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Mechanisms and clinical management of inherited channelopathies: long QT syndrome, Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia, and short QT syndrome. The following briefly reviews features and management of long QT syndrome (LQTS), Brugada Syndrome, catecholaminergic polymorphic ventricular tachycardia (CPVT), and short QT syndrome (SQTS). LQTS is marked by QT prolongation, syncope and sudden death due to torsades de pointes. Risk stratification is based on age, gender, history of symptoms, QT interval, and genetic subtype of LQTS. In addition to avoidance QT-prolonging drugs and high intensity sports, standard treatment for LQTS involves anti-adrenergic therapy, with implantable cardioverter-defibrillator (ICD) use in high risk subgroups. Brugada Syndrome is associated with right ventricular conduction delay and ST elevation in the right precordial leads, syncope, and sudden death from ventricular fibrillation. The electrocardiographic abnormality can be accentuated by sodium channel blocker, vagal stimulation or fever. Patients with aborted cardiac arrest and those with syncope and a spontaneous or sodium channel blocker-inducible type I Brugada ECG pattern are at high risk and should receive an ICD. The role of electrophysiologic testing is controversial. Although there is no reliable drug therapy for Brugada Syndrome, quinidine, which suppresses I(to) current, can reduce the incidence of arrhythmias. Patients with CPVT present with exercise-induced syncope and sudden cardiac death but normal resting electrocardiograms. Exercise or isoproterenol infusion may cause increased ventricular ectopy or bidirectional ventricular tachycardia. Treatment modalities include anti-adrenergic therapy and ICD implantation. Congenital SQTS is a relatively recently described disorder characterized by a very short QT interval and by susceptibility to atrial and ventricular fibrillation. ICD implantation is the primary therapy; quinidine may be a useful adjunctive therapy.

Could Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) cause sudden cardiac death?

52e8e96698d023950500001f_005

yes

Molecular spectrum and differential diagnosis in patients referred with sporadic or autosomal recessive osteogenesis imperfecta. BACKGROUND: Osteogenesis imperfecta (OI) is a heterogeneous bone disorder characterized by recurrent fractures. Although most cases of OI have heterozygous mutations in COL1A1 or COL1A2 and show autosomal dominant inheritance, during the last years there has been an explosion in the number of genes responsible for both recessive and dominant forms of this condition. Herein, we have analyzed a cohort of patients with OI, all offspring of unaffected parents, to determine the spectrum of variants accounting for these cases. Twenty patients had nonrelated parents and were sporadic, and 21 were born to consanguineous relationships. METHODS: Mutation analysis was performed using a next-generation sequencing gene panel, homozygosity mapping, and whole exome sequencing (WES). RESULTS: Patients offspring of nonconsanguineous parents were mostly identified with COL1A1 or COL1A2 heterozygous changes, although there were also a few cases with IFITM5 and WNT1 heterozygous mutations. Only one sporadic patient was a compound heterozygote for two recessive mutations. Patients offspring of consanguineous parents showed homozygous changes in a variety of genes including CRTAP,FKBP10,LEPRE1,PLOD2,PPIB,SERPINF1,TMEM38B, and WNT1. In addition, two patients born to consanguineous parents were found to have de novo COL1A1 heterozygous mutations demonstrating that causative variants in the collagen I structural genes cannot be overlooked in affected children from consanguineous couples. Further to this, WES analysis in probands lacking mutations in OI genes revealed deleterious variants in SCN9A,NTRK1, and SLC2A2, which are associated with congenital indifference to pain (CIP) and Fanconi-Bickel syndrome (FBS). CONCLUSION: This work provides useful information for clinical and genetic diagnosis of OI patients with no positive family history of this disease. Our data also indicate that CIP and FBS are conditions to be considered in the differential diagnosis of OI and suggest a positive role of SCN9A and NTRK1 in bone development.

Is autosomal dominant inheritanced form of Osteogenesis imperfecta caused by mutations in the genes associated with collagen production?

5a6f77d7b750ff4455000051_014

yes

Proteome of formalin-fixed paraffin-embedded pancreatic ductal adenocarcinoma and lymph node metastases. Pancreatic ductal adenocarcinoma (PDAC) is a major cause of cancer-related death, largely due to metastatic disease. To better understand PDAC metastatic spread and identify novel therapeutic targets, we analysed the proteome of primary tumours and matched lymph node (LN) metastases. As frozen specimens of metastatic lesions are scarce, we examined formalin-fixed paraffin-embedded (FFPE) tissues. This poses technical challenges because of the cross-linkages induced by fixation. Using laser capture microdissection (PALM system), we isolated malignant epithelia from seven FFPE primary PDAC tumours and matched LN metastases. Following dissection, samples were analysed in duplicate using Multidimensional Protein Identification Technology (MudPIT); this resulted in the identification of 1504 proteins, 854 of which were common to all samples analysed. Comparison of the obtained proteins with data from previous proteomics studies on pancreatic tissue, pancreatic juice, serum, and urine resulted in a less than 30% overlap, indicating that our study has substantially expanded the current database of proteins expressed in this malignancy. Statistical analysis further showed that 115/854 proteins (13.5%) were significantly differentially expressed (g-value > 3.8). Two proteins, S100P and 14-3-3 sigma, with highly significant g-values were confirmed to be significantly differentially expressed (S100P: p = 0.05 and 14-3-3 sigma: p < 0.001) in a larger series of 55 cases of matched primary PDAC and LN metastases using immunohistochemistry. Thus, laser capture microdissection of FFPE tissue coupled with downstream proteomic analysis is a valid approach for the investigation of metastatic PDAC. This is the first study to establish and compare the protein composition of primary PDAC and matched LN metastases, and has resulted in the identification of several potential epithelial-specific therapeutic targets, including 14-3-3 sigma and S100P.

Is it possible to determine the proteome of a formalin fixed and paraffin embedded (FFPE) tissue?

511a1e12df1ebcce7d000009_007

yes

Large-scale genome-wide association analysis of bipolar disorder identifies a new susceptibility locus near ODZ4. We conducted a combined genome-wide association study (GWAS) of 7,481 individuals with bipolar disorder (cases) and 9,250 controls as part of the Psychiatric GWAS Consortium. Our replication study tested 34 SNPs in 4,496 independent cases with bipolar disorder and 42,422 independent controls and found that 18 of 34 SNPs had P < 0.05, with 31 of 34 SNPs having signals with the same direction of effect (P = 3.8 × 10(-7)). An analysis of all 11,974 bipolar disorder cases and 51,792 controls confirmed genome-wide significant evidence of association for CACNA1C and identified a new intronic variant in ODZ4. We identified a pathway comprised of subunits of calcium channels enriched in bipolar disorder association intervals. Finally, a combined GWAS analysis of schizophrenia and bipolar disorder yielded strong association evidence for SNPs in CACNA1C and in the region of NEK4-ITIH1-ITIH3-ITIH4. Our replication results imply that increasing sample sizes in bipolar disorder will confirm many additional loci.

Is there any association of the chromosomal region harboring the gene ITIH3 with schizophrenia?

54d63d873706e89528000006_004

yes

Risk of progression from undifferentiated arthritis to rheumatoid arthritis: the effect of the PTPN22 1858T-allele in anti-citrullinated peptide antibody positive patients. OBJECTIVES: Anti-citrullinated peptide antibodies (ACPA) and the C1858T missense single-nucleotide polymorphism (SNP) in the PTPN22 gene are both associated with the development of rheumatoid arthritis (RA). We investigated whether the combination of these two biomarkers yielded better test characteristics to predict progression from undifferentiated arthritis (UA) to RA compared with ACPA alone. METHODS: A total of 394 individuals with UA from a Dutch population-based inception cohort were included in this study. At baseline, ACPA were measured and the PTPN22 C1858T and HLA-DRB1 genotypes determined. Progression to RA was monitored at 1 yr after entry into the cohort. RESULTS: A priori, UA patients had a 35% (95% CI 30-40%) risk of developing RA, which increased to 66% (95% CI 57-75%) in patients who were ACPA-positive. There was an additional, although non-significant (P = 0.34), increase in RA risk to 76% (95% CI 57-90%) when patients were positive for both ACPA and the PTPN22 1858T-allele. The area under the receiver operator characteristic curve increased from 0.68 for ACPA-status alone to 0.70 for the combination of ACPA-status and the PTPN22 C1858T polymorphism. In logistic regression analysis, ACPA predicted RA-development independent of PTPN22, while the PTPN22 polymorphism had no independent effect. In HLA-DRB1 shared epitope positive, ACPA-positive UA patients, ACPA-levels were significantly increased in PTPN22 1858T allele carriers compared with non-1858T carriers. CONCLUSIONS: In this Dutch cohort of UA-patients, the PTPN22 1858T allele does not markedly improve individual decision-making to predict RA-development over ACPA alone, but it is associated with higher ACPA-levels.

Is the PTPN22 gene a biomarker for Rheumatoid Arthritis?

52e7870a98d023950500001a_010

yes

Radiological malformations of the ear in Pendred syndrome. Pendred syndrome comprises the association of severe congenital sensorineural deafness with thyroid pathology. Although it is the commonest form of syndromic hearing loss, the primary genetic defect remains unknown. The variable clinical presentation allied to the difficulty in securing the diagnosis have resulted in relatively poor documentation of the radiological features of this syndrome. We now present data on 40 patients, all complying with strict diagnostic criteria for the disorder, and describe our experience of the prevalence of specific malformations of the inner ear as well as comparing the relative merits of computed tomography (CT) and magnetic resonance imaging (MRI) in the investigation of this inherited condition. Deficiency of the interscalar septum in the distal coils of the cochlea (Mondini deformity) was found to be a common but probably not a constant feature of Pendred syndrome. However, enlargement of the endolymphatic sac and duct in association with a large vestibular aqueduct was present in all 20 patients examined by MRI. We conclude that thin section high resolution MRI on a T2 protocol in the axial and sagittal planes is the imaging investigation of choice.

Do patients with Pendred syndrome present congenital deafness?

56d8b27651531f7e33000003_014

yes

In vivo transcriptional profiling of Yersinia pestis reveals a novel bacterial mediator of pulmonary inflammation. UNLABELLED: Inhalation of Yersinia pestis results in primary pneumonic plague, a highly lethal and rapidly progressing necrotizing pneumonia. The disease begins with a period of extensive bacterial replication in the absence of disease symptoms, followed by the sudden onset of inflammatory responses that ultimately prove fatal. Very little is known about the bacterial and host factors that contribute to the rapid biphasic progression of pneumonic plague. In this work, we analyzed the in vivo transcription kinetics of 288 bacterial open reading frames previously shown by microarray analysis to be dynamically regulated in the lung. Using this approach combined with bacterial genetics, we were able to identify five Y. pestis genes that contribute to the development of pneumonic plague. Deletion of one of these genes, ybtX, did not alter bacterial survival but attenuated host inflammatory responses during late-stage disease. Deletion of ybtX in another lethal respiratory pathogen, Klebsiella pneumoniae, also resulted in diminished host inflammation during infection. Thus, our in vivo transcriptional screen has identified an important inflammatory mediator that is common to two Gram-negative bacterial pathogens that cause severe pneumonia. IMPORTANCE: Yersinia pestis is responsible for at least three major pandemics, most notably the Black Death of the Middle Ages. Due to its pandemic potential, ease of dissemination by aerosolization, and a history of its weaponization, Y. pestis is categorized by the Centers for Disease Control and Prevention as a tier 1 select agent most likely to be used as a biological weapon. To date, there is no licensed vaccine against Y. pestis. Importantly, an early "silent" phase followed by the rapid onset of nondescript influenza-like symptoms makes timely treatment of pneumonic plague difficult. A more detailed understanding of the bacterial and host factors that contribute to pathogenesis is essential to understanding the progression of pneumonic plague and developing or enhancing treatment options.

Does Yersinia pestis causes a respiratory infection?

58caf86f02b8c60953000030_003

yes

Plasma magnesium concentrations and clinical outcomes in aneurysmal subarachnoid hemorrhage patients: post hoc analysis of intravenous magnesium sulphate for aneurysmal subarachnoid hemorrhage trial. BACKGROUND AND PURPOSE: Conflicting data have been obtained on optimal plasma magnesium concentrations for clinical outcomes in patients with aneurysmal subarachnoid hemorrhage. METHODS: Adults (aged 18 years or older) who had acute aneurysmal subarachnoid hemorrhage diagnosed were randomly assigned to receive either an intravenous MgSO(4) infusion (80 mmol in 500 mL normal saline per day) or a placebo (500 mL normal saline per day) for up to 14 days. Post hoc multivariable binary logistic regression analyses were performed by dividing mean plasma magnesium concentrations into 4 quartiles according to treatment group and then comparing with the lowest quartiles. RESULTS: The worst clinical outcomes at 6 months were seen in MgSO(4) group patients, with mean plasma magnesium concentrations in the fourth quartile, and in placebo group patients, with mean such concentrations in the third and fourth quartiles. CONCLUSIONS: No evidence was found to suggest that a higher mean plasma magnesium concentration improves clinical outcomes. On the contrary, we found an association between high plasma magnesium concentration and worse clinical outcomes.

Does magnesium sulfate improve outcomes of subarachnoid hemorrhage patients?

54d62ede3706e89528000002_025

no

Autophagy and bacterial clearance: a not so clear picture. Autophagy, an intracellular degradation process highly conserved from yeast to humans, is viewed as an important defence mechanism to clear intracellular bacteria. However, recent work has shown that autophagy may have different roles during different bacterial infections that restrict bacterial replication (antibacterial autophagy), act in cell autonomous signalling (non-bacterial autophagy) or support bacterial replication (pro-bacterial autophagy). This review will focus on newfound interactions of autophagy and pathogenic bacteria, highlighting that, in addition to delivering bacteria to the lysosome, autophagy responding to bacterial invasion may have a much broader role in mediating disease outcome.

Is autophagy the process where bacteria ingest viral particles?

58dd2cb08acda34529000029_003

yes

Comparison of gamma glutamyltransferase in normal and in type 2 diabetics. OBJECTIVE: Comparison of gamma glutamyltransferase in normal and type 2 diabetics. METHODS: In a cross-sectional study, 100 apparently normal healthy subjects and, 47 type 2 diabetic subjects were selected from either sex with ages between 18-65 years. Subjects were measured for waist/hip ratio, BMI and serum levels of ALT, AST, Alk phosphatase and glutamyl transferase (GGT). The study excluded by screening for AntiHCV, HBsAg and patients with aspartate amino transferase (SGOT), alanine amino transferase (SGPT), GGT levels more than three times the normal and subject with a total leukocyte count more than 10,000/microl. RESULTS: The levels of GGT levels were found to be most significant among all the liver enzymes (P = 0.001). The levels of GGT compared with type 2 diabetics was found to be significantly increased when compared with BMI, waist/circumference, cholesterol, triglycerides (TG), high density lipoprotein (HDL), low density lipoprotein (LDL), fasting blood sugar level and blood pressure (P = 0.001). The pearson regression analysis showed a positive relation with systolic, diastolic blood pressure and fasting blood sugar. CONCLUSION: These results indicate that levels of GGT were raised with increased waist girth, BMI, blood pressure TG and low HDL, all of these are the features of metabolic syndrome according to ATP III criteria. Hence, serum GGT may be an important investigation for diabetes and metabolic syndrome.

SGOT is an abbreviation for an enzyme other wise known as alanine amino transferase, yes or no?

5a67b48cb750ff4455000010_001

no

Biosynthesis of N-acetyldopamine and N-acetyloctopamine by Schistocerca gregaria nervous tissue. N-Acetyltyramine, N-acetyldopamine and N-acetyloctopamine were the major products when either L-[3H]tyrosine or [3H]tyramine were incubated with thoracic ganglia of the desert locust, Schistocerca gregaria. No label was incorporated into L-DOPA under these conditions, although 2-3% of the radioactivity could be recovered in dopamine and octopamine. Addition of the aromatic amino acid decarboxylase inhibitor, 3-hydroxybenzylhydrazine (NSD 1015), prevented the formation of N-acetylcompounds from L-[3H]tyrosine, without resulting in an accumulation of label in L-DOPA. In contrast, incubation of samples of haemolymph with L-[3H]tyrosine resulted in the recovery of 7% of label in L-DOPA, which was increased to 17% in the presence of NSD 1015. These results provide evidence that the initial step in the synthesis of dopamine and octopamine by S. gregaria nervous tissue is the conversion of L-tyrosine to tyramine, which is subsequently metabolised to N-acetyltyramine, N-acetyldopamine or N-acetyloctopamine.

Is NSD-1015 an inhibitor of Aromatic L-Amino Acid Decarboxylase?

589c334e78275d0c4a00003d_014

yes

Topoisomerase 1 provokes the formation of short deletions in repeated sequences upon high transcription in Saccharomyces cerevisiae. High transcription is associated with genetic instability, notably increased spontaneous mutation rates, which is a phenomenon termed Transcription-Associated-Mutagenesis (TAM). In this study, we investigated TAM using the chromosomal CAN1 gene under the transcriptional control of two strong and inducible promoters (pGAL1 and pTET) in Saccharomyces cerevisiae. Both pTET- and pGAL1-driven high transcription at the CAN1 gene result in enhanced spontaneous mutation rates. Comparison of both promoters reveals differences in the type of mutagenesis, except for short (-2 and -3 nt) deletions, which depend only on the level of transcription. This mutation type, characteristic of TAM, is sequence dependent, occurring prefentially at di- and trinucleotides repeats, notably at two mutational hotspots encompassing the same 5'-ACATAT-3' sequence. To explore the mechanisms underlying the formation of short deletions in the course of TAM, we have determined Can(R) mutation spectra in yeast mutants affected in DNA metabolism. We identified topoisomerase 1-deficient strains (top1Δ) that specifically abolish the formation of short deletions under high transcription. The rate of the formation of (-2/-3nt) deletions is also reduced in the absence of RAD1 and MUS81 genes, involved in the repair of Top1p-DNA covalent complex. Furthermore ChIP analysis reveals an enrichment of trapped Top1p in the CAN1 ORF under high transcription. We propose a model, in which the repair of trapped Top1p-DNA complexes provokes the formation of short deletion in S. cerevisiae. This study reveals unavoidable conflicts between Top1p and the transcriptional machinery and their potential impact on genome stability.

Is transcription-associated mutagenesis (TAM) related to gene expression levels?

