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TGF-β inducible early gene 1 regulates osteoclast differentiation and survival by mediating the NFATc1, AKT, and MEK/ERK signaling pathways. TGF-β Inducible Early Gene-1 (TIEG1) is a Krüppel-like transcription factor (KLF10) that was originally cloned from human osteoblasts as an early response gene to TGF-β treatment. As reported previously, TIEG1(-/-) mice have decreased cortical bone thickness and vertebral bone volume and have increased spacing between the trabeculae in the femoral head relative to wildtype controls. Here, we have investigated the role of TIEG1 in osteoclasts to further determine their potential role in mediating this phenotype. We have found that TIEG1(-/-) osteoclast precursors differentiated more slowly compared to wildtype precursors in vitro and high RANKL doses are able to overcome this defect. We also discovered that TIEG1(-/-) precursors exhibit defective RANKL-induced phosphorylation and accumulation of NFATc1 and the NFATc1 target gene DC-STAMP. Higher RANKL concentrations reversed defective NFATc1 signaling and restored differentiation. After differentiation, wildtype osteoclasts underwent apoptosis more quickly than TIEG1(-/-) osteoclasts. We observed increased AKT and MEK/ERK signaling pathway activation in TIEG1(-/-) osteoclasts, consistent with the roles of these kinases in promoting osteoclast survival. Adenoviral delivery of TIEG1 (AdTIEG1) to TIEG1(-/-) cells reversed the RANKL-induced NFATc1 signaling defect in TIEG1(-/-) precursors and eliminated the differentiation and apoptosis defects. Suppression of TIEG1 with siRNA in wildtype cells reduced differentiation and NFATc1 activation. Together, these data provide evidence that TIEG1 controls osteoclast differentiation by reducing NFATc1 pathway activation and reduces osteoclast survival by suppressing AKT and MEK/ERK signaling. | Has the protein TIEG1 been associated with apoptosis? | 53386282d6d3ac6a3400005a_017 | yes |
Patient-reported depression severity measured by the PHQ-9 and impact on work productivity: results from a survey of full-time employees in the United States. OBJECTIVE: To examine the burden of depression on work productivity. METHODS: Full-time employees with diagnosed depression were surveyed using the Patient Health Questionnaire for depression severity, and the Health and Work Performance Questionnaire and Work Productivity and Activity Impairment (WPAI) questionnaire for absenteeism and presenteeism. RESULTS: Of the 1051 employees with depression, 40.3% had no depressive symptoms at the time of the survey, 30.4% had mild depression, 15.8% had moderate depression, 7.8% had moderately severe depression, and 5.8% had severe depression. All levels of depression were associated with decreased work productivity. Presenteeism was positively associated with severity of depression (Health and Work Performance Questionnaire, P < 0.0001; WPAI, P < 0.0001). Absenteeism was significantly positively associated with severity of depression using the WPAI. CONCLUSIONS: Decreased overall productivity was seen at all levels of depression, and as severity increased, presenteeism and absenteeism worsened. | Is there an association between presenteeism and depression? | 54f49e56d0d681a040000004_015 | yes |
Discovery and characterization of a novel non-competitive inhibitor of the divalent metal transporter DMT1/SLC11A2. Divalent metal transporter-1 (SLC11A2/DMT1) uses the H(+) electrochemical gradient as the driving force to transport divalent metal ions such as Fe(2+), Mn(2+) and others metals into mammalian cells. DMT1 is ubiquitously expressed, most notably in proximal duodenum, immature erythroid cells, brain and kidney. This transporter mediates H(+)-coupled transport of ferrous iron across the apical membrane of enterocytes. In addition, in cells such as to erythroid precursors, following transferrin receptor (TfR) mediated endocytosis; it mediates H(+)-coupled exit of ferrous iron from endocytic vesicles into the cytosol. Dysfunction of human DMT1 is associated with several pathologies such as iron deficiency anemia hemochromatosis, Parkinson's disease and Alzheimer's disease, as well as colorectal cancer and esophageal adenocarcinoma, making DMT1 an attractive target for drug discovery. In the present study, we performed a ligand-based virtual screening of the Princeton database (700,000 commercially available compounds) to search for pharmacophore shape analogs of recently reported DMT1 inhibitors. We discovered a new compound, named pyrimidinone 8, which mediates a reversible linear non-competitive inhibition of human DMT1 (hDMT1) transport activity with a Ki of ∼20μM. This compound does not affect hDMT1 cell surface expression and shows no dependence on extracellular pH. To our knowledge, this is the first experimental evidence that hDMT1 can be allosterically modulated by pharmacological agents. Pyrimidinone 8 represents a novel versatile tool compound and it may serve as a lead structure for the development of therapeutic compounds for pre-clinical assessment. | Could divalent metal transporter 1 deficiency lead to anemia? | 58bd672d02b8c60953000011_003 | yes |
[Turcot syndrome]. Turcot syndrome is the association of colorectal polyposis with primary neuroepithelial tumors of the central nervous system such as glioblastoma and medulloblastoma. Including putative patients, more than 150 familial or sporadic cases of the syndrome have been reported in literature. Since early reports, there is considerable controversy regarding the modality of genetic transmission and the distinction from other syndromes like familial adenomatous polyposis(FAP). Recent molecular evidence suggests that Turcot syndrome could be divided into the following two entities based on the distinct genetic backgrounds. (1) True Turcot syndrome(autosomal recessive): Intestinal polyps are less in number(< 100), large in size and apt to transform to the malignant tumor. Brain tumor is mainly diagnosed as glioblastoma or astrocytoma and mismatch repair genes might be involved. (2) FAP-associated type(autosomal dominant): Predisposing to medulloblastoma. | Is Turcot syndrome associated with glioblastoma? | 533581f5d6d3ac6a3400004d_010 | yes |
[New anticoagulants - direct factor Xa-inhibitors]. The direct oral factor Xa-inhibitors are at present in clinical use as antithrombotics, after their efficiency and safety have been proved in clinical studies. Three products are actually in the market, rivaroxaban (Xarelto®) apixaban (Eliquis®) and edoxaban (Lixiana®). Efficacy and safety have been tested for rivaroxaban and apixaban in large study programmes with more than 60'000 patients each. For edoxaban large phase III studies are under way. Based on these data rivaroxaban was registered in the EU and CH for primary prophylaxis against thrombosis after major orthopaedic surgery, such as hip- and knee-joint protheses, for treatment and prophylaxis of deep vein thrombosis and pulmonary embolism and for prophylaxis against thromboembolic stroke in patients with atrial fibrillation. Apixaban is presently registered in the EU and CH for prophylaxis against thrombosis after major orthopaedic surgery, Edoxaban is registered only in Japan for the same indication. These products have been shown to be non-inferior or superior compared with vitamin K antagonists or low-molecular weight heparins, they are administered once or twice a day, they do not need laboratory monitoring. But they have disadvantages also, they depend on renal clearance, they can interact with other medicaments and they lack a specific antidote. In total, though, they are considered as a progress for the appropriate patients in terms of quality of treatment. | Are there any specific antidotes for rivaroxaban? | 532f08b8d6d3ac6a34000029_000 | no |
Subacute sclerosing panencephalitis: a case report. Subacute sclerosing panencephalitis (SSPE) is a progressive neurological disorder of childhood and early adolescence caused by persistent defective measles virus. Clinical manifestations appear many years after the acute measles infection. The incidence of SSPE has substantially declined after the introduction of an effective vaccine. We report a case of a child with SSPE that began with atonia, dysarthria, and intellectual deterioration without the presence of any particular EEG anomalies. We have reported this girl who was affected by this severe affliction in the hope that, because of the rarity of SSPE, it would not go undiagnosed. | Is subacute sclerosing panencephalitis caused by the Measles vaccine? | 5aa3fa73d6d6b54f79000008_007 | no |
Telomerase-specific oncolytic virotherapy for human cancer with the hTERT promoter. Replication-selective tumor-specific viruses present a novel approach for treatment of neoplastic disease. These vectors are designed to induce virus-mediated lysis of tumor cells after selective viral propagation within the tumor. For targeting cancer cells, there is a need for tissue- or cell-specific promoters that can express in diverse tumor types and are silent in normal cells. Recent advances in molecular biology have fostered remarkable insights into the molecular basis of neoplasm. Telomerase activation is considered to be a critical step in carcinogenesis and its activity correlates closely with human telomerase reverse transcriptase (hTERT) expression. Since only tumor cells that express telomerase activity would activate this promoter, the hTERT proximal promoter allows for preferential expression of viral genes in tumor cells, leading to selective viral replication. We constructed an attenuated adenovirus 5 vector (Telomelysin, OBP-301), in which the hTERT promoter element drives expression of E1A and E1B genes linked with an internal ribosome entry site (IRES). Telomelysin replicated efficiently and induced marked cell killing in a panel of human cancer cell lines, whereas replication as well as cytotoxicity was highly attenuated in normal human cells lacking telomerase activity. Thus, the hTERT promoter confers competence for selective replication of Telomelysin in human cancer cells, an outcome that has important implications for the treatment of human cancers. This article reviews recent findings in this rapidly evolving field: cancer therapeutic and cancer diagnostic approaches using the hTERT promoter. | Do normal cells express the protein TERT? | 58cd6d9702b8c6095300003c_000 | no |
Brown and beige fat in humans: thermogenic adipocytes that control energy and glucose homeostasis. Brown adipose tissue (BAT), a specialized fat that dissipates energy to produce heat, plays an important role in the regulation of energy balance. Two types of thermogenic adipocytes with distinct developmental and anatomical features exist in rodents and humans: classical brown adipocytes and beige (also referred to as brite) adipocytes. While classical brown adipocytes are located mainly in dedicated BAT depots of rodents and infants, beige adipocytes sporadically reside with white adipocytes and emerge in response to certain environmental cues, such as chronic cold exposure, a process often referred to as "browning" of white adipose tissue. Recent studies indicate the existence of beige adipocytes in adult humans, making this cell type an attractive therapeutic target for obesity and obesity-related diseases, including type 2 diabetes. This Review aims to cover recent progress in our understanding of the anatomical, developmental, and functional characteristics of brown and beige adipocytes and discuss emerging questions, with a special emphasis on adult human BAT. | Do brown fat cells produce heat? | 58ca906a02b8c6095300002e_020 | yes |
Lymphotoxin beta receptor induces sequential activation of distinct NF-kappa B factors via separate signaling pathways. Lymphotoxin beta receptor (LTbetaR)-induced activation of NF-kappaB in mouse embryo fibroblasts was mediated by the classical pathway and by an alternative or second pathway. The classical pathway involved the IkappaB kinase (IKK)beta- and IKKgamma-dependent degradation of IkappaBalpha and resulted in the rapid but transient activation of primarily RelA-containing NF-kappaB dimers. The alternative or second pathway proceeded via NF-kappaB-inducing kinase (NIK)-, IKKalpha-, and protein synthesis-dependent processing of the inhibitory NF-kappaB2 p100 precursor protein to the p52 form and resulted in a delayed but sustained activation of primarily RelB-containing NF-kappaB dimers. This second pathway was independent of the classical IKK complex, which is governed by its central IKKgamma regulatory subunit. The sequential engagement of two distinct pathways, coupled with the negative feedback inhibition of RelA complexes by NF-kappaB-induced resynthesis of IkappaBalpha, resulted in a pronounced temporal change in the nature of the NF-kappaB activity during the course of stimulation. Initially dominant RelA complexes were replaced with time by RelB complexes. Therefore, the alternative activation path mediated by processing of p100 was necessary for sustained NF-kappaB activity in mouse embryo fibroblasts in response to LTbetaR stimulation. Based on the phenotype of mice deficient in various components of the LTbetaR-induced activation of p100 processing, we conclude that this pathway is critically involved in the function of stromal cells during the generation of secondary lymphoid organ microarchitectures. | Is p100 the precursor protein molecule of the NF-kappaB transcription factor subunit p50? | 55088e412e93f0133a000001_016 | no |
Regulatory T cells attenuate neuropathic pain following peripheral nerve injury and experimental autoimmune neuritis. Neuroimmune crosstalk in neuropathic pain is a key contributor to pain hypersensitivity following nervous system injury. CD4+CD25+Foxp3+ regulatory T cells (Tregs) are endogenous immune suppressors, reducing T-cell proliferation and proinflammatory cytokine production. Currently, the role of Tregs in neuropathic pain is unknown. In this study, we tested the effects of expanding Tregs on pain hypersensitivity and neuroinflammation in 2 models of neuropathy; sciatic nerve chronic constriction injury and experimental autoimmune neuritis in rats. Following chronic constriction injury, treatment with CD28 superagonist (CD28SupA), a Treg population expander, significantly increased Tregs in the lymphoid tissues, injured sciatic nerve, and lumbar spinal cord of rats. CD28SupA treatment led to a significant reduction in mechanical pain hypersensitivity, alongside a decrease in the numbers of infiltrating T cells, macrophages, and antigen-presenting cells in the sciatic nerve and dorsal root ganglia. In experimental autoimmune neuritis-affected rats, CD28SupA treatment resulted in a significant improvement in disease severity and in mechanical pain hypersensitivity. This was associated with a reduction in the numbers of T cells, macrophages, and antigen-presenting cells in the sciatic nerve and dorsal root ganglia, and reduced activation of microglia and infiltration of T cells in the spinal cord. Furthermore, depletion of Tregs by a CD25 antibody in mice with a partial sciatic nerve ligation resulted in prolonged mechanical pain hypersensitivity. These findings suggest that Tregs play a role in endogenous recovery from neuropathy-induced pain. Thus, this T-cell subset may be specifically targeted to alleviate chronic neuropathic pain. | Do T-Cells regulate neuropathic pain? | 58c0825502b8c6095300001b_005 | yes |
Ophthalmic features of minimal pigment oculocutaneous albinism. PURPOSE: The purpose of this study is to describe the heterogeneous phenotype of individuals with an unusual type of albinism--minimal pigment oculocutaneous albinism. METHODS: Nine patients with minimal pigment oculocutaneous albinism were identified and followed for up to 11 years. The criteria were the presence of oculocutaneous albinism in association with low hairbulb tyrosinase activity in the patient and disparate activity in the parents with one parent having normal activity and the other having low tyrosinase activity. Changes in skin, hair, and ocular pigment were followed as the patients matured. As a measure of ocular pigment, iris transillumination and macular transparency were graded according to a previously published scheme. RESULTS: Patients were born with white scalp hair and skin, and nystagmus developed. Visual acuity was reduced to 20/50 to 20/200 for the group, but in one patient vision improved with maturity. Irides were blue. In seven patients, iris pigment developed, which was detected by transillumination with slit-lamp biomicroscopy, including the one patient with improved visual acuity. All patients had foveal hypoplasia, and melanin pigment in the fundi could not be detected by clinical examination. Visual acuity in the group did not correlate directly with the presence or development of iris transillumination or macular transparency. The pedigrees were consistent with an autosomal recessive inheritance pattern. CONCLUSION: This unique type of oculocutaneous albinism has heterogeneous clinical features. Minimal pigment oculocutaneous albinism appears to represent a new type of tyrosinase-related oculocutaneous albinism (OCA1MP). | Does oculocutaneous albinism show an autosomal recessive inheritance? | 58cbb55402b8c60953000033_010 | yes |
An overview on the genetic of rheumatoid arthritis: a never-ending story. Rheumatoid arthritis (RA) is a chronic, systemic, inflammatory, multi-factorial disease sustained by environmental and genetic factors. These seem to be necessary but not sufficient in the disease development, nonetheless they can be responsible of different clinical pictures and response to therapy, and they can represent potential therapeutic targets. Several genes have been indicated so far in the pathogenesis of RA. The most important region is the Human Leukocyte Antigen (HLA) that contributes to approximately half of the genetic susceptibility for RA. The association seems to be stronger or specific for anti-citrullinated protein antibodies positive disease. Several alleles in the epitope-recognition part of the HLA molecule that show the highest association with RA susceptibility, also share a common string of amminoacid residues (the so-called shared-epitope hypothesis). Other variants in potentially pathogenic genes located in non-MHC regions have been implicated by recently performed genome wide analysis studies. These genes include PTPN22, TRAF1-C5, PADI4, STAT4. Other polymorphisms seem to be responsible for more aggressive disease phenotype such as those located at TNF, IL-1, IL-6, IL-4, IL-5, OPN, PRF1. However, still nowadays, the genetic background of RA remains to be clearly depicted, and the efforts in the post-genomic era can bring to an estimation of the real likelihood of the genetic effect on RA. Finally, the discovery of new genes associated with the disease can be relevant in finding potential biomarkers, potentially useful in disease diagnosis and treatment. | Is the PTPN22 gene a biomarker for Rheumatoid Arthritis? | 52e7870a98d023950500001a_002 | yes |
