-year-old Caucasian male with known hypertension, hyperlipidemia, gout and sialolithiasis presenting for endoscopic endonasal resection of a recurrent intra/suprasellar mass with cavernous sinus extension with pathological specimen consistent with Rathke\u2019s cleft cyst. Cerebrospinal fluid (CSF) leak occurred intra-operatively requiring placement of a lumbar drain at a rate of 10\u2009cc/h. CSF pressure was not elevated during the initial placement. Drainage continued intermittently at the same rate for 48\u2009h. The drain was then clamped for 24\u2009h prior to removal on post-operative day three without adverse event. The patient did not complain of any headaches following the surgical intervention but developed a severe positional headache associated with nausea, vomiting, and significantly blurred vision. The headaches were worsened upon sitting upright and partially relieved in the recumbent position. The ophthalmological examination demonstrated decreased visual acuity at 20/30 bilaterally. The optic disc retained spontaneous venous pulsations, suggestive of low or normal intracranial pressure.CT of the head revealed subcortical hypodensities at the posterior tip of the occipital lobes bilaterally. MRI demonstrated patchy areas of T2 and T2 FLAIR hyper-intensity in the bilateral posterior occipital lobes as well as the bilateral parieto-occipital junction and posterior cerebellum Fig.\u00a0.Fig. 1AThe patient\u2019s systolic blood pressure is charted in Fig.\u00a0Posterior reversible encephalopathy syndrome is a rare disorder, and its mechanism remains controversial. It has been previously described occurring following lumbar CSF drainage \u201310. One Another potential mechanism of action of PRES involves endothelial dysfunction leading to an increase in membrane permeability and vasogenic edema as seen on imaging , 15. EveRecently, intracranial hypotension has also been associated with PRES . DemonstPRES is a potential consideration in post-operative patients with CSF leak with sudden neurological changes, specifically deficits in vision or seizures. The mechanism of PRES remains controversial and further investigations should be conducted whenever it does occur to advance our understanding of its etiology."}
+{"text": "Pseudomonas syringae (Ps) are recognized as the most damaging factors in fruit trees with a significant economic and sanitary impact on crops. Among them, bacterial canker of apricot is exceedingly difficult to control due to a lack of efficient prophylactic measures. Several sources of partial resistance have been identified among genetic resources but the underlying genetic pattern has not been elucidated thus far. In this study, we phenotyped bacterial canker susceptibility in an apricot core-collection of 73 accessions over 4\u2009years by measuring canker and superficial browning lengths issued from artificial inoculations in the orchard.Diseases caused by G) and genetic x year (G\u2009\u00d7\u2009Y) interaction effects extracted from linear mixed models.In order to investigate the genetic architecture of partial resistance, we performed a genome-wide association study using best linear unbiased predictors on genetic  between these two markers revealing an inter-chromosomal LD block linking the two underlying genes. This result supports the hypothesis of a co-adaptation effect due to selection through population demography. Candidate genes annotations suggest a functional pathway involving abscisic acid, a hormone mainly known for mediating abiotic stress responses but also reported as a potential factor in plant-pathogen interactions.We detected 11 significant associations over 7 candidate loci linked to disease resistance under the two most severe years. Colocalizations between Rosaceae species. It provided tools for fruit tree breeding by identifying progenitors with favorable haplotypes and by providing major-effect markers for a marker-assisted selection strategy.Our study contributed to the first detailed characterization of the genetic determinants of partial resistance to bacterial canker in a The online version of this article (10.1186/s12870-019-1631-3) contains supplementary material, which is available to authorized users. For decades, breeding programs have notably focused on the introgression of major resistant genes into crop cultivars. However multiple episodes of resistance breakdown have led research efforts to target polygenic  resistances . AlthougPrunus genus, apricot (Prunus armeniaca L.) is one of the most popular and typical crops of the Mediterranean Basin which provides 49% of the total production to the world market _[physical position in bp]. (XLSX 17724 kb)"}
+{"text": "Exploring virus\u2013host interactions is key to understand mechanisms regulating the viral replicative cycle and any pathological outcomes associated with infection. Whereas interactions at the protein level are well explored, RNA interactions are less so. Novel sequencing methodologies have helped uncover the importance of RNA\u2013protein and RNA\u2013RNA interactions during infection. In addition to messenger RNAs (mRNAs), mammalian cells express a great number of regulatory non-coding RNAs, some of which are crucial for regulation of the immune system whereas others are utilized by viruses. It is thus becoming increasingly clear that RNA interactions play important roles for both sides in the arms race between virus and host. With the emerging field of RNA therapeutics, such interactions are promising antiviral targets. In this review, we discuss direct and indirect RNA interactions occurring between RNA viruses or retroviruses and host non-coding transcripts upon infection. In addition, we review RNA virus derived non-coding RNAs affecting immunological and metabolic pathways of the host cell typically to provide an advantage to the virus. The relatively few known examples of virus\u2013host RNA interactions suggest that many more await discovery. Viruses are likely the most abundant biological entity and the known global virosphere is greatly expanding ,2. ViralHerpesviridae) or single-stranded  genomes; RNA viruses have double-stranded , or single-stranded positive sense  or negative sense  genomes, where orientation is defined for coding mRNA sequence to be of positive polarity. In addition, Hepadnaviridae are DNA viruses with RNA intermediates, and Retroviridae are (+)RNA viruses with DNA intermediates . U. U87]. U365 . . 164]. ICulex pipiens accumulate in midgut cells and display RNAi suppressor activity by counteracting Dicer. This process modulates transmission of the virus to the salivary glands and thereby its transmission to the next host [-/--IRF7-/- or IFNAR-/- mice with sfRNA defective WNV strains demonstrated that sfRNA production is critical to sustain infection in animals with intact interferon response [The biological functions of sfRNAs vary between organisms infected B. WNV deext host ,173. In ext host ,167,174.ext host . In addiresponse . An alteWhereas viral lncRNAs are well described for large DNA viruses like the PAN RNA expressed by Kaposi\u2019s sarcoma-associated herpesvirus (KSHV) , lncRNAsIn recent years, there has been an increasing interest in developing tools to systematically dissect the biological significance of RNA interactions governing cellular processes as well as pathogen\u2013host interactions. These novel methodologies are expanding our knowledge on gene expression regulation mediated by ncRNAs. It is also becoming clear that such mechanisms play central roles in the regulation of the cellular response to viral infection. Direct binding to cellular ncRNAs is further exploited by RNA viruses to their own advantage, and this could provide new modalities for therapy. Thus, virus\u2013host RNA interactions are becoming a novel focus area to fully understand the complexity of the virus life cycle, but more systematic investigation is required. The role of cellular and viral-derived small RNA is further along compared to lncRNAs and other RNA species. Despite such progress, much remains to be investigated to understand which virus\u2013host RNA interactions are the result of the cell attempting to clear the infection and which represent a viral strategy to create a favorable host cell environment. Lastly, the often narrow focus on pathogenic viral species suggests that a broader investigation of the RNA virosphere will reveal exciting discoveries in this emerging field.Unanswered questionsAre there undiscovered cases of RNA viruses benefiting from miRNA-mediated repression of replication in certain tissues?What undiscovered examples of direct viral RNA-miRNA interactions exist and what are their functions?Does virus-mediated RNA sequestration have functional consequences for pathology or immune responses?Is miRNA manipulation, even for direct use in genome replication, a feature of persistent viruses?Does non-coding RNA in post-transcriptional regulation play unappreciated roles during chronic infection?What other types of cellular RNA interact directly with viral RNA?Do other mammalian RNA viruses accumulate functional non-coding RNA species akin to sfRNAs?"}
+{"text": "SF3B1) and two splicing regulators bound to 3\u2019 splice sites (U2AF1) or exonic splicing enhancers (SRSF2) are particularly prevalent and mutually exclusive [Recent genomic characterization of cancers has revealed recurrent somatic mutations in genes encoding RNA splicing factors. As many as 119 splicing factors were implicated in a recent pan-cancer analysis [e sites UAF1 or exe sites UAF1 or exGrowing evidence suggests that defective RNA processing can induce accumulation of R-loops, transcription intermediates consisting of RNA:DNA hybrids and displaced single-stranded DNA (ssDNA) . We prevIt is not yet known how the increase of R-loops impacts the cancer genome. R-loops are known to interfere with DNA replication and induce replication stress . FurtherU2AF1 mutations [Emerging evidence has also suggested that the normal function of ATR may be altered in cells with spliceosome mutations. First, alternatively spliced ATR transcripts were found in AML patients harboring utations . An indeutations . Interesutations . How theBased on these pre-clinical findings, we recently initiated a single-arm phase Ib trial to assess safety and seek preliminary evidence of efficacy for the ATR inhibitor, AZD6738, in patients with MDS and chronic myelomonocytic leukemia who have failed first line therapy (NCT03770429). We will test the hypothesis that patients with spliceosome mutations are more likely to respond to ATR inhibition and will explore potential genetic and epigenetic mechanisms of resistance. Future goals will be to identify rational combination strategies incorporating ATR inhibition in MDS treatment. Ongoing basic and translational research should provide mechanistic insights into R-loops and the ATR response, as well as additional targetable vulnerabilities and biomarkers that can be used for patient selection and to monitor responses. Furthermore, it will be important to address whether aberrant R-loop accumulation is common in other cancers harboring spliceosome mutations. If aberrant R-loop accumulation is a common vulnerability in cancers, ATR inhibitors may have a broad therapeutic potential in cancer therapy."}
+{"text": "Transcription factors bind regulatory DNA sequences in a combinatorial manner to modulate gene expression. Deep neural networks (DNNs) can learn the cis-regulatory grammars encoded in regulatory DNA sequences associated with transcription factor binding and chromatin accessibility. Several feature attribution methods have been developed for estimating the predictive importance of individual features (nucleotides or motifs) in any input DNA sequence to its associated output prediction from a DNN model. However, these methods do not reveal higher-order feature interactions encoded by the models.in\u00a0vivo TF binding models. DFIM reveals epistatic interactions involving nucleotides flanking the core motif of the Cbf1 TF in yeast from in\u00a0vitro TF binding models. We also apply DFIM to regulatory sequence models of in\u00a0vivo chromatin accessibility to reveal interactions between regulatory genetic variants and proximal motifs of target TFs as validated by TF binding quantitative trait loci. Our approach makes significant strides in improving the interpretability of deep learning models for genomics.We present a new method called Deep Feature Interaction Maps (DFIM) to efficiently estimate interactions between all pairs of features in any input DNA sequence. DFIM accurately identifies ground truth motif interactions embedded in simulated regulatory DNA sequences. DFIM identifies synergistic interactions between GATA1 and TAL1 motifs from https://github.com/kundajelab/dfim.Code is available at: Bioinformatics online. Genome-wide biochemical profiling experiments have revealed millions of putative regulatory elements in diverse cell states. These massive datasets have spurred the development of deep neural network (DNN) models to predict cell-type specific or context-specific molecular phenotypes such as TF binding, chromatin accessibility and gene expression from DNA sequence . Beyond Advances in feature attribution methods for DNNs have enabled the identification of predictive cis-regulatory patterns in DNA sequences used as input to the models. Feature attribution methods estimate the contribution (or importance) of features, such as individual nucleotides or contiguous subsequences (e.g. motifs), in an input DNA sequence to a model\u2019s output prediction. A perturbation-based, forward-propagation approach known as in-silico mutagenesis (ISM) quantifies the importance of a nucleotide in an input DNA sequence as the maximal change in the output prediction from the DNN model when the observed nucleotide (e.g. a G) at that position is mutated to any of the alternative bases . ISM has been used to score the potential molecular impact of genetic variants in regulatory DNA sequences . HoweverCurrent feature attribution methods only provide the importance of individual features. They do not highlight predictive, higher-order feature interactions that are learned by the DNN model. Perturbation-based approaches such as ISM cannot scale to comprehensively score all pairwise and higher-order interactions between nucleotides or subsequence features. Recently, an efficient algorithm was proposed to calculate SHAP-based pairwise feature interaction scores  to estimate pairwise interactions between features (nucleotides or subsequences) in an input DNA sequence mapped to an associated regulatory phenotype by a neural network. We define a novel Feature Interaction Score (FIS) between any pair of features (source feature and target feature) in an input DNA sequence as the change in the importance score of the target feature when the source feature is perturbed, while keeping all the other features in the sequence intact. By leveraging efficient backpropagation-based feature attribution methods, we can efficiently compute FIS between all pairs of nucleotides or predictive motifs across large sets of input DNA sequence. Aggregate summary statistics of the pairwise Feature Interaction Score across multiple sequences provide insights into common, shared patterns of feature interactions.in\u00a0vivo TF binding models. We apply DFIM to reveal epistatic interactions involving nucleotides flanking the core motif of the Cbf1 TF in yeast from in\u00a0vitro TF binding models. We also apply DFIM to regulatory sequence models of in\u00a0vivo chromatin accessibility to reveal interactions between regulatory genetic variants and proximal motifs of target TFs as validated by TF binding quantitative trait loci.We benchmark DFIM in controlled simulations that explicitly encode motif interactions. We use DFIM to reveal synergistic interactions between GATA1 and TAL1 motifs from X of length L to a categorical (binary or multiclass classification) or continuous (regression) output O. Let Y refer to the scalar predicted output O from the neural network for regression tasks. For classification tasks, let Y refer to the scalar input to the final output sigmoid (i.e. logit) of the neural network.We assume that we have trained a deep neural network to accurately map one-hot encoded DNA sequences We are given a one-hot encoded input DNA sequence on 1\u2264p\u2264L .X0, the output Y0 can be approximated by a first-order Taylor expansion w0 is the partial derivative (gradient) of Y with respect to the input sequence variable X evaluated at X0 i.e. w0 can be computed efficiently in one backpropagation pass. We then perform a point-wise multiplication of the gradient matrix w0 with the one-hot encoded observed input sequence X0 to obtain the importance scores for the observed nucleotides b at each position p i.e. X0 to those obtained when using neutral \u2018reference\u2019 sequences  and the observed nucleotide at some other position (target feature) in the sequence. Let X0 where we switch the observed nucleotide \u03b1 at source position s to a different mutant nucleotide X0  of the target feature with the source feature as the maximal FIS marginalized over all possible values of the mutant nucleotide \u03b3 at the source feature We define the maximal Feature Interaction Score )  Step 5.maxFIS scores for all pairs of source and target features in an input DNA sequence (A nucleotide-resolution Deep Feature Interaction Map (DFIM) summarizes the sequence  Step 6.FIS between a source position s and target position t across a collection of input sequences iX, we first identify the subset of sequences FIS or absolute FIS corresponding to each S.  of all positions GCf i.e. the mutant sequence FIS of the target motif with the source motif is once again the difference of the sum of importance scores across all target nucleotides X0 and the mutated sequence To compute the FIS, across a collection of input sequences, we define statistically significant interactions based on an empirical null distribution of scores from dinucleotide shuffled versions of the input sequences. For each dinucleotide shuffled input sequence, we compute FIS for all nucleotide pairs. We fit a Gaussian distribution to this null empirical distribution of FIS scores. FIS values passing a P-value of 0.05 with respect to this null distribution are considered statistically significant. We use the Benjamini-Hochberg procedure for multiple hypothesis correction. Given a continuous distribution of F features (nucleotides/motifs), SHAP interaction scores scale at least quadratically to compute all pairwise interactions giving a complexity ranging from F source