5544f3005beec11c10000008_003

yes

Autonomic dysfunction in pathologically confirmed multiple system atrophy and idiopathic Parkinson's disease--a retrospective comparison. INTRODUCTION: Autonomic dysfunction (AD) can be a feature of both multiple system atrophy (MSA) and idiopathic Parkinson's disease (IPD), conditions that are frequently misdiagnosed in life. Most studies on AD in MSA and IPD are based on clinical cases without pathological verification. MATERIAL AND METHODS: We retrospectively analysed AD in 135 pathologically confirmed cases of IPD and in 33 of MSA from the UK PD Society Brain Bank. RESULTS: MSA started at a younger age than IPD (54.4 +/- 10.7 yrs versus 60.6 +/- 10.8 yrs), and AD began earlier in the course of the illness All MSA patients had some degree of AD in life whereas AD was absent in 24% of IPD patients. Although each of five autonomic domains was affected in variable numbers of IPD patients, AD in MSA generally involved more autonomic domains than in IPD, and to a more severe degree, in particular with regard to inspiratory stridor. CONCLUSIONS: These results indicate that the presence of autonomic disturbance alone does not distinguish between MSA and IPD in individual cases. However, the presence of severe AD, of AD preceding parkinsonism, or of inspiratory stridor, are all individually suggestive of MSA.

Do Parkinson's disease patients experience stridor?

54d8d4d1014675820d000006_004

yes

Endopeptidase activities of botulinum neurotoxin type B complex, holotoxin, and light chain. Botulinum neurotoxin (BoNT) serotype B (BoNT/B) is one of the serotypes of BoNT that causes deadly human botulism, though it is used clinically for treatment of many neuromuscular diseases. BoNT/B is produced by Clostridium botulinum, and it is secreted along with a group of neurotoxin-associated proteins (NAPs) in the form of a BoNT/B complex. The complex dissociates into a 150-kDa holotoxin and NAPs at alkaline pHs. The 150-kDa BoNT/B holotoxin can be nicked to produce a 50-kDa domain referred to as the light chain (LC) and a 100-kDa heavy chain, with the former possessing a unique endopeptidase activity. The two chains remain linked through a disulfide bond that can be reduced to separate the two chains. The endopeptidase activity is present in all three forms of the toxin (complex, purified BoNT/B holotoxin, and separated light chain), which are used by different researchers to develop detection methods and screen for inhibitors. In this research, the endopeptidase activities of the three forms, for the first time, were compared under the same conditions. The results show that enzyme activities of the three forms differ significantly and are largely dependent on nicking and disulfide reduction conditions. Under the conditions used, LC had the highest level of activity, and the complex had the lowest. The activity was enhanced by nicking of BoNT/B holotoxin and was enhanced even more by dithiothreitol (DTT) reduction after nicking. This information is useful for understanding the properties of BoNT endopeptidases and for comparing the efficacies of different inhibitors when they are tested with different forms of BoNT endopeptidase.

Is the toxin produced by Clostridium botulinum always deadly?

58a341a660087bc10a000017_006

no

Auto-antibodies, HLA and PTPN22: susceptibility markers for rheumatoid arthritis. OBJECTIVE: To analyse the relationship between the presence of auto-antibodies [rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP)], HLA-DRB1 alleles and PTPN22 1858 C/T polymorphism and test the value of their combination as susceptibility markers for rheumatoid arthritis (RA). METHODS: Patients with early arthritis were included. At entry in the cohort or during follow-up, 191 patients fulfilled the criteria for RA and 184 individuals suffered from other arthropathies. RF was measured by nephelometry and anti-CCP antibody by enzyme-linked immunosorbent assay. HLA class II alleles were determined by polymerase chain reaction. Samples were genotyped for PTPN22 1858C/T variants using a TaqMan 5'-allele discrimination assay. RESULTS: The presence of shared epitope (SE) alleles was strongly associated with anti-CCP and RF-positive RA [P = 7.05 x 10(-10), odds ratio (OR) 4.57, 95% confidence interval (CI) 2.76-7.57 and P = 1.68 x 10(-6), OR 2.99, 95% CI 1.89-4.74, respectively). The combination of the PTPN22 1858T variant and anti-CCP antibodies gave a high specificity for the disease, and was significantly associated with RA (P = 8.86 x 10(-5), OR 10.05, 95% CI 1.88-53.73). CONCLUSION: The combination of the T variant of the 1858 polymorphism of the PTPN22 gene in combination with the presence of anti-CCP antibodies, preferentially in a SE-positive individual, is associated with the development of RA.

Is the PTPN22 gene a biomarker for Rheumatoid Arthritis?

52e7870a98d023950500001a_040

yes

Surgical treatment of female stress urinary incontinence with a trans-obturator-tape (T.O.T.) Uratape: short term results of a prospective multicentric study. OBJECTIVE: The aim of the study was to assess the efficacy and safety of a new minimally invasive surgical procedure using the Trans-Obturator-Tape Uratape to treat female stress urinary incontinence. PATIENTS AND METHODS: 183 women with stress urinary incontinence (SUI) associated with urethral hypermobility, underwent the T.O.T. procedure (October 2001 to March 2003). 26 patients were previously operated for incontinence. 26 patients were operated at the same time for their genital prolapse. Mean age was 56 years (29-87). 50/183 patients were having mixed incontinence. A non-elastic, polypropylene tape (UraTape, Mentor-Porgès) with a silicon coated central part was placed under the mid-urethra. The surgical placement technique utilises a trans-obturator percutaneous approach. All patients underwent post-operative clinical examination, cough-stress test (full bladder), uroflowmetry, and post-voiding residual assessment. RESULTS: Mean follow-up was 7 months (1-21). At 1 year follow-up 80.5% of the patients were completely cured and 7.5% were improved. The overall peri-operative complication rate was 2.2% with no vascular, nerve or bowel injury. 6 patients (3.3%) had post-operative urinary retention. CONCLUSION: The present multicentric study confirms the results obtained by the instigator of the technique, E. Delorme, and allows us to consider T.O.T. as an effective and safe technique for the treatment of female stress urinary incontinence, alone or in combination with prolapse repair.

Has silicon been used in treatment of incontinence ?

536172d17d100faa09000009_000

yes

Hypertrophy and heart failure in mice overexpressing the cardiac sodium-calcium exchanger. BACKGROUND: The cardiac sodium-calcium exchanger (NCX1) is a key sarcolemmal protein for the maintenance of calcium homeostasis in the heart. Because heart failure is associated with increased expression of NCX1, heterozygous (HET) and homozygous (HOM) transgenic mice overexpressing NCX1 were developed and evaluated. METHODS AND RESULTS: The NCX1 transgenic mice display 2.3-fold (HET) and 3.1-fold (HOM) increases in exchanger activity from wild-type (WT) mice. Functional information was obtained by echocardiography and catheterizations before and after hemodynamic stress from pregnancy, treadmill exercise or transaortic constriction (TAC). HET and HOM mice exhibited hypertrophy and blunted responses with beta-adrenergic stimulation. Postpartum mice from all groups were hypertrophied, but only the HOM mice exhibited premature death from heart failure. HOM mice became exercise intolerant after 6 weeks of daily treadmill running. After 21 days TAC, HET, and HOM mice exhibited significant contractile dysfunction and 15% to 40% mortality with clinical evidence of heart failure. CONCLUSIONS: Hemodynamic stress results in a compensated hypertrophy in WT mice, but NCX1 transgenic mice exhibit decreased contractile function and heart failure in proportion to their level of NCX1 expression. Thus exchanger overexpression in mice leads to abnormal calcium handling and a decompensatory transition to heart failure with stress.

Is Calcium homeostasis important in cardiac physiology and pathophysiology?

54c26e29f693c3b16b000003_007

yes

Propranolol for treatment of infantile hemangiomas. Infantile hemangioma is the most common vascular tumor in early childhood. Propranolol has been successfully used recently in a limited number of children with Infantile hemangioma. We present 6 cases of Infantile hemangioma, at a single dermatological center, which responded to oral propranolol with good results.

Is propranolol used for treatment of infantile hemangioma?

5a67a72fb750ff445500000a_010

yes

ML-18 is a non-peptide bombesin receptor subtype-3 antagonist which inhibits lung cancer growth. Bombesin receptor subtype (BRS)-3 is a G protein coupled receptor (GPCR) for the bombesin (BB)-family of peptides. BRS-3 is an orphan GPCR and little is known of its physiological role due to the lack of specific agonists and antagonists. PD168368 is a nonpeptide antagonist for the neuromedin B (NMB) receptor (R) whereas PD176252 is a nonpeptide antagonist for the gastrin releasing peptide (GRP) R and NMBR but not BRS-3. Here nonpeptide analogs of PD176252 e.g. the S-enantiomer ML-18, and the R-enantiomer, EMY-98, were investigated as BRS-3 antagonists using lung cancer cells. ML-18 and EMY-98 inhibited specific (125)I-BA1 (DTyr-Gln-Trp-Ala-Val-βAla-His-Phe-Nle-NH2)BB(6-14) binding to NCI-H1299 lung cancer cells stably transfected with BRS-3 with IC50 values of 4.8 and >100μM, respectively. In contrast, ML-18 bound with lower affinity to the GRPR and NMBR with IC50 values of 16 and >100μM, respectively. ML-18 (16μM), but not its enantiomer EMY-98, inhibited the ability of 10nM BA1 to elevate cytosolic Ca(2+) in a reversible manner using lung cancer cells loaded with FURA2-AM. ML-18 (16μM), but not EMY-98, inhibited the ability of 100nM BA1 to cause tyrosine phosphorylation of the EGFR and ERK in lung cancer cells. ML-18 but not EMY-98 inhibited the proliferation of lung cancer cells. The results indicate that ML-18 is a nonpeptide BRS-3 antagonist that should serve as a template to improve potency and selectivity.

Are the human bombesin receptors, GRPR and NMBR, frequently overexpressed G-protein-coupled-receptors by lung-cancers?

5a8dc57ffcd1d6a10c000025_002

yes

Truncation of the deubiquitinating domain of CYLD in myelomonocytic cells attenuates inflammatory responses. The cylindromatosis tumor suppressor (CYLD) is a deubiquitinating enzyme that has been implicated in various aspects of adaptive and innate immune responses. Nevertheless, the role of CYLD in the function of specific types of immune cells remains elusive. In this report we have used conditional gene targeting in mice to address the role of the deubiquitinating activity of CYLD in the myelomonocytic lineage. Truncation of the deubiquitinating domain of CYLD specifically in myelomonocytic cells impaired the development of lethal LPS-induced endotoxic shock and the accumulation of thioglycollate-elicited peritoneal macrophages. Our data establish CYLD as a regulator of monocyte-macrophage activation in response to inflammatory stimuli and identify it as a potential target for therapeutic intervention in relevant inflammatory disorders in humans.

Is the protein product of the cylindromatosis gene (CYLD) a deubiquitinating enzyme?

550aef0ec2af5d5b7000000a_007

yes

Structural and immunocytochemical studies on alpha-N-acetylgalactosaminidase deficiency (Schindler/Kanzaki disease). Alpha-N-acetylgalactosaminidase (alpha-NAGA) deficiency (Schindler/Kanzaki disease) is a clinically and pathologically heterogeneous genetic disease with a wide spectrum including an early onset neuroaxonal dystrophy (Schindler disease) and late onset angiokeratoma corporis diffusum (Kanzaki disease). In alpha-NAGA deficiency, there are discrepancies between the genotype and phenotype, and also between urinary excretion products (sialyl glycoconjugates) and a theoretical accumulated material (Tn-antigen; Gal NAcalpha1-O-Ser/Thr) resulting from a defect in alpha-NAGA. As for the former issue, previously reported genetic, biochemical and pathological data raise the question whether or not E325K mutation found in Schindler disease patients really leads to the severe phenotype of alpha-NAGA deficiency. The latter issue leads to the question of whether alpha-NAGA deficiency is associated with the basic pathogenesis of this disease. To clarify the pathogenesis of this disease, we performed structural and immunocytochemical studies. The structure of human alpha-NAGA deduced on homology modeling is composed of two domains, domain I, including the active site, and domain II. R329W/Q, identified in patients with Kanzaki disease have been deduced to cause drastic changes at the interface between domains I and II. The structural change caused by E325K found in patients with Schindler disease is localized on the N-terminal side of the tenth beta-strand in domain II and is smaller than those caused by R329W/Q. Immunocytochemical analysis revealed that the main lysosomal accumulated material in cultured fibroblasts from patients with Kanzaki disease is Tn-antigen. These data suggest that a prototype of alpha-NAGA deficiency in Kanzaki disease and factors other than the defect of alpha-NAGA may contribute to severe neurological disorders, and Kanzaki disease is thought to be caused by a single enzyme deficiency.

Is Kanzaki disease associated with deficiency in alpha-N-acetylgalactosaminidase?

56f7c44109dd18d46b000013_004

yes

Circadian gene mPer2 overexpression induces cancer cell apoptosis. The Period2 gene, an indispensable component of the circadian clock, not only modulates circadian oscillations, but also regulates organic function. We examined whether overexpression of the mouse Period2 gene (mPer2) in tumor cells influences cell growth and induces apoptosis. Overexpression of PERIOD2 in the mouse Lewis lung carcinoma cell line (LLC) and mammary carcinoma cell line (EMT6) results in reduced cellular proliferation and rapid apoptosis, but not in NIH 3T3 cells. Overexpressed mPER2 also altered the expression of apoptosis-related genes. The mRNA and protein levels of c-Myc, Bcl-X(L) and Bcl-2 were downregulated, whereas the expression of p53 and bax was upregulated in mPER2-overexpressing LLC cells compared with control cells transferred with empty plasmid. Our results suggest that the circadian gene mPeriod2 may play an important role in tumor suppression by inducing apoptotic cell death, which is attributable to enhanced pro-apoptotis signaling and attenuated anti-apoptosis processes.

Is c-myc subject to regulation by the circadian clock?

531616bdb166e2b806000003_004

yes

Solitary fibrous tumor of the meninges: a lesion distinct from fibrous meningioma. A clinicopathologic and immunohistochemical study. Seven solitary fibrous tumors (SFTs) of the meninges are presented and their clinicopathologic features are compared with those of 64 fibrous meningiomas (FM). Patients with SFT included 5 females and 2 males age 47 to 73 years. The dura-based tumors involved the parasagittal region (1), tentorium (2), cerebellopontine angle (2), and spinal region (2). One each showed invasion of brain and of a spinal nerve root. Of four SFTs with at least 1-year follow-up, one subtotally resected example recurred. No tumors metastasized. All consisted of spindle cells disposed in fascicles between prominent, eosinophilic bands of collagen. Whorls and storiform cell arrangements were lacking. Mitoses ranged from 1 to 7/10 400 x fields. MIB-1 labeling indices ranged from 1% to 18% (mean 4%). All were PAS negative and showed strong immunoreactivity for vimentin and CD34. Of cases studied, half were estrogen and all were progesterone receptor immunopositive. The majority (72%) of FMs occurred in females and most (72%) were supratentorial. Recurrence was noted in 15%. Mitotic activity varied from 0 to 3 mitoses per 10 400 x fields (mean < 1). MIB-1 labeling indices ranged from 1% to 5% (mean 1.5%). Unlike SFT, FMs were glycogen-containing and variously exhibited a storiform pattern (13 of 20), psammoma body formation (9 of 20), and calcification of collagen (4 of 20). Immunoreactivities included vimentin (100%), focal to patchy EMA (80%), S-100 protein (80%), collagen IV (25%), and patchy, mild-to-moderate CD34 staining (60%). Of cases studied, nearly half were estrogen and all were progesterone receptor staining positive. Meningeal SFTs represent a distinct morphologic entity, the morphologic and immunohistochemical features of which differ from those of FM and suggest a histogenetic relationship to pleural SFT. Although a minority histologically appear to be low grade malignant, our limited experience suggests that they behave in a benign fashion. The classification of mesenchymal tumors affecting the central nervous system must be expanded to include SFT.

Are psammoma bodies characteristic to meningiomas?

514a4679d24251bc0500005b_014

yes

Phase I pharmacokinetic and pharmacodynamic study of recombinant human endostatin in patients with advanced solid tumors. PURPOSE: Endostatin is the first endogenous angiogenesis inhibitor to enter clinical trials. Laboratory investigations with endostatin have indicated broad antitumor activity coupled with remarkably low toxicity. A phase I trial of recombinant human endostatin was designed to evaluate toxicity and explore biologic effectiveness in patients with refractory solid tumors. PATIENTS AND METHODS: Endostatin was administered as a 1-hour intravenous infusion given daily for a 28-day cycle. A starting dose of 30 mg/m2 was explored with subsequent dose escalations of 60, 100, 150, 225, and 300 mg/m2. Assessment of serum pharmacokinetics was performed on all 21 patients. Western blot assay and mass spectroscopy were employed to evaluate endostatin metabolism. Circulating levels of endogenous proangiogenic growth factors were examined. Tumor and tumor blood supply were imaged by dynamic computed tomography (CT), magnetic resonance imaging, ultrasound, and positron emission tomography. RESULTS: Endostatin given on this schedule was essentially free of significant drug-related toxicity. Two transient episodes of grade 1 rash were observed. No clinical responses were observed. Endostatin pharmacokinetics were linear with dose, and serum concentrations were achieved that are associated with antitumor activity in preclinical models. No aggregate effect on circulating proangiogenic growth factors were seen, although several patients exhibited persistent declines in vascular endothelial growth factor levels while enrolled in the study. A few patients demonstrated changes in their dynamic CT scans suggestive of a decline in microvessel density, although overall, no consistent effect of endostatin on tumor vasculature was seen. CONCLUSION: Endostatin given daily as a 1-hour intravenous infusion was well tolerated without dose-limiting toxicity at doses up to 300 mg/m2.

Is endostatin a proangiogenic factor?

53124e84e3eabad02100000c_001

no

A Case of Systemic Lupus Erythematosus Presenting as Guillain-Barré Syndrome. Systemic lupus erythematosus (SLE) is an autoimmune systemic disease with multiple organ involvement with high morbidity and mortality rate. Among the severe potential fatal complications are those of the central and peripheral nervous system which usually develop during the course of the disease and very rarely from the outset of the disease. We are reporting a rare case of Miller-Fisher (MFS) variant of Guillain-Barré syndrome (GBS) as the first manifestation of SLE in a 41-year-old female who progressed to flaccid paralysis with no neurological improvement with initial immunosuppressive therapy, plasmapheresis, and first cycle of intravenous immunoglobulin (IVIG) but with remarkable and complete recovery after the second 5-day course of IVIG.