Case report of Kummell's disease with delayed onset myelopathy and the literature review. INTRODUCTION: Kummell's disease is an avascular necrosis of the vertebral body, secondary to a vertebral compression fracture. This entity is characterised by the gradual development in time of a vertebral body collapse following a trivial spinal trauma, involving a worsening back pain associated with a progressive kyphosis. PURPOSES: The aim of this article is to carry out an international literature review regarding Kummell's disease, addressing its physiopathology, histopathology, clinical presentation, radiological characteristics and treatment modalities; at the same time, the literature is updated through the description of a new and interesting case, symbol of the pathology long-term potential complications, if not diagnosed and therefore not suitably treated. CASE REPORT: A patient with osteoporosis, following a slight spinal trauma, suffered a progressive necrosis of the D11 body; although the radiological exams showed a constant worsening of the thoracic-lumbar kyphosis and a restriction of the spinal canal, in another medical centre he was only treated with a corset and painkillers. A year after the injury, motor deficits concerning the lower limbs appeared. He was then sent to us and indication for posterior internal fixation was given. On the basis of both his medical history and radiological and histological findings, Kummell's disease was diagnosed. CONCLUSION: It is necessary to have a complete knowledge of the clinical, pathological and radiological characteristics of Kummell's disease, so as to follow a correct diagnostic course enabling to prepare the most suitable therapy. | Is Kummell’s disease an avascular necrosis of the vertebral body? | 5a787544faa1ab7d2e00000b_005 | yes |
[Adverse effects of marijuana]. When admitted in an emergency unit, young patients often present acute neurological effects of smoked marijuana. Other chronic adverse effects of marijuana are probably underestimated: postural syncope, arteritis, chronic bronchitis, amnesia. Marijuana may trigger a myocardial infarction and have a vasospastic effect. Marijuana has impairing effects on driving ability. Smoked marijuana is a potential respiratory tract carcinogen. | Is marijuana use associated with increased risk for stroke? | 5149e23dd24251bc0500004b_001 | yes |
Surgical treatment of endometriosis. In this review, the pitfalls that still exist with the surgical treatment of endometriosisassociatedpelvic pain have been discussed and the best evidence regarding various aspects of surgical techniques have been reviewed. When laparoscopy is performed to evaluate a woman with pelvic pain symptoms, it is important she be counseled that the primary function of the surgery is to confirm the presence (and allow surgical treatment) of endometriosis, and that it is not the penultimate diagnostic modality for her pelvic pain. There are many etiologies of pelvic pain that present with symptoms resembling those of endometriosis-associated pelvic pain that are not diagnosable with laparoscopy, such as interstitial cystitis and irritable bowel syndrome. It is unfortunate that many women are left with the belief that if a laparoscopy fails to provide a diagnosis of a pain generator, then it means there are no diagnoses other than that the “pain is in her head,” often disparagingly termed “supratentorial” byclinicians. In fact, the pain-related diagnoses that are amenable to and possibly require a laparoscopy are quite limited, a group of diagnoses that this author terms the “dirty dozen” because there are just 12, and only the first 4 have good evidence to clearly associate them with chronic pelvic pain:1. Endometriosis 2. Ovarian remnant syndrome 3. Pelvic inflammatory disease 4. Tuberculous salpingitis 5. Adhesions 6. Benign cystic mesothelioma 7. Postoperative peritoneal cysts 8. Adnexal cysts (nonendometriotic)9. Chronic ectopic pregnancy 10. Endosalpingiosis 11. Residual accessory ovary 12. Hernias: ventral, inguinal, femoral, spigelian.I would argue that diagnostic laparoscopy in modern gynecology has a limited, if any role, and that when laparoscopy is planned for women with chronic pelvic pain, it should be with a very high suspicion of a diagnosis and with plans to treat the disease operatively. In this era, a negative diagnostic laparoscopy should be a rare event. | Is irritable bowel syndrome more common in women with endometriosis? | 54f08d4a94afd61504000016_010 | yes |
Heterotrimeric GAIT complex drives transcript-selective translation inhibition in murine macrophages. The gamma interferon (IFN-γ)-activated inhibitor of translation (GAIT) complex in human myeloid cells is heterotetrameric, consisting of glutamyl-prolyl-tRNA synthetase (EPRS), NS1-associated protein 1 (NSAP1), ribosomal protein L13a, and glyceraldehyde-3-phosphate dehydrogenase (GAPDH). The complex binds a structural GAIT element in the 3' untranslated region of VEGF-A and other inflammation-related transcripts and inhibits their translation. EPRS is dually phosphorylated by cyclin-dependent kinase 5 (Cdk5) at Ser(886) and then by a Cdk5-dependent-AGC kinase at Ser(999); L13a is phosphorylated at Ser(77) by death-associated protein kinases DAPK and ZIPK. Because profound differences in inflammatory responses between mice and humans are known, we investigated the GAIT system in mouse macrophages. The murine GAIT complex is heterotrimeric, lacking NSAP1. As in humans, IFN-γ activates the mouse macrophage GAIT system via induced phosphorylation of EPRS and L13a. Murine L13a is phosphorylated at Ser(77) by the DAPK-ZIPK cascade, but EPRS is phosphorylated only at Ser(999). Loss of EPRS Ser(886) phosphorylation prevents NSAP1 incorporation into the GAIT complex. However, the triad of Ser(999)-phosphorylated EPRS, Ser(77)-phosphorylated L13a, and GAPDH forms a functional GAIT complex that inhibits translation of GAIT target mRNAs. Thus, translational control by the heterotrimeric GAIT complex in mice exemplifies the distinctive species-specific responses of myeloid cells to inflammatory stimuli. | Is the enzyme EPRS phosphorylated? | 58cd522902b8c60953000038_003 | yes |
Abnormal capillary permeability and endothelial dysfunction in hypertension with comorbid Metabolic Syndrome. PURPOSE: Metabolic Syndrome as defined by ATP III criteria, a constellation of risk factors associated with insulin resistance, predisposes to premature atherosclerosis and early coronary events. Whether that negative risk profile is associated with endothelial dysfunction remains to be established. MATERIALS AND METHODS: Transcapillary escape rate of albumin (TERalb), a measure of capillary permeability and integrity of systemic capillary endothelium, and forearm vasodilation to intra-arterial acetylcholine (ACH), an index of nitric oxide (NO)-mediated vasomotor dysfunction, were assessed in 24 non-diabetic, uncomplicated hypertensive men with Metabolic Syndrome according to ATP III criteria (hypertension with at least two additional traits such as high triglycerides, low HDL, abdominal obesity, impaired fasting or post-load plasma glucose). Twelve age-matched lean normal hypertensive patients with normal lipid and glucose profile and nine normotensive subjects were the controls. All patients underwent lipids determination and fasting and post-OGTT insulin assessment; HOMA-IR was the index of insulin resistance. RESULTS: TERalb was higher in hypertensive patients with Metabolic Syndrome, without differences between hypertensive and normotensive controls. Blood pressure (BP), lipids, plasma glucose, insulin levels and HOMA-IR were unrelated to TERalb. Responses to acetylcholine were selectively attenuated in metabolic patients and, on an individual basis, related only to HDL cholesterol levels, independent of LDL cholesterol, BP, body size, triglycerides, and HOMA-IR values. No relationship existed between responses to acetylcholine and TERalb. CONCLUSIONS: Altered systemic capillary permeability characterizes insulin-resistant hypertensive patients with Metabolic Syndrome. That defect, which may promote early atherosclerosis development, coexists with blunted endothelial-mediated vasodilation, indicating a pervasive abnormality of endothelial function. | Is transcapillary albumin escape altered in diabetic patients? | 5321b4959b2d7acc7e000007_000 | yes |
Transient inhibition of poly(ADP-ribose) polymerase expression and activity by Toxoplasma gondii is dispensable for parasite-mediated blockade of host cell apoptosis and intracellular parasite replication. Poly(ADP-ribose) polymerase-1 (PARP-1; EC 2.4.2.30) is an abundant nuclear protein that is involved in DNA repair, cell cycle control, programmed cell death and transcriptional regulation. It also plays critical roles in the pathogenesis of inflammatory disorders. Here we have performed a detailed analysis of the interplay between the apicomplexan parasite Toxoplasma gondii and host cell PARP and its consequences for the host-parasite relationship. Our results have shown that T. gondii significantly decreased PARP expression in its host cells within 10min of infection but that the amount of PARP normalized during prolonged infection. Importantly, down-regulation of PARP expression after infection abrogated the ADP-ribosylation of acceptor proteins in response to oxidative stress. Overexpression of PARP in RAW264.7 cells revealed that elevated amounts of PARP neither affected host cell invasion nor intracellular development of T. gondii in non-stimulated or IFN-gamma/LPS-stimulated monocytes/macrophages. Furthermore, measurements of the activities of effector caspases 3 and 7 indicated that the blockade of host cell apoptosis by T. gondii occurs independently of the inhibition of PARP after infection. These findings suggest that the prominent decrease of host cell PARP and poly(ADP-ribos)ylation after parasitic infection do not affect the intracellular development of T. gondii in vitro. | Is poly (ADP- ribosylation) involved in transcriptional control? | 53380000d6d3ac6a34000059_001 | yes |
Recurrent BRAF kinase fusions in melanocytic tumors offer an opportunity for targeted therapy. BRAF is the most prevalent oncogene and an important therapeutic target in melanoma. In some cancers, BRAF is activated by rearrangements that fuse its kinase domain to 5' partner genes. We examined 848 comparative genomic hybridization profiles of melanocytic tumors and found copy number transitions within BRAF in 10 tumors, of which six could be further characterized by sequencing. In all, the BRAF kinase domain was fused in-frame to six N-terminal partners. No other mutations were identified in melanoma oncogenes. One of the seven melanoma cell lines without known oncogenic mutations harbored a similar BRAF fusion, which constitutively activated the MAP kinase pathway. Sorafenib, but not vemurafenib, could block MAP kinase pathway activation and proliferation of the cell line at clinically relevant concentrations, whereas BRAF(V) (600E) mutant melanoma cell lines were significantly more sensitive to vemurafenib. The patient from whom the cell line was derived showed a durable clinical response to sorafenib. | Are BRAF mutations common in melanoma? | 5512c91b6a8cde6b7200000b_005 | yes |
Overexpression of microRNA-21 regulating PDCD4 during tumorigenesis of liver fluke-associated cholangiocarcinoma contributes to tumor growth and metastasis. MicroRNA, an endogenous noncoding RNA modulating gene expression, is a key molecule that by its dysregulation plays roles in inflammatory-driven carcinogenesis. This study aimed to investigate the role of oncomiR miR-21 and its target, the programmed cell death 4 (PDCD4) in tumor growth and metastasis of the liver fluke Opisthorchis viverrini-associated cholangiocarcinoma (CCA). The expression levels of miR-21 and PDCD4 were analyzed using the TaqMan miRNA expression assay and immunohistochemistry in liver tissues of both O. viverrini plus N-nitrosodimethylamine (NDMA)-treated hamsters and human CCA samples (n=23 cases). The functional assay for miR-21 was performed in CCA cell lines by the anti-miR-21 and pre-miR-21 transfection procedures. The peak of miR-21 levels were reached at 2 (hyperplastic lesions) and 6 (CCA) months of the O. viverrini plus NDMA-induced group and had a reverse response with its target PDCD4 proteins. In human CCA, miR-21 was overexpressed in tumor tissues when compared with nontumor tissues (P=0.0034) and had a negative correlation with PDCD4 protein (P=0.026). It was also found that high expression of miR-21 was significantly correlated with shorter survival (P<0.05) and lymph node metastasis (P=0.037) of CCA patients. Transient transfection of pre-miR-21 reduced the PDCD4 level and resulted in an increase of M213 CCA cell growth and wound-induced migration ability. These results indicated that miR-21 plays a role in the carcinogenesis and metastasis of O. viverrini-associated CCA by suppressing the function of PDCD4. Modulation of aberrantly expressed miR-21 may be a useful strategy to inhibit tumor cell phenotypes or improve response to chemotherapy. | Is miR-21 related to carcinogenesis? | 511a4ec01159fa8212000004_031 | yes |
Mesenchymal stem cells as treatment for MS - progress to date. The unmet need for therapies capable of repairing the central nervous system (CNS) damage occurring in many diseases including multiple sclerosis (MS) has sparked the interest of the neurological community for stem cell-based therapies. An exhaustive amount of preclinical data has shown that the intravenous administration of mesenchymal stem cells (MSC), a subset of progenitor cells isolated from many mesodermal tissues, effectively ameliorates experimental autoimmune encephalomyelitis (EAE), a model of MS, through the release of anti-inflammatory and neuroprotective molecules. Based on these results, several small pilot clinical trials in subjects with advanced MS have demonstrated that MSC administration is safe and provided an early signal of clinical effectiveness. The current aim of clinicians and scientists interested in the development of MSC-based strategies for the treatment of MS is to have the ultimate demonstration in large clinical trials that MSC can inhibit CNS inflammation and foster tissue repair as realized clinically, with functional recovery, or visualized by magnetic resonance imaging (MRI). | Are there clinical trials on stem cells in multiple sclerosis | 515df5b2298dcd4e5100002c_007 | yes |
Sleep disorders and their determinants in multiple system atrophy. OBJECTIVES: To evaluate the incidence, types, determinants, and consequences of sleep disorders in patients with multiple system atrophy (MSA) and determine whether their characteristics are similar to those of patients with Parkinson's disease (PD). METHODS: Information about sleep disorders was collected using a standardised questionnaire in an unselected group of 57 patients with MSA and in 62 patients with PD matched as a group for age, sex distribution, and disease duration. RESULTS: Seventy percent of patients with MSA complained of sleep disorders compared with 51% of patients with PD (p=0.03). The most commonly reported sleep disorders were sleep fragmentation (52.5%), vocalisation (60%), REM sleep behaviour disorder (47.5%), and nocturnal stridor (19%). Except for sleep fragmentation, the incidence of these disorders was significantly higher than in PD. Sleep problems tended to be associated with more severe motor symptoms, longer disease duration, depression, and longer duration of levodopa treatment. Half of patients with MSA with sleep disorders complained of daytime somnolence compared with 30% of patients with PD. Daytime somnolence was significantly associated with disease severity in MSA. CONCLUSION: This study shows that sleep disorders are more common in patients with MSA than in those with PD after the same duration of the disease, reflecting the more diffuse underlying pathological process in MSA. | Do Parkinson's disease patients experience stridor? | 54d8d4d1014675820d000006_003 | yes |
Association of genetic variations in the mitochondrial D-loop with β-thalassemia. Beta-thalassemia, one of the most common single-gene disorders, is the result of reduced or absent production of β-globin chains. Patients with β-thalassemia show weak genotype-phenotype correlations. Mitochondrial DNA polymorphisms are a potential source for different physiological and pathological characteristics and have been found to be associated as genetic modifiers with various pathophysiologies, including cancers and neurodegenerative diseases. A group of 35 patients with β-thalassemia was investigated for the presence of mtDNA D-loop polymorphisms in comparison with 504 normal controls. We found four mtDNA D-loop polymorphisms at nucleotides 16,069C > T, 16,189T > C, 16,319G > A, and 16,519T > C that showed significant differences between patients and normal subjects. There is no strong proof for the association of these polymorphisms with β-thalassemia. It is hypothesized that iron overload or its effects on sequestration of calcium or zinc can lead to oxidative stress and ROS production inside the mitochondria. Therefore, possible accompanying of mtDNA polymorphisms with β-thalassemia disease may complicate the genotype-phenotype correlation and could affect the clinical outcomes in the patients. | Is Beta-Thalassemia is associated with a mutation or deletion of the gene that codes for alpha globin? | 58dbbbf08acda3452900001d_001 | no |
New insights into the role of thyroid hormone in cardiac remodeling: time to reconsider? Chronic ischemia or pressure overload decreases thyroid hormone (TH) signaling and activates the fetal gene program in the heart. While these features are of physiologic importance in the developing heart, their respective roles in the postnatal heart are debated. Administration of TH can prevent the changes of the fetal gene program and rebuild the heart after an "index event" such as ischemia. TH affects cardiac remodeling by limiting reperfusion injury, and, at later states, by inducing distinct changes in cardiac chamber geometry in a time-dependent manner. Furthermore, administration of TH can convert pathologic to physiologic hypertrophy. These effects are the result of favorable cellular remodeling. While preliminary clinical studies provide encouraging results, the potential and efficacy of TH in the treatment of heart disease still await evaluation in large clinical trials. | Does thyroid hormone affect cardiac remodeling? | 52efc041c8da89891000001b_009 | yes |
Phospholamban is present in endothelial cells and modulates endothelium-dependent relaxation. Evidence from phospholamban gene-ablated mice. Vascular endothelial cells regulate vascular smooth muscle tone through Ca2+-dependent production and release of vasoactive molecules. Phospholamban (PLB) is a 24- to 27-kDa phosphoprotein that modulates activity of the sarco(endo)plasmic reticulum Ca2+ ATPase (SERCA). Expression of PLB is reportedly limited to cardiac, slow-twitch skeletal and smooth muscle in which PLB is an important regulator of [Ca2+]i and contractility in these muscles. In the present study, we report the existence of PLB in the vascular endothelium, a nonmuscle tissue, and provide functional data on PLB regulation of vascular contractility through its actions in the endothelium. Endothelium-dependent relaxation to acetylcholine was attenuated in aorta of PLB-deficient (PLB-KO) mice compared with wild-type (WT) controls. This effect was not due to actions of nitric oxide on the smooth muscle, because sodium nitroprusside-mediated relaxation in either denuded or endothelium-intact aortas was unaffected by PLB ablation. Relative to denuded vessels, relaxation to forskolin was enhanced in WT endothelium-intact aortas. The endothelium-dependent component of this relaxation was attenuated in PLB-KO aortas. To investigate whether these changes were due to PLB, WT mouse aorta endothelial cells were isolated. Both reverse transcriptase-polymerase chain reaction and Western blot analyses revealed the presence of PLB in endothelial cells, which were shown to be >98% pure by diI-acetylated LDL uptake and nuclear counterstaining. These data indicate that PLB is present and modulates vascular function as a result of its actions in endothelial cells. The presence of PLB in endothelial cells opens new fields for investigation of Ca2+ regulatory pathways in nonmuscle cells and for modulation of endothelial-vascular interactions. | Is phospholamban a regulatory/inhibitory protein of the Ca ATPase SERCA? | 5501b3b3e9bde69634000007_004 | yes |