features, we need one more backpropagation pass to obtain FIS of that source with all target features. Thus, DFIM exhibits a complexity of O(F) scaling linearly in the number of features. Our proposed FIS is essentially an efficient approximation of SHAP interaction scores. Further, in contrast to SHAP interaction scores and pairwise ISM interaction scores which are necessarily symmetric over the source and target, FIS is directional and can produce asymmetric interaction scores.For an input sequence with FIS, we simulated 60\u2009K random DNA sequences (0.46\u2009G/C frequency) of length 200\u2009bp. We divided these into 3 sets of 20\u2009K sequences. We randomly embedded 1 or 2 instances of the ELF1 motif [using the highest affinity sequence from Position Weight Matrix  for all sequences in the positive class (i.e. Set 3). We used DeepLIFT with a fixed GC reference for computing importance scores since the underlying sequences were generated using a fixed GC background. Only pairs of SIX5 and ELF1 motifs (positive control) showed strong FIS (P\u2009<\u20090.05) P-values, even after multiple hypothesis correction. None of the other motif pairs show statistically significant interactions  in erythroid K562 cells from all other chromatin accessible DNase-seq peaks in K562 (negative class) (FIS (using DeepLIFT with shuffled reference as importance scores) for all pairs of GATA1, TAL1 motif instances across all sequences using GATA1 as the source motif. We observed several instances with strong FIS between proximal GATA1 and TAL1 motifs which corroborates their experimentally validated co-binding interactions  showed statistically significant higher interaction scores than all three other bins   . The CNNe class) , achievee class) . We thenractions A. To undarisons) A. Howevearisons) B, an obson GATA1 .FIS to investigate an orthogonal question\u2014What proximal sequence features are affected by (interact with) regulatory genetic variants? Tehranchi et\u00a0al. developed a pooling-based approach to identify thousands of SNVs that have allelic effects on TF binding (as measured by ChIP-seq) across a large collection of genotyped lymphoblastoid human cell-lines  CNN model to map 1kbp length DNA sequences to binary chromatin accessibility profiles across 16 primary hematopoietic cell types (with ATAC-seq data) . The modFIS to estimate the effect of mutating the reference allele to all alternate alleles at the source QTL on every target nucleotide \u00b115\u2009bp around the QTL. First, we observed strong positive  but not the A allele  will destroy the importance of the entire JUND motif.To understand proximal interactions, for each bQTL, we used positive A and negpositive B interacpositive A. The reFIS predicts that the C allele (weaker binding) destroys the importance scores of the core GGAA element  and alternate allele C. The bQTL is in the flanking nucleotides of a low affinity SPI1 site where only the core GGAA matches the canonical motif.  element A. Tehran element A. E.g. a element B. SPI1 Q element .FIS of a matched number of conservative control SNVs from the FIS (maxAbsFIS) over all target nucleotides \u00b115\u2009bp around the SNV. For all the TFs, we found that the bQTLs exhibit significantly (Mann Whitney test) stronger maxAbsFIS than control SNVs  and 5 variable flanking nucleotides on either side. They trained a feed forward neural network to predict relative binding affinity (\u0394\u0394G) for each of the TFs from the 10\u2009bp flanking sequences (using a flattened one-hot encoding) in the library (P\u2009=\u20090.25) with a final dense classification layer having a linear activation. They used a distillation approach to interpret the NN model by fitting a linear model with all mononucleotide features across all positions and all dinucleotide features across all pairs of positions to the output predictions of the NN. They found that dinucleotide features were critical for the linear model to have a good fit  that affect binding of transcription factors. Our maps link binding QTLs to nearby sequence features including high and low affinity matches to the canonical binding site of the TF whose binding is disrupted. We also find bQTLs interacting with motifs of multiple co-binding TFs. These epistatic interactions seem to capture both cooperation and competition. While our primary focus in this manuscript is on interpreting feature interactions in DNA sequence inputs, DFIM can easily be generalized to other data modalities.We present an efficient method called Deep Feature Interaction Maps (DFIM) to identify epistatic interactions between all pairs of nucleotides or motif features in any DNA sequence input to a deep learning model for regulatory genomics. Our method accurately recovers ground truth interacting motifs in simulated regulatory DNA sequences. When applied to deep learning models of Partial dependence plots are commonly used to understand the sensitivity of a prediction to a one or more features . DFIM seThere are some caveats to interpreting feature interactions derived from DFIM. Feature importance scores from any feature attribution method are only meaningful for examples that are predicted correctly. Since feature interaction scores from DFIM are based on feature importance scores, the validity of DFIM is also restricted to examples that are correctly predicted by high performance models. Further, vulnerabilities of the feature attribution method used in DFIM transfer over to the interaction scores. Hence, we recommend using multiple feature attribution methods to obtain robust estimates of interactions. Changes in model architecture can also change the interactions encoded by the model and thus the interactions learned with DFIM. Despite these mentioned caveats, the case studies we present here showcase the utility of DFIM to provide a nuanced view into the combinatorial code of regulatory DNA sequences through the lens of predictive neural network models.Supplementary DataClick here for additional data file."}
+{"text": "A similar but less dramatic effect was observed with alpha-band (8\u201312 Hz) correlation changes . DISCUSSION/SIGNIFICANCE OF IMPACT: The negative correlation between inter-electrode power envelope correlations in the beta frequency band and motor recovery indicates that activity in the motor cortex on each hemisphere may become more independent during recovery. The role of the unaffected hemisphere in stroke recovery is currently under debate; there is conflicting evidence regarding whether it supports or inhibits the lesioned hemisphere. These findings may support the notion of interhemispheric inhibition, as we observe less in common between activity in the 2 hemispheres in patients successfully achieving recovery. Future neuroimaging studies with greater spatial resolution than available with EEG will shed further light on changes in interhemispheric communication that occur during stroke rehabilitation.OBJECTIVES/SPECIFIC AIMS: The objective of this study is to determine the degree to which the use of a contralesionally-controlled brain-computer interface for stroke rehabilitation drives change in interhemispheric motor cortical activity. METHODS/STUDY POPULATION: Ten chronic stroke patients were trained in the use of a brain-computer interface device for stroke recovery. Patients perform motor imagery to control the opening and closing of a motorized hand orthosis. This device was sent home with patients for 12 weeks, and patients were asked to use the device 1 hour per day, 5 days per week. The Action Research Arm Test (ARAT) was performed at 2-week intervals to assess motor function improvement. Before the active motor imagery task, patients were asked to quietly rest for 90 seconds before the task to calibrate recording equipment. EEG signals were acquired from 2 electrodes\u2014one each centered over left and right primary motor cortex. Signals were preprocessed with a 60 Hz notch filter for environmental noise and referenced to the common average. Power envelopes for 1 Hz frequency bands (1\u201330 Hz) were calculated through Gabor wavelet convolution. Correlations between electrodes were then calculated for each frequency envelope on the first and last 5 runs, thus generating one correlation value per subject, per run. The chosen runs approximately correspond to the first and last week of device usage. These correlations were Fisher Z-transformed for comparison. The first and last 5 run correlations were averaged separately to estimate baseline and final correlation values. A difference was then calculated between these averages to determine correlation change for each frequency. The relationship between beta-band correlation changes (13\u201330 Hz) and the change in ARAT score was determined by calculating a Pearson correlation. RESULTS/ANTICIPATED RESULTS: Beta-band inter-electrode correlations tended to decrease more in patients achieving greater motor recovery (Pearson\u2019s"}
+{"text": "Individuals who received anterior cruciate ligament (ACL) reconstruction surgeries demonstrated lower extremity movement asymmetries. The purpose of this study was to determine if psychological impairment was a contributor to lower extremity movement asymmetries in walking for individuals who received ACL reconstruction surgeries. Three-dimensional videographic and force plate data were collected for 25 males after unilateral ACL reconstruction performing walking without (single-task condition) and with the concurrent cognitive task . Both uninjured and injured legs had significantly smaller peak knee flexion angle and peak knee extension moment during loading response and mid-stance phases in dual-task condition compared to single task condition (P\u2009\u2264\u20090.012). Walking condition and leg had significant interaction effects on peak hip adduction angle during mid-stance phase (P\u2009=\u20090.042) and peak hip abduction moment during loading response phase (P\u2009=\u20090.048). The inter-leg difference of peak hip adduction angle during mid-stance (P\u2009=\u20090.038) and terminal stance (P\u2009=\u20090.036) phases, and peak hip abduction moment during loading response phase (P\u2009=\u20090.024) were significantly decreased in dual-task condition compared to single-task condition. Psychological factors have significant effects on post-operative movements of both injured and uninjured knees of individuals who received ACL reconstruction surgery. Although physical factors may be primary contributors to the post-operative lower extremity movement asymmetries, psychological factors also contribute to the post-operative hip movement asymmetries. Approximately 175000 ACL reconstruction surgeries were performed in the United States annually2. Although ACL reconstruction surgeries restored knee stability, studies repeatedly reported high ACL re-injury rates and early development of knee osteoarthritis (OA) after ACL reconstruction. Literatures showed that up 12% of patients with reconstructed ACLs had ACL re-injury4 and the prevalence of radiographic knee OA of patients with combined ACL and meniscal injuries in 10 to 15 years follow-up after ACL reconstruction were 80%5.Anterior cruciate ligament (ACL) reconstruction is a commonly surgical procedure to restore knee functions after an ACL injury8. Literature showed that athletes with multiplane biomechanical asymmetries at hip and knee at the time of return to sport were at least three times more likely to have ACL re-injury within one year compared to those without these asymmetries7. Literature also showed that asymmetrical lower extremity loading altered chondrocyte synthesis and catabolic activities, which could lead to structural damage of articular cartilage and may accelerate the development of knee OA11.Lower extremity movement asymmetries were found to be predictive of ACL re-injury and knee OA after ACL reconstruction13. Patients with quadriceps strength asymmetry demonstrated increased asymmetry in lower extremity kinetics in functional activities compared to patients with quadriceps strength symmetry15. These studies appear to indicate impaired quadriceps strength was the contributor to lower extremity movement asymmetries after ACL reconstruction. A study by Roewer et al., however, showed that asymmetric knee angles, knee moments, and hip power still existed despite subjects achieving symmetric quadriceps strength after ACL reconstruction16. Lentz et al. also reported that despite quadriceps strength was improved from 6 months to 1 year, functional limitations remained unchanged17. These studies indicated that quadriceps strength deficit was not the only contributor to lower extremity movement asymmetries.Weak quadriceps strength was identified as a primary contributor to lower extremity movement asymmetries after ACL reconstruction surgery. Studies showed that impaired quadriceps strength was correlated to altered movement patterns of injured leg after ACL reconstruction surgery18. A meta-analysis of the state of play revealed that fear for re-injury was the most common reason for post-operative reduction in or cessation of sports participation19. A study on psychological changes of patients who received ACL reconstruction surgery found that patients who returned to the competitive sport at 12 months after the surgery had more positive psychological responses to sports participation at 6 and 12 months after the surgery compared to patients who had not returned to competitive sport20. Although these studies indicated that psychological impairments may contribute to patients\u2019 movement asymmetries after ACL reconstruction surgery, the effect of psychological impairment on lower extremity movement asymmetries has not been confirmed yet.In addition to physical impairments, psychological impairments could also contribute to lower extremity movement asymmetries after ACL reconstruction. Movement asymmetries after ACL reconstruction surgery may be due to patients\u2019 preference of using their uninjured leg, which could put the contralateral leg at high risk for injuryThe purpose of this study was to determine if psychological impairment was a contributor to lower extremity movement asymmetries in walking for individuals who received ACL reconstruction surgeries. We hypothesized that there would be a quadriceps strength asymmetry after ACL reconstruction surgery. We also hypothesized that there would be asymmetries in hip and knee angles and moments in walking after ACL reconstruction surgery. We further hypothesized that asymmetries of hip and knee angles and moments would be decreased when walking with a cognitive task compared to walking without the cognitive task.Twenty-five males who received unilateral ACL reconstruction using hamstring tendon autograft within 10 months before the study  volunteered to participate in this study. All participants had isolated ACL injury without other ligament and meniscus injuries that needed to be repaired with a resection or suture, or moderate or severe articular cartilage damage to the patellofemoral and tibiofemoral joint, or other current orthopaedic injuries or disorders that were still affecting lower extremity movements. All participants went through similar post-operative home-based rehabilitation programs and had normal knee range of motion at the time of participating in the study. The mean International Knee Documentation Committee (IKDC) score of the participants was 67.4\u2009\u00b1\u200911.4. The use of human subjects in this study was approved by the Institutional Review Board of Peking University Third Hospital. All participants read and signed a written informed consent before data collection.Each participant was asked to wear a pair of black spandex shorts. Passive reflective markers were placed bilaterally at the anterior superior iliac spine, posterior superior iliac spine, lateral thigh, lateral femoral condyle, medial femoral condyle, anterior superior shank, anterior inferior shank, lateral malleoli, medial malleoli, heel, and first and fifth metatarsophalangeal. The participant was instructed to walk with barefoot in two conditions: (1) without cognitive task (single-task condition), and (2) with concurrent cognitive task . In single-task condition, the participant walked along a 10-m walkway at self-selected walking speed. In dual-task condition, the participant walked along the walkway while backward counting numbers with an increment of seven starting from a randomly given number between 125 and 250. In dual-task condition, participants immediately initiated the walking task at their preferred speed once they heard the number read by the investigator and kept counting out loudly as required without repeating the given number. Participants were asked to count as fast as possible while walking task. A 5\u2009min rest was requested between single-task and dual-task test. The order of conditions was randomized for the participant. Quadriceps strength was evaluated for the participant after walking test.Three-dimensional (3-D) trajectories of the reflective markers were collected using an 8-camera motion capture system  at a sample rate of 100\u2009Hz. Ground-reaction force signals were collected using two embedded force plates  at a sample rate of 1000\u2009Hz. Each participant was asked to have three successful trials for each condition. A successful trial was defined as a trial in which the participant performed the task as required, and all kinematic and kinetic data were collected.Quadriceps isometric strength was quantified with an isokinetic dynamometer  during a maximum voluntary isometric contraction (MVIC). The participant was seated with a hip flexed at 90\u00b0 and knee flexed at 60\u00b0. The lateral femoral condyle was aligned with the dynamometer axis, and the dynamometer resistance pad was secured to the anterior aspect of the distal shank. After correcting for leg weight, the participant was asked to perform submaximal practice to familiarize themselves with the testing apparatus. After familiarization of testing apparatus, the participant was asked to have three recorded maximum-effort trials  for each leg with uninjured leg tested first.21. Kinematics and kinetics variables were calculated using Visual 3D software . Hip and knee joint angles were calculated as Cardan angles of distal segment reference frame relative to the proximal segment reference frame in an order of (1) flexion-extension, (2) abduction-adduction, and (3) internal-external rotation. Joint moments were calculated through an inverse dynamic approach and transferred into the distal segment reference frame. Joint moments and quadriceps strength were normalized to the production of body weight and standing height.The raw 3-D trajectories of the reflective markers were filtered through a Butterworth low-pass digital filter at an estimated optional cut-off frequency of 10\u2009HzLstride length was the forward distance of heel marker between successive heel contacts of the same foot, Tcycle time was the time between the first contacts of 2 consecutive footfalls of the same foot.Three phases, loading response phase, mid-stance phase, and terminal stance phase, during walking were analyzed Fig.