Is the Miller-Fisher syndrome considered to be a variant of Guillain-Barré?

571f59cd0fd6f91b68000008_012

yes

Reconstitution of the cytoplasmic interaction between phospholamban and Ca(2+)-ATPase of cardiac sarcoplasmic reticulum. Phospholamban (PLN) reversibly inhibits the Ca(2+)-ATPase of cardiac sarcoplasmic reticulum (SERCA2a) through a direct protein-protein interaction, playing a pivotal role in the regulation of intracellular Ca(2+) in heart muscle cells. The interaction between PLN and SERCA2a occurs at multiple sites within the cytoplasmic and membrane domains. Here, we have reconstituted the cytoplasmic protein-protein interaction using bacterially expressed fusion proteins of the cytoplasmic domain of PLN and the long cytoplasmic loop of SERCA2a. We have developed two methods to evaluate the binding of the fusion proteins, one with glutathione-Sepharose beads and the other with a 96-well plate. Essentially the same results were obtained by the two methods. The affinity of the binding (K(D)) was 0.70 microM. The association was inhibited by cAMP-dependent phosphorylation of the PLN fusion protein and by usage of anti-PLN monoclonal antibody. It was also diminished by substitution at the phosphorylation site of PLN of Ser(16) to Asp. These results suggest that PLN can bind SERCA2a in the absence of the membrane domains and that the modifications of the cytoplasmic domain of PLN that activate SERCA2a parallel the disruption of the association between the two fusion proteins. It has been shown that the removal of PLN inhibition of SERCA2a rescues cardiac function and morphology in the mouse dilated cardiomyopathy model. Our assay system can be applied to the screening of novel inotropic agents that remove the inhibition of SERCA2a by PLN, improving the relaxation as well as the contractility of the failing heart.

Does Serca2a bind PLN in the heart?

51680b05298dcd4e51000064_006

yes

The Sirt1 activator SRT3025 provides atheroprotection in Apoe-/- mice by reducing hepatic Pcsk9 secretion and enhancing Ldlr expression. AIMS: The deacetylase sirtuin 1 (Sirt1) exerts beneficial effects on lipid metabolism, but its roles in plasma LDL-cholesterol regulation and atherosclerosis are controversial. Thus, we applied the pharmacological Sirt1 activator SRT3025 in a mouse model of atherosclerosis and in hepatocyte culture. METHODS AND RESULTS: Apolipoprotein E-deficient (Apoe(-/-)) mice were fed a high-cholesterol diet (1.25% w/w) supplemented with SRT3025 (3.18 g kg(-1) diet) for 12 weeks. In vitro, the drug activated wild-type Sirt1 protein, but not the activation-resistant Sirt1 mutant; in vivo, it increased deacetylation of hepatic p65 and skeletal muscle Foxo1. SRT3025 treatment decreased plasma levels of LDL-cholesterol and total cholesterol and reduced atherosclerosis. Drug treatment did not change mRNA expression of hepatic LDL receptor (Ldlr) and proprotein convertase subtilisin/kexin type 9 (Pcsk9), but increased their protein expression indicating post-translational effects. Consistent with hepatocyte Ldlr and Pcsk9 accumulation, we found reduced plasma levels of Pcsk9 after pharmacological Sirt1 activation. In vitro administration of SRT3025 to cultured AML12 hepatocytes attenuated Pcsk9 secretion and its binding to Ldlr, thereby reducing Pcsk9-mediated Ldlr degradation and increasing Ldlr expression and LDL uptake. Co-administration of exogenous Pcsk9 with SRT3025 blunted these effects. Sirt1 activation with SRT3025 in Ldlr(-/-) mice reduced neither plasma Pcsk9, nor LDL-cholesterol levels, nor atherosclerosis. CONCLUSION: We identify reduction in Pcsk9 secretion as a novel effect of Sirt1 activity and uncover Ldlr as a prerequisite for Sirt1-mediated atheroprotection in mice. Pharmacological activation of Sirt1 appears promising to be tested in patients for its effects on plasma Pcsk9, LDL-cholesterol, and atherosclerosis.

Does PCSK9 (Proprotein convertase subtilisin/kexin type 9) binds with HDL-receptor (HDL-R)?

58db9aa28acda34529000018_019

no

Radiotherapy plus nimotuzumab or placebo in the treatment of high grade glioma patients: results from a randomized, double blind trial. BACKGROUND: The prognosis of patients bearing high grade glioma remains dismal. Epidermal Growth Factor Receptor (EGFR) is well validated as a primary contributor of glioma initiation and progression. Nimotuzumab is a humanized monoclonal antibody that recognizes the EGFR extracellular domain and reaches Central Nervous System tumors, in nonclinical and clinical setting. While it has similar activity when compared to other anti-EGFR antibodies, it does not induce skin toxicity or hypomagnesemia. METHODS: A randomized, double blind, multicentric clinical trial was conducted in high grade glioma patients (41 anaplastic astrocytoma and 29 glioblastoma multiforme) that received radiotherapy plus nimotuzumab or placebo. Treatment and placebo groups were well-balanced for the most important prognostic variables. Patients received 6 weekly doses of 200 mg nimotuzumab or placebo together with irradiation as induction therapy. Maintenance treatment was given for 1 year with subsequent doses administered every 3 weeks. The objectives of this study were to assess the comparative overall survival, progression free survival, response rate, immunogenicity and safety. RESULTS: The median cumulative dose was 3200 mg of nimotuzumab given over a median number of 16 doses. The combination of nimotuzumab and RT was well-tolerated. The most prevalent related adverse reactions included nausea, fever, tremors, anorexia and hepatic test alteration. No anti-idiotypic response was detected, confirming the antibody low immunogenicity. The mean and median survival time for subjects treated with nimotuzumab was 31.06 and 17.76 vs. 21.07 and 12.63 months for the control group. CONCLUSIONS: In this randomized trial, nimotuzumab showed an excellent safety profile and significant survival benefit in combination with irradiation. TRIAL REGISTRATION: Cuban National Register for clinical trials (No. 1745) (http://registroclinico.sld.cu/ensayos).

Does nimotuzumab improve survival of glioblastoma patients?

54d901ec4b1fd0d33c000006_000

yes

Effects of a single post-partum injection of a high dose of vitamin D on glucose tolerance and insulin resistance in mothers with first-time gestational diabetes mellitus. AIM: This study was performed to determine the effect of a single, large, intramuscular injection of vitamin D post-partum on glucose tolerance and insulin resistance in women with gestational diabetes. METHODS: Forty-five participants in a randomized controlled trial on gestational diabetes mellitus were divided into an intervention group and a control group. Only subjects in the intervention group received one intramuscular injection of 300,000 IU of vitamin D3. HbA(1c), serum 25-hydroxyvitamin D3, fasting insulin and blood glucose, C-peptide, homeostasis model assessment insulin resistance index (HOMA-IR), β-cell function, insulin sensitivity and the Quantitative Insulin Sensitivity Check Index (QUICKI) were measured at baseline and after 3 months of intervention. RESULTS: Approximately 80% of the mothers had a degree of vitamin D deficiency. Post-intervention, this was found in 4.2 and 71.4% in the intervention and control groups, respectively. The medians of HOMA-IR indices before and after intervention were 0.6 and 0.5 (P = 0.7), respectively, in subjects in the intervention group, and 0.5 and 0.9 (P = 0.01) in subjects in the control group. The mean of the QUICKI fell only in the control group (P = 0.008). In the control group, β-cell function increased by ~8% (P = 0.01) and insulin sensitivity decreased after 3 months (P = 0.002). Post-intervention, the median C-peptide decreased in the intervention group and increased in the control group, but the change was significant only in the control group (P = 0.03). CONCLUSIONS: A single injection of 300,000 IU of vitamin D3 achieves a 3-month serum 25-hydroxyvitamin D range of 50-80 nmol/l and is an efficient, effective and safe procedure for improving the vitamin status and indices of insulin resistance in mothers with gestational diabetes after delivery.

Is Vitamin D deficiency in pregnant women associated with gestational diabetes?

515def40298dcd4e51000028_016

yes

Dynamic interaction between the dual specificity phosphatase MKP7 and the JNK3 scaffold protein beta-arrestin 2. JNK scaffold proteins bind JNK and upstream kinases to activate subsets of JNK and localize activated JNK to specific subcellular sites. We previously demonstrated that the dual specificity phosphatases (DSPs) MKP7 and M3/6 bind the scaffold JNK-interacting protein-1 (JIP-1) and inactivate the bound subset of JNK (1). The G protein-coupled receptor (GPCR) adaptor beta-arrestin 2 is also a JNK3 scaffold. It binds the upstream kinases ASK1 and MKK4 and couples stimulation of the angiotensin II receptor AT1aR to activation of a cytoplasmic pool of JNK3. Here we report that MKP7 also binds beta-arrestin 2 via amino acids 394-443 of MKP7, the same region that interacts with JIP-1. This region of MKP7 interacts with beta-arrestin 2 at a central region near the JNK binding domain. MKP7 dephosphorylates JNK3 bound to beta-arrestin 2, either following activation by ASK1 overexpression or following AT1aR stimulation. Initial AT1aR stimulation causes a rapid (within 5 min) dissociation of MKP7 from beta-arrestin 2. MKP7 then reassociates with beta-arrestin 2 on endocytic vesicles 30-60 min after initial receptor stimulation. This dynamic interaction between phosphatase and scaffold permits signal transduction through a module that binds both positive and negative regulators.

Is protein M3/6 a dual specificity phosphatase?

5512cce26a8cde6b7200000c_008

yes

[Between symbol and symptom: pain and its meanings in classical antiquity]. According to semiotics, which may be defined as the doctrine of the essential nature and fundamental varieties of signs, objects, and interpretants, pain is considered to be a sign (significant) with very different meanings (significance) either as a naturalistic symptom (of disease) or as a symbol used in a metaphorical context. When following this methodological perspective it is possible to interpret medical as well as poetic writings on equal terms. In Graeco-Roman medical texts pain was mostly understood as a result and an indicator of disease, but nonetheless as a symptom which seemed to be actively produced by the affected body. Especially in the Corpus Hippocraticum dating from the 5th and 4th century B. C. this materialistic and at the same time psychosomatic attitude can be noticed. Aristotle (4th century B. C.), Celsus (1st century A. D.), and the famous experimental physiologist Galen (2nd century A. D.) agreed that pain was a sign of evil which should be fought without exception. It was Galen who added the disturbance of function (functio laesa) as the fifth cardinal sign of inflammation to the four well-known cardinal signs of Celsus (rubor, calor, tumor, dolor). He also coined the term [see text] to characterize an attack of migraine. In algotherapy, Galen used a complex pharmacological system which was based upon the four cardinal qualities of humoral pathology. On the other hand, pain was designed as a multi-dimensional symbol by the famous Graeco-Roman epic poets. In Homer's Odyssey (8th century B. C.), pain appears transformed into the shape of a scar which is visible and palpable on the hero's leg like an identification tag, whereas in Virgil's Aeneids (1st century B. C.) pain symbolizes weakness and defencelessness which can only be alleviated by the goddess Venus.

Is Loss of function one of the cardinal signs of inflammation?

5a7a44b4faa1ab7d2e000010_001

yes

Phenothiazines induce PP2A-mediated apoptosis in T cell acute lymphoblastic leukemia. T cell acute lymphoblastic leukemia (T-ALL) is an aggressive cancer that is frequently associated with activating mutations in NOTCH1 and dysregulation of MYC. Here, we performed 2 complementary screens to identify FDA-approved drugs and drug-like small molecules with activity against T-ALL. We developed a zebrafish system to screen small molecules for toxic activity toward MYC-overexpressing thymocytes and used a human T-ALL cell line to screen for small molecules that synergize with Notch inhibitors. We identified the antipsychotic drug perphenazine in both screens due to its ability to induce apoptosis in fish, mouse, and human T-ALL cells. Using ligand-affinity chromatography coupled with mass spectrometry, we identified protein phosphatase 2A (PP2A) as a perphenazine target. T-ALL cell lines treated with perphenazine exhibited rapid dephosphorylation of multiple PP2A substrates and subsequent apoptosis. Moreover, shRNA knockdown of specific PP2A subunits attenuated perphenazine activity, indicating that PP2A mediates the drug's antileukemic activity. Finally, human T-ALLs treated with perphenazine exhibited suppressed cell growth and dephosphorylation of PP2A targets in vitro and in vivo. Our findings provide a mechanistic explanation for the recurring identification of phenothiazines as a class of drugs with anticancer effects. Furthermore, these data suggest that pharmacologic PP2A activation in T-ALL and other cancers driven by hyperphosphorylated PP2A substrates has therapeutic potential.

Are Notch mutations related to T-cell Acute Lymphoblastic Leukemia (T-ALL)?

5522fadb7b523f2123000001_005

yes

Growth factor independent-1 maintains Notch1-dependent transcriptional programming of lymphoid precursors. Growth factor independent 1 (Gfi1) is a transcriptional repressor originally identified as a gene activated in T-cell leukemias induced by Moloney-murine-leukemia virus infection. Notch1 is a transmembrane receptor that is frequently mutated in human T-cell acute lymphoblastic leukemia (T-ALL). Gfi1 is an important factor in the initiation and maintenance of lymphoid leukemias and its deficiency significantly impedes Notch dependent initiation of T-ALL in animal models. Here, we show that immature hematopoietic cells require Gfi1 to competently integrate Notch-activated signaling. Notch1 activation coupled with Gfi1 deficiency early in T-lineage specification leads to a dramatic loss of T-cells, whereas activation in later stages leaves development unaffected. In Gfi1 deficient multipotent precursors, Notch activation induces lethality and is cell autonomous. Further, without Gfi1, multipotent progenitors do not maintain Notch1-activated global expression profiles typical for T-lineage precursors. In agreement with this, we find that both lymphoid-primed multipotent progenitors (LMPP) and early T lineage progenitors (ETP) do not properly form or function in Gfi1(-/-) mice. These defects correlate with an inability of Gfi1(-/-) progenitors to activate lymphoid genes, including IL7R, Rag1, Flt3 and Notch1. Our data indicate that Gfi1 is required for hematopoietic precursors to withstand Notch1 activation and to maintain Notch1 dependent transcriptional programming to determine early T-lymphoid lineage identity.

Are Notch mutations related to T-cell Acute Lymphoblastic Leukemia (T-ALL)?

5522fadb7b523f2123000001_017

yes

Hyperkalemia complicating propranolol treatment of an infantile hemangioma. Propranolol treatment was recently reported to be successful for the management of severe infantile hemangioma. Known adverse effects of propranolol treatment include transient bradycardia, hypotension, hypoglycemia, and bronchospasm (in patients with underlying spastic respiratory illnesses), which led to a general recommendation to gradually increase propranolol dosage and closely monitor patients' hemodynamics at the onset of therapy. To date, no serious or unexpected adverse effects that required specific intervention have been reported. In this report, we describe the case of a 17-week-old female preterm infant who presented with a large, ulcerated, cutaneous-subcutaneous hemangioma of the right lateral thoracic wall, which we treated successfully with propranolol. A few days into therapy, a potentially life-threatening adverse effect, severe hyperkalemia, was observed and required treatment with loop diuretics, fluids, and nebulized salbutamol to normalize her serum potassium levels. This therapy could be gradually tapered and finally discontinued only after several weeks of propranolol treatment. Our case report indicates that, at least during the initial phase of the propranolol treatment of infantile hemangioma, close monitoring of serum electrolytes, besides the monitoring of hemodynamics and blood glucose, is necessary.

Is propranolol used for treatment of infantile hemangioma?

5a67a72fb750ff445500000a_015

yes

Mutation analysis of the RET, the endothelin-B receptor, and the endothelin-3 genes in sporadic cases of Hirschsprung's disease. To date, three genes have been identified as susceptibility genes for Hirschsprung's disease (HSCR), the RET proto-oncogene, the endothelin-B receptor gene (EDNRB) and the endothelin-3 gene (EDN3). However, the question of whether these genes play a role in sporadically occurring HSCR has not been fully clarified. In this study, the authors performed mutation analysis of these three genes in 41 sporadic HSCR patients without any family history by using single-strand conformational polymorphism or denaturing gradient gel electrophoresis methods. Exon 2, 3, 5, 6, 12, 13, 15, and 17 of the RET gene, 7 exons of the EDNRB gene, and the region of the EDN3 gene including sequences corresponding to proteolytic cleavage sites and mature endothelin-3 were analysed. By direct sequencing, three causative RET mutations were confirmed; a Phe to Ser substitution at codon 174, a Cys to Tyr substitution at codon 197, and a point mutation at the splice acceptor site of intron 12, in patients with aganglionosis confined to the rectosigmoid colon, the transverse colon, and the total colon, respectively. In the EDNRB locus, two mutations were observed; a nonsense mutation of Trp to stop at codon 275, and a T insertion at nucleotide 878, in patients with aganglionosis confined to the rectosigmoid colon, and the descending colon, respectively. No mutation was detected in the EDN3 gene. Mutation rates were 7.3% in the RET and 5% in the EDNRB gene. Our data indicate that RET and EDNRB mutations have a role in the aetiology of some sporadically occurring HSCR. However, the low mutation rate of susceptibility genes in sporadically occurring HSCR suggests that other genes or environmental factors are involved in the development of the disease.

Are EDNRB mutations involved in the development of Hirschsprung disease?