Osteogenesis imperfecta due to recurrent point mutations at CpG dinucleotides in the COL1A1 gene of type I collagen. Most individuals with osteogenesis imperfecta (OI) are heterozygous for dominant mutations in one of the genes that encode the chains of type I collagen. Each of the more than 30 mutations characterized to date has been unique to the affected member(s) of the family. We have determined that two individuals with a progressive deforming variety of OI, OI type III, have the same new dominant mutation [alpha 1(I)gly154 to arg] and that two unrelated infants with perinatal lethal OI, OI type II, share a second new dominant mutation [alpha 1(I)gly1003 to ser]. These mutations occurred at CpG dinucleotides, in a manner consistent with deamination of a methylated cytosine residue, and raise the possibility that CpG dinucleotides are common sites of recurrent mutations in collagen genes. Further, these findings confirm that the OI type-III phenotype, previously thought to be inherited in an autosomal recessive manner, can result from new dominant mutations in the COL1A1 gene of type-I collagen. | Is autosomal dominant inheritanced form of Osteogenesis imperfecta caused by mutations in the genes associated with collagen production? | 5a6f77d7b750ff4455000051_005 | yes |
Apremilast for the treatment of psoriasis. INTRODUCTION: Psoriasis is a chronic inflammatory skin disease characterized by dysregulation of the immune system and release of pro-inflammatory mediators. Drugs available for psoriasis show some limits as tolerability and route of administration. Apremilast , Otezla®, is an oral small molecule recently approved for the treatment of patients with moderate-to-severe plaque psoriasis. Compared to biologics that target a single cytokine, apremilast, degrading phosphodiesterase 4 (PDE4), interferes with cyclic anti-microbial peptides, which is involved in the transduction of intracellular signals, controlling the balance of pro-inflammatory and anti-inflammatory signals. AREAS COVERED: This review reported the latest data available from Phase I, II and III trials on apremilast for the treatment of plaque psoriasis. A focus on the clinical management of apremilast, safety and clinical efficacy based on two pivotal clinical trials (ESTEEM 1 and ESTEEM 2) currently ongoing was described. A systematic search was conducted using the PubMed Medline database for primary articles. EXPERT OPINION: Apremilast treatment was demonstrated effective and well tolerated in Phase II and III clinical trials. Several drug peculiarities, such as the low frequency of adverse events and the oral route of administration, make apremilast an innovative treatment for moderate-to-severe psoriasis. | Is apremilast effective for psoriasis? | 589a246d78275d0c4a000033_011 | yes |
The evolutionary mechanics of domain organization in proteomes and the rise of modularity in the protein world. Protein domains are compact evolutionary units of structure and function that usually combine in proteins to produce complex domain arrangements. In order to study their evolution, we reconstructed genome-based phylogenetic trees of architectures from a census of domain structure and organization conducted at protein fold and fold-superfamily levels in hundreds of fully sequenced genomes. These trees defined timelines of architectural discovery and revealed remarkable evolutionary patterns, including the explosive appearance of domain combinations during the rise of organismal lineages, the dominance of domain fusion processes throughout evolution, and the late appearance of a new class of multifunctional modules in Eukarya by fission of domain combinations. Our study provides a detailed account of the history and diversification of a molecular interactome and shows how the interplay of domain fusions and fissions defines an evolutionary mechanics of domain organization that is fundamentally responsible for the complexity of the protein world. | Is there a difference in the rate between gene fusion and gene fission? | 5149b575d24251bc05000047_007 | yes |
Selective serotonin reuptake inhibitors for premenstrual syndrome. BACKGROUND: This is a substantive update of a previous review. Severe premenstrual syndrome (PMS) affects between 3% to 5% of women of reproductive age. Severe PMS is classified under the Diagnostic and Statistical Manual of Mental Disorders as premenstrual dysphoric disorder (PMDD). Selective serotonin reuptake inhibitors (SSRIs) are increasingly used as front-line therapy for PMS. A systematic review was undertaken on the efficacy of SSRIs in the management of severe PMS, or PMDD, to assess the evidence for this treatment option. OBJECTIVES: The objective of this review was to evaluate the effectiveness of SSRIs in reducing premenstrual syndrome symptoms in women diagnosed with severe premenstrual syndrome. SEARCH STRATEGY: Electronic searches for relevant randomised controlled trials were undertaken in the Cochrane Menstrual Disorders and Subfertility Group Specialised Register, Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library), MEDLINE, EMBASE, PsycInfo, and CINAHL (March 2008). Where insufficient data were presented in a report the original authors were contacted for further details. SELECTION CRITERIA: All trials were considered in which women with a prospective diagnosis of PMS, PMDD or late luteal phase dysphoric disorder (LPDD) were randomised to receive SSRIs or placebo for the treatment of premenstrual syndrome in a blinded trial. DATA COLLECTION AND ANALYSIS: Forty randomised controlled trials were identified which reported the use of SSRIs in the management of PMS. Fifty-six trials were excluded. The review authors extracted the data independently and estimated standardised mean differences for continuous outcomes. MAIN RESULTS: Due to heterogeneity, analyses were subgrouped into change and absolute scores. The primary analysis of reduction in overall symptomatology included data on 2294 women with premenstrual syndrome. SSRIs were found to be highly effective in treating the premenstrual symptoms (SMD -0.53, 95% CI 0.68 to -0.39; P < 0.00001). Secondary analysis showed that they were effective in treating physical (SMD -0.34, 95% CI -0.45 to -0.22; P < 0.00001), functional (SMD -0.30, 95% CI -0.43 to -0.17; P < 0.00001), and behavioural symptoms (SMD -0.41, 95% CI -0.53 to -0.29; P < 0.00001). Luteal phase only and continuous administration were both effective and there was no influence of a placebo run-in period on reduction in symptoms. All SSRIs (fluoxetine, paroxetine, sertraline, fluvoxamine, citalopram, and clomipramine) were effective in reducing premenstrual symptoms. Withdrawals due to side effects were twice as likely to occur in the treatment group (OR 2.18, 95% CI 1.62 to 2.92; P < 0.00001). AUTHORS' CONCLUSIONS: The evidence supports the use of selective serotonin reuptake inhibitors in the management of severe premenstrual syndrome. | Is paroxetine effective for treatment of premenstrual dysphoric disorder? | 514a59c2d24251bc0500005d_008 | yes |
Efficacy, safety, and tolerability of desvenlafaxine 50 mg/day and 100 mg/day in outpatients with major depressive disorder. OBJECTIVE: To assess the efficacy, safety, and tolerability of 50- and 100-mg/day doses of desvenlafaxine (administered as desvenlafaxine succinate), a serotonin-norepinephrine reuptake inhibitor, for the treatment of major depressive disorder (MDD). RESEARCH DESIGN AND METHODS: Patients with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) MDD and 17-item Hamilton Rating Scale for Depression (HAM-D(17)) scores > or =20 were randomly assigned to double-blind placebo or desvenlafaxine treatment (fixed dose of 50 mg/day or 100 mg/day) for 8 weeks. The primary efficacy measure was the HAM-D(17). Changes from baseline in HAM-D(17) scores were analyzed using analysis of covariance. The final on-therapy evaluation was the primary endpoint for efficacy analyses, using last-observation-carried-forward data. MAIN OUTCOMES MEASURES AND RESULTS: The intent-to-treat population included 447 patients. Desvenlafaxine 50 mg was associated with a significantly greater adjusted mean change from baseline on the HAM-D(17) (-11.5) compared with placebo (-9.5, p=0.018); the 100-mg dose group (-11.0) did not achieve statistical significance (p=0.065). The 100-mg dose group experienced significant improvements compared with placebo on several secondary efficacy measures, including the 6-item Hamilton Depression Rating Scale (p=0.038) and the Visual Analog Scale-Pain Intensity total score (p=0.041). Both desvenlafaxine doses were generally well-tolerated. The most common adverse events (incidence > or =10% in either desvenlafaxine group and twice the rate of placebo) were dry mouth, constipation, insomnia, decreased appetite, hyperhidrosis, and dizziness. CONCLUSIONS: These results demonstrate efficacy, safety, and tolerability of desvenlafaxine 50 mg/day for treating MDD. The significant findings on secondary measures support the efficacy of desvenlafaxine 100 mg, as seen in other trials. Conclusions may be limited by the exclusion of MDD patients with comorbid conditions and the short-term desvenlafaxine treatment duration. | Can desvenlafaxine be used at a dose of 50mg/day? | 530cf4fe960c95ad0c00000c_005 | yes |
The kinetics of highly sensitive cardiac troponin T release after prolonged treadmill exercise in adolescent and adult athletes. The nature and kinetics of postexercise cardiac troponin (cTn) appearance is poorly described and understood in most athlete populations. We compared the kinetics of high-sensitivity cTn T (hs-cTnT) after endurance running in training-matched adolescents and adults. Thirteen male adolescent (mean age: 14.1 ± 1.1 yr) and 13 male adult (24.0 ± 3.6 yr) runners performed a 90-min constant-load treadmill run at 95% of ventilatory threshold. Serum hs-cTnT levels were assessed preexercise, immediately postexercise, and at 1, 2, 3, 4, 5, 6, and 24 h postexercise. Serum NH(2)-terminal pro-brain natriuretic peptide (NT-pro-BNP) levels were recorded preexercise and 3, 6, and 24 h postexercise. Left ventricular function was assessed preexercise, immediately postexercise, and 6 h postexercise. Peak hs-cTnT occurred at 3-4 h postexercise in all subjects, but was substantially higher (P < 0.05) in adolescents [median (range): 211.0 (11.2-794.5) ng/l] compared with adults [median (range): 19.1 (9.7-305.6) ng/l]. Peak hs-cTnT was followed by a rapid decrease in both groups, although adolescent data had not returned to baseline at 24 h. Substantial interindividual variability was noted in peak hs-cTnT, especially in the adolescents. NT-pro-BNP was significantly elevated postexercise in both adults and adolescents and remained above baseline at 24 h in both groups. In both groups, left ventricular ejection fraction and the ratio of early-to-atrial peak Doppler flow velocities were significantly decreased immediately postexercise. Peak hs-cTnT was not related to changes in ejection fraction, ratio of early-to-atrial peak Doppler flow velocities, or NT-pro-BNP. The present data suggest that postexercise hs-cTnT elevation 1) occurred in all runners, 2) peaked 3-4 h postexercise, and 3) the peak hs-cTnT concentration after prolonged exercise was higher in adolescents than adults. | Does BNP increase after intensive exercise in athletes? | 531d2aa5267d7dd053000003_006 | yes |
The neurovascular complications of cocaine. BACKGROUND: Cocaine use has been temporally associated with neurovascular complications, including the rupture of intracerebral aneurysms. The purpose of the current study was to determine the type of neurovascular complications associated with cocaine use in our patient population, the temporal relationship between cocaine use and their onset, and whether cocaine users with subarachnoid hemorrhage (SAH) presented with smaller aneurysms at an earlier age than a control group of noncocaine users with SAH. METHODS: Thirty-three patients who presented to the Detroit Medical Center with neurovascular sequelae associated with cocaine use were identified. All patients were chronic cocaine users who related a history of recent use confirmed by a drug screen. Cocaine users with SAH were compared to a control group of 44 patients with SAH who presented without evidence of cocaine use. RESULTS: Sixteen patients presented with SAH. Twelve patients subsequently underwent four-vessel cerebral arteriogram revealing 14 aneurysms; six patients presented with intracerebral hemorrhage (ICH) and seven patients with evidence of ischemic stroke. Eighteen (54.5%) patients noted onset of their symptoms while using cocaine, 87.9% noted onset within 6 hours of use. Delayed presentation occurred predominantly in patients who suffered ischemic strokes. The average age of patients who used cocaine and presented with SAH secondary to a ruptured intracerebral aneurysm was 32.8 years with an average aneurysm diameter of 4.9 mm versus an average age of 52.2 years with an average aneurysm diameter of approximately 11.0 mm in noncocaine users. Population differences were statistically significant at the p < 0.05 level. Mortality was 27.3% for patients who presented with neurovascular sequelae of their cocaine use, with 77.8% of deaths occurring in patients who presented with SAH. CONCLUSIONS: Chronic cocaine use appears to predispose patients who harbor incidental neurovascular anomalies to present at an earlier point in their natural history than similar non-cocaine users. | Is cocaine use associated with increased risk for intracerebral hemorrhage? | 5159b990d24251bc050000a3_011 | yes |
Mowat-Wilson syndrome: the first two Malaysian cases. Mowat-Wilson syndrome (MWS) is a recently delineated mental retardation; a multiple congenital anomaly syndrome characterised by a typical facial gestalt, Hirschsprung disease or severe constipation, genitourinary anomaly, congenital heart defects, agenesis of corpus callosum and eye defects. Some cases also present with epilepsy, growth retardation with microcephaly and speech impairment. MWS was first described in 1998 by Mowat et al, and approximately 180 cases have been reported as of August 2008. The syndrome occurs as a result of heterozygous mutations or deletions in the zinc finger E-box-binding homeobox 2 gene, ZEB2, previously called ZFHX1B (SIP1). Most cases reported so far were sporadic occurrences; however, rare cases of sibling recurrence have been cited. The facial phenotype is particularly important for the initial clinical diagnosis and provides the hallmark, warranting ZEB2 mutational analysis even in the absence of Hirschsprung disease. We present the first two molecularly confirmed Malaysian MWS patients, one of whom has a novel mutation. | Is corpus callosum involved in the Mowat–Wilson syndrome? | 5314896adae131f847000001_008 | yes |
Synemin interacts with the LIM domain protein zyxin and is essential for cell adhesion and migration. Synemin is a unique cytoplasmic intermediate filament protein for which there is limited understanding of its exact cellular functions. The single human synemin gene encodes at least two splice variants named alpha-synemin and beta-synemin, with the larger alpha-synemin containing an additional 312 amino acid insert within the C-terminal tail domain. We report herein that, by using the entire tail domain of the smaller beta-synemin as the bait in a yeast two-hybrid screen of a human skeletal muscle cDNA library, the LIM domain protein zyxin was identified as an interaction partner for human synemin. The synemin binding site in human zyxin was subsequently mapped to the C-terminal three tandem LIM-domain repeats, whereas the binding site for zyxin within beta-synemin is within the C-terminal 332 amino acid region (SNbetaTII) at the end of the long tail domain. Transient expression of SNbetaTII within mammalian cells markedly reduced zyxin protein level, blocked localization of zyxin at focal adhesion sites and resulted in decreased cell adhesion and increased motility. Knockdown of synemin expression with siRNAs within mammalian cells resulted in significantly compromised cell adhesion and cell motility. Our results suggest that synemin participates in focal adhesion dynamics and is essential for cell adhesion and migration. | Is zyxin a focal adhesion protein? | 54f4b319d0d681a040000005_007 | yes |
Reduced heterozygosity at intragenic and flanking microsatellites of pfcrt gene establishes natural selection based molecular evolution of chloroquine-resistant Plasmodium falciparum in India. The positive selection of a nucleotide substitution in exon 2 of Plasmodium falciparum chloroquine resistance transporter (pfcrt) gene (mutation responsible for chloroquine resistance) causes a reduction in variation of neutral loci close to the gene. This reduction in allelic diversity around flanking regions of pfcrt gene was reported in worldwide chloroquine resistant isolates and referred as selective sweep. In Plasmodium falciparum isolates of India, the selective sweep in flanking loci of pfcrt gene is well established, however, high allelic diversity observed in intragenic microsatellites of pfcrt gene implied an ongoing genetic recombination. To understand, if molecular evolution of chloroquine-resistant P. falciparum isolates in India follow a selective sweep model, we analyzed genetic diversity at both seven intragenic and seven flanking microsatellites of pfcrt (-24 to +106kb) gene in chloroquine sensitive and resistant parasites originating from high and low transmission areas. We observed low expected heterozygosity at all loci of resistant pfcrt-haplotypes (He=0-0.77) compared to the wild-type (He=0.38-0.96). Resistant SVMNT from high transmission areas showed significantly higher mean He (P=0.03, t-test) at both intragenic and pfcrt-flanking loci (-24 to +22 kb) in comparison to low transmission areas. Our observation of reduction in variation at both intragenic and flanking loci of mutant pfcrt gene confirmed the selective sweep model of natural selection in chloroquine resistant P. falciparum isolates in India. | Does a selective sweep increase genetic variation? | 5540a8d20083d1bf0e000001_000 | no |
Peripheral neuropathies in Sjogren syndrome: a new reappraisal. BACKGROUND: The prevalence of peripheral neuropathy in patients with Sjögren syndrome remains unclear owing to conflicting results in the published series, with numbers ranging from 2% to over 60% of Sjögren syndrome patients. Whether peripheral neuropathy is a feature of the systemic or glandular disease or whether it is related to a circulating antineuronal antibody remains also uncertain. METHODS: The authors reviewed the records of patients with primary Sjögren syndrome (pSS), fulfilling the Revised European-American Classification Criteria, seen in their department from 1992 to 2009. The patients with previously recorded neuropathic features were re-examined clinically and electrophysiologically. Other causes of polyneuropathy were excluded. The authors also searched for circulating antineural antibodies using immunofluorescence and western blot and for antibodies against muscarinic and nicotinic acetylcholine receptors as potential biomarkers. RESULTS: 509 cases met the diagnostic criteria for pSS. Among these, 44 patients were recorded as having neuropathic symptoms. After completing the evaluation, however, only nine (1.8%) had polyneuropathy with objective clinical signs and abnormal electrophysiological findings. The neuropathy was axonal in all, in five pure sensory and in four sensorimotor. The patients with peripheral neuropathy had extraglandular manifestations such as palpable purpura and vasculitis. No evidence of antineural autoimmunity was found, and no candidate biomarkers were identified. CONCLUSION: Polyneuropathy is a rare manifestation of pSS occurring in 1.8% of patients. In the majority of patients, it is a late event and frequently associated with systemic disease or risk factors for lymphoma development. | Are patients with Sjogren syndrome at increased risk for lymphoma? | 5a6f87c5b750ff4455000056_011 | yes |