\u00a0. Knee ra22Yuninjured leg and Yinjured leg were magnitudes of a given joint angle or moment of uninjured leg and injured leg.The inter-leg difference (ILD) between injured and uninjured legs was also calculated for joint angles and moments as described in literaturePaired t-test was performed to compare the walking speed between single-task and dual-task conditions and isometric quadriceps strength between injured and uninjured legs. Two-way analyses of variance (ANOVA) with repeated measures were performed to compare the kinematic and kinetic variables of interest between conditions  and legs (injured leg and uninjured leg). In case a significant interaction effect of condition and leg was detected, paired t-tests were performed to compare the dependent variables between legs in a given condition and between conditions on a given leg. Paired t-tests were performed to compare the ILD between single-task and dual-task conditions. All statistical analyses were performed using SPSS computer program package, version 16.0 . A type I error rate less than or equal to 0.05 was considered as the indication of statistical significance.Walking speed in dual task condition (1.15\u2009\u00b1\u20090.13\u2009m/s) was significantly lower than that in single task condition (1.24\u2009\u00b1\u20090.14\u2009m/s) (P\u2009=\u20090.003). The quadriceps strength of injured leg (0.096\u2009\u00b1\u20090.028 BW\u2009\u00d7\u2009BH) was significantly smaller than that of uninjured leg (0.129\u2009\u00b1\u20090.028 BW\u2009\u00d7\u2009BH) (P\u2009=\u20090.001).No significant interaction effect of condition and leg on knee angular kinematics were detected P\u2009\u2265\u20090.162). Injured leg had smaller peak knee flexion angle during loading response and mid-stance phases compared to uninjured leg  (Table\u00a062. InjurNo significant interaction effects of condition and leg on knee moments were detected (P\u2009\u2265\u20090.193). Injured leg had smaller peak knee flexion moment during terminal stance phase compared to uninjured leg (P\u2009=\u20090.001) Table\u00a0. Both unA significant interaction effect of condition and leg on peak hip adduction angle during mid-stance phase was detected (P\u2009=\u20090.042). Injured leg had significant smaller peak hip adduction angle during mid-stance phase compared to uninjured leg in single-task condition (P\u2009=\u20090.050) while no significant difference was found in this variable between legs in dual-task condition (P\u2009=\u20090.256) Table\u00a0. Both unNo significant interaction effects of condition and leg on other hip angular kinematics were detected (P\u2009\u2265\u20090.055). Injured leg had smaller minimum hip flexion angle during loading response phase compared to uninjured leg (P\u2009=\u20090.004) Table\u00a0. InjuredA significant interaction effect of condition and leg on peak hip abduction moment during loading response phase was detected P\u2009=\u20090.048). Injured leg had significantly smaller peak hip abduction moment during loading response phase compared to uninjured leg in both single task and dual task condition  (Table\u00a08. InjureNo significant interaction effects of condition and leg on other hip moments were detected P\u2009\u2265\u20090.214). Injured leg had smaller peak hip abduction moment during mid-stance phase compared to uninjured leg (P\u2009=\u20090.023) (Table\u00a0. Injured24. These results of this study combined with the literatures indicated that participants in this study indeed had quadriceps asymmetries as defined in literatures. A previous study demonstrated that increased quadriceps strength was associated with increased knee cartilage and greater cartilage cross-sectional area25, indicating quadriceps weakness as a possible contributor to the development of knee osteoarthritis of individuals received ACL reconstruction surgeries. Extended rehabilitation programs, therefore, are needed to correct quadriceps strength asymmetry after ACL reconstruction surgery to minimize the risk of early knee osteoarthritis.The results of this study support our hypothesis that there would be a quadriceps strength asymmetry after ACL reconstruction surgery. The decreased quadriceps strength of injured leg in this study was consistent with the quadriceps strength asymmetries reported in literatures28. These results suggested that individuals who received ACL reconstruction surgeries tended to walk with increased leg stiffness29. The results of this study further showed that injured leg had smaller peak knee flexion moment during terminal stance phase while having no significant difference in peak knee abduction moments during mid-stance and terminal stance phases between injured and uninjured legs, which is also consisitent with literature31. Literatures show that knee moment in the sagittal plane is positively correlated with medial femoral cartilage thickness in healthy individuals32, and that approximately 85% of the mechanical work during gait is done in the sagittal plane33. The sagittal-plane moments appears to be more revelant to the knee joint degeneration after ACL reconstruction surgery than peak knee abduction moment. The results of current study also showed that injured leg had smaller peak hip abduction moment during the mid-stance phase compared to uninjured leg while having no significant difference in peak hip abduction moment during terminal stance phase. The decreased peak hip abduction moment in the mid-stance phase in this study was likely due to weaker hip abductors. Hip abductors assist in stabilizing pelvis in the frontal plane. Ipsilateral hip abductor weakness may cause the pelvis to drop towards the contralateral swing leg34. A recent study showed that patients who develop medial compartment knee OA within 5 years after ACL reconstruction surgery walked with asymmetrically lower peak hip abduction moments compared to those who did not develop knee OA at 5 years35. These results combined together suggested that altered hip movement patterns in the frontal plane may be a vital predictor to initiate knee degeneration and may need to be addressed during rehabilitation.The results of this study support our hypothesis that there would be asymmetries in hip and knee motion patterns in walking after ACL reconstruction surgery. The decreased peak knee flexion angle during the loading response phase of injured leg observed in this study is consistent with literatureset al. reported that patients after ACL reconstruction surgery increased brain activation in attentional and sensory areas during force reproduction task compared to the healthy control group, which reflect an increased focused attention and therefore an increased neurocognitive involvement36. According to the limited capacity theory of attention, when an attention-demanding cognitive task imposed on an attention-demanding task, concurrent execution of both tasks may require more attentional capacity than the existing capacity and therefore one or both tasks could not have sufficient attention37. Walking while performing a cognitive task decreased attention distribution to walking in the dual task condition compared to single task condition in this study. In this situation, the decreased ILD should be considered as a result of decreased psychological effects on asymmetries of walking. These results, therefore, indicate that psychological as well as physical factors contribute to movement asymmetries post ACL reconstruction surgeries.The results of this study partially support our hypothesis that asymmetries of hip and knee angular kinematics and moments would be decreased when walking with a cognitive task compared to walking without the cognitive task. Interaction effects of condition and leg on hip adduction angles and abduction moments and decreased corresponding ILDs observed this study suggested that asymmetries of hip movements in the frontal plane was decreased while walking in dual task condition. No similar results were obtained for knee angles and moments. Baumeister 38. Considering these results, although we don\u2019t know the cost of the performance of the cognitive task when participants walking in dual task condition in current study, the results of current study indicated that performing cognitive task while walking was indeed at the cost of the performance of gait for individuals who received ACL reconstruction surgery, which is similar to that of patients with Parkinson\u2019s disease, but different from that of healthy individuals. This means that psychological factors still affect post-operative gait for individuals who received ACL reconstruction surgeries, but this effect may be similar for both injured and uninjured legs.Although the asymmetries of knee angular kinematics and moments were not decreased while walking with a cognitive task, post-operative knee movements of patients who received ACL reconstruction surgery were still affected by psychological factors. The results of this study showed that participants significantly decreased their knee angles and moments while walking with a cognitive task. A study showed that healthy individuals prioritized gait control at the cost of performance of the cognitive task in dual task condition, while patients with Parkinson\u2019s disease prioritized performance of the cognitive task at the cost of performance of gaitet al. suggested that postural stability in the frontal plane was controlled primarily by activation of the hip abductors and adductors designed to alternately load and unload the hips, thereby controlling the movement of center of mass39. Abnormal hip movements could have a deleterious effect on the tibiofemoral and patellofemoral mechanics in multiple planes40. This means that the effects of psychological factors on lower extremity movements could be mainly through their effects on the movements of hip joints. Interventions which address proximal movement impairments may be beneficial for patients who had various knee movement impairments. As participants had lower quadriceps strength of injured leg compared to uninjured leg in this study, their knee movements might be mainly affected by physical factors while hip movements affected by both physical as well as psychological factors.Psychological factors might have different influence on post-operative hip and knee movement patterns in walking for individuals who received ACL reconstruction surgeries. The results of this study showed that ILDs of hip angular kinematics and moments in the frontal plane were decreased in dual task condition compared to single task condition, while ILDs of knee angular kinematics and moments were essentially the same between conditions. These results indicated that effects of psychological factors on asymmetries of hip and knee movements are different. The hip joint is the most proximal joint in the lower extremity kinematic chain and shares the femur with the knee joint. Winter 41, likely due to either poor movement strategies or lingering impairments that were not addressed by surgical reconstruction and post-surgery rehabilitation. Movement strategies are modifiable and represent important targets for successful clinical interventions. The results of this study indicated that psychological factors are contributors to the post-operative lower extremity movement asymmetries of individuals who received ACL reconstruction surgeries. As psychological differences regarding returning to sports among athletes who received surgeries treating injuries occur as early as six months postoperatively20. Clinicians should address psychological factors early to help patients modify the abnormal movement patterns and facilitate their returns to competitive sport. Though the results of this study indicated that the immediate effect of the secondary cognitive task did not decrease the asymmetry of knee movements, the asymmetry of hip movements in frontal plane could be modified in dual-task condition. Dual-task training could be used as an intervention to improve movement performance and motor control in rehabilitation programs42.Our findings have important implications for post ACL reconstruction rehabilitation programs. The risk of ACL re-injury remains higher than that of the initial ACL injury15, the effect of the concurrent cognitive task on walking may be different between the group with symmetrical quadriceps strength and the group with asymmetrical quadriceps strength. Future studies may be needed to assess the effects of physical factors on the effects psychological factors on lower extremity movement asymmetries. In addition, since gender differences in lower extremity movement patterns exist43, psychological factors may affect lower extremity movement asymmetries differently between genders. Future studies should include both females and males to investigate the gender differences in psychology.Several limitations of this study may need to be addressed in the future studies. Since the asymmetry of quadriceps strength could affect the lower extremity movement symmetryThere were significant post-operative asymmetries in quadriceps strength, and hip and knee movements of individuals who received ACL reconstruction surgery.Psychological factors have significant effects on post-operative movements of both injured and uninjured knees of individuals who received ACL reconstruction surgery.Although physical factors may be primary contributors to the post-operative lower extremity movement asymmetries, psychological factors also contribute to the post-operative hip movement asymmetries.The results of this study appear to warrant the following conclusions:"}
+{"text": "The high-order structure of metaphase chromosomes remains still under investigation, especially the 30-nm structure that is still controversial. Advanced 3D imaging has provided useful information for our understanding of this detailed structure. It is evident that new technologies together with improved sample preparations and image analyses should be adequately combined. This mini review highlights 3D imaging used for chromosome analysis so far with future imaging directions also highlighted. The DNA in chromosomes holds the genomic information of all eukaryotes. Throughout the cell cycle progression, chromosomes condense into the higher-order compact structures until they reach mitosis. The biological implications of this chromosome higher-order structure is for packaging the long DNA molecules into chromatin fibers within chromosomes facilitating upon cell division, the separation of the chromatids for transportation of DNA fibers evenly to two new daughter cells without damage Sumner . The higThe 30-nm chromatin fibers have frequently been observed by scanning electron microscopy (SEM)  has Angstrom resolution, it is not a suitable microscopy for studying intact mitotic chromosomes because chromosomes are too thick for the electrons to penetrate through biological samples over 1 micron thick Ris . Whole hScanning electron microscopy (SEM) images the sample surface by scanning it with a focused electron beam and collection of backscattered electrons. The major limitation has been due to sample preparation as MAA chromosomes show an artificial surface \u201cskin\u201d layer over the chromosomes following air-drying   allows 3D information and is similar to FIB-SEM but uses a diamond knife instead of focused GIn contrast to TEM, X-rays have the ability to penetrate through whole intact chromosomes. Imaging intact chromosomes is advantageous and simplifies the procedure saving time for sample preparation. Coherent diffraction imaging (CDI) using X-ray diffraction was achieved on intact mitotic chromosomes in both 2D and 3D  may be another strong tool to visualize 3D chromosome structure. AFM gives us images which are similar to those obtained using SEM by scanning the solid sample surface with a sharp probe tip and detecting the interaction force between the tip and the sample to get height information. From this principle, AFM does not require metal coating and the observation can be performed either in vacuum, air, or liquid condition , a super-resolution technique, has been performed on mitotic chromosomes Carlton . SIM allDespite the impressive nature of imaging methods mentioned above, the detailed higher-order structure is still under debate. Optical super-resolution microscopy techniques are under development and present an opportunity to study the structure of the chromosomes below the diffraction limit. Such methods should allow the study of live cells that has not been possible with any previous high-resolution method and with development in 3D. Optical super-resolution techniques are already being applied to study chromatin contacts  after labelling with H2AvD-EGFP, a histone H2A variant in the presence of background (Matsuda et al. 3D studies done to date have tended to require harsh chemical fixation, dehydration, and drying steps that may not represent the true nature of the sample under investigation. Cryo-electron microscopy enables us to observe biological samples close to the native state (Eltsov et al."}