551910c5622b194345000007_023

yes

DNA repair gene XRCC3 polymorphisms and bladder cancer risk: a meta-analysis. The X-ray repair cross-complementing group 3 (XRCC3) in homologous recombination repair (HRR) pathway plays a vital role in DNA double-strand break repair (DSBR). Variants in the XRCC3 gene might result in altered protein structure or function which may influence DSBR efficiency and lead to cancer. Numerous epidemiological studies have been conducted to evaluate the association between XRCC3 polymorphisms and bladder cancer risk. However, the results of these previous studies have been inconsistent. To derive a more precise estimation of the association, we performed a meta-analysis of all available studies relating XRCC3 polymorphisms and bladder cancer. All studies published up to April 2013 on the association between XRCC3 polymorphisms and bladder cancer risk were identified by searching electronic databases PubMed, EMBASE, and Chinese Biomedical Literature databases. The association between the XRCC3 polymorphisms and bladder cancer risk was assessed by odds ratios (ORs) together with their 95% confidence intervals (CIs). A total of 16 case-control studies met the inclusion criteria and were selected. With respect to C18067T polymorphism, significant increased bladder cancer risk was found when all eligible studies were pooled into the meta-analysis (TT vs. CC: OR = 1.174, 95%CI = 1.033-1.335, P = 0.014 and recessive model TT vs. TC + CC: OR = 1.147, 95%CI = 1.020-1.290, P = 0.022, respectively). The results were still significant after excluding the Hardy-Weinberg equilibrium violation studies (TT vs. CC: OR = 1.178, 95%CI = 1.036-1.339, P = 0.013 and recessive model TT vs. TC + CC: OR = 1.144, 95%CI = 1.017-1.287, P = 0.025, respectively). In subgroup analysis by ethnicity, significant elevated risk was found among Asians (dominant model TT + TC vs. CC: OR = 1.285, 95%CI = 1.012-1.631). In the subgroup analyses according to smoking status, no significant association was detected in all genetic comparison models. With respect to A17893G and A4541G polymorphisms, no significant association with bladder cancer risk was observed in the overall and subgroup analyses. This meta-analysis suggests that the XRCC3 C18067T polymorphism was associated with increased bladder cancer risk especially among Asians. However, the XRCC3 A17893G and A4541G polymorphisms may not play important roles in bladder carcinogenesis. Further studies with larger sample sizes are needed to validate our finds.

Are defects in recombination repair involved in carcinogenesis?

52f77f752059c6d71c00002b_005

yes

Recurrent inactivating RASA2 mutations in melanoma. Analysis of 501 melanoma exomes identified RASA2, encoding a RasGAP, as a tumor-suppressor gene mutated in 5% of melanomas. Recurrent loss-of-function mutations in RASA2 were found to increase RAS activation, melanoma cell growth and migration. RASA2 expression was lost in > 30% of human melanomas and was associated with reduced patient survival. These findings identify RASA2 inactivation as a melanoma driver and highlight the importance of RasGAPs in cancer.

Is RASA2 involved in melanoma?

5896399978275d0c4a00000b_000

yes

Immune-mediated mechanisms in the pathoprogression of amyotrophic lateral sclerosis. Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease with selective loss of upper and lower motor neurons. At sites of motor neuron injury, neuroinflammation is a prominent pathological finding and is characterized by microglial activation, astrogliosis, and infiltration of monocytes and T-cells. Both innate and adaptive immune responses actively influence disease progression in animal models and in ALS patients, and promote neuroprotection or neurotoxicity at different stages of disease. The early immune reaction to signals from injured motor neurons is to rescue and repair damaged tissue. As disease accelerates, a shift occurs from beneficial immune responses (involving M2 microglia and regulatory T-cells) to deleterious immune responses (involving M1 microglia and Th1 cells). In this review, we underscore the importance of immune-mediated mechanisms in the pathogenesis of ALS and discuss the alterations and distinct phenotypes of immune cells at the different stages of disease. The better we understand the dynamic changes that occur within the immune system over the course of disease, the better we will be able to develop effective therapeutic regimens in ALS.

Are immune cells affected in Amyotrophic Lateral Sclerosis?

56cae51f5795f9a73e000025_000

yes

Inverse association between glutathione peroxidase activity and both selenium-binding protein 1 levels and Gleason score in human prostate tissue. BACKGROUND: Data from human epidemiological studies, cultured mammalian cells, and animal models have supported a potentially beneficial role of selenium (Se) in prostate cancer prevention. In addition, Se-containing proteins including members of the glutathione peroxidase (GPx) family and Selenium-Binding Protein 1 (SBP1) have been linked to either cancer risk or development. For example, SBP1 levels are typically reduced in tumors compared to non-cancerous tissue, with the degree of reduction associated with increasingly poor clinical outcome. METHODS: In order to investigate inter-relationships between blood and tissue Se levels and GPx activity, tissue SBP1 levels, and disease aggressiveness using the Gleason score, we measured levels of selenium and selected selenoproteins in fasting serum and histologically normal prostate tissues obtained from 24 men undergoing radical prostatectomy for the treatment of localized prostate cancer. RESULTS: GPx enzyme activity was inversely correlated with SBP1 levels in prostate tissue as determined by densitometry of Western blots obtained using anti-SBP1 antibodies [partial Spearman's correlation coefficients and corresponding P-values overall and in African-Americans = -0.42 (0.08) and -0.53 (0.10), respectively], which is consistent with previous observations in cultured cells and mice. Of particular interest was the positive correlation between tissue GPx activity and Gleason score, with this relationship achieving statistical significance among African-Americans (r = 0.67, P = 0.02). CONCLUSION: These studies support the continued investigation of the role of Se and selenoproteins in prostate cancer prevention, development, and prognosis.

Do selenoproteins and selenium play a role in prostate cancer prevention?

515ed87c298dcd4e51000032_002

no

Paroxetine: safety and tolerability issues. Paroxetine is a selective serotonin re-uptake inhibitor (SSRI) available in immediate release and controlled release (CR) formulations. Paroxetine is the most potent inhibitor of serotonin re-uptake among the now available SSRIs. Paroxetine has been approved for the treatment of major depressive disorder (MDD), obsessive-compulsive disorder, panic disorder (PD), generalised anxiety disorder, post traumatic stress disorder (PTSD), and social anxiety disorder (SAD) in adults, whereas paroxetine CR is approved for the treatment of MDD, SAD, PD and premenstrual dysphoric disorder in adults. The overall efficacy of paroxetine seems to be comparable to other SSRIs in the treatment of approved indications, although paroxetine treatment induces more sedation, constipation, sexual dysfunction, discontinuation syndrome and weight gain than other SSRIs. Recent data suggest that paroxetine treatment leads to increased rates of congenital malformations, although this evidence is not conclusive. Paroxetine and paroxetine CR are not indicated for use in the paediatric population and are categorised as Pregnancy Class D. In conclusion, whether the tolerability profile of paroxetine differs substantially from other new antidepressants (including other SSRIs) needs to be determined in adequately powered well-designed randomised controlled comparative clinical trials.

Is paroxetine effective for treatment of premenstrual dysphoric disorder?

514a59c2d24251bc0500005d_014

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.

Can RG7112 inhibit MDM2?

56ed08062ac5ed1459000005_007

yes

Thyroid hormone analog 3,5-diiodothyropropionic acid promotes healthy vasculature in the adult myocardium independent of thyroid effects on cardiac function. Patients with hypothyroidism are at a higher risk for coronary vascular disease. Patients with diabetes and related vascular complications also have an increased incidence of low thyroid function. While thyroid hormones (THs) may be key regulators of a healthy vasculature, potential undesirable side effects hinder their use in the treatment of vascular disorders. TH analogs such as 3,5-diiodothyropropionic acid (DITPA) may provide a safer treatment option. However, the relative potency of DITPA on vascular growth, cardiac function, and metabolism is poorly understood. We hypothesized that the vascular growth-promoting effects of DITPA can be obtained with a minimum effect on cardiac function. Thyroidectomized Sprague-Dawley rats were given slow-release pellets with either thyroxine (T4, 2.7 or 5.2 mg) or DITPA (80 mg) for 6 wk and were compared with placebo. Heart mass, body mass, body temperature, serum THs, cardiac function (echocardiograms and hemodynamics), and myocardial arteriolar density were determined. Hypothyroidism led to reductions in cardiac function, heart mass, body temperature, and myocardial arterioles. High-dose T4 prevented arteriolar loss and the development of hypothyroidism. Low-dose T4 partially prevented the reduction in cardiac function but had minimal effects on arteriolar loss. In contrast, DITPA treatment prevented myocardial arteriolar loss but not the progression of hypothyroid-induced changes in cardiac function. The results suggested that DITPA can promote a healthy vasculature independently from its thyroid-related metabolic effects. Drugs in this class may provide new therapeutic options for patients with vascular disease.

Is DITPA a thyroid hormone analog utilized in experimental and clinical studies

52fb4b462059c6d71c00005f_001

yes

Chimeras of channelrhodopsin-1 and -2 from Chlamydomonas reinhardtii exhibit distinctive light-induced structural changes from channelrhodopsin-2. Channelrhodopsin-2 (ChR2) from the green alga Chlamydomonas reinhardtii functions as a light-gated cation channel that has been developed as an optogenetic tool to stimulate specific nerve cells in animals and control their behavior by illumination. The molecular mechanism of ChR2 has been extensively studied by a variety of spectroscopic methods, including light-induced difference Fourier transform infrared (FTIR) spectroscopy, which is sensitive to structural changes in the protein upon light activation. An atomic structure of channelrhodopsin was recently determined by x-ray crystallography using a chimera of channelrhodopsin-1 (ChR1) and ChR2. Electrophysiological studies have shown that ChR1/ChR2 chimeras are less desensitized upon continuous illumination than native ChR2, implying that there are some structural differences between ChR2 and chimeras. In this study, we applied light-induced difference FTIR spectroscopy to ChR2 and ChR1/ChR2 chimeras to determine the molecular basis underlying these functional differences. Upon continuous illumination, ChR1/ChR2 chimeras exhibited structural changes distinct from those in ChR2. In particular, the protonation state of a glutamate residue, Glu-129 (Glu-90 in ChR2 numbering), in the ChR chimeras is not changed as dramatically as in ChR2. Moreover, using mutants stabilizing particular photointermediates as well as time-resolved measurements, we identified some differences between the major photointermediates of ChR2 and ChR1/ChR2 chimeras. Taken together, our data indicate that the gating and desensitizing processes in ChR1/ChR2 chimeras are different from those in ChR2 and that these differences should be considered in the rational design of new optogenetic tools based on channelrhodopsins.

Is the optogenetics tool ChR2 light-sensitive?

56e073ad51531f7e3300000e_006

yes

The next generation proteasome inhibitors carfilzomib and oprozomib activate prosurvival autophagy via induction of the unfolded protein response and ATF4. The proteasome inhibitor bortezomib has shown remarkable clinical success in the treatment of multiple myeloma. However, the efficacy and mechanism of action of bortezomib in solid tumor malignancies is less well understood. In addition, the use of this first-in-class proteasome inhibitor is limited by several factors, including off-target effects that lead to adverse toxicities. We recently reported the impact and mechanisms of carfilzomib and oprozomib, second-in-class proteasome inhibitors with higher specificities and reduced toxicities, against head and neck squamous cell carcinoma (HNSCC). Carfilzomib and oprozomib potently inhibit HNSCC cell survival and the growth of HNSCC tumors. Both compounds promote upregulation of proapoptotic BIK and antiapoptotic MCL1, which serves to mediate and attenuate, respectively, the killing activities of these proteasome inhibitors. Both compounds also induce complete autophagic flux that is partially dependent on activation of the unfolded protein response (UPR) and upregulation of ATF4. Carfilzomib- and oprozomib-induced autophagy acts to promote HNSCC cell survival. Our study indicates that the therapeutic benefit of these promising proteasome inhibitors may be improved by inhibiting MCL1 expression or autophagy.

Are proteasome inhibitors good candidates for treatment of leukemia and solid tumors?

517179718ed59a060a00000e_003

yes

[Influence of genetic factors on development and severity of rheumatoid arthritis--part I]. Both genetic and environmental factors affect susceptibility, severity and probably drugs' efficacy in patients with rheumatoid arthritis (RA). After initial completion of the Human Genome Project on the 16th February 2001, significant progress has been made in identifying other than HLA genome regions linked to the increased RA susceptibility. As an effect several new genes have been recognized as an HLA-independent genetic risk factors of RA. PTPN22 gene polymorphism, C5/TRAF1 genes region polymorphism and TNFAIP3-OLIG3 genes region polymorphism(s) are among newly identified and already confirmed genetic risk factors, whereas STAT 4, CTLA4, PADI4 and IRF5 genes polymorphisms are listed among probable RA development genetic risk factors.

Is the PTPN22 gene a biomarker for rheumatoid arthritis?

52ffb5d12059c6d71c00007c_018

yes

Histomorphologic parameters and CXCR4 mRNA and protein expression in sentinel node melanoma metastasis are correlated to clinical outcome. INTRODUCTION: Sentinel lymph node (SLN) biopsy is an important independent prognostic factor for invasive cutaneuos melanoma, although its role is strongly debated. In clinical practice SLN leads to complete lymph node dissection of basin draining melanoma site. However only 7-30% of positive sentinel node patients present additional non SLN metastasis. Melanoma cells diffusion through SLN and extranodal spreading depends upon biological features, such as cell chemokine receptors and adhesion molecules. CXCR4 has been proposed in melanoma patients as prognostic marker. Therefore we have analyzed both histopathological parameters and CXCR4 expression in melanoma infiltrate of SLN, in order to evaluate its potential prognostic role. RESULTS: Micrometastases were detected in 23 cases (48.93%); metastases >2 mm in 23 cases (48.93%) and isolated metastatic cells in one case (2.01%). High CXCR4 expression was observed in 21 nodal metastases. Node metastases in complete dissection were associated to >10% relative tumor area (RTA) in all lymph nodes (p = 0.006). Extranodal invasion (p = 0.006) and >2 mm centripetal metastasis thickness (p = 0.01), while shorter Disease Free Survival (DFS) was significantly associated to high CXCR4 expression (p = 0.02). MATERIALS AND METHODS: Forty-seven positive lymph node metastases were collected and analysed for both histopathological parameters and CXCR4 expression. CONCLUSION: More than 10% RTA in SLN, extranodal invasion and centripetal metastasis thickness all predict additional lymph node metastases in melanoma site draining basins. Moreover, high CXCR4 expression is correlated to shorter DFS and could be used as a prognostic marker in order to stratify melanoma patients at higher progression risk.

Is protein CXCR4 used as a prognostic marker of cancer?

56e68967edfc094c1f000002_006

yes

Patients as collaborators: using focus groups and feedback sessions to develop an interactive, web-based self-management intervention for chronic pain. OBJECTIVES: To describe the development of an interactive, web-based self-management intervention for opioid-treated, chronic pain patients with aberrant drug-related behavior. METHODS: Fifty-three chronic pain patients participated in either focus groups (N = 23) or individual feedback sessions (N = 30). Focus groups probed interest in and relevance of the planned content and structure of the program. Individual session participants reviewed draft program modules and provided feedback on acceptability, ease of use, and usefulness. Focus group transcripts were thematically analyzed, and summary statistics were performed on feedback data. RESULTS: Focus group participants stressed the need for additional pain management strategies and emphasized themes consistent with planned program content related to: 1) ambivalence about opioids; 2) reciprocal relationships among cognition, mood, and pain; 3) importance of recognizing physical limitations; and 4) effectiveness of goal setting for increasing motivation and functioning. Participants also offered insights on: 5) the loss of identity due to chronic pain; and 6) the desire to connect with pain peers to share strategies for managing daily life. Feedback session data demonstrate that participants believed that a web-based tool would be potentially useful and acceptable, and that exposure to program sections significantly increased participants' knowledge of key topics related to self-management of chronic pain. CONCLUSIONS: Results suggest the potential value of self-management for chronic pain patients and the potential acceptability of web-based delivery of intervention content. Focus group and feedback methodologies highlight the usefulness of including potential program users in intervention development.

Are there web based self management strategies for chronic pain ?

54fefff26ad7dcbc1200000b_004

yes

Intrinsic transcript cleavage in yeast RNA polymerase II elongation complexes. Transcript elongation can be interrupted by a variety of obstacles, including certain DNA sequences, DNA-binding proteins, chromatin, and DNA lesions. Bypass of many of these impediments is facilitated by elongation factor TFIIS through a mechanism that involves cleavage of the nascent transcript by the RNA polymerase II/TFIIS elongation complex. Highly purified yeast RNA polymerase II is able to perform transcript hydrolysis in the absence of TFIIS. The "intrinsic" cleavage activity is greatly stimulated at mildly basic pH and requires divalent cations. Both arrested and stalled complexes can carry out the intrinsic cleavage reaction, although not all stalled complexes are equally efficient at this reaction. Arrested complexes in which the nascent transcript was cleaved in the absence of TFIIS were reactivated to readthrough blocks to elongation. Thus, cleavage of the nascent transcript is sufficient for reactivating some arrested complexes. Small RNA products released following transcript cleavage in stalled ternary complexes differ depending upon whether the cleavage has been induced by TFIIS or has occurred in mildly alkaline conditions. In contrast, both intrinsic and TFIIS-induced small RNA cleavage products are very similar when produced from an arrested ternary complex. Although alpha-amanitin interferes with the transcript cleavage stimulated by TFIIS, it has little effect on the intrinsic cleavage reaction. A mutant RNA polymerase previously shown to be refractory to TFIIS-induced transcript cleavage is essentially identical to the wild type polymerase in all tested aspects of intrinsic cleavage.

Does RNA polymerase II have RNA cleavage activity?

5a468785966455904c00000d_008

yes

TLR9 is required for MAPK/NF-κB activation but does not cooperate with TLR2 or TLR6 to induce host resistance to Brucella abortus. Brucella abortus is a Gram-negative intracellular bacterial pathogen that causes a zoonosis of worldwide occurrence, leading to undulant fever in humans and abortion in domestic animals. B. abortus is recognized by several pattern-recognition receptors triggering pathways during the host innate immune response. Therefore, here, we determined the cooperative role of TLR9 with TLR2 or TLR6 receptors in sensing Brucella Furthermore, we deciphered the host innate immune response against B. abortus or its DNA, emphasizing the role of TLR9-MAPK/NF-κB signaling pathways in the production of proinflammatory cytokines. TLR9 is required for the initial host control of B. abortus, but this TLR was dispensable after 6 wk of infection. The susceptibility of TLR9(-/-)-infected animals to Brucella paralleled with lower levels of IFN-γ produced by mouse splenocytes stimulated with this pathogen compared with wild-type cells. However, no apparent cooperative interplay was observed between TLR2-TLR9 or TLR6-TLR9 receptors to control infection. Moreover, B. abortus or its DNA induced activation of MAPK/NF-κB pathways and production of IL-12 and TNF-α by macrophages partially dependent on TLR9 but completely dependent on MyD88. In addition, B. abortus-derived CpG oligonucleotides required TLR9 to promote IL-12 and TNF-α production by macrophages. By confocal microscopy, we demonstrated that TLR9 redistributed and colocalized with lysosomal-associated membrane protein-1 upon Brucella infection. Thus, B. abortus induced TLR9 traffic, leading to cell signaling activation and IL-12 and TNF-α production. Although TLR9 recognized Brucella CpG motifs, our results suggest a new pathway of B. abortus DNA-activating macrophages independent of TLR9.