Successful treatment of catecholaminergic polymorphic ventricular tachycardia with flecainide: a case report and review of the current literature. Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmogenic disease that can cause sudden cardiac death due to ventricular fibrillation (VF). While pharmacological therapy with beta-blockers and/or Ca(2)(+) antagonists is often unreliable, a recent study has demonstrated that flecainide can effectively suppress arrhythmia in a murine model of CPVT as well as clinically in two human subjects suffering from CPVT. We here present the case of an 11-year-old boy suffering from CPVT-1 as well as a review of the current relevant literature. After resuscitation due to VF at age 9, an automated implantable cardioverter-defibrillator (ICD) was implanted in 2007. Under beta-blocker therapy, repeated shocks were delivered due to either fast ventricular tachycardia (VT) or VF. This persisted under additional therapy with verapamil. Implantable cardioverter-defibrillator routine interrogations showed frequent non-sustained VT with an average of 8.8 per day. Additionally, the patient suffered from impaired physical performance due to decreased chronotropic competence. In July 2009, flecainide was added to the beta-blocker/verapamil regimen, resulting in a plasma level of 0.20 mg/L. No ICD shock or sustained VT occurred until December 2010. Genetic testing revealed an RyR2 receptor mutation. The case demonstrates the challenge of diagnosis and management of CPVT. It furthermore supports recent experimental evidence that the class 1 antiarrhythmic drug flecainide can suppress CPVT. The presented case supports a novel strategy in treating CPVT with the class I antiarrhythmic agent flecainide. | Could Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) cause sudden cardiac death? | 530cf4fe960c95ad0c000003_007 | yes |
A role for CTCF and cohesin in subtelomere chromatin organization, TERRA transcription, and telomere end protection. The contribution of human subtelomeric DNA and chromatin organization to telomere integrity and chromosome end protection is not yet understood in molecular detail. Here, we show by ChIP-Seq that most human subtelomeres contain a CTCF- and cohesin-binding site within ∼1-2 kb of the TTAGGG repeat tract and adjacent to a CpG-islands implicated in TERRA transcription control. ChIP-Seq also revealed that RNA polymerase II (RNAPII) was enriched at sites adjacent to the CTCF sites and extending towards the telomere repeat tracts. Mutation of CTCF-binding sites in plasmid-borne promoters reduced transcriptional activity in an orientation-dependent manner. Depletion of CTCF by shRNA led to a decrease in TERRA transcription, and a loss of cohesin and RNAPII binding to the subtelomeres. Depletion of either CTCF or cohesin subunit Rad21 caused telomere-induced DNA damage foci (TIF) formation, and destabilized TRF1 and TRF2 binding to the TTAGGG proximal subtelomere DNA. These findings indicate that CTCF and cohesin are integral components of most human subtelomeres, and important for the regulation of TERRA transcription and telomere end protection. | Does the CTCF protein co-localize with cohesin? | 5344310baeec6fbd0700000c_015 | yes |
Frameshift mutation of the zinc finger homeo box 1 B gene in syndromic corpus callosum agenesis (Mowat-Wilson syndrome). We report a girl who had Hirschsprung disease in association with distinct facial appearance, microcephaly, agenesis of the corpus callosum and mental retardation (Mowat-Wilson syndrome). Mutation analysis of the zinc finger homeo box 1 B (ZFHX1 B) gene revealed a de novo 7 bp deletion (TGGCCCC) at nucleotide 1773 (1773 delTGGCCCC) resulting in a frameshift and leading to a termination codon at amino acid residue 604 (604 X) in exon 8 C. The zinc finger homeo box 1 B (Smad interacting protein-1) is a transcription corepressor of Smad target genes with functions in the patterning of neural crest derived cells, CNS, and midline structures. Mutations in ZFHX1 B can lead to neurological disorders in addition to dysmorphic features, megacolon, and other malformations. | Is corpus callosum involved in the Mowat–Wilson syndrome? | 5314896adae131f847000001_017 | yes |
Intraoperative radiotherapy for gliomas. Intraoperative radiotherapy (IORT) was performed in 20 of 36 patients with glioma; 11 glioblastomas, 7 malignant astrocytomas, 2 benign astrocytomas. Twenty or 25 Gy of irradiation was delivered in a single fraction intraoperatively, followed by external beam irradiation. The electron beam energy was selected so that the 80% isodose line fell at 2 or 3 cm below the residual tumor surface. Median survival time of IORT group was 14 months and that of the control group was 10 months. Difference of survival curve was significant. There were 6 incidences of complication caused by IORT; 1 radionecrosis, 1 convulsion, 1 abscess, and 3 severe brain edemas. IORT is suited for the treatment of malignant gliomas. | Is intraoperative radiotherapy used for treatment of glioblastoma? | 589a245478275d0c4a000022_008 | no |
Euglycemic Diabetic Ketoacidosis with Persistent Diuresis Treated with Canagliflozin. Diabetic ketoacidosis is characterized by hyperglycemia, anion-gap acidosis, and increased plasma ketones. After the resolution of hyperglycemia, persistent diuresis is rare. We herein report the case of a 27-year-old Asian woman with type 2 diabetes who was treated with a sodium-glucose cotransporter 2 (SGLT2) inhibitor (canagliflozin) who developed euglycemic diabetic ketoacidosis and persistent diuresis in the absence of hyperglycemia. Physicians should consider euglycemic diabetic ketoacidosis in the differential diagnosis of patients treated with SGLT2 inhibitors. | Can canagliflozin cause euglycemic diabetic ketoacidosis? | 5a6f922fb750ff4455000059_003 | yes |
Molecular signature of primary retinal pigment epithelium and stem-cell-derived RPE cells. Age-related macular degeneration (AMD) is characterized by the loss or dysfunction of retinal pigment epithelium (RPE) and is the most common cause of vision loss among the elderly. Stem-cell-based strategies, using human embryonic stem cells (hESCs) or human-induced pluripotent stem cells (hiPSCs), may provide an abundant donor source for generating RPE cells in cell replacement therapies. Despite a significant amount of research on deriving functional RPE cells from various stem cell sources, it is still unclear whether stem-cell-derived RPE cells fully mimic primary RPE cells. In this report, we demonstrate that functional RPE cells can be derived from multiple lines of hESCs and hiPSCs with varying efficiencies. Stem-cell-derived RPE cells exhibit cobblestone-like morphology, transcripts, proteins and phagocytic function similar to human fetal RPE (fRPE) cells. In addition, we performed global gene expression profiling of stem-cell-derived RPE cells, native and cultured fRPE cells, undifferentiated hESCs and fibroblasts to determine the differentiation state of stem-cell-derived RPE cells. Our data indicate that hESC-derived RPE cells closely resemble human fRPE cells, whereas hiPSC-derived RPE cells are in a unique differentiation state. Furthermore, we identified a set of 87 signature genes that are unique to human fRPE and a majority of these signature genes are shared by stem-cell-derived RPE cells. These results establish a panel of molecular markers for evaluating the fidelity of human pluripotent stem cell to RPE conversion. This study contributes to our understanding of the utility of hESC/hiPSC-derived RPE in AMD therapy. | Have hESC been tested for the treatment of age-related macular degeneration? | 56f553aa09dd18d46b000005_001 | yes |
Conserved Nonexonic Elements: A Novel Class of Marker for Phylogenomics. Noncoding markers have a particular appeal as tools for phylogenomic analysis because, at least in vertebrates, they appear less subject to strong variation in GC content among lineages. Thus far, ultraconserved elements (UCEs) and introns have been the most widely used noncoding markers. Here we analyze and study the evolutionary properties of a new type of noncoding marker, conserved nonexonic elements (CNEEs), which consists of noncoding elements that are estimated to evolve slower than the neutral rate across a set of species. Although they often include UCEs, CNEEs are distinct from UCEs because they are not ultraconserved, and, most importantly, the core region alone is analyzed, rather than both the core and its flanking regions. Using a data set of 16 birds plus an alligator outgroup, and ∼3600-∼3800 loci per marker type, we found that although CNEEs were less variable than bioinformatically derived UCEs or introns and in some cases exhibited a slower approach to branch resolution as determined by phylogenomic subsampling, the quality of CNEE alignments was superior to those of the other markers, with fewer gaps and missing species. Phylogenetic resolution using coalescent approaches was comparable among the three marker types, with most nodes being fully and congruently resolved. Comparison of phylogenetic results across the three marker types indicated that one branch, the sister group to the passerine + falcon clade, was resolved differently and with moderate (>70%) bootstrap support between CNEEs and UCEs or introns. Overall, CNEEs appear to be promising as phylogenomic markers, yielding phylogenetic resolution as high as for UCEs and introns but with fewer gaps, less ambiguity in alignments and with patterns of nucleotide substitution more consistent with the assumptions of commonly used methods of phylogenetic analysis. | Are Conserved Nonexonic Elements (CNEEs) important in phylogenomics research? | 5a6e18d8b750ff4455000038_000 | yes |
Can transcription factors function as cell-cell signalling molecules? Recent data support the view that transcription factors - in particular, homeoproteins - can be transferred from cell to cell and have direct non-cell-autonomous (and therefore paracrine) activities. This intercellular transfer, based on atypical internalization and secretion, has important biotechnological consequences. But the real excitement stems from the physiological and developmental implications of this mode of signal transduction. | Could transcription factors act as cell-cell signalling molecules? | 56a7d32fa17756b72f000001_000 | yes |
Exercise performance in young and middle-aged female patients with subclinical hyperthyroidism. Subclinical hyperthyroidism (SH) may be responsible for many cardiovascular changes, including an impaired exercise performance. The aim of our study was to evaluate the response to the treadmill cardiopulmonary test in patients with SH. We studied 14 female patients from our endocrine clinic with exogenous SH, free from cardiovascular diseases, with mean age of 38.6 +/- 10.2 years, body mass index (BMI) of 24.4 +/- 4.0 kg/m(2), and disease duration of 4.9 +/- 4.9 years. The mean serum thyrotropin (TSH) was 0.03 +/- 0.03 mU/L, serum free thyroxine (FT(4)), 1.72 +/- 0.21 ng/dL, and serum triiodothyronine level, 137 +/- 32 ng/dL. The control group comprised 15 euthyroid, healthy women, with mean age of 35.4 +/- 7.4 years and BMI of 27.3 +/- 5.9 kg/m(2). Both groups had a sedentary lifestyle and underwent the cardiopulmonary test using a treadmill with the Balke protocol. Gas concentrations and the respiratory outflow were measured and the electrocardiogram (ECG) was registered in real time. We calculated the minute ventilation (V(E)), the oxygen consumption (peak VO(2)), the carbonic gas exhalation (peak VCO(2)) and the anaerobic threshold (AT). The heart rate (HR) at rest (90.9 +/- 15.7 versus 78.9 +/- 8.7 beats per minute; p = 0.03) was higher in the patients from our clinic. There was no difference between groups regarding age, BMI, fat percentage, blood pressure, peak HR, exercise duration, mean treadmill peak inclination, V(E), peak VO(2), peak VCO(2), and AT. There was no correlation between peak VO(2) and FT(4), TSH, or disease duration. Our results show that exercise capacity in young and middle-aged female patients is not significantly affected by exogenous SH. | Is physical performance influenced by thyroid hormone metabolism? | 5151b8efd24251bc0500007a_000 | yes |
Role of Telomeres and Telomerase in Aging and Cancer. UNLABELLED: Telomeres progressively shorten throughout life. A hallmark of advanced malignancies is the ability for continuous cell divisions that almost universally correlates with the stabilization of telomere length by the reactivation of telomerase. The repression of telomerase and shorter telomeres in humans may have evolved, in part, as an anticancer protection mechanism. Although there is still much we do not understand about the regulation of telomerase, it remains a very attractive and novel target for cancer therapeutics. This review focuses on the current state of advances in the telomerase area, identifies outstanding questions, and addresses areas and methods that need refinement. SIGNIFICANCE: Despite many recent advances, telomerase remains a challenging target for cancer therapy. There are few telomerase-directed therapies, and many of the assays used to measure telomeres and telomerase have serious limitations. This review provides an overview of the current state of the field and how recent advances could affect future research and treatment approaches. Cancer Discov; 6(6); 584-93. ©2016 AACR. | Can telomere length shortening be reversed by telomerase? | 58cd675c02b8c6095300003b_003 | yes |
Unintentional weakness of cancers: the MEK-ERK pathway as a double-edged sword. Recent advances in molecular targeted therapies have greatly improved treatment outcomes for cancers driven by oncogenic mutations. Despite initial and dramatic clinical responses, tumors eventually acquire resistance to these targeted therapies, showing flexible and diverse responses. Interestingly, cancer cells sometimes overadapt to the drug treatment environment, leading to a state in which cancer cells cannot survive without the drug. This interesting phenomenon (often called "drug dependency" or "drug addiction") is exemplified in preclinical acquired resistance models of BRAF-mutated melanoma treated with vemurafenib and EGFR-mutated lung cancer treated with EGFR tyrosine kinase inhibitors. A number of intriguing parallels in drug-addicted cancers became apparent in a comparison of the two models: (i) overexpression of driver oncogenes as causes of acquired resistance; (ii) overexpression of driver oncogenes causing MEK-ERK hyperactivation under drug-free conditions; (iii) hyperactivation of the MEK-ERK pathway as critical to this drug addiction phenomenon; (iv) ongoing dependence on the oncogenic driver; and (v) morphologic changes in resistant cells under drug-free conditions. This Perspective article not only focuses on this interesting and peculiar phenomenon but also discusses weapon strategies to exploit this unintentional weakness of cancers. | Are BRAF mutations common in melanoma? | 5512c91b6a8cde6b7200000b_022 | yes |
Developmental regulation and spatiotemporal redistribution of the sumoylation machinery in the rat central nervous system. BACKGROUND: Small Ubiquitin-like MOdifier protein (SUMO) is a key regulator of nuclear functions but little is known regarding the role of the post-translational modification sumoylation outside of the nucleus, particularly in the Central Nervous System (CNS). METHODOLOGY/PRINCIPAL FINDINGS: Here, we report that the expression levels of SUMO-modified substrates as well as the components of the sumoylation machinery are temporally and spatially regulated in the developing rat brain. Interestingly, while the overall sumoylation is decreasing during brain development, there are progressively more SUMO substrates localized at synapses. This increase is correlated with a differential redistribution of the sumoylation machinery into dendritic spines during neuronal maturation. CONCLUSIONS/SIGNIFICANCE: Overall, our data clearly demonstrate that the sumoylation process is developmentally regulated in the brain with high levels of nuclear sumoylation early in the development suggesting a role for this post-translational modification during the synaptogenesis period and a redistribution of the SUMO system towards dendritic spines at a later developmental stage to modulate synaptic protein function. | Is SUMOylation a post-translational modification in eukaryotes? | 58a6b98860087bc10a000028_024 | yes |
HDAC6 is a microtubule-associated deacetylase. Reversible acetylation of alpha-tubulin has been implicated in regulating microtubule stability and function. The distribution of acetylated alpha-tubulin is tightly controlled and stereotypic. Acetylated alpha-tubulin is most abundant in stable microtubules but is absent from dynamic cellular structures such as neuronal growth cones and the leading edges of fibroblasts. However, the enzymes responsible for regulating tubulin acetylation and deacetylation are not known. Here we report that a member of the histone deacetylase family, HDAC6, functions as a tubulin deacetylase. HDAC6 is localized exclusively in the cytoplasm, where it associates with microtubules and localizes with the microtubule motor complex containing p150(glued) (ref. 3). In vivo, the overexpression of HDAC6 leads to a global deacetylation of alpha-tubulin, whereas a decrease in HDAC6 increases alpha-tubulin acetylation. In vitro, purified HDAC6 potently deacetylates alpha-tubulin in assembled microtubules. Furthermore, overexpression of HDAC6 promotes chemotactic cell movement, supporting the idea that HDAC6-mediated deacetylation regulates microtubule-dependent cell motility. Our results show that HDAC6 is the tubulin deacetylase, and provide evidence that reversible acetylation regulates important biological processes beyond histone metabolism and gene transcription. | Is tubulin acetylation involved in cell motility? | 5317606eb166e2b80600000d_006 | yes |
¹H, ¹³C and ¹⁵N backbone and side-chain resonance assignments of the N-terminal ubiquitin-binding domains of USP25. Ubiquitin Specific Protease 25 (USP25), a member of the deubiquitinase family, is involved in several disease-related signal pathways including myogenesis, immunity and protein degradation. It specially catalyzes the hydrolysis of the K48-linked and K63-linked polyubiquitin chains. USP25 contains one ubiquitin-associated domain and two ubiquitin-interacting motifs (UIMs) in its N-terminal region, which interact with ubiquitin and play a role in substrate recognition. Besides, it has been shown that the catalysis activity of USP25 is either impaired by sumoylation or enhanced by ubiquitination within its UIM. To elucidate the structural basis of the cross-regulation of USP25 function by non-covalent binding and covalent modifications of ubiquitin and SUMO2/3, a systematic structural biology study of USP25 is required. Here, we report the (1)H, (13)C and (15)N backbone and side-chain resonance assignments of the N-terminal ubiquitin binding domains (UBDs) of USP25 with BMRB accession number of 19111, which is the first step of the systematic structural biology study of the enzyme. | Is sumoylation implicated in myogenesis? | 56cca4da5795f9a73e000034_001 | yes |
Human mutation rate associated with DNA replication timing. Eukaryotic DNA replication is highly stratified, with different genomic regions shown to replicate at characteristic times during S phase. Here we observe that mutation rate, as reflected in recent evolutionary divergence and human nucleotide diversity, is markedly increased in later-replicating regions of the human genome. All classes of substitutions are affected, suggesting a generalized mechanism involving replication time-dependent DNA damage. This correlation between mutation rate and regionally stratified replication timing may have substantial evolutionary implications. | Does replication timing affect the rate of somatic mutations? | 5710dd61cf1c32585100002e_009 | yes |