+{"text": "Linkage disequilibrium (LD)\u2014the non-random association of alleles at different loci\u2014defines population-specific haplotypes which vary by genomic ancestry. Assessment of allelic frequencies and LD patterns from a variety of ancestral populations enables researchers to better understand population histories as well as improve genetic understanding of diseases in which risk varies by ethnicity.We created an interactive web module which allows for quick geographic visualization of linkage disequilibrium (LD) patterns between two user-specified germline variants across geographic populations included in the 1000 Genomes Project. Interactive maps and a downloadable, sortable summary table allow researchers to easily compute and compare allele frequencies and LD statistics of dbSNP catalogued variants. The geographic mapping of each SNP\u2019s allele frequencies by population as well as visualization of LD statistics allows the user to easily trace geographic allelic correlation patterns and examine population-specific differences.https://ldlink.nci.nih.gov/?tab=ldpopLDpop is a free and publicly available cross-platform web tool which can be accessed online at  Linkage disequilibrium (LD)\u2014the non-random association of alleles at different loci\u2014defines population-specific haplotypes which vary by genomic ancestry . Assessm2) for each included population. The reference genetic data is from the 1000 Genomes Project Phase 3, which includes sequencing data for 2504 individuals in 26 ancestral populations which are divided into 5 super populations  [ftp://ftp.1000genomes.ebi.ac.uk/vol1/ftp/release/20130502/).LDpop is an online module designed to allow researchers to query LD patterns of two variants across ancestral populations of interest. LDpop estimates allele frequencies and measures of LD D\u2032 and R for eachhttps://github.com/CBIIT/nci-webtools-dceg-linkage/.LDpop is written in Python 2.7.15) and runs on a web-accessible virtual machine with UNIX operating system. The genomic coordinates are retrieved for each query variant from an indexed MongoDb database of dbSNP version 151 and subsequently extracted from the phased 1000 Genomes Project variant call format (VCF) file using Tabix (0.2.5). LDpop uses the Google Maps API to produce the interactive geographic mapping for each population using latitude and longitudinal coordinates for each 1000 Genomes Project ancestral population. The LDpop web-accessible page is programed in HTML5 for cross-browser and cross-platform compatibility and is part of the larger LDlink collection of LD web tools  and runs. All cod2) to report for the geographic mapping. LDpop supports queried dbSNP variants which are biallelic including both single nucleotide polymorphism (SNP) and small insertion and deletion (indel) queries. LDpop allows the user to specify any subset of populations from the subpopulations, super populations, and all populations, they are interested in examining for the analysis.LDpop takes as input two dbSNP reference SNP numbers (rsIDs), a selection of desired populations from the 1000 Genomes Project, and a choice of which LD statistic (D\u2032 or R2) for the two query variants for every population selected. The mapped data point is colored in proportion to the gradient shown in the legend, with darker red signifying a higher degree of LD. All geographic mapping utilizes the Google Maps API for smooth and rapid performance. The interactive summary table at the bottom of the page has a row for each selected 1000 Genomes Project population and displays data in the number of samples in each population, allele frequencies for each variant, and calculated LD values (D\u2032 and R2). This table is sortable by column and has a search bar to quickly navigate through it. The table is also downloadable as a text file for local storage and future data integration and analysis.LDpop produces three geographic maps and one sortable, filterable table as output Fig.\u00a0. For eachttps://ldlink.nci.nih.gov/?tab=ldpop.LDpop is an online module designed to allow researchers to query LD patterns of two variants across ancestral populations of interest. It is designed to allow users to easily calculate and geographically visualize these LD patterns and changes in allele frequency across ancestral populations. This web tool is freely available and can be accessed at"}
+{"text": "Nitrogen (N) loss from agricultural systems raises concerns about the potential impact of farming practices on environmental quality. N is a critical input to agricultural production. However, there is little understanding of the interactions among crop water use, N application rates, and soil types. This study was designed to quantify these interactions in corn (Zea mays L.) grown in production-size fields in central Iowa on the Clarion-Nicollet-Webster soil association. Seasonal water use varied by soil type and N application rate. Yield varied with N application rate, with the highest average yield obtained at 100 kg ha. N use efficiency (NUE) decreased with increasing N application rates, having values around 50%. Water use efficiency (WUE) decreased as N fertilizer rates increased. Analysis of plant growth patterns showed that in the low organic matter soils (lower water-holding capacities), potential yield was not achieved because of water deficits during the grain-filling period. Using precipitation data coupled with daily water use throughout the season, lower organic matter soils showed these soils began to drain earlier in the spring and continued to drain more water throughout the season. The low NUE in these soils together with increased drainage lead to greater N loss from these soils. Improved management decisions have shown that it is possible to couple water use patterns with N application to increase both WUE and NUE."}
+{"text": "Hospitalization of older adults with cognitive impairment (CI) has been associated with higher risk for adverse outcomes. Acute Care for Elders (ACE) Units were developed to meet the unique hospital care needs of older adults and have been associated with reductions in functional decline and readmissions. The Virtual ACE intervention was developed to disseminate ACE principles across hospital units. Virtual ACE included training interprofessional providers to utilize screens and care protocols to optimize care for older adults on eight units at a large academic medical center. We conducted a preliminary analysis of mobility and patient outcomes before and after Virtual ACE among 192 older adults with CI on hospital admission. Chi-Square tests were used to examine the associations between Virtual ACE and patient outcomes. There were statistically significant pre vs. post improvements in patients\u2019 mobility from bed to chair  and on the unit hallway . Although not statistically significant, there were also improvements in hospital room mobility  and documentation of activities of daily living (ADL) screens . There were non-significant reductions in pressure ulcer prevalence (26% vs. 22%) and restraint use (5% vs. 0%) during the hospital stay. Pain was similar before and after Virtual ACE. Virtual ACE was associated with increased mobility and slight reductions in adverse outcomes. As increased hospital mobility improves patient functioning post-discharge, Virtual ACE has the potential to maintain function and enhance outcomes in hospitalized older adults with CI."}
+{"text": "OBJECTIVES/SPECIFIC AIMS: The goal of this study is to evaluate a potential strategy to overcome tamoxifen (tam) resistance by using tam in combination with high-intensity focused ultrasound (HIFU). Tam is the most commonly used anti-cancer therapeutic agent in estrogen receptor positive (ER+) breast cancer (BC) which accounts for ~70% of BC cases. Tam treatment decreases a woman\u2019s risk of recurrence by 50%; however, BC that is initially responsive to tam often develops resistance. METHODS/STUDY POPULATION: HIFU deposits acoustic energy locally to a cancerous region, which induces strong vibrations of molecules inside and outside of the cells. The resulting absorption causes rapid heating and mechanical disruption. This clinically relevant, noninvasive, and nonionizing physical force modality, has been shown to synergistically enhance chemical anticancer therapies. RESULTS/ANTICIPATED RESULTS: In this study we found that treatment of MCF7 cells with HIFU and tam has additive antiproliferative effects and mediates increased cell death. Additionally, we used tam resistant (TR) MCF7 cells that had been exposed to low-dose tam over time until they acquired resistance. When MCF7 TR are treated with tam there is no change in viability; however, treatment with HIFU in combination with tam decreased viability of both MCF7 and MCF7 TR to 19% and the viability of the cell lines was indistinguishable. We next evaluated the effect on MCF7 Y537S mutant ESR1, where ER is mutated to be constitutively active. Treatment of MCF7 Y537S had no significant decrease in viability of combination therapy compared with viability after HIFU alone. Analysis of ERalpha gene expression showed that HIFU treatment increased ERalpha expression in MCF7 TR cells, thus resensitizing these cells to tam and allowing these therapies to work synergistically. Our team developed a system to evaluate the potential of this combination of therapies in a patient-derived xenografts (PDX) model. PDX have emerged as a novel translational tool for cancer research with the potential to more accurately recapitulate the molecular and behavioral aspects of cancer. The WHIM20 PDX is a tamoxifen resistant tumor where the patient developed the Y537S mutation in ESR1. Ex vivo experiments on PDX tumor pieces demonstrated that combination therapy of HIFU and tam work synergistically to increase cell death of these tumors. Further, cryogenic-scanning electron microscopy was utilized to directly demonstrate the physical disruption to both cellular and tumor microenvironment post exposure to combination treatment. DISCUSSION/SIGNIFICANCE OF IMPACT: These studies present a novel translational strategy to overcome tamoxifen resistance in ER+BC."}
+{"text": "A 13-year-old child had left orbital trauma by wood. He consulted 2 week after for decreased visual acuity and eye pain. The ophthalmological examination showed the presence of a wound of autotight cornea a wooden foreign body incarcerated in the iris and the lens. Extraction of the foreign body associated with an adapted antibiotic treatment led to clinical improvement."}
+{"text": "Killian-Jamieson diverticulum (KJD) is a rare entity resulting from the mucosal herniation through a lateral area of weakness known as the Killian-Jamieson space below the cricopharyngeal muscle. Ultrasonographic diagnosis is exceptional. Moreover, symptoms are found in only eleven percent of patients. KJD in its symptomatic form must be correctly identified because its therapeutic management is in some points different of Zenker\u2019s diverticulum. A 73-year-old woman was suffering of mild dysphagia with occasional regurgitations and depressible swelling during swallowing on the left side of her neck which appeared two years earlier. Ultrasonographic examination showed a hypoechoic mass surrounded by a digestive wall measuring 45mm located just behind the left thyroid lobe Fig. . No concKJD is rare entity related to the more common Zenker\u2019s diverticulum (ZD) with its classic posterior development. It results from the mucosal herniation through a lateral area of weakness known as the Killian-Jamieson space below the cricopharyngeal muscle . This spThe authors declare that they have no competing interests."}
+{"text": "The characteristics of where older adults live have strong links with disability. Although lower income older adults experience disability at higher rates, less is known about the link between housing characteristics and functional health in this group. A within group comparison among this population is needed to understand how aspects of this vulnerable subgroup\u2019s housing context are associated with health outcomes. The present study examines the association between housing and functional health among a U.S. nationally representative sample of independent living  lower income adults age 65+. Using data from round one of the National Health and Aging Trends Study, a sub-sample of N=2,865 lower income  older adults was selected for analysis. Regression analyses indicate that lower income older adults living in multiunit buildings reported better functional health compared to those in other housing contexts . This link also significantly varied by age and gender. Living in multiunit housing was associated with better functional health among those age 90+, not associated among those age 80-90, and was negatively associated among those age 65-79. In terms of gender, the link between multiunit housing and better functional health was only significant among women. Findings highlight variation in health across lower income older adults\u2019 housing contexts. Potential explanatory mechanisms  will be discussed. Such information can inform senior housing policy regarding best approaches to providing housing for older adults that optimizes and promotes independent living."}
+{"text": "Women diagnosed with Triple Negative Breast Cancer (TNBC) have worse overall survival rates than other forms of breast cancer partly due to the absence of novel and targeted treatment modalities in this aggressive subtype . The intAs an influential oncogene, MYC can potentially regulate \u223cover 4,000 genes at any given moment. Although the relationship between MYC and DNA repair has been investigated extensively, therapeutic modalities that exploit MYC directed DNA repair vulnerability are absent. Our study cultivates the direct link between MYC and DNA repair to exploit an increased response to PARP inhibitors . EvaluatIn vitro and in vivo analysis of MYC downregulation via genomic and therapeutic inhibition induced PARP inhibitor sensitivity independent of BRCA status. The pan CDK  inhibitor dinaciclib demonstrated superior efficacy versus other MYC inhibitors in combination with PARP inhibition. The use of MYC as a driver of biomarker targeted therapy for TNBC provides hope for a patient population lacking in therapeutic treatment options while also addressing a validated association between MYC and TNBC, with approximately \u223c50% of TNBC patients demonstrating upregulation of MYC in tumors [After reinforcing the relationship between MYC and the DNA repair pathway via RAD51, our study demonstrated a regulatory relationship between MYC and RAD51 gene expression . In vitrn tumors . Our anan CDK 1, , 5, 9 inThe relationship between CDK inhibition and MYC expression has illuminated a regulatory role of the cell cycle over MYC expression Figure . AdditioOur study also alludes to the evolution of PARP inhibitors in the clinical setting beyond BRCA status. Respected for their efficacious treatment responses in HR defect tumors with measurably decreased adverse events versus standard chemotherapy, PARP inhibitors offer a new horizon for cancer treatment . The shiMore recently, Sun et al. demonstrated that BRD4 inhibition induces PARP inhibitor sensitivity in ovarian cancers independent of BRCA status . Our stuin vivo. The down regulation of PD-L1 signals that checkpoint inhibitors may work in combination with dual dinaciclib + PARP inhibition. Two recent studies support the role that MYC plays in immune regulation; specifically MYC cooperates with KRAS to drive tumor growth via IL-23 and CCL9 immune suppression [To further advance the clinical application of PARP inhibitors, the investigations into novel immune-oncology agents are promising Figure . Studiespression . In anotpression . These sDinaciclib is a pan-CDK inhibitor that has not made it past Phase 2 clinical trial evaluation due to high toxicity . The reaAs we search for novel combination therapies that increase the efficacy and scope of the patient population eligible for PARP inhibitor treatment, it is paramount to remain focused on a clearly defined outcome. The use of efficacious biomarkers such as MYC that dictate response to therapy is essential to the evolution of targeted treatment option for TNBC patients Figure . We unde"}
+{"text": "A 50-year-old woman with widely metastatic melanoma presented to the emergency department with dyspnea. She was found to be tachypneic, hypoxic, tachycardic, and hypotensive. A non-rebreather oxygen mask was placed and her oxygen saturation improved mildly. We obtained a semi-erect chest radiograph (CXR) followed by chest computed tomography angiography (CTA) \u20133, due tThe diagnosis was a tension hydrothorax due to a massive, malignant pleural effusion causing hemodynamic compromise. The hemodynamic effects of a tension hydrothorax are analogous to those of a tension pneumothorax. Elevated intrathoracic pressure caused by the effusion impairs venous return and compresses the left ventricle, causing reduced stroke volume and subsequent hypotension.6A CXR will show a large pleural effusion.The emergency physician must be aware of this entity when a hemodynamically-compromised patient arrives with a pleural effusion, even if mediastinal shift is not evident on the CXR.What do we already know about this clinical entity?A tension hydrothorax due to a massive pleural effusion is a rare event that can cause hemodynamic instability due to compromised thoracic venous return.What is the major impact of the image(s)?The images demonstrate how increased intrathoracic pressure can cause mediastinal shift and vena cava compression.How might this improve emergency medicine practice?In a hemodynamically compromised patient with a large pleural effusion, emergent thoracentesis should be considered due to possible tension physiology."}
+{"text": "Given the association between functional disability and suicidal ideation (SI) in late life , this study examined associations between functional disability and SI among older adults receiving problem solving therapy (PST) for depression. PST is a promising intervention for SI  and has been shown to be effective in reducing functional disability among older adults with depression . Regression analyses with adults age 65-91 (n=65) found that level of SI  at baseline was not significantly associated with change in SI from pre- to post-treatment. However, lower baseline disability  and greater reduction in disability  were significantly associated with greater reduction in SI after controlling for age and baseline SI. These results suggest that treatments that decrease disability may be particularly advantageous for reducing SI in older depressed adults."}
+{"text": "The textilome or still called gossybipoma is a very rare but well known and not insignificant post-operative grave lesion in the abdominal and gynecological surgery. It is a foreign body compound of gauze or surgical drape omitted in the operation site. The difficulties of diagnosis delay generally the discovery of abdominal textilome. The clinicals symptoms are: chronic disorders of the transit in sub-occlusive or occlusive syndromes. Erect Abdominal X-ray has little contributory in the diagnosis, but the ultrasound remains more reliable. Abdominal CT Scan allows a precise topographic diagnosis; certain teams propose explorations by MRI. We report a case of intra-colic textilome (sigmo\u00efde), presenting acute abdomen in forme of an occlusive syndrome in patient who was operated 3 years ago for uterine fibroid."}