Is Brucella abortus the organism that causes brucillosis known to cause spontaneous abortions in humans?

5aa6800ad6d6b54f79000011_015

no

Ovarian endometriomas and IVF: a retrospective case-control study. We performed this retrospective case-control study analyzing 428 first-attempt in vitro fertilization (IVF) cycles, among which 254 involved women with a previous or present diagnosis of ovarian endometriosis. First, the results of these 254 cycles were compared with 174 cycles involving patients with proven non-endometriotic tubal infertility having similar age and body mass index. Women with ovarian endometriosis had a significantly higher cancellation rate, but similar pregnancy, implantation and delivery rates as patients with tubal infertility. Second, among the women with ovarian endometriosis, the women with a history of laparoscopic surgery for ovarian endometriomas prior to IVF and no visual endometriosis at ovum pick-up (n = 112) were compared with the non-operated women and visual endometriomas at ovum pick-up (n = 142). Patients who underwent ovarian surgery before IVF had significantly shorter period, lower antral follicle count and required higher gonadotropin doses than patients with non-operated endometriomas. The two groups of women with a previous or present ovarian endometriosis did, however, have similar pregnancy, implantation and live birth rates. In conclusion, ovarian endometriosis does not reduce IVF outcome compared with tubal factor. Furthermore, laparoscopic removal of endometriomas does not improve IVF results, but may cause a decrease of ovarian responsiveness to gonadotropins.

Does surgery for ovarian endometriomas improve fertility?

54f088ee94afd61504000015_000

yes

Mfd is required for rapid recovery of transcription following UV-induced DNA damage but not oxidative DNA damage in Escherichia coli. Transcription-coupled repair (TCR) is a cellular process by which some forms of DNA damage are repaired more rapidly from transcribed strands of active genes than from nontranscribed strands or the overall genome. In humans, the TCR coupling factor, CSB, plays a critical role in restoring transcription following both UV-induced and oxidative DNA damage. It also contributes indirectly to the global repair of some forms of oxidative DNA damage. The Escherichia coli homolog, Mfd, is similarly required for TCR of UV-induced lesions. However, its contribution to the restoration of transcription and to global repair of oxidative damage has not been examined. Here, we report the first direct study of transcriptional recovery following UV-induced and oxidative DNA damage in E. coli. We observed that mutations in mfd or uvrA reduced the rate that transcription recovered following UV-induced damage. In contrast, no difference was detected in the rate of transcription recovery in mfd, uvrA, fpg, nth, or polB dinB umuDC mutants relative to wild-type cells following oxidative damage. mfd mutants were also fully resistant to hydrogen peroxide (H(2)O(2)) and removed oxidative lesions from the genome at rates comparable to wild-type cells. The results demonstrate that Mfd promotes the rapid recovery of gene expression following UV-induced damage in E. coli. In addition, these findings imply that Mfd may be functionally distinct from its human CSB homolog in that it does not detectably contribute to the recovery of gene expression or global repair following oxidative damage.

Are there any functional differences between Mfd and its human Cocaine syndrome protein B (CSB) homolog?

553f8bc11d53b76422000002_001

yes

Combination with bortezomib enhances the antitumor effects of nanoparticle-encapsulated thiostrepton. Bortezomib is well-known for inducing cell death in cancer cells, specifically through the mechanism of proteasome inhibition. Thiostrepton, a thiazole antibiotic, has also been described for its proteasome inhibitory action, although differing slightly to bortezomib in the proteasomal site to which it is active. Previously we had shown the synergic effect of bortezomib and thiostrepton in breast cancer cells in vitro, where sub-apoptotic concentrations of both proteasome inhibitors resulted in synergic increase in cell death when combined as a treatment. Here, we administered such a combination to MDA-MB-231 xenograft tumors in vivo, and found that the effect of complementary proteasome inhibitors reduced tumor growth rates more efficiently than compared with when administered alone. Increased induction of apoptotic activity in tumors was found be associated with the growth inhibitory activity of combination treatment. Further examination additionally revealed that combination-treated tumors exhibited reduced proteasome activity, compared with non-treated and single drug-treated tumors. These data suggest that this drug combination may be useful as a therapy for solid tumors.

Are proteasome inhibitors good candidates for treatment of leukemia and solid tumors?

517179718ed59a060a00000e_005

yes

[Members of the Vaccine Central Committee: a group of men deserving their native land and even humanity]. Two hundred years ago, in May 1800, a private initiative set up a "Central Committee of Vaccine" in Paris. A handful of men launched an extraordinary research: how to implement a still recent and little-known discovery, a method to protect people against small pox. The news came from England, with which France was on bad terms. Smallpox was a fearsome disease killing one tenth of the population and disfiguring or maiming as many again. After several failed attempts, success was reached and the value of the method demonstrated. The committee played a major role in spreading the vaccine (thanks to Jenner) not only in France but also in the whole of the Napoleonic Empire. His remarkable experiments were published and made known to the whole western world. The Committee was made official en 1804 and operated until the foundation of the Academy of medicine, which took over its duties and responsibilities. The French owe a lot to this Central Committee of Vaccine, which greatly contributed to fighting small pox and eradicating the disease finally.

Has small pox been eradicated from the world?

58a1da4e78275d0c4a000059_006

yes

Accumulation of p100, a precursor of NF-κB2, enhances osteoblastic differentiation in vitro and bone formation in vivo in aly/aly mice. We previously reported that alymphoplasia (aly/aly) mice, which have a natural loss-of-function mutation in the Nik gene, which encodes a kinase essential for the processing of p100 to p52 in the alternative nuclear factor-κB (NF-κB) pathway, show mild osteopetrosis with an increase in several parameters of bone formation: bone formation rate, mineral apposition rate, and osteoblast number. We therefore investigated the molecular mechanisms triggered by the alternative NF-κB pathway in the regulation of osteoblast differentiation using primary osteoblasts (POB) prepared from aly/aly mice. Alkaline phosphatase (ALP) activity and mineralization induced by the presence of β-glycerophosphate and ascorbic acid were enhanced in POB from aly/aly compared with wild-type (WT) mice. Furthermore, osteoblastic differentiation induced by bone morphogenetic protein 2 (BMP2), as shown by ALP activity, mRNA expression of osteocalcin, Id1, Osterix and Runx2, and Sma- and Mad-related protein (Smad)1/5/8 phosphorylation, was also enhanced in POB from aly/aly mice. The ectopic bone formation in vivo that was induced by BMP2 was enhanced in aly/aly mice compared with controls. Transfection of a mutant form of p100, p100ΔGRR, which cannot be processed to p52, stimulated ALP activity and Smad phosphorylation. In contrast to p100ΔGRR, overexpression of p52 inhibited these events. Both BMP2-induced ALP activity and Smad phosphorylation were reduced in POB from p100-deficient mice, which carry a homozygous deletion of the COOH-terminal ankyrin repeats of p100 but still express functional p52 protein. p52 and p100ΔGRR interacted with a BMP receptor, ALK2, in overexpressed COS7 cells and changed the ALK2 protein levels in opposite directions: p52 reduced ALK2 and p100 increased it. Thus, the alternative the NF-κB pathway via the processing of p52 from p100 negatively regulates osteoblastic differentiation and bone formation by modifying BMP activity.

Is p100 the precursor protein molecule of the NF-kappaB transcription factor subunit p50?

55088e412e93f0133a000001_013

no

Weight gain associated with antipsychotic drugs. Weight gain has been reported with nearly every antipsychotic drug on the market (molindone is an exception). Weight gain occurs no matter what the patient's age, sex, or race and is seen with both oral and depot drug formulations. Numerous studies have found that patients gain weight when treated with a conventional antipsychotic, such as chlorpromazine, fluphenazine, and haloperidol. The newer, novel antipsychotics offer advantages over conventional antipsychotics, especially a relative lack of extrapyramidal symptoms, but some still have the disadvantage of causing weight gain. Clozapine and olanzapine in particular appear to cause substantial weight gain, much more so than do most conventional neuroleptics and novel agents such as risperidone. Given the risks to health and treatment compliance associated with weight gain and obesity, clinicians should monitor weight during the course of antipsychotic therapy and consider switching agents if excessive weight gain occurs.

Does molindone affect body weight?

52cae04c03868f1b06000024_010

yes

Photoaging and tretinoin. Premature skin aging caused by repeated exposure to solar radiation is called photoaging. Although once considered an irreversible process, it is now established that photoaging can be treated by topical tretinoin. Both from carefully designed controlled clinical studies; and basic investigations into the mechanism by which tretinoin improves photoaged skin, our understanding of photoaging has been enhanced. This article highlights some of these studies which have contributed to our knowledge.

Is tretinoin effective for photoaging?

5a68f2bab750ff4455000017_007

yes

The SNORD115 (H/MBII-52) and SNORD116 (H/MBII-85) gene clusters at the imprinted Prader-Willi locus generate canonical box C/D snoRNAs. The imprinted Snurf-Snrpn chromosomal domain contains two large arrays of tandemly repeated, paternally expressed box C/D small-nucleolar RNA (snoRNA) genes: the SNORD115 (H/MBII-52) and SNORD116 (H/MBII-85) gene clusters believed to play key roles in the fine-tuning of serotonin receptor (5-HT2C) pre-mRNA processing and in the etiology of the Prader-Willi Syndrome (PWS), respectively. SNORD115 and SNORD116 were recently proposed to undergo significant conversion into shorter RNA species, the so-called psnoRNAs. Here, we provide evidence that argues against the existence of abundant psnoRNAs in human or mouse brain. Instead, we characterize a previously unsuspected low-abundance, fibrillarin-associated SNORD115-derived smaller RNA species. Based on these findings, we strongly recommend that PWS-encoded SNORD115 and SNORD116 be considered as bona fide box C/D snoRNAs.

Is the Snord116 cluster associated with the Prader-Willi syndrome?

52b2f0d84003448f55000009_004

yes

Pharmacokinetics of 8-hour intravenous infusion of NXY-059: a phase I, randomized, double-blind (within dose panels), placebo-controlled study in healthy Chinese volunteers. BACKGROUND: NXY-059 is a free radical-trapping neuroprotectant that has been reported to reduce infarct size and preserve brain function in experimental models of acute ischemic stroke. NXY-059 administered as an 8- or 72-hour IV infusion has been reported to be well tolerated in healthy young (age, 20-45 years) and older (55-75 years) white volunteers. NXY-059 is no longer in development following a lack of efficacy found in a Phase III trial in patients with acute ischemic stroke. OBJECTIVES: The primary objectives of this study were to determine the pharmacokinetic (PK) properties of an 8-hour IV infusion of NXY-059 in healthy Chinese volunteers and to compare those data with those previously reported in the white population, therefore exploring any differences in PK properties between the 2 ethnic groups. Secondary objectives were to evaluate PK linearity and tolerability. METHODS: This Phase I, randomized, double-blind (within dose panels), placebo-controlled study was conducted at Peking Union Medical College Hospital, Beijing, China. Healthy male and female Chinese volunteers aged 20 to 45 years were recruited. NXY-059 was administered as a continuous 8-hour IV infusion, starting with a 1-hour loading dose (dosing rate, 3 x maintenance infusion rate) followed by a 7-hour maintenance dose infusion. Subjects were randomly assigned, in a 3:1 ratio, to receive doses calculated (based on creatinine clearance in individual subjects) to achieve 1 of 3 concentration targets, or inactive vehicle (sodium chloride; placebo). The target unbound plasma NXY-059 concentrations during constant rate infusion (steady state) (Cu(ss)) in the 3 dose panels were 100,200, and 300 micromol/L. An explorative bridging analysis was used to compare PK data from this study with those previously reported in the white population. Linearity of NXY-059 PK properties was assessed. Tolerability was assessed using adverse events (spontaneous reporting, study staff observation, and open questioning), physical examination, including vital sign measurement; and electrocardiography and laboratory analysis. RESULTS: Thirty-six subjects were randomized (mean age, 32 years [range, 20-41 years]; mean body mass index, 22.6 kg/m(2) [range, 20-26 kg/m(2)]). The target exposures of NXY-059 were achieved (mean [SD] Cu(ss) values, 98.3 [8.9], 202.1 [18.3], and 287.9 [25.4] micromol/L, respectively). Steady-state concentrations appeared to have been reached after 4 hours. From the bridging analysis, comparison of PK properties in the 27 Chinese volunteers versus those in 28 white volunteers found similar total plasma clearance of NXY-059 (estimated Chinese:white clearance ratio, 1.077 [95% CI, 1.009-1.150]). There were no apparent differences in other PK parameters between the 2 ethnic groups. The PK properties of NXY-059 in Chinese volunteers were suggestive of linearity. A total of 7 adverse events were reported, all of mild intensity, in the NXY-059 and placebo groups (thirst and polyuria [each in 2 subjects who received NXY-059 and 1 subject who received placebo]; urinary tract infection [1 subject who received NXY-059]). CONCLUSIONS: The results from the present study suggest that the PK properties of NXY-059 were similar in the Chinese and historical white healthy volunteer populations.

Can NXY-059 be used for treatment of acute ischemic stroke patients?

54d62faf3706e89528000003_018

no

Extensive alternative polyadenylation during zebrafish development. The post-transcriptional fate of messenger RNAs (mRNAs) is largely dictated by their 3' untranslated regions (3' UTRs), which are defined by cleavage and polyadenylation (CPA) of pre-mRNAs. We used poly(A)-position profiling by sequencing (3P-seq) to map poly(A) sites at eight developmental stages and tissues in the zebrafish. Analysis of over 60 million 3P-seq reads substantially increased and improved existing 3' UTR annotations, resulting in confidently identified 3' UTRs for >79% of the annotated protein-coding genes in zebrafish. mRNAs from most zebrafish genes undergo alternative CPA, with those from more than a thousand genes using different dominant 3' UTRs at different stages. These included one of the poly(A) polymerase genes, for which alternative CPA reinforces its repression in the ovary. 3' UTRs tend to be shortest in the ovaries and longest in the brain. Isoforms with some of the shortest 3' UTRs are highly expressed in the ovary, yet absent in the maternally contributed RNAs of the embryo, perhaps because their 3' UTRs are too short to accommodate a uridine-rich motif required for stability of the maternal mRNA. At 2 h post-fertilization, thousands of unique poly(A) sites appear at locations lacking a typical polyadenylation signal, which suggests a wave of widespread cytoplasmic polyadenylation of mRNA degradation intermediates. Our insights into the identities, formation, and evolution of zebrafish 3' UTRs provide a resource for studying gene regulation during vertebrate development.

Is there alternative polyadenylation during zebrafish development?

58963b0278275d0c4a00000c_000

yes

Differential effects of fingolimod on B-cell populations in multiple sclerosis. BACKGROUND: Fingolimod is an oral drug approved for multiple sclerosis (MS) with an ability to trap central memory T cells in secondary lymphoid tissues; however, its variable effectiveness in individual patients indicates the need to evaluate its effects on other lymphoid cells. OBJECTIVE: To clarify the effects of fingolimod on B-cell populations in patients with MS. METHODS: We analysed blood samples from 9 fingolimod-treated and 19 control patients with MS by flow cytometry, to determine the frequencies and activation states of naive B cells, memory B cells, and plasmablasts. RESULTS: The frequencies of each B-cell population in peripheral blood mononuclear cells (PBMC) were greatly reduced 2 weeks after starting fingolimod treatment. Detailed analysis revealed a significant reduction in activated memory B cells (CD38(int-high)), particularly those expressing Ki-67, a marker of cell proliferation. Also, we noted an increased proportion of activated plasmablasts (CD138(+)) among whole plasmablasts, in the patients treated with fingolimod. CONCLUSIONS: The marked reduction of Ki-67(+) memory B cells may be directly linked with the effectiveness of fingolimod in treating MS. In contrast, the relative resistance of CD138(+) plasmablasts to fingolimod may be of relevance for understanding the differential effectiveness of fingolimod in individual patients.

Is there a relationship between B cells and Multiple Sclerosis?

58c0836102b8c6095300001c_013

yes

Developmental determinants of the independence and complexity of the enteric nervous system. Enteric nervous system (ENS) development is relevant to Hirschsprung's disease (HSCR; congenital aganglionosis of the terminal bowel), which is still imperfectly treated. Mutations in genes encoding the RET receptor tyrosine kinase and endothelin receptor type B (EDNRB) are involved in HSCR pathogenesis; however, also important in ENS development are molecules that mediate events that are more restricted than those of RET and EDNRB, act later in development and which might not be HSCR-associated. Examples are molecules that function in the guidance of enteric neural crest-derived cells (ENCDCs) and vagal axons, and in regulating the terminal differentiation of enteric neurons from ENCDCs. It is probable that highly prevalent disorders of gastrointestinal sensation and motility result from subtle defects in ENS development.

Are EDNRB mutations involved in the development of Hirschsprung disease?

551910c5622b194345000007_016

yes

[Schindler disease/Kanzaki disease]. Schindler disease and Kanzaki disease are caused by a deficient lysosomal enzyme, alpha-N-acetylgalactosaminidase (E.C.3.2.1.49). Two German children were first reported in 1987 and other two Dutch children were recently reported in 1993. These children were very similar clinically and characterized by maked neuroaxonal dystrophy of an infantile onset. This disease (type 1) was named Schindler disease. On the other hand, an adult patient with profuse angiokeratoma corporis diffusum but minimum involvement in nervous system was reported in 1987 from Japan. This disease (type 2) was named Kanzaki disease (Mckusick catalog No. 104170). Molecular analyses of these diseases revealed one each point mutation in the encoding gene. Clinical, ultrastructural and molecular studies of these disease were described.

Is Kanzaki disease associated with deficiency in alpha-N-acetylgalactosaminidase?

56f7c44109dd18d46b000013_000

yes

The role of DNA repair by homologous recombination in oncogenesis. DNA repair by homologous recombination (HR) may be regarded as the two faces of a coin: lowering the oncogenetic potential (precise repair with no consequences on genomic status) or increasing it (deleterious action which may determine chromosome rearrangements such as loss of heterozigosity). Inherited mutations in genes involved in HR are associated with gene rearrangement and may be a prerequisite for tumor development in some cancer-prone hereditary diseases like Bloom, Werner and Rothmund-Thomson syndromes. Normal eukaryotic cells show some degree of balance between various mechanisms of repair. This review presents the main mechanisms and pathways of homologous recombination repair (synthesis-dependent single strand annealing, constitution of Hollidayjunctions with their resolution mechanisms and repair by break induced replication), the proteins involved in it and their contribution to oncogenesis.