A genome-wide analysis indicates that yeast pre-mRNA splicing is predominantly posttranscriptional. Recent ChIP experiments indicate that spliceosome assembly and splicing can occur cotranscriptionally in S. cerevisiae. However, only a few genes have been examined, and all have long second exons. To extend these studies, we analyzed intron-containing genes with different second exon lengths by using ChIP as well as whole-genome tiling arrays (ChIP-CHIP). The data indicate that U1 snRNP recruitment is independent of exon length. Recursive splicing constructs, which uncouple U1 recruitment from transcription, suggest that cotranscriptional U1 recruitment contributes to optimal splicing efficiency. In contrast, U2 snRNP recruitment, as well as cotranscriptional splicing, is deficient on short second exon genes. We estimate that > or =90% of endogenous yeast splicing is posttranscriptional, consistent with an analysis of posttranscriptional snRNP-associated pre-mRNA. | Are transcription and splicing connected? | 517395b98ed59a060a00001a_001 | yes |
5-ALA-PDT induces RIP3-dependent necrosis in glioblastoma. Glioblastoma constitute the most frequent and deadliest brain tumors of astrocytic origin. They are resistant to all current therapies and are associated with a high rate of recurrence. Glioblastoma were previously shown to respond to treatments by 5-aminolevulinic acid (5-ALA)-based photodynamic therapy (PDT) mainly by activating a necrotic type of cell death. The receptor-interacting protein 3 (RIP3) has recently been outlined as a key mediator of this caspase-independent form of programmed cell death. In the present study, we analyzed the necrotic mechanism induced by 5-ALA-PDT in human glioblastoma cells and explored the role of RIP3 in this context. Our results show that PDT-induced necrosis is dependent on RIP3, which forms aggregates and colocalizes with RIP1 following photosensitization. We demonstrate that PDT-mediated singlet oxygen production is the cause of RIP3-dependent necrotic pathway activation. We also prove that PDT induces the formation of a pro-necrotic complex containing RIP3 and RIP1 but lacking caspase-8 and FADD, two proteins usually part of the necrosome when TNF-α is used as a stimulus. Thus, we hypothesize that PDT might lead to the formation of a different necrosome whose components, besides RIP1 and RIP3, are still unknown. In most cases, glioblastoma are characterized by a constitutive activation of NF-κB. This factor is a key regulator of various processes, such as inflammation, immune response, cell growth or apoptosis. Its inhibition was shown to further sensitize glioblastoma cells to PDT-induced necrosis, however, no difference in RIP3 upshift or aggregation could be observed when NF-κB was inhibited. | Is RIP1 (RIP-1) part of the necrosome? | 532bfd15d6d3ac6a34000017_004 | yes |
[Neurocristopathies: a high incidence of cerebral dysgenesis in patients with Hirschsprung's disease]. INTRODUCTION: Hirschsprung's disease (HD), or aganglionic megacolon, is a congenital disorder that is characterised by the absence of ganglion cells in the submucosal and myenteric plexuses of the intestine, which is caused by the failure of these cells to migrate from the neural crest (neurocristopathy). Cerebral dysgenesis and polymalformation syndromes have been reported in association with HD, thus suggesting an abnormal morphogenesis. AIM: To study the frequency of cerebral malformations in patients with HD in our environment. PATIENTS AND METHODS: We conducted a retrospective study of 41,666 live newborn infants, over the period 1993-2003, and 17 cases of HD where identified. RESULTS: The incidence of HD in the health district of the province of Albacete is 1.68 per 5,000 live newborn infants. Of the 17 patients with HD who were studied, 10 were isolated (58.8%) and seven (41.1%) were associated to other structural abnormalities and psychomotor retardation. Three of the cases in this latter group were due to chromosome pathology (trisomy 21, Down syndrome), two were caused by specific polymalformation syndromes (one Mowat-Wilson syndrome and one possible FG syndrome), one was due to a pattern of abnormalities that did not fit any known syndrome, and one had a normal phenotype and isolated cerebral dysgenesis. In all of cases the neuroimaging studies identified cerebral dysgenesis that was compatible with neuronal migration disorders. CONCLUSIONS: The frequency of association of HD, either isolated or within the context of a specific malformation syndrome, with neuronal migration disorders is high (23.5%). We suggest a full genetic and neurological evaluation should be carried out in patients with HD, together with brain imaging studies in order to rule out the possibility of cerebral dysgenesis. | Is aganglionic megacolon a feature of Down syndrome? | 550311dae9bde69634000018_000 | yes |
Health-related quality of life in elderly patients with newly diagnosed glioblastoma treated with short-course radiation therapy plus concomitant and adjuvant temozolomide. PURPOSE: To describe the quality of life (QOL) in elderly patients with glioblastoma (GBM) treated with an abbreviated course of radiation therapy (RT; 40 Gy in 15 fractions) plus concomitant and adjuvant temozolomide (TMZ). METHODS AND MATERIALS: Health-related QOL (HRQOL) was assessed by European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core-30 (QLQ-C30, version 3) and EORTC Quality of Life Questionnaire Brain Cancer Module (QLQ-BN20). Changes from baseline in the score of 9 preselected domains (global QLQ, social functioning, cognitive functioning, emotional functioning, physical functioning, motor dysfunction, communication deficit, fatigue, insomnia) were determined 4 weeks after RT and thereafter every 8 weeks during the treatment until disease progression. The proportion of patients with improved HRQOL scores, defined as a change of 10 points or more, and duration of changes were recorded. RESULTS: Sixty-five patients completed the questionnaires at baseline. The treatment was consistently associated with improvement or stability in most of the preselected HRQOL domains. Global health improved over time; mean score differed by 9.6 points between baseline and 6-month follow-up (P=.03). For social functioning and cognitive functioning, mean scores improved over time, with a maximum difference of 10.4 points and 9.5 points between baseline and 6-month follow-up (P=.01 and P=.02), respectively. By contrast, fatigue worsened over time, with a difference in mean score of 5.6 points between baseline and 4-month follow-up (P=.02). CONCLUSIONS: A short course of RT in combination with TMZ in elderly patients with GBM was associated with survival benefit without a negative effect on HRQOL until the time of disease progression. | Is fatigue prevalent in patients receiving treatment for glioblastoma? | 530e42e65937551c09000007_004 | yes |
Hypnosis in breast cancer care: a systematic review of randomized controlled trials. INTRODUCTION: Many breast cancer patients and survivors experience pain and emotional stress related to their disease, its diagnostic procedures, or treatment. Hypnosis has long been used for the treatment of such symptoms. The aim of this review was to systematically assess the effectiveness of hypnosis in women with breast cancer, breast cancer survivors, and in women undergoing diagnostic breast biopsy. METHODS: PubMed, Scopus, the Cochrane Library, PsycINFO, and CAMBASE were screened through February 2014 for randomized controlled trials (RCTs) of hypnosis in women with breast cancer or undergoing diagnostic breast biopsy. RCTs on postmenopausal women without a history of breast cancer were also eligible. Primary outcomes were pain, distress, fatigue, nausea/vomiting, and hot flashes. Safety was defined as secondary outcome measure. Risk of bias was assessed by 2 reviewers independently using the Cochrane Risk of Bias Tool. RESULTS: Thirteen RCTs with 1357 patients were included. In women undergoing diagnostic breast biopsy (3 RCTs), hypnosis positively influenced pain and distress; 1 RCT on breast cancer surgery found effects of hypnosis on pain, distress, fatigue, and nausea. For women undergoing radiotherapy (3 RCTs), hypnosis combined with cognitive-behavioral therapy improved distress and fatigue. In 3 RCTs on women with and without a history of breast cancer experiencing hot flashes, hypnosis improved hot flashes and distress. Three RCTs on women with metastatic breast cancer found effects on pain and distress. CONCLUSIONS: This systematic review found sparse but promising evidence for the effectiveness of hypnosis in breast cancer care. While more research is needed to underpin these results, hypnosis can be considered as an ancillary intervention in the management of breast cancer-related symptoms. | Can cognitive behavioral therapy improve fatigue in cancer patients? | 54d762653706e89528000014_014 | yes |
Clinical and imaging findings of lymphoma in patients with Sjögren syndrome. OBJECTIVE: To describe and correlate the clinical and imaging findings of lymphomas in patients with Sjögren syndrome. METHODS: The authors reviewed the medical and imaging records of 27 cases of lymphoma from among a total of 463 patients with Sjögren syndrome. The estimated prevalence of lymphoma in patients with Sjögren syndrome was 5.8%. There were 22 women and 5 men. Histopathologically, 26 of the 27 neoplasms were non-Hodgkin lymphoma, including 6 mucosa-associated lymphoid tissue lymphomas, and the other neoplasm was Hodgkin lymphoma. The clinical and imaging findings of lymphomas were analyzed. RESULTS: No obvious correlations were present between the duration or severity of Sjögren syndrome and the lymphoma development. At the initial diagnosis, extranodal involvement was observed in 14 (52%) of the 27 patients, including the salivary gland (n = 9), lacrimal gland (n = 2), lung (n = 2), and thyroid gland (n = 1), mostly in the neck organs. On the other hand, nodal involvement was observed in 21 (78%) of the 27 patients. Of these 21 patients, 19 had at least cervical lymph node involvement. CONCLUSION: Patients with Sjögren syndrome are at increased risk of lymphoma development. Because most lymphomas initially involve the neck organs, including the lymph nodes, meticulous imaging studies mainly focused on the cervical regions are recommended in the follow-up of patients with Sjögren syndrome. | Are patients with Sjogren syndrome at increased risk for lymphoma? | 5a6f87c5b750ff4455000056_012 | yes |
Molecular basis of asymptomatic beta-thalassemia major in an African American individual. The beta-thalassemia syndromes are a heterogeneous group of genetic disorders characterized by reduced or absent expression of the beta-globin gene. To date, over 300 beta-thalassemia alleles have been characterized in or around the beta-globin region. Thalassemia major is severe anemia necessitating chronic blood transfusions, splenectomy, iron chelation therapy, and bone marrow transplantation. Usually thalassemia major results from homozygosity or compound heterozygosity for severe betaO- and/or beta+-thalassemia mutations. Thalassemia intermedia is a clinical diagnosis that describes a symptomatic but less severe condition than beta-thalassemia major. beta-thalassemia intermedia may arise from several different combinations of alpha- and/or beta-thalassemia mutations. Heterozygous beta-thalassemia is typically characterized by a mild microcytic hypochromic anemia without any significant clinical implications. In this report, we describe a 63-year-old Africian American woman with asymptomatic homozygous beta-thalassemia, who seems to carry 2 copies of the -29 mutation in the promoter region of the beta-globin gene. Her elevated hemoglobin F level of 83% was associated with heterozygosity for the Xmn I polymorphism upstream of the Ggamma-globin gene. Southern blot analysis at the alpha-globin locus did not show any deletion that would account for the mildness of her phenotype. Therefore, homozygosity for the -29 mutation along with the Xmn I polymorphism appears to confer an extremely mild beta-thalassemia phenotype. This observation has important implications in the prenatal diagnosis and genetic counseling of families segregating this type of genetic defect. | Is Beta-Thalassemia is associated with a mutation or deletion of the gene that codes for alpha globin? | 58dbbbf08acda3452900001d_000 | no |
Association of the 19S proteasomal ATPases with the ATPase-binding domain of CIITA is essential for CIITA stability and MHC class II expression. Major histocompatibility class II (MHC class II) molecules are glycoproteins that present extracellular antigens to CD4(+) T cells and are essential for initiation of adaptive immune responses. MHC class II expression requires recruitment of a master regulator, the class II transactivator (CIITA), to the MHC class II promoter. Others and we have earlier linked CIITA to the ubiquitin-proteasome system by showing that mono-ubiquitination of CIITA increases its transactivity, whereas poly-ubiquitination of CIITA leads to its degradation. We have further shown that the 26S proteasome also has non-proteolytic functions in MHC class II transcription, as 19S ATPase subunits of the 26S proteasome positively regulate MHC class II transcription and are necessary for stable promoter binding of CIITA. Although these basic requirements of the proteasome to initiate MHC class II transcription are known, how CIITA is recruited, stabilized, and degraded remains unclear. Here, we identify a novel N-terminal 19S ATPase-binding domain of CIITA. The ATPase-binding domain lies within the proline/serine/threonine-rich region of CIITA and encompasses a majority of the CIITA degron sequence. Absence of the ATPase-binding domain increases the half-life of CIITA, but blocks MHC class II surface expression, indicating that CIITA requires interaction with the 19S ATPases for both appropriate deployment and destruction. | Is there any protein that undergoes both mono-ubiquitination and poly-ubiquitination? | 530c7cfd970c65fa6b00000c_003 | yes |
The dual specificity phosphatases M3/6 and MKP-3 are highly selective for inactivation of distinct mitogen-activated protein kinases. The mitogen-activated protein (MAP) kinase family includes extracellular signal-regulated kinase (ERK), c-Jun NH2-terminal kinase/stress-activated protein kinase (JNK/SAPK) and p38/RK/CSBP (p38) as structurally and functionally distinct enzyme classes. Here we describe two new dual specificity phosphatases of the CL100/MKP-1 family that are selective for inactivating ERK or JNK/SAPK and p38 MAP kinases when expressed in COS-7 cells. M3/6 is the first phosphatase of this family to display highly specific inactivation of JNK/SAPK and p38 MAP kinases. Although stress-induced activation of p54 SAPKbeta, p46 SAPKgamma (JNK1) or p38 MAP kinases is abolished upon co-transfection with increasing amounts of M3/6 plasmid, epidermal growth factor-stimulated ERK1 is remarkably insensitive even to the highest levels of M3/6 expression obtained. In contrast to M3/6, the dual specificity phosphatase MKP-3 is selective for inactivation of ERK family MAP kinases. Low level expression of MKP-3 blocks totally epidermal growth factor-stimulated ERK1, whereas stress-induced activation of p54 SAPKbeta and p38 MAP kinases is inhibited only partially under identical conditions. Selective regulation by M3/6 and MKP-3 was also observed upon chronic MAP kinase activation by constitutive p21(ras) GTPases. Hence, although M3/6 expression effectively blocked p54 SAPKbeta activation by p21(rac) (G12V), ERK1 activated by p21(ras) (G12V) was insensitive to this phosphatase. ERK1 activation by oncogenic p21(ras) was, however, blocked totally by co-expression of MKP-3. This is the first report demonstrating reciprocally selective inhibition of different MAP kinases by two distinct dual specificity phosphatases. | Is protein M3/6 a dual specificity phosphatase? | 5512cce26a8cde6b7200000c_002 | yes |
Peptide aptamer mimicking RAD51-binding domain of BRCA2 inhibits DNA damage repair and survival in Trypanosoma brucei. The eukaryotic DNA recombination repair protein BRCA2 is functional in the parasitic protozoan Trypanosoma brucei. The mechanism of the involvement of BRCA2 in homologous recombination includes its interaction with the DNA recombinase proteins of the RAD51 family. BRCA2 is known to interact with RAD51 through its unique and essential BRC sequence motifs. T. brucei BRCA2 homolog (TbBRCA2) has fifteen repeating BRC motifs as compared to mammalian BRCA2 that has only eight. We report here our yeast 2-hybrid analysis studies on the interactions of TbBRCA2 BRC motifs with five different RAD51 paralogues of T. brucei. Our study revealed that a single BRC motif is sufficient to bind to these RAD51 paralogues. To test the possibility whether a single 44 amino acid long repeating unit of the TbBRCA2 BRC motif may be exploited as an inhibitor of T. brucei growth, we ectopically expressed this peptide segment in the procyclic form of the parasite and evaluated its effects on cell survival as well as the sensitivity of these cells to the DNA damaging agent methyl methane sulfonate (MMS). Expression of a single BRC motif led to MMS sensitivity and inhibited cellular proliferation in T. brucei. | Can a peptide aptamer be used as protein inhibitor? | 53443b13aeec6fbd0700000e_003 | yes |
Turcot's syndrome associated with intestinal non-Hodgkin's lymphoma: case report and review of literature. A 15-year-old boy was admitted with the diagnosis of colonic polyposis, and during a 2-year follow-up, he underwent operation for right parieto-occipital anaplastic astrocytoma, left-side colonic non-Hodgkin lymphoma (NHL) and cerebella glioblastoma which were all confirmed by histology. Although cases of Turcot's syndrome (TS) (colonic polyposis and primary brain tumour occurring in the same patient) have been previously described, association with haematological malignancy is rare. We hereby report such a case with TS. | Is Turcot syndrome associated with glioblastoma? | 533581f5d6d3ac6a3400004d_002 | yes |
Initial testing of the MDM2 inhibitor RG7112 by the Pediatric Preclinical Testing Program. BACKGROUND: RG7112 is a selective inhibitor of p53-MDM2 binding that frees p53 from negative control, activating the p53 pathway in cancer cells leading to cell cycle arrest and apoptosis. RG7112 was selected for evaluation by the Pediatric Preclinical Testing Program (PPTP) due to the relatively low incidence of p53 mutations in pediatric cancers compared with adult malignancies. PROCEDURES: RG7112 and its inactive enantiomer RG7112i were evaluated against the 23 cell lines of the PPTP in vitro panel using 96 hours exposure (1 nM to 10 µM). It was tested against the PPTP in vivo panel focusing on p53 wild-type (WT) xenografts at a dose of 100 mg/kg daily for 14 days followed by 4 weeks of observation. Response outcomes were related to MDM2 and p53 expression datasets (http://pptp.nchresearch.org/data.html). RESULTS: RG7112 demonstrated cytotoxic activity with a lower median IC(50) for p53 WT versus p53 mutant cell lines (approximately 0.4 µM vs. >10 µM, respectively). RG7112 induced tumor growth inhibition meeting criteria for intermediate activity (EFS T/C > 2) in 10 of 26 (38%) solid tumor xenografts. Objective responses included medulloblastoma, alveolar rhabdomyosarcoma, Wilms, rhabdoid and Ewing sarcoma xenografts. For the ALL panel, there was one partial response, five complete responses and one maintained complete response. The ALL xenografts expressed the highest levels of p53 among the PPTP panels. CONCLUSIONS: RG7112 induced tumor regressions in solid tumors from different histotype panels, and exhibited consistent high-level activity against ALL xenografts. This high level of activity supports prioritization of RG7112 for further evaluation. | Could RG7112 be used as cancer therapy? | 56ed0a372ac5ed1459000006_003 | yes |