+{"text": "The specific aim of this case study was to describe how monitoring ballistocardiogram (BCG) waveforms can detect early heart failure (HF) changes. HF significantly impairs quality of life and is the principal cause for hospital readmissions in older adults. HF prevalence in American adults aged 65 years and older is expected to increase over 70% by 2030. Detecting worsening HF is challenging. Invasive arterial waveforms display blood pressure changes with each heartbeat; BCG waveforms display repetitive body motions resulting from ejection of blood into the great vessels. BCG waveforms change as cardiac function changes. Currently, BCG signals can be captured non-invasively using sensors placed under a bed mattress and provide heart and respiratory rates. We have developed a new way to analyze the BCG waveform using an innovative closed-loop physiological model of the cardiovascular system. The subject, a 94-year old female with hypertension, presented to her physician with symptoms associated with a new diagnosis of acute mixed congestive HF. Mean heart and respiratory rate trends obtained from her bed sensor in the prior two months did not indicate HF. We simulated cardiac cycles using normal cardiac function data, mildly impaired diastolic function data, and the subject\u2019s echocardiography data. The results demonstrated BCG waveform changes that correlated with decreasing cardiac output related to worsening diastolic function. New methods for clinically interpreting BCG waveforms present a significant opportunity for improving early HF detection and improving outcomes. Working on a clinical problem from an engineering perspective merges two disciplines, creating a new methodology."}
+{"text": "A 74-year-old female with a history of diabetes mellitus, hypertension, atrial fibrillation  presented with chest and back pain. A 12-lead electrocardiogram (ECG) was ordered at triage demonstrating possible aberrant pacemaker activity .Upon evaluation, the treatment team determined that the patient had no history of pacemaker placement. Physical examination revealed that the patient had an over-the-counter transcutaneous electrical nerve stimulation (TENS) unit adhered to her back to treat her back pain. Once the TENS device was removed, a repeat ECG demonstrated rate-controlled atrial fibrillation without any other electrical discharges .TENS units are external electrostimulators that produce electrical current with variable frequency, amplitude and duration, delivered through skin electrodes.3Artifactual ECG changes inconsistent with a patient\u2019s presentation, particularly in patients with back pain, should prompt consideration by the emergency physician of the presence of a TENS unit causing artifacts.What do we already know about this clinical entity?Electrocardiogram (ECG) artifacts are well described phenomena attributable to various sources. While traditional Transcutaneous Electrical Nerve Stimulation (TENS) units have been known to cause ECG changes, ECG abnormalities due to over the counter TENS units in the emergency department (ED) setting have not been previously reported.What is the major impact of the image(s)?TENS devices are a known pain treatment modality that are now increasingly available over the counter. These devices may induce artifactual changes on ECGsHow might this improve emergency medicine practice?Careful and thorough history and physical exam in the emergency department may prompt the emergency physician to the presence of a TENS device as the cause of electrocardiographic artifact."}
+{"text": "China has about 20% of the world\u2019s total dementia population. Since most elders with dementia are living at home with care by family members, communities are fundamental support resources for families as well as patients. Dementia-friendly community initiatives aim to empower families with dementia and increase their social inclusion. Within the Chinese political context, the community level governmental organization called Ju-wei-hui has played a key role in community engagement. Within this context, a Community Based Participatory Action Research (CBPAR) process is utilized to increase public awareness on dementia and caring strategies. Our team collaborated with 15 Ju-wei-hui offices across Beijing to design a series of courses and teaching modules together. Five hundred community residents participated and positively evaluated the project. A major finding is that CBPAR could be an effective strategy to develop dementia-friendly communities across China."}
+{"text": "Remote measurements of thermal radiation are very important for analyzing the solar effect in various environments. This paper presents a novel real-time remote temperature estimation method by applying a deep learning-based regression method to midwave infrared hyperspectral images. A conventional remote temperature estimation using only one channel or multiple channels cannot provide a reliable temperature in dynamic weather environments because of the unknown atmospheric transmissivities. This paper solves the issue  with the proposed surface temperature-deep convolutional neural network (ST-DCNN) and a hyperspectral thermal camera (TELOPS HYPER-CAM MWE). The 27-layer ST-DCNN regressor can learn and predict the underlying temperatures from 75 spectral channels. Midwave infrared hyperspectral image data of a remote object were acquired three times a day  for 7 months to consider the dynamic weather variations. The experimental results validate the feasibility of the novel remote temperature estimation method in real-world dynamic environments. In addition, the thermal stealth properties of two types of paint were demonstrated by the proposed ST-DCNN as a real-world application. The relationships between solar radiance and emitted thermal radiative energy are important for infrared stealth technology. Radiated solar energy (6000 K) heats an object, which then radiates thermal energy according to Planck\u2019s law . One of The surface temperature of an object is independent of the wavelength, and can be estimated from even a single spectral band with a known atmospheric transmissivity and surface emissivity. In addition, the atmospheric conditions are crucial for surface temperature estimation . The atmConventional approaches usually require an atmospheric correction to remotely estimate the temperature . A previA two-channel-based method such as a split window algorithm can estimate the surface temperature as a linear function of two brightness temperatures . AlthougA four channel-based surface temperature estimation method was proposed in Reference . They reA multi-channel method was proposed using longwave hyperspectral thermal infrared for high-emissivity surfaces . They usAn accurate remote surface temperature estimation is difficult under dynamically varying weather conditions. The above-mentioned approaches  have their own advantages and disadvantages. These methods work if the specific conditions are satisfied, such as the known atmospheric transmissivity, known water vapor contents, and known surface emissivity. On the other hand, they cannot guarantee the temperature accuracy if the required atmospheric information is unavailable online or the weather conditions change abruptly.In this paper, the problem of a remote surface temperature estimation in a dynamic weather environment is solved by focusing on the sensor, database (DB), and deep learning scheme. A new hyperspectral thermal infrared camera  was adopted to analyze both the solar radiance and thermal radiation in the 1.5\u20135.5 The remainder of this paper is organized as follows. The remote surface temperature estimation was based on the brightness temperature as shown in An open path Michelson interferometer can be prepared using an active or passive approach for outdoor applications . The forA Michelson interferometer receives an input beam of radiation, divides the beam into two paths, and then recombines the two beams after a path difference . A beam p and wavenumber The intensity as a function of the path difference in the interferometer This is a Fourier cosine transformation. The inverse transform can extract the desired spectrum . If two BBs with known temperatures M(\u03bd\u02dc)Equation :(5)LBB(\u03bdquations  and 7)..(4)M(\u03bd\u02dc)Equation .(6)G(\u03bd\u02dcIf an unknown scene spectrum is measured (Equation :(8)LS can be estimated from the spectral radiance L is adopted to extract the spectral information. The midwave thermal hyperspectral images usually show lower sensitivity than longwave thermal hyperspectral images on the surface emissivity in a remote temperature estimation . The surThe proposed ST-DCNN consisted of 27 layers, as shown in The TELOPS HYPER-CAM MWE model was used in this study, as shown in The object surface was painted with a gray color and was located in a coastal area with a 78 m distance to the FTIR sensor system. The object surface data were acquired from 1 December\u201330 June, three times a day  with 75 spectral bands   and meanOne of many applications of remote temperature estimation is to check the thermal stealth effect of different types of paint on ships, buildings, etc. by solar radiation. This paper proposed a novel remote surface temperature estimation method using a surface temperature-deep convolutional neural network (ST-DCNN) from midwave hyperspectral thermal images. Estimating the surface temperature remotely in a dynamically varying weather environment is a very challenging problem. The key idea was to apply the specially designed 27-layer deep convolutional neural network to a huge database consisting of spectral radiance\u2013surface temperature sensor pairs. The spectral radiance data were extracted successfully by applying the FFT to the interferogram followed by wavenumber calibration and two blackbody-based radiometric calibrations. The inverse of Planck\u2019s law to the spectral radiance produced the spectral brightness temperature containing both the surface emissivity and atmospheric transmissivity implicitly. The proposed ST-DCNN learned the weight parameters successfully using the 65,920 training samples. According to the experimental results, the proposed ST-DCNN showed an RMSE of"}
+{"text": "Kaposi's Sarcoma is a general angiosarcoma induced by viral growth factors, including interleukin 6 of Human Herpes Virus Type 8 ( HHV-8 ). It is preferably localized at limbs extremeties. The eyelid localization is very rare. This is an old patient of 68 years, which has since 3 years superior eyelid swelling of the right eye (A). Biopsy histopathological examination shows an aspect of Kaposi 's sarcoma. HIV serology was negative. The treatment then is surgical excision without safety margins with reconstruction in a the same operative time: external canthotomy and upper eyelid sliding flap sutured end-to-end. The outcome was favorable with a good cosmetic result without local recurrence after 6 months follow up (B)."}
+{"text": "Parkin ablation. The quantitative proteomic data was obtained using SWATH-MS methodology and mitochondrial function was assessed through measurement of oxygen consumption rate using the Seahorse XF Analyzer. This data facilitates comparisons with previous proteomic and functional data obtained using the exact same methods. A complete set of proteomic data is contained in In this paper, we provide proteomic and functional data for synaptic mitochondria from the striatum of rats with  Specifications TableValue of the data\u2022These data sets provide a useful resource to identify different synaptic mitochondrial processes that are affected due to loss of Parkin.\u2022This data will aid in comparisons of synaptic mitochondrial changes in Parkin KO rats with other PD animal models.1e96 Extracellular Flux Analyzer is provided. No significant alteration of either the respiratory state . All protocols were conducted within NIH-approved guidelines for the Care and Use of Laboratory Animals with the approval and oversight of the University of Nebraska Medical Center Institutional Animal Care and Use Committee.Male Long Evans Hooded (LEH) (RRID:RGD_2308852) control and Parkin KO rats 2.2Brains were rapidly isolated from the animals, and the striatum , protein concentration was determined using a Pierce 660\u2009nm Protein Assay , and the filter aided sample preparation method 2.4RRID:SCR_015786) using our published reference spectral library http://cybert.ics.uci.edu/) q-values < 0.05.Striatal synaptic mitochondrial peptides were analyzed using SWATH data-independent analysis (DIA) mode on a TripleTOF 5600 (SCIEX) followed by targeted data extraction as described previously Michael J Fox Foundation (Grant #9524).Funding support was provided by a grant from the"}
+{"text": "Cystic lesion around knee usually presents as painless swelling and diagnosed incidentally by imaging for any internal derangement of the knee. Few cases presented with pain. Intra-tendinous patellar ganglion is very rare in location for the disease. Ganglionic cyst usually treated by aspiration followed by steroid and surgical excision in some cases. We reported a case with anterior knee pain due to patellar intra-tendinous ganglion cyst which treated conservatively with no recurrence even after one year. A ganglion is a benign cystic mass containing clear high-viscosity mucinous fluid with a dense fibrous connective tissue capsule lined by flat spindle-shaped cells that is rich in hyaluronic acid and other mucopolysaccharides , 2. GangA 39-year-old boy presented to us with complaints of dull anterior knee pain for three months. He had visited several general practitioners for which he was given symptomatic analgesics. On examination, there was minimal swelling in form of the fullness of paratendon area and slight extensor lag with quadriceps muscle wasting 1 cm) without any instability with active range of motion 150-1200  confirmed a moving well-defined echogenic lesion within the patellar tendon with approximate 1.2 ml volume. The radiological diagnosis was an intratendinous patellar ganglion (ITPG) cyst. The patient was explained regarding treatment option like aspiration and anti-inflammatory injections/surgery if conservative therapy fails, but he chooses to observe and follow up. Even after one-year follow-up the patient is doing well with no recurrence of symptom.Ganglia arise from the mucoid degeneration and occurs in tendon sheath though they can occur in bones, joints and even other soft tissues . HistoloThe intra-tendinous patellar ganglion is a rare location for the disease but should be kept as one of the differential diagnosis for anterior knee pain. Imaging study is key to diagnosis in an unusual location."}
+{"text": "As the number of indicated malignancies for which immune checkpoint inhibitor therapy such as pembrolizumab grows the descriptions of associated immune-related adverse events (irAEs) increases as well. On rare occasions immunotherapy can lead to development of Hemophagocytic Lymphohistiocytosis (HLH) which is a potentially lethal inflammatory disorder characterized by histiocyte activation and cytokine storm. At this time no cases of HLH developing in head and neck squamous cell carcinoma (HNSCC) patients receiving pembrolizumab have been reported.Here we describe the first documented case of pembrolizumab-induced HLH in a 61\u2009year-old male with metastatic HNSCC after having received multiple prior cycles of pembrolizumab without event. Following cycle 14 the patient developed fever associated with new pancytopenia and transaminitis prompting hospital admission. Infectious workup was negative, his metastatic lesions were found to be stable, and there was no evidence of new malignancy. Further workup demonstrated hyperferritinemia and bone marrow biopsy demonstrated hemophagocytosis concerning for pembrolizumab-induced HLH. Etoposide and dexamethasone therapy was initiated leading to clinical improvement and safe discharge.Immunotherapy is a groundbreaking therapeutic intervention for patients with malignancy, however by nature of their mechanism carry a risk of inflammatory side effects. In rare circumstances these inflammatory reactions include potentially deadly syndromes such as HLH. As immunotherapeutics such as pembrolizumab become more widely utilized increased awareness of complications such as HLH is clinically relevant. Checkpoint inhibitors such as pembrolizumab are an innovative therapeutic intervention for patients with an ever-expanding number of malignancies and have led to profound clinical responses. However, this same class of drugs carries a significant risk for inflammatory side effects known as immune-related adverse events (irAEs). As an unintended consequence of their mechanism wherein they are thought to enhance cytotoxic T-cell activity against cancer cells they may also promote the pathologic hyperinflammatory state known as Hemophagocytic Lymphohistiocytosis (HLH). Here we present the first documented case of HLH arising secondary to pembrolizumab therapy in a patient with metastatic head and neck squamous cell carcinoma (HNSCC) who responded well to classical HLH therapy including dexamethasone and etoposide. By presenting this case we aim to increase awareness of potentially lethal complications of immunotherapy given the increasing number of indications for checkpoint inhibitors such as pembrolizumab.A 61\u2009year-old gentleman with a history of p16+ squamous cell carcinoma of the oropharynx with metastatic spread to bilateral lungs initially received cisplatin and radiotherapy with subsequent transition to clinical trial involving 6\u2009weeks of anti-platelet therapy (aspirin/clopidogrel) with concurrent pembrolizumab followed by pembrolizumab monotherapy after completion of the trial. He demonstrated stable disease while on treatment with excellent tolerance to immunotherapy over his first nine months of treatment with no significant irAEs.Four days following cycle 14 of pembrolizumab the patient developed fever >\u200939.5\u2009\u00b0C and malaise prompting a visit to his primary care provider who prescribed a course of oral antibiotics without symptomatic improvement. He subsequently presented to his Oncology clinic, was found to have a new pancytopenia and transaminitis as well as tender hepatomegaly on exam concerning for autoimmune hepatitis, and was admitted to the hospital for methylprednisolone therapy. Admission bloodwork compared to most recent values from 3\u2009weeks prior is presented in Table 2 and etoposide 150\u2009mg/m2 per published guidelines for HLH [Infectious workup including acute hepatitis panel was negative while haptoglobin was within normal limits. Peripheral smear demonstrated pancytopenia with rare schistocytes. Abdominal CT demonstrated periportal edema and gallbladder wall thickening consistent with acute