Are defects in recombination repair involved in carcinogenesis?

52f77f752059c6d71c00002b_003

yes

[Selenium deficiency in celiac disease: risk of autoimmune thyroid diseases]. The essential trace mineral selenium is of fundamental importance to human health. It is incorporated in the proteome in the forms of the genetically encoded amino acids selenocysteine and selenomethionine, which are the characteristic components of selenoproteins (SeP) such as glutathione peroxidases (GPx), thioredoxin reductases and iodothyronine deiodinase families. Thyroid is especially sensitive to selenium deficiency, because SeP can modify thyreocytes function by acting as antioxidants and modifying redox status and thyroid hormone metabolism. SeP are also involved in apoptosis, cell growth and modification of the action of cell signalling systems and transcription factors. Some intestinal GPx modulate apoptosis by removing the cells affected by oxidative damage preserving tissue integrity. The malfunctioning of the GPx antioxidant system in intestinal mucosa can trigger a continuous cycle of reactive oxygen species and inflammation. Selenium deficiency is a risk factor, due to the malabsorption, in celiac disease (CD) because the inflammatory damage affects the small intestine; this deficiency can modulate SeP genes expression, with consequent reiteration of inflammation and increase of mucosal damage. In active CD, overexpression of interleukin-15 (IL-15) may increase activation of effector mechanisms of epithelial damage by stimulating T helper 1 cytokine proliferation and production and intraepithelial lymphocytes cytotoxicity by protecting these lymphocytes from apoptosis. Blocking IL-15 has the potential to provide new therapeutic tools to prevent both tissue damage and complication of CD such as autoimmune thyroid diseases (AITD) where IL-15 expression is also increases. In view of the role played by SeP in apoptosis inhibition, the presence of environmental factors such as selenium deficiency can be considered an important direct factor of thyroidal damage in development of AITD.

Is selenium deficiency involved in autoimmune thyroid disease?

550c1ca3a103b78016000003_003

yes

[Safety of immunosuppressants]. METABOLISM: Cyclosporin A and leflunomide may increase the blood pressure, whereas administration of prednisolone and tacrolimus may cause hyperglycemia. Azathioprine, chloroquine, methotrexate and mycophenolate mofetil seem to be metabolically neutral. Tocilizumab and tumor necrosis factor (TNF) alpha blockers have a negative effect on the lipid profile. INFECTIONS: The overall infection risk for prednisolone is estimated to be 1.3. This risk for methotrexate is also 1.3 compared to other disease modifying antirheumatic drugs (DMARDs). Regarding biologics, the highest risk of serious infections was associated with certolizumab pegol and tocilizumab, in contrast to abatacept and rituximab which showed the lowest risk. CANCER RISK: Azathioprine and cyclosporin A are associated with a markedly increased risk of non-melanoma skin cancer. According to the RABBIT registry no significant increase in tumor rate has been reported for biologics. PREGNANCY: Azathioprine, chloroquine, cyclosporin A, prednisolone, sulfasalazine, tacrolimus and cyclophosphamide (only after the second trimester) may be administered during pregnancy. Biologics should be avoided unless there is a treatment need in cases of uncontrolled disease activity. BREAST FEEDING: Only chloroquine, prednisolone, sulfasalazine and tacrolimus may be taken during breast feeding. There are insufficient data on the safety of biologics.

Is it safe to use Abatacept during pregnancy?

52bf1aa503868f1b06000006_000

no

Jarid2 links MicroRNA and chromatin in Th17 cells. In this issue of Immunity, Escobar et al. (2014) bring microRNAs and chromatin together by showing how activation-induced miR-155 targets the chromatin protein Jarid2 to regulate proinflammatory cytokine production in T helper 17 cells.

Is there any association between Jarid2 and miR-155 in Th17 cells?

56b8f28a156496395c000006_001

yes

ZEB2 zinc-finger missense mutations lead to hypomorphic alleles and a mild Mowat-Wilson syndrome. Mowat-Wilson syndrome (MWS) is a severe intellectual disability (ID)-distinctive facial gestalt-multiple congenital anomaly syndrome, commonly associating microcephaly, epilepsy, corpus callosum agenesis, conotruncal heart defects, urogenital malformations and Hirschsprung disease (HSCR). MWS is caused by de novo heterozygous mutations in the ZEB2 gene. The majority of mutations lead to haplo-insufficiency through premature stop codons or large gene deletions. Only three missense mutations have been reported so far; none of which resides in a known functional domain of ZEB2. In this study, we report and analyze the functional consequences of three novel missense mutations, p.Tyr1055Cys, p.Ser1071Pro and p.His1045Arg, identified in the highly conserved C-zinc-finger (C-ZF) domain of ZEB2. Patients' phenotype included the facial gestalt of MWS and moderate ID, but no microcephaly, heart defects or HSCR. In vitro studies showed that all the three mutations prevented binding and repression of the E-cadherin promoter, a characterized ZEB2 target gene. Taking advantage of the zebrafish morphant technology, we performed rescue experiments using wild-type (WT) and mutant human ZEB2 mRNAs. Variable, mutation-dependent, embryo rescue, correlating with the severity of patients' phenotype, was observed. Our data provide evidence that these missense mutations cause a partial loss of function of ZEB2, suggesting that its role is not restricted to repression of E-cadherin. Functional domains other than C-ZF may play a role in early embryonic development. Finally, these findings broaden the clinical spectrum of ZEB2 mutations, indicating that MWS ought to be considered in patients with lesser degrees of ID and a suggestive facial gestalt, even in the absence of congenital malformation.

Is Hirschsprung disease one of the characteristics of the Mowat-Wilson syndrome?

55001420e9bde69634000005_007

yes

Over-expressing CYLD augments antitumor activity of TRAIL by inhibiting the NF-κB survival signaling in lung cancer cells. The death ligand tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) can selectively induce apoptosis in tumor cells. But studies have demonstrated that many tumor cells were resistant to TRAIL-induced apoptosis. CYLD is recognized as a negative regulator of nuclear factor-kappa B(NF-κB) activity. To explore a correlation between CYLD expression and responsiveness to TRAIL in lung cancer cell lines, we established lung cancer cell lines that stably express CYLD. Our data provided the first evidence that increased expression of CYLD directly blocks TRAIL-induced NF-κB activation, and consequently increases TRAIL-induced apoptosis in lung cancer cells. CYLD may act as a therapeutic target of lung cancer. Targeting CYLD, in combination with TRAIL, may be a new strategy to treat lung cancer with high NF-κB activity.

Is there a role for the cylindromatosis tumor suppressor (CYLD) in lung cancer?

5545e926d355485447000002_001

yes

Lenalidomide: targeted anemia therapy for myelodysplastic syndromes. Lenalidomide, an IMiD drug (a novel type of immunomodulating drug) was recently approved by the US Food and Drug Administration for the treatment of transfusion-dependent anemia in patients with myelodysplastic syndromes (MDS) and interstitial deletions of chromosome 5q [del(5q)]. This review examines the clinical experience from the MDS-001 and MDS-003 clinical trials that led to this approval, the results of biological correlates supporting the targets of drug action, and the results from a non-del(5q) multicenter study (MDS-002). Lenalidomide treatment resulted in both erythroid and cytogenetic responses in the majority of patients with del(5q), accompanied by reductions in inflammatory cytokine generation and marrow microvessel density and improvement in primitive hematopoietic progenitor recovery. Central pathology review showed that resolution of cytologic dysplasia was common in patients with del(5q) but was infrequent in erythroid-responding patients without the chromosome 5 deletion. These findings indicate that lenalidomide promotes erythropoiesis in lower-risk MDS, with two apparently distinct mechanisms of action: suppression of the ineffective del(5q) clone and promotion of effective erythropoiesis in non-del(5q) MDS progenitors. These studies identified lenalidomide as a highly active erythropoietic- and cytogenetic-remitting agent in lower-risk MDS patients who otherwise would not be expected to benefit from recombinant erythropoietin therapy. The most common adverse reactions include dose-dependent neutropenia and thrombocytopenia that are more pronounced in patients with del(5q) in whom early suppression of the clone is expected.

Has Revlimid been approved by the US Food and Drug Administration?

56ed0ba22ac5ed1459000007_006

yes

Cardiovascular Profile of Propranolol after Multiple Dosing in Infantile Hemangioma. Propranolol is becoming the treatment of choice for complicated infantile hemangioma. We report here data on peripheral blood flow, O2-saturation, electrocardiographic PR-interval, left ventricular function, blood pressure and heart rate that were assessed before and during treatment for > 4 weeks with propranolol 2 mg/kg of body weight daily in 67 infants <12 months of age in normal sinus rhythm and with structurally normal hearts. Management with propranolol was well tolerated in all and did not modify peripheral blood flow, O2-saturation, electrocardiographic PR-interval and left ventricular fractional shortening or ejection fraction. Absolute blood pressure levels were similar without and with propranolol. However, age-adjusted centile levels for both systolic and diastolic levels were significantly lower while on propranolol. The heart rate was significantly lower both when expressed as absolute value and when expressed as age-adjusted centile on treatment with propranolol. In conclusion, propranolol 2 mg/kg of body weight daily causes a statistically though not clinically relevant decrease in blood pressure and heart rate in cardially healthy infants affected by infantile hemangioma. Temporary discontinuation during acute febrile illnesses and during diarrheal diseases should be considered to prevent excessive hypotension.

Is propranolol used for treatment of infantile hemangioma?

5a67a72fb750ff445500000a_009

yes

Comparison of pharmacological activity of macitentan and bosentan in preclinical models of systemic and pulmonary hypertension. AIMS: The endothelin (ET) system is a tissular system, as the production of ET isoforms is mostly autocrine or paracrine. Macitentan is a novel dual ETA/ETB receptor antagonist with enhanced tissue distribution and sustained receptor binding properties designed to achieve a more efficacious ET receptor blockade. To determine if these features translate into improved efficacy in vivo, a study was designed in which rats with either systemic or pulmonary hypertension and equipped with telemetry were given macitentan on top of maximally effective doses of another dual ETA/ETB receptor antagonist, bosentan, which does not display sustained receptor occupancy and shows less tissue distribution. MAIN METHODS: After establishing dose-response curves of both compounds in conscious, hypertensive Dahl salt-sensitive and pulmonary hypertensive bleomycin-treated rats, macitentan was administered on top of the maximal effective dose of bosentan. KEY FINDINGS: In hypertensive rats, macitentan 30 mg/kg further decreased mean arterial blood pressure (MAP) by 19 mm Hg when given on top of bosentan 100 mg/kg (n=9, p<0.01 vs. vehicle). Conversely, bosentan given on top of macitentan failed to induce an additional MAP decrease. In pulmonary hypertensive rats, macitentan 30 mg/kg further decreased mean pulmonary artery pressure (MPAP) by 4 mm Hg on top of bosentan (n=8, p<0.01 vs. vehicle), whereas a maximal effective dose of bosentan given on top of macitentan did not cause any additional MPAP decrease. SIGNIFICANCE: The add-on effect of macitentan on top of bosentan in two pathological models confirms that this novel compound can achieve a superior blockade of ET receptors and provides evidence for greater maximal efficacy.

Is macitentan an ET agonist?

56c863385795f9a73e000015_002

no

Effects of dexmedetomidine on adrenocortical function, and the cardiovascular, endocrine and inflammatory responses in post-operative patients needing sedation in the intensive care unit. We have compared the effects of dexmedetomidine and propofol on endocrine, metabolic, inflammatory and cardiovascular responses in patients in the intensive care unit (ICU) after major surgery. Twenty patients who were expected to require 8 h of post-operative sedation and ventilation were allocated randomly to receive either an infusion of dexmedetomidine 0.2-2.5 microg kg(-1) h(-1) or propofol 1-3 mg kg(-1) h(-1). Arterial pressure, heart rate and sequential concentrations of circulating cortisol, adrenocorticotrophic hormone (ACTH), growth hormone, prolactin, insulin, glucose and interleukin 6 were measured. An ACTH stimulation test was performed in all patients who received dexmedetomidine. Heart rate was significantly lower in the dexmedetomidine patients. There were no differences in arterial pressure, cortisol, ACTH, prolactin and glucose concentrations between the two groups. A positive response to the ACTH stimulation test varied depending on the diagnostic criteria used. The insulin concentration was significantly lower in the dexmedetomidine group at 2 h (P=0.021), although this did not affect blood glucose concentrations. Growth hormone concentrations were significantly higher in dexmedetomidine-treated patients overall (P=0.036), but circulating concentrations remained in the physiological range. Interleukin 6 decreased in the dexmedetomidine group. We conclude that dexmedetomidine infusion does not inhibit adrenal steroidogenesis when used for short-term sedation after surgery.

Is Propofol used for short-term sedation?

515d9a42298dcd4e5100000d_009

yes

Absence of sensory neuropathy among workers with occupational exposure to chlorpyrifos. Several studies have reported the occurrence of sensory neuropathy with exposure to chlorpyrifos and other organophosphorus insecticides, at levels not associated with overt toxicity. We evaluated 113 chemical workers, including 53 of 66 (80%) eligible chlorpyrifos workers and 60 of 74 (81%) randomly selected referent workers, to identify evidence of sensory neuropathy or subclinical neuropathy. Compared to referents, chlorpyrifos subjects had significantly longer duration of work in chlorpyrifos-exposed areas (9.72 vs. 0.01 years; P < 0.0001), greater cumulative chlorpyrifos exposure (64.16 vs. 0.69 mg/m(3). day; P < 0.0001), higher urine 3,5,6-trichloro-2-pyridinol (TCP) excretion (108.6 vs. 4.3 microg/g creatinine; P < 0.0001), and lower plasma butyrylcholinesterase (BuChE) activity (7281 vs. 8176 mU/ml; P = 0.003). Despite exposures among chlorpyrifos subjects to levels at which well-described physiological effects on B-esterases exist, the frequency of symptoms or signs of neuropathy did not differ significantly between groups, and the only 2 subjects fulfilling criteria for confirmed neuropathy were both in the referent group. Mean nerve conduction study results were comparable to established control values and did not differ significantly between groups. We found no evidence of sensory neuropathy or isolated peripheral abnormalities among subjects with long-term chlorpyrifos exposure at levels known to be associated with the manufacturing process.

Is pesticide exposure associated with polyneuropathy?

530cefaaad0bf1360c000010_005

yes

Chronic systemic administration of serotonergic ligands flibanserin and 8-OH-DPAT enhance HPA axis responses to restraint in female marmosets. BACKGROUND: Flibanserin, a novel serotonin (5-HT)(1A) agonist and 5-HT(2A) antagonist, has been shown to increase sexual desire and reduce distress in women with Hypoactive Sexual Desire Disorder (HSDD). In marmoset monkeys, flibanserin has demonstrated pro-social effects on male-female pairmates, while the classic 5-HT(1A) agonist 8-OH-DPAT suppresses female sexual behavior and increases aggressive interactions between pairmates. Activation of 5-HT(1A) and 5-HT(2A) receptors is known to stimulate the hypothalamic-pituitary-adrenal (HPA) axis. This study aims to characterize the effects of repeated flibanserin and 8-OH-DPAT administration on the marmoset HPA axis and to elucidate endocrine correlates of altered marmoset pair behavior. METHODS: Adrenocorticotropic hormone (ACTH) and cortisol were examined at baseline and during 5-HT(1A) agonist and restraint challenges in 8 female marmoset monkeys receiving daily flibanserin (15mg/kg) and an additional 8 female marmosets receiving 8-OH-DPAT (0.1mg/kg) for 15-16weeks. Corresponding vehicle treatments were administered in a counterbalanced, within-subject design. All females were housed in stable male-female pairs. Treatment-induced changes in ACTH and cortisol levels were correlated with previously assessed marmoset pair behavior. RESULTS: While morning basal cortisol levels and HPA responses to a 5-HT(1A) agonist challenge were not altered by chronic flibanserin or 8-OH-DPAT, both treatments increased the responsiveness of the marmoset HPA axis to restraint. Enhanced ACTH responses to restraint correlated with reduced sexual receptivity and increased aggression in 8-OH-DPAT-, but not in flibanserin-treated female marmosets. CONCLUSIONS: Unaltered HPA responses to a 5-HT(1A) agonist challenge after chronic flibanserin and 8-OH-DPAT treatments indicate little or no de-sensitization of the HPA axis to repeated 5-HT(1A) manipulation. Chronic 8-OH-DPAT, but not flibanserin, leads to aggravated ACTH responses to stress that may contribute to anti-sexual and anti-social behavior between 8-OH-DPAT-treated females and their male pairmates. Despite similar flibanserin and 8-OH-DPAT induced ACTH responses to restraint stress, flibanserin-treated females show unchanged cortisol profiles. This is possibly due to flibanserin's regional selectivity in 5-HT(1A) activation and concurrent 5-HT(2A) inhibition. The contrasting restraint-related cortisol responses emulate contrasting behavioral phenotypes of diminished pair-bond of 8-OH-DPAT-treated females compared to the more affiliative pair-bond of flibanserin-treated females.

Is flibanserin effetive for Hypoactive Sexual Desire Disorder?

56bb6b0eac7ad1001900000e_002

yes

Gene silencing of MIR22 in acute lymphoblastic leukaemia involves histone modifications independent of promoter DNA methylation. Aberrant epigenetic regulation has recently been implicated in the downregulation of tumour suppressor microRNAs (miRNAs). Histone modification and DNA methylation can have different roles in gene silencing in cancer. To investigate whether histone modifications would contribute to the dysregulation of miRNAs in acute lymphoblastic leukaemia (ALL), the effect of a histone deacetylase inhibitor, trichostatin A (TSA), on miRNA expression profile was analysed by microarray assay in a precursor B-cell ALL cell line NALM-6. A total of 10 miRNAs were downregulated and 31 were upregulated significantly following TSA treatment. Among TSA-upregulated miRNAs, MIR22 is an extronic miRNA and resides in the second exon of the non-coding transcript MGC14376. Upregulation of MIR22 transcription was found in both NALM-6 cells and primary human ALL malignant cells treated with TSA. Whereas a CpG island was identified within the promoter element of MIR22, no promoter DNA methylation was detected in these cells. In contrast, accumulation of the repressive histone marker H3K27 trimethylation (H3K27triM) was identified around the transcriptional start point of the gene, which was reduced by TSA treatment. Thus, accumulation of H3K27triM independent of promoter DNA methylation may be a novel epigenetic mechanism for MIR22 silencing in ALL.