Crohn's disease: the cold chain hypothesis. A recent published hypothesis proposed that Crohn's disease was provoked by infantile exposure to micro-organisms that can survive refrigerator temperature. A case-control study was accordingly devised. The mean age at first fridge was 5.6 years amongst 88 patients with Crohn's disease, 5.5 years in 88 patients with ulcerative colitis (UC) and 7.6 years in 88 controls, but a majority of individuals had always been exposed to refrigerated food. Differences were more striking in subjects aged above the median (10.3, 10.9 and 15.0 years for Crohn's disease, UC and controls, respectively). This support for the hypothesis reached statistical significance for those with Crohn's disease compared to the controls (p=0.045). | Is Crohn's disease (CD) linked to the consumption of refrigerated food? | 56cae40b5795f9a73e000022_002 | yes |
TERT promoter mutations in gliomas, genetic associations and clinico-pathological correlations. BACKGROUND: The role of telomerase reverse transcriptase (TERT) in gliomagenesis has been recently further strengthened by the frequent occurrence of TERT promoter mutations (TERTp-mut) in gliomas and evidence that the TERT SNP genetic rs2736100 influences glioma risk. TERTp-mut creates a binding site for Ets/TCF transcription factors, whereas the common rs2853669 polymorphism disrupts another Ets/TCF site on TERT promoter. METHODS: We sequenced for TERTp-mut in 807 glioma DNAs and in 235 blood DNAs and analysed TERT expression by RT-PCR in 151 samples. TERTp-mut status and TERTp polymorphism rs2853669 were correlated with histology, genomic profile, TERT mRNA expression, clinical outcome and rs2736100 genotype. RESULTS: TERTp-mut identified in 60.8% of gliomas (491 out of 807) was globally associated with poorer outcome (Hazard ratio (HR)=1.50). We defined, based on TERTp-mut and IDH mutation status, four prognostic groups: (1) TERTp-mut and IDH-mut associated with 1p19q codeletion, overall survival (OS)>17 years; (2) TERTp-wt and IDH-mut, associated with TP53 mutation, OS=97.5 months; (3) TERTp-wt and IDH-wt, with no specific association, OS=31.6 months; (4) TERTp-mut and IDH-wt, associated with EGFR amplification, OS=15.4 months. TERTp-mut was associated with higher TERT mRNA expression, whereas the rs2853669 variant was associated with lower TERT mRNA expression. The mutation of CIC (a repressor of ETV1-5 belonging to the Ets/TCF family) was also associated with TERT mRNA upregulation. CONCLUSIONS: In addition to IDH mutation status, defining the TERTp-mut status of glial tumours should afford enhanced prognostic stratification of patients with glioma. We also show that TERTp-mut, rs2853669 variant and CIC mutation influence Tert expression. This effect could be mediated by Ets/TCF transcription factors. | Is there an association between TERT promoter mutation and survival of glioma patients? | 56c095b7ef6e394741000025_002 | yes |
The imprinted NPAP1/C15orf2 gene in the Prader-Willi syndrome region encodes a nuclear pore complex associated protein. The Prader-Willi syndrome (PWS) region in 15q11q13 harbours a cluster of imprinted genes expressed from the paternal chromosome only. Whereas loss of function of the SNORD116 genes appears to be responsible for the major features of PWS, the role of the other genes is less clear. One of these genes is C15orf2, which has no orthologues in rodents, but appears to be under strong positive selection in primates. C15orf2 encodes a 1156 amino acid protein with six nuclear localisation sequences. By protein BLAST analysis and InterProScan signature recognition search, we found sequence similarity of C15orf2 to the nuclear pore complex (NPC) protein POM121. To determine whether C15orf2 is located at nuclear pores, we generated a stable cell line that inducibly expresses FLAG-tagged C15orf2 and performed immunocytochemical studies. We found that C15orf2 is present at the nuclear periphery, where it colocalizes with NPCs and nuclear lamins. At very high expression levels, we observed invaginations of the nuclear envelope. Extending these observations to three-dimensional structured illumination microscopy, which achieves an 8-fold improved volumetric resolution over conventional imaging, we saw that C15orf2 is located at the inner face of the nuclear envelope where it strongly associates with the NPC. In nuclear envelope isolation and fractionation experiments, we detected C15orf2 in the NPC and lamina fractions. These experiments for the first time demonstrate that C15orf2 is part of the NPC or its associated molecular networks. Based on our findings, we propose 'Nuclear pore associated protein 1' as the new name for C15orf2. | Is the Snord116 cluster associated with the Prader-Willi syndrome? | 52b2f0d84003448f55000009_011 | yes |
A(H1N1)v2009: a controlled observational prospective cohort study on vaccine safety in pregnancy. BACKGROUND: A(H1N1)v2009 influenza vaccination of pregnant women was a challenge for health care providers, as little safety data were available. METHODS: We prospectively followed the pregnancies of women who were vaccinated at any time during pregnancy or < 4 weeks prior to conception and compared these outcomes to a control cohort matched by the estimated date of birth. Primary endpoints: rate of spontaneous abortion and major malformations. Secondary endpoints: preeclampsia, gestational age at birth, and birth weight. RESULTS: Pregnancy outcome of 323 women immunized with adjuvanted or non-adjuvanted A(H1N1)v2009 influenza vaccines from 2009-09-28 to 2010-03-31 were compared to 1329 control subjects. The risk for spontaneous abortions (HR 0.89; 95% CI 0.36-2.19) and the rate of major malformations (all trimesters: OR 0.87; 95% CI 0.38-1.77; preconception and first trimester exposure: OR 0.79; 95% CI 0.13-2.64) did not vary between the two cohorts. Furthermore, there was no increase in preeclampsia, prematurity, and intrauterine growth retardation in the vaccinated cohort. CONCLUSION: The results of our study do not indicate a risk for the pregnant woman and the developing embryo/fetus after H1N1 vaccination. We provide and apply methods novel in observational studies on pregnancy outcome, especially if a single dose exposure is investigated. | Is pregnancy an additional risk during during H1N1 infection? | 531a3fe3b166e2b806000038_011 | yes |
Orthostatic intolerance is not necessarily related to a specific mutation (Ala457Pro) in the human norepinephrine transporter gene. BACKGROUND: Orthostatic intolerance (OI) is a syndrome characterized by lightheadedness, palpitations, fatigue, blurred vision, dizziness, chest discomfort, cognitive impairment, and occasionally syncope. These symptoms usually occur after upright posture and are associated with tachycardia and high plasma concentrations of norepinephrine. It has been proposed that a mutation in exon 9 of the norepinephrine transporter gene (Ala457Pro), resulting in more than 98% loss of function compared with the wild type, might provide a pathogenetic mechanism to explain the clinical symptoms of patients with OI. METHODS: We studied 46 young men from military service who had sought medical advice because of dizziness while standing. Every patient underwent a tilt-table test, with monitoring of blood pressure, heart rate, and plasma catecholamines in supine position and during 30 minutes of standing. Fourteen patients showing the full-blown OI syndrome (30 bpm increase in heart rate and 600 pg/mL plasma norepinephrine levels while standing) underwent direct DNA sequencing of exon 9 of the norepinephrine-transporter gene. RESULTS AND CONCLUSIONS: The specific mutation (Ala457Pro) was not detected in any of the 14 OI patients. Based on these findings, we doubt that this specific genetic transport defect is a frequent cause of the impaired uptake of norepinephrine in OI patients. Its routine determination will therefore not be helpful to establish the clinical diagnosis of OI. | Is the gene SLC6A2 associated with orthostatic intolerance? | 56d8ba1851531f7e33000005_001 | yes |
[Anticoagulation of older patients: what is new?]. Vitamin-K antagonists (VKA) are the current standard for oral anticoagulation. However, they carry several problems in older patients: frequent bleeding complications, complex management, risk of interactions with multiple drugs. Two new classes of oral anticoagulants (NOA) are now available: direct thrombin inhibitors (dabigatran); and direct factor Xa inhibitors (rivaroxaban, apixaban) and others. Their management is easier: quickly effective after administration, they are given at fixed doses and do not need regular laboratory monitoring. Several randomized trials have shown that NOA are non-inferior to heparins and VKA for treating venous thromboembolic disease (prophylactic or curative treatment) and atrial fibrillation (prevention of associated embolisms). NOA are also being studied for long-term treatment after acute coronary syndromes. Data regarding older people is still sparse. No trial has specifically studied older patients. In the context of atrial fibrillation, subgroup analysis show similar results between patients above and below 75 years old, except for dabigatran which seems to carry more bleeding complications in people older than 75 years, specially with the highest dose employed. All NOA are eliminated at least partly by kidneys. Their dose must be reduced in moderate renal failure (filtration glomerular rate (FGR) 30 to 50 ml/min) and they are contra-indicated in severe renal failure (FGR<30 ml/min). Doses of dabigatran and apixaban should be reduced in older people too. NOA also have other unresolved problems: drug interactions are still possible, specific coagulation test to assess them must be developed, and no specific antidote is currently available in case of hemorrhagic complication. | Are there any specific antidotes for dabigatran? | 532f08dcd6d3ac6a3400002a_009 | no |
Cri du chat syndrome due to meiotic recombination in a pericentric inversion 5 carrier. A female infant presented at birth with hypotonia, growth retardation, distinctive facies, multiple congenital anomalies, and a high-pitched mewing cry characteristic of cri du chat syndrome. Chromosome studies from both peripheral blood and fibroblasts showed a 46,XX,5p- karyotype. Parental chromosome studies revealed that the mother carried an apparently balanced pericentric inversion of one chromosome no. 5, 46,XX,inv(5)(p14q35). Meiotic crossing-over in the mother within the inverted segment of chromosome 5 gave rise to the unbalanced karyotype, 46,XX,rec(5)dup q, inv(5)(p14q35)mat in the infant. A small terminal segment of the long arm of chromosome 5 (q35-pter) is duplicated with a deletion of the short arm of chromosome 5 (p14-pter), accounting for the features of cri du chat syndrome. Fewer than 1 in 200 of cri du chat syndrome cases are due to recombination aneusomy arising from a parental inversion of chromosome 5. Some of these cases, however, do not have typical cri du chat syndrome, reflecting significant duplication of 5q material. These cases are reviewed with the present case, and recombination behaviour leading to chromosome imbalance is discussed. | Is Cri Du Chat associated with an expansion of a repeat with in the gene found on chromosome 5? | 58dbba438acda3452900001c_003 | no |
Effects of manganese on extracellular levels of dopamine in rat striatum: an analysis in vivo by brain microdialysis. The aim of this study is to determine the effects of intrastriatal administration of MnCl2, on the extracellular levels of dopamine (DA) and metabolites dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in basal conditions and stimulated by depolarization with KCl and pargyline administration. Also, we studied the effect of MnCl2 on extracellular levels of l-Dopa in the presence of aromatic amino acid decarboxylase (AADC) inhibitor 3-hydroxybencilhydracine-HCl (NSD 1015). This study concluded that MnCl2, reduced the basal and K+-stimulated DA-release in striatum, without notably affecting the DOPAC and HVA levels. Intraperitoneal injection of pargyline increased striatal DA levels, decreasing DOPAC and HVA levels. The infusion of MnCl2 removed the increase in DA levels, without affecting DOPAC and HVA levels. Perfusion of NSD 1015 increased the extracellular levels of L-DOPA in striatum, and MnCl2 increased the effect of NSD1015 on L-Dopa. | Is NSD-1015 an inhibitor of Aromatic L-Amino Acid Decarboxylase? | 589c334e78275d0c4a00003d_008 | yes |
Polymorphic hCHK2/hCds1 codon 84 allele and risk of squamous cell carcinoma of the head and neck--a case-control analysis. Checkpoint kinase 2 (hCHK2/hCds1) is a tumor suppressor gene involved in cell-cycle control. A hCHK2/hCds1 polymorphism in codon 84 (A-->G at nucleotide 252) was recently identified in Li-Fraumeni syndrome patients. Because cell cycle regulates DNA repair that is associated with cancer risk, we hypothesized that this new polymorphism exists in the general population and is associated with cancer risk. To test this hypothesis, we evaluated the role of this polymorphism in a case-control study of 215 non-Hispanic white patients with newly diagnosed squamous cell carcinoma of the head and neck (SCCHN) and 229 frequency-matched cancer-free controls. We found that the hCHK2/hCds1 codon 84 variant was rare and less frequent in non-Hispanic white cases (0.0186) than in controls (0.0437; P = 0.033). Although no variant homozygotes were detected in these cases and controls, heterozygosity protected against SCCHN, representing a 60% reduction of risk (adjusted odds ratio = 0.40; 95% confidence intervals, 0.17-0.93) compared with wild-type homozygotes. The variant allele was also rare in other ethnic groups (0.0487, 0.0095 and 0.0541 in 115 African Americans, 105 Hispanic Americans and 111 native Chinese, respectively), and only one variant homozygous individual (a Chinese subject) was identified. These results suggest that this hCHK2/hCds1 codon 84 polymorphism is rare and may have a protective role in the aetiology of SCCHN in non-Hispanic whites. Larger studies are warranted to confirm this finding and further mechanistic studies are needed to understand biological relevance of this polymorphism. | Is CHEK2 involved in cell cycle control? | 53175e25b166e2b806000007_004 | yes |
Immunohistochemical profile of monoclonal antibody O13: antibody that recognizes glycoprotein p30/32MIC2 and is useful in diagnosing Ewing's sarcoma and peripheral neuroepithelioma. Ewing's sarcoma (ES) and peripheral neuroepithelioma (PN) are closely related tumors, and it can be difficult to distinguish them from other small-round-cell tumors (SRCTs). The glycoprotein p30/32MIC2 is highly, but not exclusively, expressed in both ES and PN. Although the monoclonal antibody (Mab) HBA71, which reacts with P30/32MIC2, has been reported to be relatively specific and highly sensitive for both neoplasms, it is not readily available. Yet, Mab O13 is commercially available, and it purportedly displays the same immunostaining characteristics as HBA71. Because O13 has not been studied extensively, we immunostained 21 ES/PNs and 147 other tumors or lesions that might show SRCT-like features with O13. The results were similar to those reported for HBA71. We found O13 to be 100% sensitive for ES/PN; and, no immunostaining was noted on the SRCTs often included in the differential diagnosis of ES/PN (i.e., conventional neuroblastoma, rhabdomyosarcoma, and non-lymphoblastic lymphomas). But, O13 immunoreacted with lymphoblastic lymphomas and some other tumors and normal tissues. Nonetheless, this nonspecific reactivity should not cause diagnostic problems, if an antibody panel containing anti-desmin and anti-leukocyte common antigen is used in conjunction with O13. We conclude that, within the proper diagnostic context, strong immunoreactivity of a SRCT tumor for O13 should be considered good evidence that the tumor is ES/PN. | Is peripheral neuroepithelioma related to Ewing sarcoma? | 552fa6f5bc4f83e828000002_004 | yes |
[Conservative and surgical therapy of urinary incontinence and bladder complaints in the man]. Treatment of incontinence and bladder complaints in the male should be directed to the cause whenever possible. Frequently, however, only symptomatic therapy is possible. Urge incontinence or overactive bladder due to obstruction should primarily be treated by eliminating the obstruction. Medical and surgical treatment methods are available for benign prostatic hyperplasia, bladder neck hypertrophy and prostatic cancer. In contrast, bladder neck sclerosis and uretheral strictures can only be treated surgically. Anticholinergics are primarily indicated if urge symptoms/incontinence persist after obstruction has been relieved or if urge incontinence occurs without obstruction. Seldom, in special cases injection of Botulinustoxin A or augmentation of the bladder may be indicated. Another possible cause of urge symptoms is urinary tract infection. This should be adequately treated according to resistance studies and the cause of the infection determined. In cases of overflow incontinence the infravesicle obstruction must be sought and treated. If limited detrusor contractability is the cause of overflow incontinence and the bladder cannot be emptied through pressmicturition, parasympathicometics may be of help. By insufficient effect, the procedure of intermittent self-catheterization must be taught. If this is not possible, the last resort is placement of a transuretheral or percutaneous catheter for continuous drainage. Stress incontinence is a rare complication in men, usually following prostatic surgery. It can be treated conservatively with pelvic floor training and alpha-adrenergic receptor agonists and if necessary surgically with submucosal collagen or silicon injections in the sphincter area or implantation of a sphincter prosthesis. Supravesicular urinary diversion is occasionally necessary after conservative and less invasive surgical measures have been exhausted and symptomatic suffering persists. Neurogenic disturbances in bladder capacity and/or emptying can be treated conservatively, medically, surgically or a combination of these depending upon the site of the lesion and the resulting urodynamic patterns. | Has silicon been used in treatment of incontinence ? | 536172d17d100faa09000009_006 | yes |
Weight reduction in schizophrenics by molindone. The weight-reducing property of molindone, a recently introduced antipsychotic drug, was tested in 9 hospitalized chronic schizophrenic patients. There was an average weight loss of 7.6 kg after 3 months on molindone; most of the loss occurred during the first month. The mechanism producing this weight loss is uncertain, but a central anorexigenic effect may be an important factor. | Does molindone affect body weight? | 52cae04c03868f1b06000024_001 | yes |
[The exploding head syndrome]. The case is reported of a 47-year old female suffering from the exploding head syndrome. This syndrome consists of a sudden awakening due to a loud noise shortly after falling asleep, sometimes accompanied by a flash of light. The patient is anxious and experiences palpitations and excessive sweating. Most patients are more than fifty years of age. Further investigations do not reveal any abnormality. The pathogenesis is unknown, and no therapy other than reassurance is necessary. | Is there a disease or condition called Exploding Head Syndrome? | 5a8ee9d1fcd1d6a10c000027_007 | yes |