hepatitis as well as new splenomegaly. Due to progressive pancytopenia despite methylprednisolone bone marrow biopsy was performed demonstrating widespread hemophagocytosis Fig.  while adThe patient\u2019s hospital course was complicated by neutropenia with eventual count improvement allowing for safe discharge on dexamethasone taper and outpatient etoposide infusions. Ferritin was trended as a marker of treatment response as demonstrated in Fig. The patient\u2019s outpatient course was notable for an ESBL soft-tissue abscess requiring hospital admission for incision/drainage and antibiotics, which delayed his 4th week of etoposide. In addition, his 7th week dose of etoposide was held due to transient neutropenia and thrombocytopenia. He otherwise completed a standard HLH regimen and by the time of restaging scans 3\u2009months after HLH diagnosis he had returned to his woodworking business, regained all lost weight (~\u200911.5\u2009kg), and demonstrated normalization of his liver function testing as well as improvement in his WBC and platelet counts. Initial restaging scans demonstrated stable pulmonary metastatic disease and no new visceral metastases. The patient was monitored off immunotherapy for 8\u2009months without disease progression before developing progressive mediastinal lymphadenopathy and a painful ischial metastatic lesion. He otherwise exhibited unchanged pulmonary disease. The patient underwent radiation to the osseous lesion with clinical improvement and pembrolizumab was restarted. To date the patient has received 5\u2009cycles pembrolizumab since immunotherapy re-initiation with interval reduction in lymph node size, stable pulmonary metastases, no new or progressive bony disease, and no clinical evidence of recurrent HLH.HLH is an uncommon yet life-threatening hematologic disorder characterized by aberrant immune-cell activation, pro-inflammatory cytokine release, and multi-organ dysfunction. HLH is diagnosed based on meeting at least 5 of 8 criteria set forth by the Histiocyte Society representing common pathologic findings in patients with HLH . These cImmunotherapy represents a revolutionary cancer treatment modality that via a wide array of mechanisms increases immune cell activity against tumor cells. Two programmed cell death-1 (PD-1) receptor inhibitors, nivolumab and pembrolizumab, are approved for the treatment of recurrent/metastatic HNSCC. PD-1 is expressed by immune cells and helps regulate self-tolerance by downregulating the immune response. Binding of PD-1 by PD-1 ligand (PD-L1) in the tumor microenvironment compromises normal T-cell function and may promote conversion of cytotoxic T-cells into T-regulatory cells . InterfeHematologic side effects of immunotherapy are less commonly described however reviews of immunotherapeutic complications report the most common hematologic aberrations are hemolytic anemia and immune thrombocytopenic purpura . On veryOn literature review, the case reports discussing immunotherapy-induced HLH have described a wide range of underlying malignancies including Squamous Cell Carcinoma of the Lung, Urothelial Carcinoma, Thymic Carcinoma, Merkel Cell Carcinoma, Breast Cancer, and Melanoma however to our knowledge this is the first report of immunotherapy-induced HLH in a HNSCC patient \u201311. The The optimal management of irAEs continues to evolve with organizations like the Society for Immunotherapy of Cancer (SITC), National Comprehensive Cancer Network (NCCN), and American Society for Clinical Oncology (ASCO) recently publishing management guidelines , 13. GenThe treatment armamentarium for irAEs such as HLH is rapidly expanding with increasing observational evidence and numbers of clinical trials evaluating cytokine and immune modulation with targeted agents. Daclizumab  has been described as having successfully treated secondary HLH with the proposed mechanism being depletion of pathologically-activated T-cells that demonstrate increased CD25 expression , 17. OthIn addition to studies evaluating novel therapeutics for irAEs there is increasing interest in understanding the safety and efficacy of rechallenging patients with immunotherapy following irAE resolution. To this end, a recent cohort study of patients with lung cancer who developed irAEs evaluated restarting immunotherapy once the initial event had resolved; retreated patients who did not have a tumor response prior to the irAE demonstrated increased overall survival compared to those that were not retreated while retreated patients who exhibited tumor response prior to the irAE demonstrated similar overall survival to those that were not retreated . As prevTo our knowledge, this is the first described case of pembrolizumab-induced HLH in HNSCC. The patient\u2019s HLH was treated successfully with dexamethasone and etoposide. Due to disease progression while on observation pembrolizumab was restarted without complication to date. As the applications of immunotherapy continue to expand there will be more patients who suffer very rare side effects such as immunotherapy-induced HLH. Given the increasing numbers of case reports of immunotherapy-induced HLH as well as the lack of data regarding optimal treatment for HLH increased awareness of the potential development of HLH in patients receiving immunotherapy is clinically relevant and warrants further research."}
+{"text": "Aedes triseriatus) (La Crosse virus (LACV) is the most common cause of pediatric arthropod-borne viral  encephalitis in the United States  was notified of a suspected LACV encephalitis case in a boy aged 2 years from western North Carolina. The following day, NCDPH was notified that the patient\u2019s brother, aged 11 years, was also ill with symptoms consistent with viral meningoencephalitis. Laboratory testing confirmed that both siblings had evidence of recent LACV infection .Aedes mosquito larvae  were found on the premises, multiple windows and doors lacked effective screens, and the yard was within close proximity (<50 m) to a mixed hardwood forest. Additional mosquito samples (adult mosquitoes collected by large-bore aspirator and mosquitoes reared from eggs collected by ovitraps) were obtained; mosquitoes from egg collections were tested for LACV infection by real-time reverse transcription\u2013polymerase chain reaction (RT-PCR) (An interagency environmental assessment team who visited the siblings\u2019 residence identified multiple risk factors associated with increased risk for LACV transmission (To identify additional LACV patients among two or more persons residing at the same location, 331 confirmed or probable LACV case reports meeting the case definitionhttps://www.cdc.gov/lac/index.html.These identified cases indicate that LACV disease risk can occur coincidently or noncoincidentally in time in persons at the same physical residence and further support surveillance data indicating that the disease is highly focal, occurring in a limited geographic area ("}
+{"text": "Nature leads this week with a story about a modern potato famine - this time in Russia. Science explores the continuing skirmishes over drug-patent profits."}
+{"text": "The paper presents spatio-temporal dataset of building occupants captured using 200 Bluetooth Low Energy (BLE) beacons installed on different locations in two buildings. It contains 8426 data points of 11 building occupants collected with a sampling rate of 5 seconds during different times in a 12 days' interval. Each spatio-temporal data point comprises location and time components correspond to a building location which can be visualized using an OpenStreetMap (OSM) file of a building. As thThe different values of step length and turning angle exists in a user trajectory which spans over 1000 spatio-temporal points are shown in The provided spatio-temporal dataset collected for developing the applications lack the building information context and require semantic enrichment processes . ConventThe presented dataset is primarily used for developing the applications of safety management in dynamic environments. Analyzing the pre-processed spatio-temporal trajectories can lead to important insights about user movements in facilities. The data article presents a very basic data processing of spatio-temporal trajectories. For advanced trajectory-based applications to understand occupant behaviors, processed trajectories need to be transformed into matrixes, tensors, and graphs for performing additional computations to extract knowledge . Eventua"}
+{"text": "Bioscience Reports (2018)https://doi.org/10.1042/BSR20180231KD analysis of FP binding data as shown in Table 2 in the Accepted Manuscript. Further investigation using non-reducing SDS\u2013PAGE found previously undetected PDZ\u2013PDZ dimerization triggered by extended incubation with the small-molecule compounds under stringent labeling conditions. This dimerization is not accounted for by our mixed-KD model. The final Version of Record instead reports apparent KD values determined from FP titrations with PDZ domains treated to minimize PDZ\u2013PDZ dimerization while preserving high levels of small-molecule adduct formation, together with associated changes in text.After acceptance and the publication of the Accepted 3, follow-up experiments revealed unexpected variability in the binding constants obtained by the mixed-Bioscience Reports.This has been approved by the Editorial Board of"}
+{"text": "OBJECTIVES/SPECIFIC AIMS: Bladder cancer patients being considered for immune checkpoint blockade are often judged on immunohistochemical staining for the checkpoint target protein PD-L1 in the original surgery or biopsy sample. However, sampling error or the clinical evolution of most patients\u2019 cancer can render the original PD-L1 assessment no longer accurate. In contrast, circulating tumor cells (CTCs) allow serial noninvasive sampling of the current tumor status throughout a patient\u2019s clinical course including those with the highest metastatic potential. We therefore sought to develop a method for quantifying PD-L1 expression in CTCs towards addressing inherent limitations of current UC management. METHODS/STUDY POPULATION: This work utilizes both cancer cell lines as well as patient samples. Positive and negative control cancer cell lines were assessed via \u201cindustry standard\u201d antibodies for PD-L1 expression via Western blots and immunofluorescence, and a threshold-based method was developed for reliable quantification. PDL-1 expression was additionally verified via interferon-mediated up-regulation. CTCs isolated from bladder cancer patient samples via a density centrifugation method were then assessed for PD-L1 via the same antibodies. RESULTS/ANTICIPATED RESULTS: We will show preliminary preclinical and clinical data that validates the sensitivity and specificity of our assay. A case study will be presented that illustrate the potential useful of the novel approach we describe and which should be complementary to current clinical practices. In a patient with metastatic bladder cancer, this method effectively detected the PD-L1 expression in CTCs taken at a time coincident to when the patient derived an excellent response to the PD-L1 checkpoint inhibitor Pembrolizumab. DISCUSSION/SIGNIFICANCE OF IMPACT: This work highlights the potential utility of CTCs in the management of bladder cancer. It may be the case that this assay in conjunction with current methods of patient selection for immunotherapy may allow for better response prediction than either method alone."}
+{"text": "OBJECTIVES/SPECIFIC AIMS: We aim to show that amyloid accumulation in an animal model of Alzheimer\u2019s disease leads to a preferential disruption of inhibitory parvalbumin-expressing interneurons, and the peri-neuronal nets that surround them, resulting in downstream network alterations to potentially explain early mechanisms of memory impairment in the disease. METHODS/STUDY POPULATION: We employ the 5xFAD mouse model of familial Alzheimer\u2019s disease crossed with transgenic mouse lines which fluoresce red or green in specific neuronal populations. We conducted immunostaining and immunoblotting in amyloid accumulating animals compared with healthy littermate control. Future experiments will be performed in human postmortem tissue to translate these results from mouse model to the human population. Electrophysiological recordings from acute mouse brain slices were conducted as a functional assay. RESULTS/ANTICIPATED RESULTS: Preliminary results indicate that PNNs are disrupted and that activity-associated levels of PV are reduced. Both inhibitory PV and excitatory pyramidal cell populations exhibit altered spiking and synaptic activity during sharp wave ripple events. DISCUSSION/SIGNIFICANCE OF IMPACT: By elucidating the specific neuronal sub-type that is responsible for hippocampal network disruption, future studies could attempt a targeted optogenetic or pharmacological intervention to restore network activity important for memory consolidation."}
+{"text": "The patient was operated via the pterional approach but resection had been halted due to severe haemorrhage and only tumour biopsy could be obtained. The diagnosis of cavernous sinus haemangioma was established by histopathology and confirmed by subsequent digital subtraction angiography. The patient refused second surgery or adjuvant radiosurgery and the treatment strategy was observation and follow-up. Retrospectively, we included the key radiographic features of cavernous sinus haemangioma which would facilitate pre-operative diagnosis and avoid unforeseen operative complications. Diagnostic radiographic features include a well-defined mass in the cavernous sinus which shows isodense to slightly hyperdense attenuation on non-contrast CT scan with possible adjacent pressure bone remodelling. On MRI, it shows remarkable high T2 signal; intense homogenous enhancement or characteristic progressive contrast enhancement on sequential enhanced images. On digital subtraction angiography, it may demonstrate a vascular blush.Cavernous haemangioma of the cavernous sinus is a rare vascular malformation. It's often confused with other parasellar masses. Here, we report a case of a female with a left parasellar mass which was misdiagnosed as schwannoma  A 48-year-old female presented with a history of progressive headache and blurring of vision of 1 year duration. Her physical and neurological examinations were unremarkable. Routine laboratory investigations and pituitary hormonal profile were all normal.Non-contrast CT scan of the brain revealed a large extra axial mass at the sellar and left parasellar regions. It appears homogeneous and shows isodense to slightly hyperdense attenuation relative to the adjacent brain parenchyma. No internal calcifications or necrosis. The lesion effaces the prepontine cistern. Examination of the bone window showed smooth bone remodelling and erosion of the medial part of the sphenoid wing. No evidence of bone hyperostosis. T1 weighted images and remarkable high signal on T2 weighted images  vascular spaces lined by flat endothelial lining. Some vascular spaces were empty but most spaces were filled with blood cells ; a pictuFollowing surgery, digital subtraction angiography was performed and showed a tumour blush at the lateral projection during the late arterial and venous phases supplied from small meningeal branches of the internal carotid artery . It alsoPost-operative neurological examination revealed paralysis of the left third cranial nerve with ptosis in the left eye and loss of light reflex; however, it gradually improved. The patient refused second surgery for total excision of the lesion or adjuvant radiosurgery and preferred the strategy of follow up and observation.1,2 Cavernous haemangioma is one of the four most common types of cerebral vascular malformations.2 They commonly occur intra axially within cerebral parenchyma1,3 ; however, they can also occur within extra axial spaces and when they occur extra axially they have the propensity to develop at the cavernous sinus.4 Extra axial haemangiomas have the same histologic features as intra axial lesions but have a different clinical picture, radiologic findings, and management.3Cavernous haemangiomas, also known as cavernous angiomas or cavernomas, are defined as vascular malformations formed of abnormal dilated vascular spaces with no intervening neural tissue.5 as in our case. Cavernous sinus haemangioma has not been reported before in the Egyptian population; however, several cases were documented in Japan.1,4,6,7 The clinical presentation is insidious and patients usually suffer from headache and dysfunction of the cranial nerves passing through the cavernous sinus, presenting by ptosis, diplopia or facial neuralgia. Optic chiasm may be compressed in large masses and patients may thus present with decreased visual acuity.5Cavernous sinus haemangioma has a predilection to middle-aged females7,8Cavernous sinus haemangiomas are divided pathologically into three types. Type A is a sponge-like lesion with intact pseudocapsule which consists of thin-walled vascular sinusoids with scanty intervening connective tissue; this type usually demonstrates homogeneous contrast enhancement on MRI. Type B is a mulberry-like lesion with absent or incomplete pseudocapsule which contains ample solid parenchyma with well-formed vasculature and connective tissue, and Type C which has both Type A and Type B compositions. Types B and C usually demonstrate heterogeneous contrast enhancement on contrast enhanced MRI studies.7,8 Jinhu and colleagues retrospectively reported MRI features of 21 surgically confirmed cavernous haemangiomas of the cavernous sinus. Most of the cases presented with a well-demarcated dumbbell-shaped appearance at the parasellar region extending to the middle cranial fossa laterally and sellar regions medially. Similar to our case, the cavernous haemangioma usually encircles the cavernous segment of the internal carotid artery without occluding it.7 Non-contrast CT shows a well-demarcated lesion of similar density or slightly higher density to the brain parenchyma . It also shows intense homogeneous post-contrast enhancement. Calcifications are not common in haemangiomas however adjacent bony remodeling and erosion may happen.2 MRI reveals mass which elicits isointense or hypointense signal on T1 weighted images and remarkably hyperintense (CSF like) signal on T2 weighted images with homogeneous post-contrast enhancement.1 Some studies observed heterogeneous enhancement on the first contrast-enhanced series and subsequent homogeneous contrast enhancement or progressive \u201cfilling in\u201d