Are microRNA (miR) regulated through DNA methylation of their promoters?

53636e727d100faa0900000d_002

yes

Nonpharmacologic approach to fatigue in patients with cancer. Cancer-related fatigue is a common yet underappreciated problem with a significant impact on functional ability and quality of life. Practice guidelines mandate that all cancer patients and survivors be screened for cancer-related fatigue (CRF) at regular intervals. Comorbidities that could contribute to fatigue should be treated, and patients with moderate to severe fatigue should undergo a comprehensive evaluation. Nonpharmacologic interventions are important tools to combat CRF and should be incorporated into routine practice. Physical activity, educational interventions, and cognitive-behavioral therapy have the most supportive data and can be recommended to patients with confidence. From a practical standpoint, general education on CRF is something that most care providers can readily offer patients as part of routine care. Other interventions that appear promising but are as yet lacking convincing evidence include mindfulness-based stress reduction, yoga, and acupuncture. Reiki, Qigong, hypnosis, and music therapy may be worthy of further investigation.

Can cognitive behavioral therapy improve fatigue in cancer patients?

54d762653706e89528000014_016

yes

Awakenings and awareness recovery in disorders of consciousness: is there a role for drugs? Disorders of consciousness (DOC) include coma, vegetative state (VS) and minimally conscious state (MCS). Coma is a condition of unarousability with a complete absence of wakefulness and awareness, whereas VS is characterized by a lack of awareness despite a preserved wakefulness. Patients in coma are unconscious because they lack both wakefulness and awareness. Patients in a VS are unconscious because, although they are wakeful, they lack awareness. Patients in a MCS show minimal but definite behavioural evidence of self and environmental awareness. Coma results from diffuse bilateral hemispheric lesions or selective damage to the ascending reticular system (which is functionally connected to the cerebral cortex by intralaminar thalamic nuclei). VS is a syndrome that is considered to be the result of a disconnection of different cortical networks rather than a dysfunction of a single area or a global reduction in cortical metabolism. As revealed by functional imaging studies, clinical recovery is often associated with a functional restoration of cortico-thalamo-cortical connections. Depending on the amount of network restored, patients may regain full consciousness or remain in a MCS. Molecular and neural mediators may indirectly contribute to the above restoration processes owing to their role in the phenomenon of neural synaptic plasticity. Therefore, there is growing interest in the possible effects of drugs that act at the level of the CNS in promoting emergence from DOC. Sporadic cases of dramatic recovery from DOC after the administration of various pharmacological agents, such as baclofen, zolpidem and amantadine, have been recently supported by intriguing scientific observations. Analysis of the reported cases of recovery, with particular attention paid to the condition of the patients and to the association of their improvement with the start of drug administration, suggests that these treatments might have promoted the clinical improvement of some patients. These drugs are from various and diverging classes, but can be grouped into two main categories, CNS stimulants and CNS depressants. Some of these treatments seem to directly encourage a consciousness restoration, while others play a more determinant role in improving cognitive domains, especially in patients with residual cognitive impairment, than in the field of consciousness. Given the great interest recently generated in the scientific community by the increasing number of papers addressing this issue, further investigation of the above treatments, with particular attention paid to their mechanisms of action, the neurotransmitters involved and their effects on cortico-thalamo-cortical circuitry, is needed.

Is amantadine effective for treatment of disorders conciousness?

530f7cdde3eabad021000001_004

yes

Elevated quantitative vibrotactile threshold among workers previously poisoned with methamidophos and other organophosphate pesticides. To evaluate chronic effects of acute organophosphate pesticide poisoning, quantitatively determined vibrotactile thresholds were measured as an index of peripheral neuropathy among agricultural workers in Nicaragua. Thirty-six male workers were evaluated between 10 and 34 months after hospitalization for acute organophosphate poisoning and compared to an age- and sex-matched community reference group. Vibrotactile thresholds were measured quantitatively in right and left index fingers and right and left great toes. Study subjects were stratified into three groups: 1) never poisoned; 2) poisoned with organophosphates other than methamidophos, agents which have not been reported to cause peripheral neuropathy; and 3) poisoned with methamidophos, a peripheral neurotoxin. For all digits, there was a statistically significant trend of increasing age- and height-adjusted thresholds across these three exposure categories. Over one fourth of patients previously poisoned with methamidophos we studied had abnormal vibrotactile thresholds. These results suggest that previously reported cases of organophosphate-induced delayed polyneuropathy may represent only the worst disease in a spectrum of impairment, a sequela of exposure that may be much more common than previously thought.

Is pesticide exposure associated with polyneuropathy?

530cefaaad0bf1360c000010_022

yes

Phenotypic spectrum of disorders associated with glycyl-tRNA synthetase mutations. We describe clinical, electrophysiological, histopathological and molecular features of a unique disease caused by mutations in the glycyl-tRNA synthetase (GARS) gene. Sixty patients from five multigenerational families have been evaluated. The disease is characterized by adolescent onset of weakness, and atrophy of thenar and first dorsal interosseus muscles progressing to involve foot and peroneal muscles in most but not all cases. Mild to moderate sensory deficits develop in a minority of patients. Neurophysiologically confirmed chronic denervation in distal muscles with reduced compound motor action potentials were features consistent with both motor neuronal and axonal pathology. Sural nerve biopsy showed mild to moderate selective loss of small- and medium-sized myelinated and small unmyelinated axons, although sensory nerve action potentials were not significantly decreased. Based on the presence or absence of sensory changes, the disease phenotype was initially defined as distal spinal muscular atrophy type V (dSMA-V) in three families, Charcot-Marie-Tooth disease type 2D (CMT2D) in a single family, and as either dSMA-V or CMT2D in patients of another large family. Linkage to chromosome 7p15 and the presence of disease-associated heterozygous GARS mutations have been identified in patients from each of the five studied families. We conclude that patients with GARS mutations present a clinical continuum of predominantly motor distal neuronopathy/axonopathy with mild to moderate sensory involvement that varies between the families and between members of the same family. Awareness of these overlapping clinical phenotypes associated with mutations in GARS will facilitate identification of this disorder in additional families and direct future research toward better understanding of its pathogenesis.

Have mutations in the GARS gene been identified to cause Charcot-Marie-Tooth Disease Type 2D (CMT2D)?

52b2ecd34003448f55000003_006

yes

Flibanserin: initial evidence of efficacy on sexual dysfunction, in patients with major depressive disorder. INTRODUCTION: Flibanserin, a novel 5-HT(1A) agonist and 5-HT(2A) antagonist, has the potential to treat sexual dysfunction. AIM: Provide historical perspective on the rationale for development of flibanserin to treat sexual dysfunction, based on post hoc analyses of data. MAIN OUTCOME MEASURES: The Arizona Sexual Experiences (ASEX) scale and the Hamilton depression rating scale (HAMD) Genital Symptoms item. METHODS: Sexual function outcomes are presented from four double-blind, randomized controlled studies involving a total of 369 men and 523 women diagnosed with Major Depressive Disorder. Each study had an active treatment arm to confirm assay sensitivity on the primary antidepressive endpoint. Two studies placebo, flibanserin (50mg bid), or fluoxetine (20mg qd) for 6 weeks and two involved placebo, flibanserin (50-100mg bid), or paroxetine (20-40mg qd) for 8 weeks. RESULTS: Individual study completion rates were 77-80%. At baseline, 38% of men and 67% of women reported sexual dysfunction. Assay sensitivity was not demonstrated in the fluoxetine trials and sexual function outcomes were inconsistent. Flibanserin and placebo were associated with low rates of treatment-emergent sexual dysfunction in women during the paroxetine studies. In one study, 70% of flibanserin-treated women with baseline sexual dysfunction reported improvement in sexual function, compared with 30% of placebo-treated women. Mean change from baseline on the HAMD "Genital Symptoms" item in one paroxetine study was significantly better among flibanserin- than placebo-treated women at weeks 4, 6, and 8 (P<0.05). Sexual function adverse events across flibanserin groups were generally comparable to placebo. CONCLUSIONS: Although these studies were not designed or powered to compare sexual function outcomes, results suggested a potential benefit of flibanserin on sexual function, particularly on female sexual desire, and provided a rationale to evaluate the efficacy of flibanserin as a treatment for female hypoactive sexual desire disorder.

Is flibanserin effetive for Hypoactive Sexual Desire Disorder?

56bb6b0eac7ad1001900000e_004

yes

Lipoplex mediated silencing of membrane regulators (CD46, CD55 and CD59) enhances complement-dependent anti-tumor activity of trastuzumab and pertuzumab. The therapeutic potential of anticancer antibodies is limited by the resistance of tumor cells to complement-mediated attack, primarily through the over-expression of membrane complement regulatory proteins (mCRPs: CD46, CD55 and CD59). Trastuzumab, an anti- HER2 monoclonal antibody, approved for the treatment of HER2-positive breast and gastric cancers, exerts only minor complement-mediated cytotoxicity (CDC). Pertuzumab is a novel anti-HER2 monoclonal antibody, which blocks HER2 dimerization with other ligand-activated HER family members. Here, we explored the complement-mediated anti-tumor effects of trastuzumab and pertuzumab on HER2-positive tumor cells of various histological origins. Delivery of chemically stabilized anti-mCRP siRNAs using cationic lipoplexes, AtuPLEXes, to HER2-over-expressing BT474, SK-BR-3 (breast), SKOV3 (ovarian) and Calu-3 (lung) cancer cells reduced mCRPs expression by 85-95%. Knockdown of individual complement regulators variably led to increased CDC only upon combined treatment with trastuzumab and pertuzumab. The combined down-regulation of all the three regulators augmented CDC by 48% in BT474, 46% in SK-BR-3 cells, 78% in SKOV3 cells and by 30% in Calu-3 cells and also increased complement-induced apoptosis and caspase activity on mCRP neutralized tumor cells. In addition, antibody-induced C3 opsonization of tumor cells was significantly enhanced after mCRP silencing and further augmented tumor cell killing by macrophages. Our findings suggest that siRNA-induced inhibition of complement regulator expression clearly enhances complement- and macrophage-mediated anti-tumor activity of trastuzumab and pertuzumab on HER2-positive tumor cells. Thus - if selectively targeted to the tumor - siRNA-induced inhibition of complement regulation may serve as an innovative strategy to potentiate the efficacy of antibody-based immunotherapy.

Is HER2 active only when it dimerizes?

5509ec41c2af5d5b70000006_005

yes

Atrial natriuretic peptide as a marker for doxorubicin-induced cardiotoxic effects. Doxorubicin is an effective antineoplastic agent, but it frequently causes dose-related cardiotoxic effects. Because the atrial natriuretic peptide (ANP) level is elevated in children with heart defects, the authors measured the ANP levels in children to determine whether ANP might serve as a simple diagnostic indicator of cardiotoxic effects. Sixteen patients, 5 to 19 years of age, who were being treated with doxorubicin (45 mg/m2 body surface area) for various malignancies had ANP levels measured in plasma. There was a group of six children, with a significant peak of plasma ANP (pANP) levels 3 weeks after the administration of the drug. Of these six patients, five had received high cumulative doses of doxorubicin (160 to 370 mg/m2), and two of them went into congestive heart failure without a previous decline in left ventricular ejection fraction, a standard technique for monitoring cardiac function during treatment with doxorubicin. The other ten patients had normal ANP levels throughout the study, and signs of cardiac dysfunction did not develop. None of the patients in the control group who had cancer and were not treated with doxorubicin and none of the healthy volunteers had elevated ANP levels. These preliminary results suggest that pANP may be useful as an early and sensitive indicator for doxorubicin-related myocardial damage.

Is Doxorubicin cardiotoxic?

58cdb80302b8c60953000043_019

yes

DNA-methylation effect on cotranscriptional splicing is dependent on GC architecture of the exon-intron structure. DNA methylation is known to regulate transcription and was recently found to be involved in exon recognition via cotranscriptional splicing. We recently observed that exon-intron architectures can be grouped into two classes: one with higher GC content in exons compared to the flanking introns, and the other with similar GC content in exons and introns. The first group has higher nucleosome occupancy on exons than introns, whereas the second group exhibits weak nucleosome marking of exons, suggesting another type of epigenetic marker distinguishes exons from introns when GC content is similar. We find different and specific patterns of DNA methylation in each of the GC architectures; yet in both groups, DNA methylation clearly marks the exons. Exons of the leveled GC architecture exhibit a significantly stronger DNA methylation signal in relation to their flanking introns compared to exons of the differential GC architecture. This is accentuated by a reduction of the DNA methylation level in the intronic sequences in proximity to the splice sites and shows that different epigenetic modifications mark the location of exons already at the DNA level. Also, lower levels of methylated CpGs on alternative exons can successfully distinguish alternative exons from constitutive ones. Three positions at the splice sites show high CpG abundance and accompany elevated nucleosome occupancy in a leveled GC architecture. Overall, these results suggest that DNA methylation affects exon recognition and is influenced by the GC architecture of the exon and flanking introns.

Is DNA methylation correlated with nucleosome occupancy?

5a43a214966455904c000009_004

yes

Loss of productivity due to depression among Korean employees. OBJECTIVES: The aim of this study was to investigate the difference in productivity between those who are depressed and those who are not. METHODS: A cross-sectional study of depressive and non-depressive employees at a workplace was performed. Data was collected between April and June 2008 through self-reported questionnaires including the Stanford Presenteeism Scale. One thousand employees participated in this study. Inappropriate responses including missing data or non-relevant responses were excluded. Finally, data of 612 subjects was analyzed using the SPSS program. RESULTS: The productivity of employees with depression was lower than that of employees without depression. The difference in productivity loss due to impaired presenteeism was significantly different between the two groups, but the productivity loss due to absenteeism was not. CONCLUSIONS: From the results of this study, we can deduce that depression among employees leads to productivity loss. Therefore, we must consider the management of depression in the workplace and improve the activities of occupational nurses and doctors during the mental health screening of employees.

Is there an association between presenteeism and depression?

54f49e56d0d681a040000004_003

yes

Nifedipine, an L-type calcium channel blocker, restores the hypnotic response in rats made tolerant to the alpha-2 adrenergic agonist dexmedetomidine. Rats were made tolerant to the hypnotic effects of the alpha-2 adrenergic agonist dexmedetomidine by a 7- or 14-day continuous systemic administration of the same, and the ability of nifedipine to reverse dexmedetomidine tolerance was assessed. Acute administration of nifedipine (10 mg/kg i.p.) restored the hypnotic response to dexmedetomidine in the alpha-2 tolerant rats. Concurrent administration of nifedipine during induction of tolerance, either partially (continuous administration 10 mg/kg/day delivered by minipumps) or completely (twice daily injections, 20 mg/kg s.c.) restored hypnotic responsiveness to control levels. Induction of tolerance reduced the affinity of [3H]PN200-110 for the L-type calcium channel. Chronically administered nifedipine treatment (20 mg/kg s.c. twice daily), at doses that partially restored the behavioral response to normal, did not change ligand binding affinity of [3H]PN200-110. An increase in Bmax for [3H]PN200-110 was noted in the dexmedetomidine tolerant state which did not change with chronic nifedipine. In naive rats, the phosphodiesterase inhibitor rolipram (275 microg/kg i.p.), mimicked the state of tolerance, as it resulted in a decreased hypnotic response to dexmedetomidine. Nifedipine (10 mg/kg i.p.) also reversed the rolipram-induced attenuation of the hypnotic response to dexmedetomidine. These data implicate a role for the L-type calcium channel in the mechanism of the hypnotic response in alpha-2 tolerant rats and suggest the involvement of the cAMP pathway.

Does nifedipine inhibit L-type calcium channels?

56c313d150c68dd416000002_009

yes

[The Supernatant Obtained from Cultured Anip973 Cells Enhances the Biological Activities of HUVEC]. BACKGROUND AND OBJECTIVE: Unlike normal tissue-derived microvascular endothelial cells, tumor microvessel endothelial cells are highly reactive to growth factors and exhibit more adhesion molecules. Thus, vascular tumors are highly permeable and grow vigorously; this occurrence results in rapid growth and metastasis cancer cells. Therefore, understanding the characteristics of endothelial cells in the tumor microenvironment guides anti-angiogenic therapy. To this end, we explore the effect of the supernatant obtained from cultured Anip973 cells (high-metastatic human lung adenocarcinoma cells) on the biological behavior and on the cell surface markers of the human umbilical vein endothelial cell (HUVEC). METHODS: The HUVEC that was cultured in a medium (RPMI-1640 + 10% fetal bovine serum) containing various concentrations of Anip973 supernatants was categorized into experimental groups. The HUVEC cultured in a medium without Anip973 supernatants served as the control group. Proliferation was determined with CCK-8; blood vessel formation was investigated with three-dimensional culture techniques in vitro; and HUVEC migration was observed via transwell assay. At the same time, the expressions of CD105, CD31, and the apoptotic marker of Annexin V were detected through flow cytometry for analyzing the relationship between the expression of cell surface markers and biological behavior. RESULTS: Following incubation with the supernatant obtained from cultured Anip973 cells, HUVEC proliferated more than the control group did, and the proliferation rate was maximized when incubated in a supernatant concentration of 250 μL/mL for 24 h (P=0.002). In addition, the experimental groups exhibited varying degrees of migration and forms of vascular lumen sample structure, especially at supernatant concentrations of 125 µL/mL (P<0.001) and 250 µL/mL (P=0.002), respectively. CD105 expression was optimized at 250 μL/mL (P=0.028), and CD31 expression also increased with an increase in concentration. However, the percentage of apoptotic cells decreased. Correlation analysis results showed that cell proliferation, migration, and CD105 expression were significantly and positively correlated with one another. By contrast, no significant correlation was detected between CD31 expression and biological behavior. CONCLUSIONS: Anip973 supernatants can promote HUVEC proliferation and migration, as well as angiogenesis. In addition, cell surface markers can change concurrently and relatively. To a certain extent, changes in CD105 expression can be attributed to shifts in its biological behavior.
.

Is Annexin V an apoptotic marker?