A framework to identify gene expression profiles in a model of inflammation induced by lipopolysaccharide after treatment with thalidomide. BACKGROUND: Thalidomide is an anti-inflammatory and anti-angiogenic drug currently used for the treatment of several diseases, including erythema nodosum leprosum, which occurs in patients with lepromatous leprosy. In this research, we use DNA microarray analysis to identify the impact of thalidomide on gene expression responses in human cells after lipopolysaccharide (LPS) stimulation. We employed a two-stage framework. Initially, we identified 1584 altered genes in response to LPS. Modulation of this set of genes was then analyzed in the LPS stimulated cells treated with thalidomide. RESULTS: We identified 64 genes with altered expression induced by thalidomide using the rank product method. In addition, the lists of up-regulated and down-regulated genes were investigated by means of bioinformatics functional analysis, which allowed for the identification of biological processes affected by thalidomide. Confirmatory analysis was done in five of the identified genes using real time PCR. CONCLUSIONS: The results showed some genes that can further our understanding of the biological mechanisms in the action of thalidomide. Of the five genes evaluated with real time PCR, three were down regulated and two were up regulated confirming the initial results of the microarray analysis. | Is Thalidomide currently a marketed drug? | 58a0d87a78275d0c4a000053_007 | yes |
Tofacitinib for the treatment of tumor necrosis factor-α inhibitor refractory esophageal Crohn's disease: a case report. BACKGROUND: Esophageal Crohn's disease is reported as a rare manifestation, although its prevalence may be underestimated because upper endoscopies are not routinely performed in asymptomatic adults. Tofacitinib, an oral janus kinase inhibitor, is a new biologic that has shown promise in the treatment of ulcerative colitis and may be effective in the treatment of Crohn's disease according to phase 2 trials. We report the first case of esophageal Crohn's disease successfully treated with tofacitinib in a patient with worsening symptoms despite maintenance therapy with a tumor necrosis factor-α inhibitor. CASE PRESENTATION: A 67-year-old Caucasian woman presented with new dysphagia and had findings of esophageal Crohn's disease on endoscopy. The dosage of her current biologic therapy-adalimumab-was increased in frequency, without improvement. Our patient was started on tofacitinib and demonstrated an improvement in symptoms, with a repeat endoscopy showing resolution of the previous lesions. CONCLUSION: Esophageal Crohn's disease is likely underdiagnosed but is an important consideration in a patient with new symptoms of dysphagia and known Crohn's disease. Tofacitinib, while a novel agent, could have a role in the treatment of esophageal Crohn's disease that does not improve with intensification of the current biologic therapy. It provides a different mechanism in patients who become refractory to maintenance therapy. | Is Tofacitinib effective for Ulcerative Colitis? | 5a723edd2dc08e987e00000c_002 | yes |
Cardiorenal syndromes. Cardiorenal syndromes (CRS) have been subclassified as five defined entities which represent clinical circumstances in which both the heart and the kidney are involved in a bidirectional injury and dysfunction via a final common pathway of cell-to-cell death and accelerated apoptosis mediated by oxidative stress. Types 1 and 2 involve acute and chronic cardiovascular disease (CVD) scenarios leading to acute kidney injury or accelerated chronic kidney disease. Types 2 and 3 describe acute and chronic kidney disease leading primarily to heart failure, although it is possible that acute coronary syndromes, stroke, and arrhythmias could be CVD outcomes in these forms of CRS. Finally, CRS type 5 describes a simultaneous insult to both heart and kidneys, such as sepsis, where both organs are injured simultaneously. Both blood and urine biomarkers are reviewed in this paper and offer a considerable opportunity to enhance the understanding of the pathophysiology and known epidemiology of these recently defined syndromes. | Are there any urine biomarkers for chronic kidney disease? | 52fa73c62059c6d71c000058_002 | yes |
A cardiac microRNA governs systemic energy homeostasis by regulation of MED13. Obesity, type 2 diabetes, and heart failure are associated with aberrant cardiac metabolism. We show that the heart regulates systemic energy homeostasis via MED13, a subunit of the Mediator complex, which controls transcription by thyroid hormone and other nuclear hormone receptors. MED13, in turn, is negatively regulated by a heart-specific microRNA, miR-208a. Cardiac-specific overexpression of MED13 or pharmacologic inhibition of miR-208a in mice confers resistance to high-fat diet-induced obesity and improves systemic insulin sensitivity and glucose tolerance. Conversely, genetic deletion of MED13 specifically in cardiomyocytes enhances obesity in response to high-fat diet and exacerbates metabolic syndrome. The metabolic actions of MED13 result from increased energy expenditure and regulation of numerous genes involved in energy balance in the heart. These findings reveal a role of the heart in systemic metabolic control and point to MED13 and miR-208a as potential therapeutic targets for metabolic disorders. | Does thyroid hormone signaling affect microRNAs expression in the heart? | 516c1041298dcd4e51000070_003 | yes |
Identification of novel miR-21 target proteins in multiple myeloma cells by quantitative proteomics. Substantial evidence indicates that microRNA-21 (miR-21) is a key oncomiR in carcinogenesis and is significantly elevated in multiple myeloma (MM). In this study, we explored the role of miR-21 in human MM cells and searched for miR-21 targets. By knocking down the expression of endogenous miR-21 in U266 myeloma cells, we observed reduced growth, an arrested cell cycle, and increased apoptosis. To further understand its molecular mechanism in the pathogenesis of MM, we employed a SILAC (stable isotope labeling by amino acids in cell culture)-based quantitative proteomic strategy to systematically identify potential targets of miR-21. In total, we found that the expression of 178 proteins was up-regulated significantly by miR-21 inhibition, implying that they could be potential targets of miR-21. Among these, the protein inhibitor of activated STAT3 (PIAS3) was confirmed as a direct miR-21 target by Western blotting and reporter gene assays. We further demonstrated that miR-21 enhances the STAT3-dependent signal pathway by inhibiting the function of PIAS3 and that down-regulation of PIAS3 contributes to the oncogenic function of miR-21. This elucidation of the role of PIAS3 in the miR-21-STAT3 positive regulatory loop not only may shed light on the molecular basis of the biological effects of miR-21 observed in MM cells but also has direct implications for the development of novel anti-MM therapeutic strategies. | Is miR-21 related to carcinogenesis? | 511a4ec01159fa8212000004_039 | yes |
Complete deficiency of methylenetetrahydrofolate reductase in mice is associated with impaired retinal function and variable mortality, hematological profiles, and reproductive outcomes. Severe deficiency of methylenetetrahydrofolate reductase (MTHFR) with homocystinuria can result in early demise or later-onset neurological impairment, including developmental delay, motor dysfunction, and seizures. We previously characterized BALB/c Mthfr (-/-)mice as a model for this disorder and have recently backcrossed the disrupted allele onto the C57Bl/6 background to examine the variable phenotypes in MTHFR deficiency. Compared with BALB/c Mthfr (-/-)mice, C57Bl/6 Mthfr (-/-)mice have enhanced survival rates (81% vs 26.5%). Four-day-old BALB/c mutant pups had lower body, brain, and spleen weights relative to their wild-type counterparts compared with C57Bl/6 mutants. Pregnant BALB/c Mthfr (+/-)mice had increased resorptions and embryonic delays compared with wild-type littermates, whereas these outcomes in C57Bl/6 c Mthfr (+/-)mice were similar to those of wild-type C57Bl/6 mice. BALB/c-mutant pups had altered hematological profiles (higher hematocrit, hemoglobin, and white blood cell counts, with lower platelet counts) compared with C57Bl/6 mutants. Mutants of both strains had similar degrees of hepatic steatosis, hepatic activity of betaine:homocysteine methyltransferase, and altered cerebellar histology. Electroretinograms (ERG) in C57Bl/6 Mthfr (-/-)mice revealed decreased amplitude of scotopic and photopic waves in 6-week-old mice, with normalized ERGs at 13 weeks. Plasma homocysteine was modestly higher in C57Bl/6 compared with BALB/c mice. Our results emphasize the variable presentation of MTHFR deficiency in different genetic backgrounds and suggest that plasma homocysteine is not a predictor of severity. In addition, our novel findings of decreased spleen weights, thrombocytopenia, and impaired retinal function warrant investigation in patients with severe MTHFR deficiency or other forms of homocystinuria. | Can methylenetetrahydrofolate reductase (MTHFR) gene mutations cause homocystinuria? | 58d8d0cc8acda34529000008_016 | yes |
The serotonergic system in the neurobiology of depression: Relevance for novel antidepressants. The monoamine hypothesis of depression posits that an imbalance in monoaminergic neurotransmission is causally related to the clinical features of depression. Antidepressants influencing serotonin mainly aim at raising serotonin concentrations, thereby increasing serotonergic transmission at the level of the synapse, for example by inhibiting the serotonin transporter. However, the serotonin system is multifaceted. Different serotonin receptor subtypes turn the serotonergic system into a complex neurochemical arrangement that influences diverse neurotransmitters in various brain regions. Classical antidepressants as well as other psychopharmacological agents have various crucial effects on serotonin receptors. We aim at providing a clinically useful characterization of serotonin receptor subtypes in the treatment of depression. Clarifying the mode of action and the interplay of serotonin receptors with pharmacological agents should help antidepressant mechanisms and typical side effects to be better understood. Against this background, we feature the novel antidepressants vortioxetine, vilazodone and milnacipran/levomilnacipran with regard to their serotonin receptor targets such as the 5-HT1A, 5-HT3 and 5-HT7 which may account for their specific effects on certain symptoms of depression (e.g. cognition and anxiety) as well as a characteristic side-effect profile. | Is vortioxetine effective for treatment of depression? | 589a246878275d0c4a000030_004 | yes |
Assessing the citrullinome in rheumatoid arthritis synovial fluid with and without enrichment of citrullinated peptides. Protein citrullination is a posttranslational modification that has attracted increased attention, especially for its involvement in rheumatoid arthritis (RA). Here, we assess the citrullinome in RA synovial fluid by direct LC-MS/MS analysis and by the use of an enrichment strategy based on citrulline specific biotinylation. RA synovial fluid was depleted for abundant proteins, and total and depleted fractions were analyzed. Frequency of citrullinated peptides and their degree of citrullination could be determined for four known RA autoantigens, as well as a novel in vivo autocitrullination site of peptidylarginine deiminase 4. From the analysis of total and depleted synovial fluid after enrichment we could estimate the numbers of citrullinated peptides to be approximately 3600 and 2100, respectively. However, identification of these biotinylated peptides by MS/MS turned out to be very difficult due to fragmentation of the biotin moiety. By direct MS analysis of the total and depleted synovial fluid without enrichment, 119 and 157 citrullinated peptides were identified, respectively. This indicates that direct analysis allows identification of only a fraction of the citrullinated proteins present in synovial fluid and that specific enrichment is still needed for a comprehensive in-depth elucidation of the citrullinome. | Has protein citrullination been implicated in rheumatoid arthritis? | 54d796f93706e8952800001e_003 | yes |
PGC-1 alpha accelerates cytosolic Ca2+ clearance without disturbing Ca2+ homeostasis in cardiac myocytes. Energy metabolism and Ca(2+) handling serve critical roles in cardiac physiology and pathophysiology. Peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1 alpha) is a multi-functional coactivator that is involved in the regulation of cardiac mitochondrial functional capacity and cellular energy metabolism. However, the regulation of PGC-1 alpha in cardiac Ca(2+) signaling has not been fully elucidated. To address this issue, we combined confocal line-scan imaging with off-line imaging processing to characterize calcium signaling in cultured adult rat ventricular myocytes expressing PGC-1 alpha via adenoviral transduction. Our data shows that overexpressing PGC-1 alpha improved myocyte contractility without increasing the amplitude of Ca(2+) transients, suggesting that myofilament sensitivity to Ca(2+) increased. Interestingly, the decay kinetics of global Ca(2+) transients and Ca(2+) waves accelerated in PGC-1 alpha-expressing cells, but the decay rate of caffeine-elicited Ca(2+) transients showed no significant change. This suggests that sarcoplasmic reticulum (SR) Ca(2+)-ATPase (SERCA2a), but not Na(+)/Ca(2+) exchange (NCX) contribute to PGC-1 alpha-induced cytosolic Ca(2+) clearance. Furthermore, PGC-1 alpha induced the expression of SERCA2a in cultured cardiac myocytes. Importantly, overexpressing PGC-1 alpha did not disturb cardiac Ca(2+) homeostasis, because SR Ca(2+) load and the propensity for Ca(2+) waves remained unchanged. These data suggest that PGC-1 alpha can ameliorate cardiac Ca(2+) cycling and improve cardiac work output in response to physiological stress. Unraveling the PGC-1 alpha-calcium handling pathway sheds new light on the role of PGC-1 alpha in the therapy of cardiac diseases. | Is Calcium homeostasis important in cardiac physiology and pathophysiology? | 54c26e29f693c3b16b000003_019 | yes |
Fat-laden macrophages modulate lobular inflammation in nonalcoholic steatohepatitis (NASH). Nonalcoholic steatohepatitis (NASH) is characterized by extensive hepatic monocyte infiltration and monocyte-derived macrophages have an important role in regulating the disease evolution. However, little is known about the functional changes occurring in liver macrophages during NASH progression. In this study, we investigated phenotypic and functional modifications of hepatic macrophages in experimental NASH induced by feeding C57BL/6 mice with a methionine-choline deficient (MCD) diet up to 8weeks. In mice with steatohepatitis liver F4/80-positive macrophages increased in parallel with the disease progression and formed small clusters of enlarged and vacuolated cells. At immunofluorescence these cells contained lipid vesicles positive for the apoptotic cell marker Annexin V suggesting the phagocytosis of apoptotic bodies derived from dead fat-laden hepatocytes. Flow cytometry revealed that these enlarged macrophages expressed inflammatory monocyte (CD11b, Ly6C, TNF-α) markers. However, as compared to regular size macrophages the enlarged sub-set was characterized by an enhanced production of arginase-1 and of the anti-inflammatory mediators IL-10 and annexin A1. Similar vacuolated macrophages producing annexin A1 were also evident in liver biopsies of NASH patients. In mice with NASH, the accumulation of enlarged F4/80(+) cells paralleled with a decline in the expression of the macrophage M1 activation markers iNOS, IL-12 and CXCL10, while the levels of M2 polarization markers arginase-1 and MGL-1 were unchanged. Interestingly, the lowering of IL-12 expression mainly involved the macrophage sub-set with regular size. We conclude that during the progression of NASH fat accumulation within liver macrophages promotes the production of anti-inflammatory mediators that influence hepatic inflammatory responses. | Is Annexin V an apoptotic marker? | 5894597e7d9090f353000004_027 | yes |
Cholesterol-reducing agents for aneurysmal subarachnoid haemorrhage. BACKGROUND: Cerebral vasospasm and related delayed ischaemic deficits (DIDs) occur in about 17% to 40% of patients with aneurysmal subarachnoid haemorrhage (SAH) and lead to a poor outcome. Cholesterol-reducing agents might improve unfavourable outcomes. OBJECTIVES: To assess the effects of cholesterol-reducing agents for improving outcomes in patients with aneurysmal SAH. SEARCH METHODS: We searched the Cochrane Stroke Group Trials Register (May 2012), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2012, Issue 5), MEDLINE (1948 to May 2012) and EMBASE (1980 to May 2012). We also searched three Chinese databases: SinoMed, CNKI and VIP (May 2012). In an effort to identify further published, ongoing and unpublished trials we searched relevant clinical trials and research registers (May 2012), contacted pharmaceutical companies and investigators known to be involved in previous trials and screened the reference lists of all relevant articles identified. SELECTION CRITERIA: We included randomised controlled trials (RCTs) that compared cholesterol-reducing agents with control or placebo treatment in participants with aneurysmal SAH. DATA COLLECTION AND ANALYSIS: Two review authors independently applied the inclusion criteria, reviewed the relevant trials and extracted data. We did not perform meta-analysis as we only included one RCT in the review. MAIN RESULTS: We included one study in which 39 patients received either simvastatin (80 mg daily; n = 19) or placebo (n = 20) for 14 days. The incidence of DIDs (secondary outcome) was 26% (5/19) in the simvastatin group versus 60% (12/20) in the placebo group (risk ratio (RR) 0.44, 95% confidence interval (CI) 0.19 to 1.01, P = 0.05). This means that, in this study, simvastatin had no effect on DIDs. Two patients in the simvastatin group and one patient in the placebo group had elevated levels of aspartate transaminase or alanine transaminase. One patient in the simvastatin group had a raised creatine phosphokinase. There were no results from this trial for the primary outcome of death or dependency at six months. AUTHORS' CONCLUSIONS: We cannot draw any conclusions about the effectiveness and safety of lowering cholesterol in aneurysmal SAH because of insufficient reliable evidence from only one small trial. More RCTs are needed. | Is statin use associated with improved outcomes after aneurysmal subarachnoid hemorrhage? | 530e131b5937551c09000002_000 | yes |
A mouse model for luminal epithelial like ER positive subtype of human breast cancer. BACKGROUND: Generation of novel spontaneous ER positive mammary tumor animal model from heterozygous NIH nude mice. METHODS: Using brother-sister mating with pedigree expansion system, we derived a colony of heterozygous breeding females showing ER-Positive tumors around the age of 6 months. Complete blood picture, differential leukocyte count, and serum levels of Estrogen, Alanine amino transferase (SGPT), Aspartate amino transferase (SGOT), total protein and albumin were estimated. Aspiration biopsies and microbiology were carried out. Gross pathology of the tumors and their metastatic potential were assessed. The tumors were excised and further characterized using histopathology, cytology, electron microscopy (EM), molecular markers and Mouse mammary Tumor Virus - Long Terminal Repeats (MMTV LTR) specific RT-PCR. RESULTS: The tumors originated from 2nd or 5th or both the mammary glands and were multi-nodulated with variable central necrosis accompanied with an accumulation of inflammatory exudate. Significant increases in estrogen, SGPT, SGOT and neutrophils levels were noticed. Histopathologically, invasive nodular masses of pleomorphic tubular neoplastic epithelial cells invaded fibro-vascular stroma, adjacent dermis and subcutaneous tissue. Metastatic spread through hematogenous and regional lymph nodes, into liver, lungs, spleen, heart and dermal lymphatics was observed. EM picture revealed no viral particles and MMTV-negativity was confirmed through MMTV LTR-specific RT-PCR. High expression of ER alpha, moderate to high expression of proliferating cell nuclear antigen (PCNA), moderate expression of vimentin and Cytokeratin 19 (K19) and low expression of p53 were observed in tumor sections, when compared with that of the normal mammary gland. CONCLUSION: Since 75% of human breast cancer were classified ER-positive and as our model mimics (in most of the characteristics, such as histopathology, metastasis, high estrogen levels) the ER-positive luminal epithelial-like human breast cancer, this model will be an attractive tool to understand the biology of estrogen-dependant breast cancer in women. To our knowledge, this is the first report of a spontaneous mammary model displaying regional lymph node involvement with both hematogenous and lymphatic spread to liver, lung, heart, spleen and lymph nodes. | SGOT is an abbreviation for an enzyme other wise known as alanine amino transferase, yes or no? | 5a67b48cb750ff4455000010_004 | no |