enhancement on subsequent contrast-enhanced series especially in histopathological types B and C.7 Unlike intra-axial cavernous angiomas, cavernous sinus haemangioma does not demonstrate T2 hypointense margin or blooming effect on gradient-echo sequences secondary to scanty hemosiderin deposition.9 Angiographically, haemangiomas exhibit a high degree of vascularity and a vascular blush has been reported5 ; however, they may be angiographically subtle.2 Tc-99m tagged red blood cell (RBC) imaging was recently recommended for the diagnosis of cavernous sinus haemangioma in the setting of nondiagnostic surgical biopsy.8,9Radiological imaging is essential for the prediction of cavernous sinus haemangioma and differentiation of haemangioma from similar intracavernous sinus masses. CT, MRI and digital subtraction angiography are helpful for diagnosis of cavernous sinus haemangioma.2 Our case was similar to meningiomas as it elicited homogeneous signal on T1 and T2 weighted images and was similar to trigeminal schwannomas as it elicited high T2 signal and caused widening of the ipsilateral foramen ovale; however, unlike meningiomas and schwannomas; the mass elicited characteristic remarkably high (CSF like) signal on T2 weighted images. Cartilaginous masses such as chondrosarcomas or chordomas are also hard to differentiate from cavernous sinus haemangiomas because they elicit high signal on T2 weighted images and demonstrate intense contrast enhancement; however, they are usually associated with calcifications and adjacent bone destruction.10 A characteristic MR feature of the lesion in our case was its dynamic enhancement pattern. Following contrast administration, the lesion showed early heterogeneous contrast enhancement on the initial axial images that changed to homogeneous enhancement on the subsequent coronal and sagittal post-contrast images. This progression of contrast enhancement took only the acquisition time for obtaining the contrast enhanced T1 weighted sequences (about 2 min per sequence); this can be explained by the pathological nature of the lesion being composed of thick-walled vascular sinusoids which caused this short delay to achieve homogeneous contrast enhancement. This rapid increase in the degree of contrast enhancement is characteristic for cavernous sinus hemangioma as it is not seen in other lesions7 ; angioblastic meningiomas, neurilemomas, and chondrosarcomas may display heterogeneous enhancement however they usually lack progressive \u201cfilling in\u201d enhancement pattern or delayed homogeneous enhancement on subsequent sequences.7The differential diagnosis includes similar cavernous sinus masses.11 However, the reported perioperative mortality rate was high due to uncontrollable severe bleeding.12 Therefore the pre-operative diagnosis is important because it requires the surgeon to be ready to tackle such pathology with low surface bipolar coagulation with no attempt to debulk the lesion without complete coagulation and shrinkage. Thus, the surgeon mindset should be delivered to that pathology.1,2 Also, piecemeal removal can be performed after the main feeding arteries are interrupted.4 Stereotactic radiosurgery or radiation therapy has been proposed as primary therapy for patients with inoperable lesions, for those that undergo limited subtotal resection as adjuvant therapy or as a pre-treatment for direct surgical excision as it suppresses tumour growth and decreases vascularity of the mass.13,14Treatment of choice is surgical excision.Cavernous sinus cavernous haemangioma is a rare vascular malformation and an uncommon cause of cavernous sinus masses.Differentiation of cavernous sinus haemangioma from similar intracavernous sinus masses like meningiomas and schwannomas is often challenging.Preoperative diagnosis is crucial as it requires a different surgical technique to avoid intraoperative profuse bleeding.MRI, CT and angiography studies can help to predict the diagnosis and to differentiate cavernous sinus haemangioma from similar cavernous sinus masses.Cavernous sinus haemangioma on non-contrast CT scan appears as a mass in the cavernous sinus which shows isodense to slightly hyperdense attenuation with intense homogeneous contrast enhancement and possible adjacent smooth bone remodeling and erosion.T2 signal; intense homogenous enhancement or characteristic progressive contrast enhancement on sequential enhanced images.Cavernous sinus haemangioma has characteristic MRI features of remarkably high Angiographically, cavernous haemangiomas may show vascular blush as they exhibit a high degree of vascularity but sometimes they might be angiographically subtle."}
+{"text": "Background and Aims: Postpolypectomy bleeding and incomplete polyp removal are important complication and quality concerns of colonoscopy for colon cancer prevention. We investigated if endoscopic mucosal stripping (EMS) as a technical modification of traditional cold snare polypectomy to avoid submucosal injury during removal of non-pedunculated colon polyps could prevent postpolypectomy bleeding and facilitate complete polyp removal.Methods: This is an Internal Review Board exemption-granted retrospective analysis of 5,142 colonoscopies with snare polypectomy performed by one of the authors (ZJC) at Minnesota Gastroenterology ambulatory endoscopy centers during a 12-year period divided into pre-EMS era  and EMS era  with systemic adoption of EMS starting 2013. Change in postpolypectomy bleeding rate before and after EMS adoption and EMS polypectomy completeness were evaluated.Results: Zero postpolypectomy bleeding case was found during EMS era (rate 0%) compared with 10 bleeding cases during pre-EMS era (rate 0.336%). This difference was statistically significant (P = 0.0055) and remained so after excluding 2 bleeding cases of pedunculated polyps (P = 0.012). All bleeding cases involved hot snare polypectomy. Histological examination of the involved polyps showed substantial submucosal vascular damage in contrast to a remarkable paucity of submucosa in comparable advanced polyps removed using EMS. Both biopsy and follow-up colonoscopy examination of the polypectomy sites confirmed that EMS more completely removed non-pedunculated advanced polyps.Conclusions: EMS polypectomy was effective in preventing postpolypectomy bleeding and facilitated complete polyp removal. Colonoscopy for colon cancer screening is effective at both mortality reduction through early detection and prevention through removal of precancerous polyps \u20138. TheseAside from EMR and ESD, little attention has been given to polypectomy technique as a risk factor for postpolypectomy bleeding. Indeed, the generally accepted and widely used traditional snare polypectomy technique to guillotine the ensnared polyp with or without heat coagulation has not changed much for nearly 5 decades \u201337. To pThis was a retrospective investigation of data incorporating electronic medical record and pathology slides at Minnesota Gastroenterology, PA (MNGI). An Internal Review Board exemption was granted for the investigation. The patients were those who had colonoscopy with snare polypectomy under Current Procedural Terminology (CPT) code 45385 by ZJC at MNGI ambulatory endoscopy centers during a 12-year period divided into pre-EMS era (2005\u20132012) and EMS era (2013\u20132016). A database search was performed for postpolypectomy bleeding cases requiring hospitalization and advanced polyps defined as polyps with villous features, high-grade dysplasia, sessile serrated adenoma with cytological dysplasia (SSACD) as well as any adenomatous polyps 10 mm or larger. Because MNGI had extensive local practice coverage and a 24-h staffed complication telephone line, it had an almost complete catch rate for complications which were peer-reviewed and fed-back to the involved endoscopists for quality improvement.Endoscopic mucosal stripping (EMS) is the endoscopic removal of polyp-containing mucosa by mechanical stripping using a cold snare. It is a modification of TCSP in that EMS strips the mucosa off the ensnared submucosa at the potential space between them Figure  rather tFor small polyps (\u2264 5 mm), TCSP generally works well. To ensure complete resection, we prefer snare over biopsy forceps except for diminutive polyps 2 mm or smaller  and routWhile submucosal entrapment can be avoided for smaller polyps by optimally placing the snare and gently lifting the polyp, this may become inevitable with larger polyp removal. Although the above described technique still applies, the entrapped submucosa often prevents separation of snare from polypectomy site even after the polyp-containing mucosa has already been stripped off. Under such circumstances, there is no need to further pull the snare by brute force. Instead, opening the snare slightly and sliding it over the entrapped submucosa will release the snare and any stripped off yet still seemingly attached polyp-containing mucosa from the polypectomy site. The entrapped submucosa from these larger polyps frequently forms a thicker pseudostalk but submucosal injury remains minimal.For even larger polyps that cannot be removed in one piece, EMS piecemeal polypectomy can be performed. Because EMS' lack of submucosal injury creates a less bloody or deformed polypectomy site in comparison with traditional cold or hot snare polypectomy, any residual polyp tissue is better visualized facilitating complete polyp removal Figure .Hospitalization-requiring postpolypectomy bleeding rates of all and non-pedunculated colon polyps before and after EMS adoption.Completeness of EMS polyp removal determined by polypectomy site biopsy and examination during follow-up colonoscopy at intervals recommended by national society guidelines , 14.Colonoscopies were performed using variable stiffness colonoscopes  for most cases and FUSE full spectrum colonoscopes  for a few cases as part of a trial. Polypectomies were performed using mostly oval snares  and, in a few cases, spiral snare  and Exacto snare .As part of MNGI quality measurement, the following annual colonoscopy statistics were reported for ZJC for 2014 and 2016: cecum reach rate 99.5\u2013100%, screening colonoscopy adenomatous polyp detection rates 50.3\u201360.1% for males and 42.1\u201354.0% for females.Statistical analysis was performed using Fisher's exact test.n = 2973) and EMS era  (Table P = 0.0055) and remained so after excluding the 2 pedunculated polyp cases (P = 0.012).A total of 5,142 colonoscopies with snare polypectomy performed by ZJC at MNGI ambulatory endoscopy centers during 12 years were divided into pre-EMS era  that were removed using a cold snare, all were removed using a hot snare. These included ten 8\u201340 mm TAs , one 25 mm tubulovillous adenoma (TVA), four 6\u201310 mm sessile serrated adenomas (SSA) and one 5 mm lipoma. Except for one case which only had partial retrieval of the resected polyp and had no submucosa microscopically, all remaining nine cases showed evidence of cauterized submucosa often with visible blood vessels near cauterized edge as illustrated in Figure For comparison, we also microscopically examined 20 consecutive cases of advanced colon polyps removed using EMS. These polyps contained only variable amount of muscularis mucosae and scanty, if any, submucosa with no blood vessels Table . These fExtensive biopsies were performed on the edge x4) and pseudostalk (x1) of 10 randomly selected advanced polyp sites after endoscopically complete removal by EMS. No polyp residue was found in any samples. Ninety-seven neoplastic EMS polypectomy sites were followed from 6 months to 4 years, including 38 polypectomy sites in 23 patients after removal of advanced polyps. None of the 59 non-advanced neoplastic polyp (< 10 mm and without advanced features) sites had any residual or recurrent polyps on follow-up colonoscopy. The vast majority  advanced polyp sites also had no polyps on follow-up colonoscopy  and was carried out in accordance with the approved protocol of Clinical and Histopathological Review of Mucosal Stripping as a Colonoscopy Polypectomy Technical Innovation and the recommendations of Minnesota Gastroenterology Quality Committee. All subjects gave written informed consent to the colonoscopy procedures and treatment in accordance with the Declaration of Helsinki.This retrospective study was granted Exemption from IRB Review Determination on May 12, 2016 (IRB ID: 5502) by Sterling IRB (ZC initiated the investigation concept and design, acquisition, analysis and interpretation of data, drafting and revising of the manuscript. KB participated in the acquisition, analysis and interpretation of data as well as critical revision of the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."}
+{"text": "Inhibitory control, a key modulatory component of cognition guiding strategy and behaviour, can be affected by diverse contingencies. We explore here the effect of expectation of reward over behavioural adjustment in a Stop Signal Task modulated by reward. We hypothesize that cognitive control is modulated by different expectation of the reward.N\u2009=\u200921) were informed of the different monetary feedbacks they would receive after each successful inhibition. Unexpected Reward participants (N\u2009=\u200924) were only told that they would receive monetary reward after correct inhibitory trials, but not the amounts or differences.Participants were allocated to two groups differing in their degree of knowledge in what to expect from rewards. Expected Specific Reward participants -, compared to the Unexpected Reward group.Knowledge of reward magnitudes seems to play a role in cognitive control irrespective of feedback magnitude. The manipulation of reward expectation appears to trigger different strategies for cognitive control, inducing a bottom-up effect of external cues, or a top-down effect given by the anticipation of incoming rewards. This is an early exploration to unearth possible higher order modulators - expectation and motivation- of cognitive control. This approach aims to gain insight into diverse psychopathological conditions related to impulsivity and altered reward systems such as Attention Deficit Hyperactive Disorder (ADHD), personality disorders, substance abuse, pathological gambling and cognitive aspects of Parkinson Disease.The online version of this article (10.1186/s40359-019-0332-x) contains supplementary material, which is available to authorized users. The concept of inhibitory control in human cognition can be approached from its basic motor and reflexive aspects to elaborate control processes such as planned actions and strategies , it can reactive control process  group analyzes. Between conditions [Increasing Vs Decreasing]. GLM Univariate between blocks [effect of order] Group analysis for block comparison between groups [ESRG Vs URG]. Table S6. Reward Stop Signal Task (RSST). Group analysis for block comparison between groups [ESRG Vs URG] and between conditions [Increasing Vs Decreasing]. GLM Univariate between blocks [effect of order]. Table S7. Group analysis for reward magnitude comparison between groups [ESRG Vs URG] and between conditions [Increasing Vs Decreasing]. GLM Univariate between rewards [effect of reward magnitudes] Figure S1. Time performances for Expected (ESRG) and Unexpected (URG) reward groups. (PDF 445 kb)"}
+{"text": "A 57-year-old woman with a 15-year history of a slowly growing fibrous dysplastic maxillary bony tumor underwent total left maxillectomy with subsequent maxillary reconstruction with anterolateral thigh single perforator free flap and orbital floor reconstruction with a titanium mesh implant. A 57-year-old woman presented with a 15-year history of a slowly growing left maxillary bony tumor causing significant proptosis and distortion of her left orbit with associated loss of vision . The patWhat are the material options for reconstruction of the orbital floor after orbital-content sparing total maxillectomy?What are the options for soft tissue reconstruction after total maxillectomy?What is fibrous dysplasia?What are the treatment options for fibrous dysplasia tumors?Numerous materials, both alloplastic and autogenous, are available for reconstructing damaged or resected orbital walls to restore orbital structure and volume. Autogenous calvarial bone graft has traditionally been the standard material used and shown to have a slight advantage in donor site morbidity over the use of rib and ilium.The use of local, regional, or distant free flaps for soft tissue reconstruction after total maxillectomy can result in good function and aesthetics. Free flaps are commonly used; however, a temporalis muscle flap may be used for small- to medium-sized palate defects.GNAS1) gene, which encodes the alpha subunit of the stimulatory G protein.10Fibrous dysplasia is a noninherited developmental anomaly of bone where bone marrow in the medullary cavity is replaced by fibrous connective tissue and poorly formed trabecular bone.Incidentally discovered, asymptomatic, radiographically characteristic fibrous dysplasia lesions do not require further assessment, and follow-up radiographs every 6 months to look for new progression are recommended.A 57-year-old woman with a 15-year history of a slowly growing fibrous dysplastic maxillary bony tumor underwent total left maxillectomy with subsequent maxillary reconstruction with anterolateral thigh single perforator free flap and orbital floor reconstruction with a titanium mesh implant."}
+{"text": "The remainder of laboratory studies were normal. Computed tomography (CT) images were obtained  with periumbilical and left upper quadrant abdominal pain. The pain began abruptly 12 hours prior to presentation and was worsening. Her pain increased with supine position and was associated with nausea and vomiting. Her past medical history was significant for hypertension, gastroesophageal reflux disease and obesity. Prior to presentation in our ED, she underwent a laparoscopic Roux-en-Y procedure for weight loss 10 years prior at an outside hospital. On arrival, pertinent vitals included a heart rate of 115 beats per minute, 20 breaths per minute and blood pressure of 190/100 mmHg. Laboratory studies in the ED were significant for a leukocytosis  imaging showing a characteristic \u201cswirl sign.\u201dWhat is the major impact of the images?While the surgically altered abdomen may seem intimidating anatomically, there are tell-tale abnormalities that can be easily recognized on CT by the informed physician.How might this improve emergency medicine practice?We can be better advocates for bariatric surgery patients by knowing their potential post-operative complications and associated findings on imaging."}