Catecholaminergic-induced arrhythmias in failing cardiomyocytes associated with human HRCS96A variant overexpression. The histidine-rich calcium binding protein (HRC) Ser96Ala polymorphism was shown to correlate with ventricular arrhythmias and sudden death only in dilated cardiomyopathy patients but not in healthy human carriers. In the present study, we assessed the molecular and cellular mechanisms underlying human arrhythmias by adenoviral expression of the human wild-type (HRC(WT)) or mutant HRC (HRC(S96A)) in adult rat ventricular cardiomyocytes. Total HRC protein was increased by ∼50% in both HRC(WT)- and HRC(S96A)-infected cells. The HRC(S96A) mutant exacerbated the inhibitory effects of HRC(WT) on the amplitude of Ca(2+) transients, prolongation of Ca(2+) decay time, and caffeine-induced sarcoplasmic reticulum Ca(2+) release. Consistent with these findings, HRC(S96A) reduced maximal sarcoplasmic reticulum calcium uptake rate to a higher extent than HRC(WT). Furthermore, the frequency of spontaneous Ca(2+) sparks, which was reduced by HRC(WT), was increased by mutant HRC(S96A) under resting conditions although there were no spontaneous Ca(2+) waves under stress conditions. However, expression of the HRC(S96A) genetic variant in cardiomyocytes from a rat model of postmyocardial infarction heart failure induced dramatic disturbances of rhythmic Ca(2+) transients. These findings indicate that the HRC Ser96Ala variant increases the propensity of arrhythmogenic Ca(2+) waves in the stressed failing heart, suggesting a link between this genetic variant and life-threatening ventricular arrhythmias in human carriers. | Is the HRC Ser96Ala variant associated with sudden cardiac death in patients with dilated cardiomyopathy? | 54d8f37b4b1fd0d33c000004_004 | yes |
Computational study on the drug resistance mechanism against HCV NS3/4A protease inhibitors vaniprevir and MK-5172 by the combination use of molecular dynamics simulation, residue interaction network, and substrate envelope analysis. Hepatitis C virus (HCV) NS3/4A protease is an important and attractive target for anti-HCV drug development and discovery. Vaniprevir (phase III clinical trials) and MK-5172 (phase II clinical trials) are two potent antiviral compounds that target NS3/4A protease. However, the emergence of resistance to these two inhibitors reduced the effectiveness of vaniprevir and MK-5172 against viral replication. Among the drug resistance mutations, three single-site mutations at residues Arg155, Ala156, and Asp168 in NS3/4A protease are especially important due to their resistance to nearly all inhibitors in clinical development. A detailed understanding of drug resistance mechanism to vaniprevir and MK-5172 is therefore very crucial for the design of novel potent agents targeting viral variants. In this work, molecular dynamics (MD) simulation, binding free energy calculation, free energy decomposition, residue interaction network (RIN), and substrate envelope analysis were used to study the detailed drug resistance mechanism of the three mutants R155K, A156T, and D168A to vaniprevir and MK-5172. MD simulation was used to investigate the binding mode for these two inhibitors to wild-type and resistant mutants of HCV NS3/4A protease. Binding free energy calculation and free energy decomposition analysis reveal that drug resistance mutations reduced the interactions between the active site residues and substituent in the P2 to P4 linker of vaniprevir and MK-5172. Furthermore, RIN and substrate envelope analysis indicate that the studied mutations of the residues are located outside the substrate (4B5A) binding site and selectively decrease the affinity of inhibitors but not the activity of the enzyme and consequently help NS3/4A protease escape from the effect of the inhibitors without influencing the affinity of substrate binding. These findings can provide useful information for understanding the drug resistance mechanism against vaniprevir and MK-5172. The results can also provide some potential clues for further design of novel inhibitors that are less susceptible to drug resistance. | Are there any HCV replication inhibitors available? | 53353927d6d3ac6a34000043_006 | yes |
A new resorufin-based alpha-glucosidase assay for high-throughput screening. Mutations in alpha-glucosidase cause accumulation of glycogen in lysosomes, resulting in Pompe disease, a lysosomal storage disorder. Small molecule chaperones that bind to enzyme proteins and correct the misfolding and mistrafficking of mutant proteins have emerged as a new therapeutic approach for the lysosomal storage disorders. In addition, alpha-glucosidase is a therapeutic target for type II diabetes, and alpha-glucosidase inhibitors have been used in the clinic as alternative treatments for this disease. We have developed a new fluorogenic substrate for the alpha-glucosidase enzyme assay, resorufin alpha-d-glucopyranoside. The enzyme reaction product of this new substrate emits at a peak of 590 nm, reducing the interference from fluorescent compounds seen with the existing fluorogenic substrate, 4-methylumbelliferyl-alpha-D-glucopyranoside. Also, the enzyme kinetic assay can be carried out continuously without the addition of stop solution due to the lower pK(a) of the product of this substrate. Therefore, this new fluorogenic substrate is a useful tool for the alpha-glucosidase enzyme assay and will facilitate compound screening for the development of new therapies for Pompe disease. | Is acid alpha-glucosidase the enzyme that causes Pompe disease when mutant? | 572099930fd6f91b6800000f_022 | yes |
Management of osteoporosis in men on androgen deprivation therapy. Osteoporosis is a common consequence of androgen deprivation therapy (ADT) for prostate cancer. Up to 20% of men on ADT for localized prostate cancer will fracture within 5 years. Fortunately, generally safe and effect therapy is available. Although once considered non-controversial, there is some concern about calcium supplementation, but all studies of osteoporosis therapy in men have included calcium. In most older men, serum 25-hydroxyvitamin D levels are likely to be low, although again there is controversy about the ideal level. Many experts believe that all older men, including those on ADT, need to have a level of >30 ng/ml, which is easily accomplished. Bone mineral density (BMD) testing by dual energy X-ray absorptiometry (DXA) is indicated for men on ADT. Interestingly, forearm DXA may be particularly important in ADT men, in addition to spine and hip. Some experts have suggested that men on ADT with a T-score of < -1.5 should be treated. Alternatively FRAX or another risk calculator can be used. Oral and intravenous bisphosphonates are FDA approved treatments for men with osteoporosis and increase BMD in men on ADT. Potential off-label agents include raloxifene and toremifene. The latter and denosumab have been shown to increase bone density and decrease vertebral fractures in men on ADT. Raloxifene and denosumab are only FDA approved for postmenopausal osteoporosis. Thus, prevention of fractures can be accomplished in this high risk population. | Has Denosumab (Prolia) been approved by FDA? | 52bf1db603868f1b06000011_005 | yes |
[Case-control study on transverse carpal ligament resection for the prevention of delayed carpal tunnel syndrome after distal radius fracture]. OBJECTIVE: To investigate the effects of open reduction by palm side for the distal radius fracture and T shape plate internal fixation with simultaneous anterior transverse carpal ligament resection for the prevention of delayed carpal tunnel syndrome after operation. METHODS: From March 2000 to March 2007, 32 patients (8 males and 24 females, ranging in age from 46 to 66 years) with distal radius fracture were treated with open reduction by palm side and T shape plate internal fixation with simultaneous anterior transverse carpal ligament resection; while 30 patients (7 males and 23 females,ranging in age from 45 to 65 years) only with open reduction by palm side and T shape plate internal fixation. The incidences of delayed carpal tunnel syndrome between the two groups were compared. RESULTS: Among 32 patients treated with open reduction by palm side and T shape plate internal fixation with anterior transverse carpal ligament resection, 3 patients had delayed carpal tunnel syndrome; while in 30 patients treated with open reduction by palm side and T shape plate internal fixation, 10 patients had delayed carpal tunnel syndrome. There was significant statistically difference (P < 0.05%). CONCLUSION: Simultaneous anterior transverse carpal ligament resection can effectively prevent the delayed carpal tunnel syndrome occurrence for the distal radius fracture with open reduction by palm side. | Can radius fracture cause carpal tunnel syndrome? | 5a72284b2dc08e987e000001_002 | yes |
Phenotypic transformation of CD52(pos) to CD52(neg) leukemic T cells as a mechanism for resistance to CAMPATH-1H. Immunotherapy utilizing CAMPATH-1H for patients with chemotherapy-refractory chronic lymphocytic leukemia has yielded encouraging results with many reports of complete remission. Here we report the outcome of two patients with CD4-positive T cell prolymphocytic leukemia treated with CAMPATH-1H. Both patients responded rapidly to treatment and subsequently developed CD4 lymphopenia. One patient remained in complete remission after 14 weeks of treatment. Serial peripheral blood flow cytometry revealed that the CD52 antigen was present throughout treatment. The other patient who was initially CD52-positive, became CD52-negative after 6 weeks of treatment, and developed progressive symptoms of T cell prolymphocytic leukemia. Immunotherapy was stopped, chemotherapy proved futile, and the patient died. This change in phenotype from CD52-positive to -negative during CAMPATH-1H therapy points out a need to develop strategies for maintaining antigenic expression during monoclonal antibody therapy. | Is alemtuzumab effective for remission induction in patients diagnosed with T-cell prolymphocytic leukemia? | 530cefaaad0bf1360c000001_005 | yes |
Thyroid hormone and coronary artery disease: from clinical correlations to prognostic implications. BACKGROUND: Overt thyroid dysfunction, hypothyroidism in particular, may lead to coronary artery disease (CAD). Whether more subtle anomalies of thyroid hormone metabolism influence the progression of CAD remains a matter of speculation. HYPOTHESIS: The occurrence of CAD and long-term prognosis in patients without a history of either primary thyroid disease, myocardial infarction, or chronic heart failure is related to serum levels of biologically active free triiodothyronine (fT3). METHODS: The cohort consisted of 1047 clinically and biochemically euthyroid patients (median age 65.6 y and 69% male) who underwent coronary angiography in our institute for suspected CAD. RESULTS: Lower fT3 levels were predictive of both single-vessel (p = 0.012) and multivessel (p = 0.009) CAD. Through a multivariate logistic regression analysis, fT3 was still linked to the presence of CAD (hazard ratio [HR]: 0.48, 95% confidence interval [CI]: 0.34-0.68, p < 0.001). After a mean follow-up of 31 months, the survival rate was 95% and total mortality (log-rank 6.75, p = 0.009), as well as cardiac mortality (log-rank 8.26, p = 0.004), was greater among patients with low T3 (fT3 < 2.10 pg/mL) syndrome. At subsequent multivariate Cox regression analysis, the association between low T3 syndrome and survival was maintained (total mortality HR: 1.80, 95% CI: 1.05-3.10, p = 0.034; cardiac mortality HR: 2.58, 95% CI: 1.13-5.93, p = 0.025). CONCLUSIONS: In this selected population, fT3 levels were inversely correlated to the presence of CAD and low T3 syndrome conferred an adverse prognosis, even after adjusting for traditional coronary risk factors. | Is there a relationship between thyroid hormone altered metabolism and coronary artery disease? | 531d1279b166e2b806000042_003 | yes |
Mowat-Wilson syndrome: an underdiagnosed syndrome? Mowat-Wilson syndrome (MWS) is an autosomal dominant developmental disorder with mental retardation and variable multiple congenital abnormalities due to mutations of the ZEB2 (ZFHX1B) gene at 2q22. MWS was first described in 1998 and the causative gene was delineated in 2001. Since then, 115 different mutations of ZEB2 have been published in association with this syndrome in 161 individuals. However, recent reports suggest that due to the variability of the congenital abnormalities, this syndrome may still be underdiagnosed. We report two unrelated patients with MWS where the clinical diagnosis was established only after finding of disruption of the ZEB2 gene by a balanced translocation breakpoint and an interstitial microdeletion, respectively. | Have mutations in the ZEB2 gene been found in any human syndrome? | 53552ed7f1005d6b58000001_029 | yes |
Overall survival of newly diagnosed glioblastoma patients receiving carmustine wafers followed by radiation and concurrent temozolomide plus rotational multiagent chemotherapy. BACKGROUND: Glioblastoma multiforme (GBM), the most lethal type of brain tumor, has a 1-year median survival. The effect of carmustine wafers on the survival of newly diagnosed GBM patients treated with radiotherapy (RT) and concurrent temozolomide (TMZ) plus RT plus rotational chemotherapy was investigated. METHODS: An institutional review board-approved retrospective study was conducted in 85 newly diagnosed GBM patients who received surgical resection with and without carmustine wafers followed by RT and concurrent TMZ plus rotational chemotherapy. Treatment group comparisons were conducted using the log-rank test. Survival experience of the Duke cohort was examined within specific patient subgroups defined by the original Radiation Therapy Oncology Group (RTOG) recursive partition analysis (RPA) class and compared with the European Organization for Research and Treatment of Cancer (Stupp) and RTOG trial. RESULTS: Overall 1- and 2-year survival for the noncarmustine wafer cohort were 69% and 29%, respectively, with a median survival of 72.7 weeks. One- and 2-year survival for the carmustine wafer cohort were 81% and 47%, with median survival of 89.5 weeks. Carmustine wafer was not an independent predictor (P=.110) of survival after adjustment for RPA class. The proportion of patients in the carmustine wafer cohort who lived longer than predicted based upon Stupp regimen results was significantly greater than 0.5 (P<.006); similar results based upon the RTOG trial data were observed (P<.001). CONCLUSIONS: Carmustine wafer with concurrent TMZ and radiation followed by rotational chemotherapy is a well tolerated, effective therapy, and has a survival benefit compared with radiation alone. Prospective randomized trials are needed to rigorously compare the carmustine wafer regimen to the Stupp and postradiation multimodality regimens. | Do carmustine wafers improve survival of glioblastoma patients? | 54d630283706e89528000004_019 | yes |
Widespread transcription at neuronal activity-regulated enhancers. We used genome-wide sequencing methods to study stimulus-dependent enhancer function in mouse cortical neurons. We identified approximately 12,000 neuronal activity-regulated enhancers that are bound by the general transcriptional co-activator CBP in an activity-dependent manner. A function of CBP at enhancers may be to recruit RNA polymerase II (RNAPII), as we also observed activity-regulated RNAPII binding to thousands of enhancers. Notably, RNAPII at enhancers transcribes bi-directionally a novel class of enhancer RNAs (eRNAs) within enhancer domains defined by the presence of histone H3 monomethylated at lysine 4. The level of eRNA expression at neuronal enhancers positively correlates with the level of messenger RNA synthesis at nearby genes, suggesting that eRNA synthesis occurs specifically at enhancers that are actively engaged in promoting mRNA synthesis. These findings reveal that a widespread mechanism of enhancer activation involves RNAPII binding and eRNA synthesis. | Are there enhancer RNAs (eRNAs)? | 56a8adb0a17756b72f000003_010 | yes |
Landscape changes influence the occurrence of the melioidosis bacterium Burkholderia pseudomallei in soil in northern Australia. BACKGROUND: The soil-dwelling saprophyte bacterium Burkholderia pseudomallei is the cause of melioidosis, a severe disease of humans and animals in southeast Asia and northern Australia. Despite the detection of B. pseudomallei in various soil and water samples from endemic areas, the environmental habitat of B. pseudomallei remains unclear. METHODOLOGY/PRINCIPAL FINDINGS: We performed a large survey in the Darwin area in tropical Australia and screened 809 soil samples for the presence of these bacteria. B. pseudomallei were detected by using a recently developed and validated protocol involving soil DNA extraction and real-time PCR targeting the B. pseudomallei-specific Type III Secretion System TTS1 gene cluster. Statistical analyses such as multivariable cluster logistic regression and principal component analysis were performed to assess the association of B. pseudomallei with environmental factors. The combination of factors describing the habitat of B. pseudomallei differed between undisturbed sites and environmentally manipulated areas. At undisturbed sites, the occurrence of B. pseudomallei was found to be significantly associated with areas rich in grasses, whereas at environmentally disturbed sites, B. pseudomallei was associated with the presence of livestock animals, lower soil pH and different combinations of soil texture and colour. CONCLUSIONS/SIGNIFICANCE: This study contributes to the elucidation of environmental factors influencing the occurrence of B. pseudomallei and raises concerns that B. pseudomallei may spread due to changes in land use. | Is Melioidosis caused by the bacterium Burkholderia pseudomallei? | 58caf88c02b8c60953000031_023 | yes |
Toward a Molecular Classification of Colorectal Cancer: The Role of BRAF. Different genetic aberrations of BRAF have been reported in various malignancies. BRAF is member of the RAS/RAF/MEK/ERK pathway and constitutive activity of this pathway can lead to increased cellular growth, invasion, and metastasis. The most common activating BRAF mutation in colorectal cancer is the V600E mutation, which is present in 5-15% of all tumors, and up to 80% of tumors with high microsatellite instability (MSI) harbor this mutation. BRAF mutation is associated with proximal location, higher age, female gender, MSI-H, high grade, and mucinous histology, and is a marker of poor prognosis in colorectal cancer. The role of BRAF mutation as a predictive marker in respect of EGFR targeted treatments is controversial. BRAF V600 selective inhibitors have been approved for the treatment of V600 mutation positive metastatic melanoma, but the response rates in colorectal cancer are poor. This might be due to innate resistance mechanisms of colorectal cancers against the treatment solely targeting BRAF. To overcome resistance the combination of treatments, simultaneous inhibition of BRAF and MEK or PI3K/mTOR, might emerge as a successful therapeutic concept. | Are BRAF mutations common in melanoma? | 5512c91b6a8cde6b7200000b_024 | yes |