+{"text": "We present a 31-year-old male who sustained an isolated stellate corneal laceration associated with an open globe injury. The patient presented with mild, right eye pain one hour after glass was sustained to the face during a motor vehicle collision. Visual acuity was 20/100 (baseline 20/20), but no obvious facial or ocular trauma was noted. Extraocular movements were intact. Slit lamp examination revealed a central stellate corneal laceration, peaked 4mm non-reactive pupil, flat anterior chamber, and a falsely negative Seidel sign . IntraocOcular trauma accounts for roughly 3% of emergency department visits and is a major cause of unilateral visual impairment and permanent visual loss in young individuals.Documented patient informed consent and/or Institutional Review Board approval has been obtained and filed for publication of this case report.What do we already know about this clinical entity?Open globe rupture is an ophthalmologic emergency. Speedy recognition by the emergency department provider and ophthalmologic intervention are essential to restoring functional outcome.What is the major impact of the image(s)?A globe rupture with false negative Seidel sign is a rare but known occurrence when ocular contents \u201cplug\u201d the opening, as seen in this patient image.How might this improve emergency medicine practice?The case highlights the importance of good clinical exam after ocular trauma. Providers should consider further workup with computed tomography imaging with any injury involving high-velocity metal or glass."}
+{"text": "Metastases to the orbit occur rarely in midgut neuroendocrine tumor (NET) patients with only 20 cases reported to date. Patients typically present with bilateral involvement of the recti muscles and experience symptoms such as diplopia, proptosis, and decreased vision. Although orbital MRI remains the gold standard for imaging orbital disease, many orbital lesions are now detected on somatostatin-receptor (SSTR) based imaging such as 68Ga-DOTATATE PET-CT.Patient 1 is a 72\u2009year-old female with a well-differentiated G3 ileal NET who was incidentally diagnosed with orbital metastases during a hospitalization for pre-septal cellulitis in 2018. Her disease has been controlled with capecitabine rather than local therapy.Patient 2 is a 68\u2009year-old male with a G2 ileal NET who was diagnosed with orbital involvement after developing left peri-orbital swelling in 2017. He was found to have bilateral rectus muscle involvement and was treated with image-guided radiation therapy (IGRT) to both orbits and achieved disease control.Patient 3 is a 63\u2009year-old female with a well-differentiated G3 ileal NET who was incidentally diagnosed with bilateral orbital masses in her recti after undergoing a 68Ga-DOTATATE PET-CT in 2015. She was asymptomatic initially however has now developed diplopia. She will be starting 177Lu-DOTATATE peptide radionuclide receptor therapy (PRRT) shortly.Patient 4 is a 72\u2009year-old male with a grade 2 ileal NET who was incidentally diagnosed with a left lateral rectus metastasis in 2007. This was monitored via surveillance MRI until it began to grow and became symptomatic in 2015. The patient received stereotactic radiation to the site and has been asymptomatic since.Patient 5 is a 61\u2009year-old female with a grade 2 ileal NET who developed progressive diplopia in 2016. Bilateral orbital metastases were noted on orbital MRI and she completed IGRT to the sites shortly thereafter. In the setting of continued growth of the masses she was switched to chemotherapy with capecitabine which has controlled her orbital disease.NETs can metastasize to the orbits. Orbital disease now often is detected on SSTR-based imaging rather than orbital MRI; when found, it changes treatment approach and surveillance for patients. Orbital metastases represent an exceedingly rare metastatic manifestation of neuroendocrine tumors (NETs) and occur through hematogenous dissemination via the carotid and ophthalmic artery . OrbitalThe most common symptoms at presentation for patients with metastatic orbital involvement include diplopia, proptosis, and decreased vision. Other common symptoms include eyelid swelling, chemosis and redness. Unilateral rather than bilateral involvement is more frequent, and the rectus muscles are often involved , 8. The Patients with orbital involvement from NETs typically carry an excellent prognosis with 10-year survival rates of close to 40%, which is in stark contrast to the poor systemic prognosis seen in other malignancies when orbital involvement is detected . This maPatient 1 is a 72-year-old female who was initially diagnosed in 1997 with a well differentiated G3 (Ki-67 20%) metastatic jejunal NET. Her primary tumor was resected after diagnosis and a liver transplant was performed in 1998 for bulky symptomatic liver metastases. She has received a series of therapies including octreotide, lanreotide, and everolimus for her carcinoid syndrome (CS) and disease control. In May 2017, a 68Ga-DOTATATE PET-CT revealed somatostatin receptor (SSTR) avidity in bilateral orbits although she was asymptomatic from a visual symptom standpoint  metastatic ileal NET in 2012. Post-resection of his primary, the patient began treatment with octreotide. Eventually, he enrolled on a clinical trial with 177Lu-DOTATATE PRRT. During a hospitalization in November 2017, while admitted for abdominal pain, he developed left peri-orbital swelling. This prompted an orbital MRI which demonstrated bilateral extraocular masses in his recti muscles  disease on later biopsies. She had stable disease controlled on octreotide until 2014 when she had disease progression which required everolimus, multiple hepatic artery embolizations and debulking of bulky adenopathy in her right paratracheal region. She underwent her first 68Ga-DOTATATE PET-CT in April 2015 which revealed bilateral extraocular masses in her right medial and left infraorbital rectus muscles. She was asymptomatic initially from these lesions; however, during her initial visit at VUMC in June 2018 for consideration of 177Lu-DOTATATE PRRT, due to persistent CS, she mentioned worsening diplopia and visual acuity. A pre-treatment 68Ga-DOTATATE PET-CT was repeated which revealed increased SSTR avidity in the recti at the site of the previously known lesions  metastatic small intestine (not otherwise specified) NET in February 2010. She remained symptom free until April 2014 when she was started on monthly octreotide. In the setting of progressive disease, she subsequently received sunitinib and everolimus. She began to develop progressive diplopia and right ocular pain in August 2016. This prompted an orbital MRI which revealed bilateral recti masses in the right lateral and superior left medial muscles. She was evaluated by radiation oncology shortly thereafter and was treated with IGRT to 52Gy, which completed in October 2016. Although her right ocular pain improved, she had persistent diplopia. Her post-treatment orbital MRI in January 2017 revealed a mild increase in size of her right lateral rectus mass (Fig.\u00a0We have described here five cases of midgut NET patients who presented with orbital metastases at various stages of their disease presentation. Of the five patients, three were initially asymptomatic from their orbital involvement. Four out of the five patients presented with bilateral involvement, which is different from the unilateral predominant pattern described in the literature. This discrepancy may be due to the increased sensitivity of current imaging modalities which capture lesions missed by prior imaging techniques. All the patients had rectus muscle involvement which is the most common orbital structure involved from existing case descriptions Table\u00a0. OrbitalThree of the five patients were treated with external beam radiation; two of these patients received IGRT and one received five fractions of stereotactic radiosurgery. Two of the three patients who received radiation achieved improved visual symptoms and disease control locally. One patient progressed through IGRT, but eventually achieved disease control with capecitabine. Of the two patients who did not receive radiation therapy, one achieved intra-orbital disease control with capecitabine plus temozolomide. We are hopeful the other patient will also achieve orbital disease control with PRRT. None of the patients in our series had any attempt at surgical resection.Prior to the 1980s, orbital exenteration was considered the recommended treatment for orbital metastases . With imOne of the therapeutic areas of great promise in midgut NET is PRRT. 177Lu-DOTATATE PRRT was FDA approved in January 2018 and represents another cytoreductive treatment option available for patients. In Europe, PRRT approaches with other radionuclides such as 90Y have been utilized successfully. 177Lu-DOTATATE PRRT involves targeted radiation where lutetium 177, a beta emitting radionuclide, is conjugated to a SSTR analog and is internalized by neuroendocrine cells expressing SSTR2 . ReportsOrbital metastases are rare, occurring in 2\u20133% of all malignancies . Of the"}
+{"text": "Intracranial lipomas represent approximately 1% of intracranial lesions generally felt to represent the abnormal persistence of the meninx primitiva and are commonly accompanied by various developmental brain abnormalities. We report a case of midline intracranial lipoma and evolving frontal lobe fluid-attenuated inversion recovery (FLAIR) abnormality concerning for glial neoplasm\u00a0in a patient with intractable epilepsy.\u00a0Our case shows evolving magnetic resonance imaging (MRI) features over two decades raising suspicion for low-grade neoplasm which was ultimately found to represent cortical dysplasia. Intracranial lipomas are rare lesions generally felt to represent the abnormal persistence of the meninx primitiva. They represent approximately 1% of intracranial lesion and are commonly accompanied by various developmental brain abnormalities. Most lipomas reported are located near the midline and are pericallosal in nature with agenesis of the corpus callosum commonly observed ,3. We reOur patient is a 43-year-old ambidextrous male with a 20-year history of intractable seizures. His seizure semiology typically included a hot flash and other sensory auras with evolution into focal motor activity predominately on the right. Workup for seizure etiology included magnetic resonance imaging (MRI) revealing the large midline lipoma, partial callosal agenesis, and an adjacent lesion in the left frontal lobe presumed to represent a glial neoplasm based on the radiographic appearance. The left anterior medial frontal lobe lesion consisted of nodular calcification with peripheral enhancement and extensive FLAIR signal changes involving bilateral cingulate gyri and the left frontal lobe Figure .Medical management efforts had failed to control his seizures and he was referred for surgical treatment options. The enhancing lesion was noted to progress with additional imaging and the extent of edema also expanded. The concern for progressive glial neoplasia and poor seizure control prompted a recommendation for surgical resection. The decision was made to proceed with neuronavigation-guided resection of the left frontal enhancing mass and partial frontal lobectomy utilizing intraoperative electroencephalogram (EEG), cortical mapping, and somatosensory evoked potentials (SSEP) monitoring.Intraoperative samples sent for frozen pathology were found to have Rosenthal fibers and focal calcification and felt to likely represent glial neoplasm.\u00a0Permanent pathologic evaluation revealed a lipoma and focal cortical dysplasia, Palmini Type IA, in the adjacent brain.\u00a0The mild cortical architectural abnormalities and associated white matter gliosis can be seen on hematoxylin and eosin (H&E) and glial fibrillary acidic protein (GFAP) stains and neurofilament protein (NFP) staining in the areas of gliosis shows no evidence of dysmorphic neurons, giant neurons or balloon cells Figure .Post-operative imaging Figure  shows a Post-resection recovery included a moderate supplementary motor area syndrome including hemiparesis, delayed speech, and changes in effect. These changes gradually resolved and the patient was found to be neurologically intact at outpatient follow-up. Seizure control occurred immediately after resection.\u00a0Antiepileptic agents were continued and gradually removed over subsequent months without recurrence. The patient remained seizure-free\u00a0three years post resection.\u00a018-month follow-up imaging found stable T2/FLAIR changes with small unchanged areas of perilesional enhancement Figure .Intracranial lipomas are commonly accompanied by other abnormalities of development which are likely a result of a defect in differentiation of the meninx primitiva during neural tube flexion. Although various cortical abnormalities have been described in association with intracranial lipomas, the underlying pathology remains poorly understood ,5. A fewWhile concurrent abnormalities are often related to a common underlying developmental pathology, this is simply unknown.\u00a0In the setting of lipomas, cortical dysplasias may change over time."}
+{"text": "Atrioventricular groove hematomas during mitral valve surgery range from simple hematomas to complex atrioventricular disruptions that cause frank rupture with massive bleeding and subsequent mortality. A small or moderate-sized hematoma is reported to be present in the left atrioventricular groove in 10 to 30% of all patients immediately after mitral valve replacement. Despite the fact that atrioventricular groove hematomas are inherently unstable and unpredictable, conservative strategies are recommended due to the high mortality associated with additional surgical repair. Such conservative strategies, however, would not resolve the potential risk of rupture, and there also appears to be a certain degree of uncertainty to be overcome using the current advances in cardiac surgery.We present a case of atrioventricular hematoma during double valve replacement which was treated with conservative management. A left ventricular pseudoaneurysm developed after surgery, but spontaneously resolved completely within six months. After reflecting on our case, we developed a check sheet, including the anesthesiologist\u2019s transesophageal echocardiography findings, for reasonable intraoperative decision-making regarding conservative management vs. additional surgical repair. Our check sheet helps organize the pathophysiological understanding of the injury and integrates partial findings from complementary viewpoints, and can be used to accurately assess intense situations and develop a common understanding among surgical team members.Our case involved an atrioventricular groove hematoma that occurred during mitral valve surgery and caused a left ventricular pseudoaneurysm. Conservative strategies yielded positive results. We hope our experience and original check sheet will be of value to surgical teams facing similar situations. Atrioventricular groove (AVG) hematomas during mitral valve surgery range from simple hematomas to complex AVG disruptions that cause frank rupture with massive bleeding and subsequent mortality . KirklinA 64-year-old man, with severe multi-valvular disease detected during preoperative evaluation for colon diverticulitis, was referred for heart valve surgery. He had suffered recurrent life-threatening diverticular bleeding and accompanying heart failure. Transthoracic echocardiography (TTE) showed severe aortic regurgitation classified as type II (cusp prolapse) according to the functional classification developed by El Khoury et al., and severe mitral regurgitation caused by degenerative bi-leaflet prolapse with multiple eccentric regurgitant jets, exacerbated by secondary factors, including mitral annular and left ventricular (LV) dilation. Secure mitral repair with a shorter cardiopulmonary bypass (CPB) time would have been difficult due to the complex lesion; double valve replacement (DVR) was a safer and simpler procedure.The anterior leaflet of the mitral valve was excised and its chordae cut at their insertion into the papillary muscles. The posterior leaflet and its subvalvular apparatus were preserved. A 29-mm bovine pericardial bioprosthesis was implanted in the intra-annular position and a 25-mm bovine pericardial bioprosthesis replaced the prolapsed aortic valve .After DVR completion, extensive hematoma occurred surrounding the posterior atrioventricular groove during weaning from CPB. We suspected that deeply placed sutures around the posterior mitral annulus might have cut through the left ventricular wall. Full CPB support, aimed at a prompt reduction of the intraventricular pressure, was re-instituted immediately, and inotropic agents were tapered off to weaken the force of muscular contractions with the hope of suppressing the exacerbation of the injury. Routine intraoperative transesophageal echocardiography (TEE) monitoring was not utilized in this case; stable left ventricular contractility without bleeding was confirmed only by direct inspection before choosing conservative management. The re-weaning process was performed without any hemodynamic instability. The sternum was closed under stable conditions after administration of protamine sulfate.The patient was taken into intensive care and extubated 12\u2009h postoperatively. Postoperative routine TTE was unremarkable, whereas contrast-enhanced, electrocardiography (ECG)-gated, multi-detector computed tomography (CT) imaging on postoperative day 18 revealed a pseudoaneurysm (20\u2009\u00d7\u200912\u2009mm) arising from the posterior wall of the left ventricle just below the implanted mitral valve (Fig.\u00a0Six months postoperatively, the pseudoaneurysm had completely disappeared on CT imaging Fig.\u00a0. Three yRupture of the posterior wall of the left ventricle following mitral valve surgery is a rare but potentially fatal complication . This coAVG hematoma is usually detected at the termination of CPB when the heart starts beating again on its own , 6\u20138. WhWith intraoperative TEE , 7, 8, tAVG hematoma occasionally causes LV pseudoaneurysms in the chronic phase , 5. AlthWe presented a case of AVG hematoma that occurred during mitral valve surgery and caused left ventricular pseudoaneurysm. Conservative strategies yielded positive results in our case. We hope our experience and original check sheet designed for reasonable intraoperative decision-making are valuable for surgical team members facing similar situations."}