5894597e7d9090f353000004_008

yes

Nystagmus: an uncommon neurological manifestation of thiamine deficiency as a serious complication of sleeve gastrectomy. Wernicke encephalopathy--a debilitating acute or subacute neurological disorder-is caused by a deficiency in thiamine (vitamin B(1)). It is characterized by a classical clinical triad of symptoms: ocular impairment, cerebellar dysfunction, and confusion. Although bariatric surgery can certainly improve the overall health of an obese individual, it can also make him or her more susceptible to serious nutrition deficiencies. Following surgery, inadequate caloric intake, rapid and excessive weight loss, food intolerance, lack of adherence to nutrition supplementation, and/or the onset of prolonged vomiting can lead to severe nutrition deficiencies. It is generally believed that the more malabsorptive the surgery proves, the more likely is it that such a deficiency will occur. The case presented here shows that after sleeve gastrectomy (SG), a patient may also develop dangerous nutrition deficits that can negatively affect his or her life. In this particular case, a patient presented with a severe vitamin B(1) deficiency following SG for morbid obesity. Although patients may exhibit pathophysiologies similar to Wernicke encephalopathy after this surgery, only 2 cases of severe vitamin B(1) deficiency following sleeve gastrectomy have been reported. The grave consequences of thiamine deficiency observed in this patient underscore the importance of supplementation after SG.

Can vitamin B1 deficiency cause encephalopathy?

572211540fd6f91b68000016_011

yes

Characterizing ligands for farnesoid X receptor--available in vitro test systems for farnesoid X receptor modulator development. INTRODUCTION: Farnesoid X receptor (FXR) is an ascending target for metabolic and inflammatory diseases. As a nuclear receptor, FXR exhibits many physiological effects in transcription control of several genes. Therefore, the development of synthetic FXR ligands requires elaborate in vitro test systems to characterize novel ligands and to estimate their in vivo activities. AREAS COVERED: This work gathers and describes published in vitro test systems for FXR ligands including cell-based functional assays as well as binding assays. It also evaluates the information which can be provided by these assays. EXPERT OPINION: In vitro screening of FXR ligands widely relies on reporter gene assays. Additionally, some co-activator re-cruitment assays are described and for the characterization of potent compounds the pattern of affected target genes is evaluated by qPCR. Compared to other nuclear receptors such as PPARs the variety of test systems is quite low for FXR and might eventually not be enough to sufficiently characterize FXR targeting drug candidates.

Is farnesoid X receptor (FXR) a nuclear receptor?

55263a1898daae017c000001_006

yes

Tele-pain management: use of videoconferencing technology in the delivery of an integrated cognitive-behavioral and physical therapy group intervention. Chronic pain has been recognized as a highly prevalent problem, and interdisciplinary treatments have been shown to be effective in the treatment of chronic pain. An integrated cognitive-behavioral and physical therapy group protocol has been developed and then implemented at remote sites using videoconferencing technology to provide pain management for veterans. The treatment model is summarized and recommendations are made for addressing challenges in implementing this type of treatment via videoconferencing.

Are there telemedicine applications for chronic pain management?

54ff106b6ad7dcbc1200000c_004

yes

The direct factor Xa inhibitor rivaroxaban. Warfarin and heparin are the traditional mainstay anticoagulant therapies for treating thromboembolic disease. These drugs, with a documented history of utility, also have inherent difficulties in usage; in particular, the complicated monitoring and numerous drug-drug interactions of warfarin, and the need for parenteral administration of heparins. New agents have recently emerged that target specific elements of the clotting pathway. Rivaroxaban, which inhibits activated factor X (Xa), is currently in clinical trials and is the most advanced factor Xa inhibitor. The drug offers once-daily oral dosing, with no need for injections, dose titration, or frequent blood tests to monitor the international normalised ratio. It has a rapid onset of action and, although there is no specific antidote, it has a short plasma elimination half-life (about 5-9 hours). Evidence from recently published large-scale phase III clinical trials shows rivaroxaban to be superior to enoxaparin for prophylaxis of venous thromboembolism after major orthopaedic surgery. Studies have shown rivaroxaban to have a sound safety profile, with an incidence of bleeding similar to enoxaparin in phase III clinical trials. Few side effects and drug-drug interactions between rivaroxaban and common medications have been found thus far, although some interactions with potent cytochrome P450 3A4 inhibitors have been observed. It is hoped that rivaroxaban may be used as a first-line anticoagulant for prophylaxis of venous thromboembolic disease in postsurgical patients.

Are there any specific antidotes for rivaroxaban?

532f08b8d6d3ac6a34000029_009

no

Tumor suppression and circadian function. Circadian clock and cell division cycle are two fundamental biological processes. The circadian clock is the body's molecular time-keeping system, while the cell division cycle regulates development and cellular renewal. The expression of cell cycle genes such as Wee1, Cyclins, and c-Myc are under circadian control and could be directly under the regulation of the circadian transcriptional complex. This complex is composed of heterodimer transactivators CLOCK/NPAS2 with BMAL1, which regulate the transcription of PER1, PER2, CRY1, and CRY2. In turn, the repressors CRY1 and CRY2 turn off the gene expressions of Per1/Per2, Cry1/Cry2 in a periodic manner by acting on the transcriptional complex. Two of these circadian rhythm regulators, PER1 and PER2, have now been linked to DNA damage response pathways in a series of papers that examined gene dosage. Overexpression of either Per1 or Per2 in cancer cells inhibits their neoplastic growth and increases their apoptotic rate. In vivo studies showed that mice deficient in mPer2 showed significant higher incidences of tumor development after genotoxic stress. Loss and dysregulation of Per1 and Per2 gene expression have been found in many types of human cancers. Recent studies demonstrate that both PER1 and PER2 are involved in ATM-Chk1/Chk2 DNA damage response pathways and implicate normal circadian function as a factor in tumor suppression.

Is c-myc subject to regulation by the circadian clock?

531616bdb166e2b806000003_009

yes

Effect of AZD1480 in an epidermal growth factor receptor-driven lung cancer model. OBJECTIVE: STAT3 plays a vital role in inducing and maintaining a pro-carcinogenic inflammatory microenvironment and is reported to be a critical mediator of the oncogenic effects of EGFR mutations. STAT3 activation is mediated through JAK family kinases. We investigated the effect of the JAK1/2 inhibitor AZD1480 on lung tumors induced by an activating EGFR mutation. MATERIALS AND METHODS: Three EGFR tyrosine kinase inhibitor-resistant cell lines (RPC-9, PC-9/Van-R and PC-9/ER3) established from PC-9 harboring an EGFR exon19 deletion mutation were used. Growth inhibition was measured using an MTT assay. Effects of AZD1480 were also evaluated in the xenograft model and in the EGFR transgenic mice model. Protein expressions were assessed by immunoblotting and immunohistochemistry. Group differences were compared using Student's t-test. To evaluate the efficacy of AZD1480 on survival, AZD1480 or vehicle was administered orally from 7 weeks of age of the transgenic mice. Overall survival curves were calculated using the Kaplan-Meier method. RESULTS: The sensitivities of resistant and parent cells to AZD1480 were similar in vitro. AZD1480 (30 or 50 mg/kg/day, per os) reduced angiogenesis and revealed significant tumor regression in a mouse xenograft model. Subsequently, the transgenic mice were treated with AZD1480 (30 mg/kg/day) or vehicle alone. The numbers of lung tumors (long axis exceeding 1mm) in the AZD1480-treated group and control group were 0.37±0.18 and 2.25±0.53 (p<0.001), respectively. AZD1480 treatment suppressed pSTAT3, pJAK1, pJAK2 and angiogenesis. The median survival time in the AZD1480-treated group (217 days) was significantly greater than that in the control group (106 days) (log-rank test, p<0.0001). CONCLUSION: AZD1480 may be effective against lung tumors driven by an activating EGFR mutation.

Is signal transducer and activator of transcription-3 (STAT3) critical for tumor angiogenesis progression?

533d0f44c45e13371400000e_006

yes

Current perspective new insights into the molecular basis of familial dilated cardiomyopathy. Genetic disease transmission has been identified in a significant proportion of patients with dilated cardiomyopathy (DCM). Variable clinical characteristics and patterns of inheritance, as well as recent molecular genetic data, indicate the existence of several genes causing the disease. Several distinct subtypes of familial DCM have been identified. Autosomal dominant DCM is the most frequent form (56% of our cases), and several candidate disease loci have been identified by linkage analysis. Three disease genes are presently known: the cardiac actin gene, the desmin gene, and the lamin A/C gene. This latter gene has recently been found to be responsible for both the autosomal dominant form of DCM with subclinical skeletal muscle disease (7.7% of cases) and the familial form with conduction defects (2.6% of cases) or the autosomal dominant variant of Emery-Dreifuss muscular dystrophy. The autosomal recessive form of DCM accounts for 16% of cases and is characterized by a worse prognosis. An X-linked form of DCM (10% of cases) manifests in the adult population and is due to mutations in the dystrophin gene. In the rare infantile form of DCM, mutations in the G4.5 gene have been identified. Finally, some of the rare unclassifiable forms (7.7% of cases) may be due to mitochondrial DNA mutations. Clinical and experimental evidence based on animal models suggest that, in a large number of cases, DCMs are diseases of the cytoskeleton. However, other causes, such as alterations in regulatory elements and in signaling molecules, are possible. Moreover, other genes called modifier genes can influence the severity, penetrance, and expression of the disease, and they will be a main objective of future investigations. Familial DCM is frequent, cannot be predicted on a clinical or morphological basis and requires family screening for identification. The advances in the genetics of familial DCM can allow improved diagnosis, prevention and genetic counseling, and represent the basis for the development of new therapies.

Is desmin an intermediate filament protein involved in Dilated Cardiomyopathy (DCM)?

55031963e9bde6963400002a_001

yes

Optimizing the purification and analysis of miRNAs from urinary exosomes. BACKGROUND: Exosomes are cytoplasm containing vesicles released by many cells that can be found in several biological fluids including urine. Urinary exosomes are released from every segment of the nephron, are detectable in urine, constitutively contain RNA (small RNAs and mRNAs) and harbor unique subset of proteins, reflecting their cellular source. METHODS: With the aim of establishing the optimal protocol for high throughput analysis of exosomal miRNAs, we compared three different urinary exosomes isolation methods and six RNA extraction techniques. Exosomal RNA yield, size and quality were assessed respectively by specific staining with fluorescent dye, capillary electrophoresis and analysis of spectrophotometric parameters. MiRNAs detection and abundance was determined by RT-qPCR. RESULTS: Among the exosomes isolation methods, Ultrafiltration resulted to be the most suited. The highest exosomal RNA yield quantified by RiboGreen® staining was obtained with the combination of TRI Reagent™ with miRNeasy®, followed by TRI Reagent™, SeraMir™, miRCURY™, mirVana™ and miRNeasy®; but after a multivariate analysis, SeraMir™ scored as the method of choice in terms of miRNA yield, purity and RT-qPCR miRNAs quantification accuracy. Storage conditions were also analyzed, showing that the relative abundance of urinary exosomal miRNAs is not influenced by urine freezing. CONCLUSIONS: The selection of appropriate urinary exosomal miRNA isolation method was dependent on various validation results. Ultrafiltration in combination with SeraMir™ exoRNA columns represents the optimal procedure for a rapid, cost-effective and efficient purification of miRNAs from urinary exosomes, perfectly suited for further applicative research in the field of miRNAs in kidney physiology and pathology.

Can exosomes be detected in urine?

550895c12e93f0133a000002_002

yes

Six-month paroxetine treatment of premenstrual dysphoric disorder: continuous versus intermittent treatment protocols. AIMS: Several trials have proved the efficacy of selective serotonin re-uptake inhibitors (SSRI) in the treatment of premenstrual dysphoric disorder (PMDD) in Western society. The SSRI can be administered continuously throughout the entire cycle or intermittently from ovulation to the onset of menstruation (luteal phase). The purpose of the present study was to compare continuous and intermittent paroxetine treatment in oriental PMDD women during 6 months follow up. METHODS: Thirty-six subjects were evaluated and drug free for two menstrual cycles, and they received daily paroxetine (20 mg) for two further full cycles. They were then randomly divided into continuous or intermittent treatment groups (n = 16, 14) over the next four cycles. Responses were assessed every 2 weeks. Outcome measures included scores on the Prospective Record of the Impact and Severity of Menstrual Symptomatology (PRISM) calendar, Hamilton Rating Scale for Depression/Anxiety (HAMD/HAMA), and the Clinical Global Impression scale (CGI). RESULTS: All these women had significant improvements in the HAMA, HAMD, CGI, and PRISM calendar. The rate of response to paroxetine treatment lay between 50% and 78.6% in the continuous-treatment group, and 37.5-93.8% in the intermittent-treatment group, as determined at the study end-point. Limitations of the present study included the open-label design and the incorporation of a limited sample size. CONCLUSIONS: The present results indicate that paroxetine is effective in both continuous and intermittent treatment of oriental PMDD women, and that the effects of active treatment lasted for six consecutive treatment menstrual cycles.

Is paroxetine effective for treatment of premenstrual dysphoric disorder?

514a59c2d24251bc0500005d_006

yes

The molecular autopsy: an indispensable step following sudden cardiac death in the young? Annually thousands of sudden deaths involving young individuals (<35 years of age) remain unexplained following a complete medicolegal investigation that includes an autopsy. In fact, epidemiological studies have estimated that over half of sudden deaths involving previously healthy young individuals have no morphological abnormalities identifiable at autopsy. Cardiac channelopathies associated with structurally normal hearts such as long QT syndrome (LQTS), catecholaminergic polymorphic ventricular tachycardia (CPVT), and Brugada syndrome (BrS), leave no evidence to be found at autopsy, leaving investigators to only speculate that a lethal arrhythmia might lie at the heart of a sudden unexplained death (SUD). In cases of autopsy-negative SUD, continued investigation, through the use of a cardiological and genetic evaluation of first- or second-degree relatives and/or a molecular autopsy, may pinpoint the underlying mechanism attributing to the sudden death and allow for the identification of living family members with the pathogenic substrate that renders them vulnerable to an increased risk for cardiac events, including sudden death.

Could Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) cause sudden cardiac death?

52e8e96698d023950500001f_026

yes

Proteomics applied to the study of platelet-related diseases: aiding the discovery of novel platelet biomarkers and drug targets. Platelets play a fundamental role in hemostasis. Because they do not have a nucleus, proteomics is an ideal way to approach their biochemistry. Platelet proteomics is still a young field that emerged a decade ago. Initial platelet proteomic research focused on general proteome mapping followed by the exploration of sub-cellular compartments, the membrane proteome, and signaling pathways. The initial studies were later completed with the analysis of the platelet releasate and microparticle proteome. The success of these studies led to the application of platelet proteomics to the study of several pathologies where platelets play a fundamental role. Those include platelet-related disorders, such as storage pool disease, gray platelet syndrome, and Quebec platelet disorder; diseases where unwanted platelet activation is highly relevant, such as thrombosis and cardiovascular disease; and other diseases, such as cystic fibrosis, uremia, or Alzheimer's disease. In the present review article, we revise the most relevant proteomic studies on platelet-related diseases carried out to date, paying special attention to sample preparation requirements for platelet clinical proteomic studies. This article is part of a Special Issue entitled: Integrated omics.

Can we use platelet biomarkers to study Alzheimer's disease?

530b4f49970c65fa6b00000a_002

yes

Natural variation for alleles under epigenetic control by the maize chromomethylase zmet2. The contribution of epigenetic alterations to natural variation for gene transcription levels remains unclear. In this study, we investigated the functional targets of the maize chromomethylase ZMET2 in multiple inbred lines to determine whether epigenetic changes conditioned by this chromomethylase are conserved or variable within the species. Gene expression microarrays were hybridized with RNA samples from the inbred lines B73 and Mo17 and from near-isogenic derivatives containing the loss-of-function allele zmet2-m1. A set of 126 genes that displayed statistically significant differential expression in zmet2 mutants relative to wild-type plants in at least one of the two genetic backgrounds was identified. Analysis of the transcript levels in both wild-type and mutant individuals revealed that only 10% of these genes were affected in zmet2 mutants in both B73 and Mo17 genetic backgrounds. Over 80% of the genes with expression patterns affected by zmet2 mutations display variation for gene expression between wild-type B73 and Mo17 plants. Further analysis was performed for 7 genes that were transcriptionally silent in wild-type B73, but expressed in B73 zmet2-m1, wild-type Mo17, and Mo17 zmet2-m1 lines. Mapping experiments confirmed that the expression differences in wild-type B73 relative to Mo17 inbreds for these genes were caused by cis-acting regulatory variation. Methylation-sensitive PCR and bisulfite sequencing demonstrated that for 5 of these genes the CpNpG methylation in the wild-type B73 genetic background was substantially decreased in the B73 zmet2-m1 mutant and in wild-type Mo17. A survey of eight maize inbreds reveals that each of these 5 genes exhibit transcriptionally silent and methylated states in some inbred lines and unmethylated, expressed states in other inbreds, providing evidence for natural variation in epigenetic states for some maize genes.

Are chromomethylases present in animal genomes?

5171833c8ed59a060a00000f_004

no

Indistinguishable patterns of protooncogene expression in two distinct but closely related tumors: Ewing's sarcoma and neuroepithelioma. Genetic characterization of human tumors promises new insights of biological importance and clinical relevance. We have found that two solid tumors, peripheral neuroepithelioma and Ewing's sarcoma of bone, which share a common cytogenetic rearrangement, are characterized by an indistinguishable and highly reproducible pattern of protooncogene expression. c-myc, N-myc, c-myb, and c-mil/raf-1 are all expressed at similar levels in these tumors. c-fes and c-sis expression was not detected in any specimens of either tumor. In contrast, the protooncogene c-ets-1, located near the breakpoint of the chromosomal translocation in these tumors, is variable in its expression. We also detected high levels of choline acetyltransferase in these tumors, which suggests a common neural origin. Since it is likely that the clinical behavior and therapeutic responsiveness of tumors relate closely to their biological and genetic features, the pattern of protooncogene expression of individual tumors may provide a novel basis for their characterization.

Is peripheral neuroepithelioma related to Ewing sarcoma?

552fa6f5bc4f83e828000002_008

yes

Maternal and paternal thrombophilia: risk factors for perinatal mortality. BACKGROUND: Although some paternal components to the predisposition to pre-eclampsia have been demonstrated recently, it is not known whether such paternal factors play a role to thrombophilia-related perinatal mortality. OBJECTIVE: To compare the paternal and maternal contribution to perinatal mortality. STUDY DESIGN: Data from a prospective registry of perinatal mortality in a Dutch healthcare region were used. Between December 1999 and May 2000, the prevalence of thrombophilia was studied in 74 women with a history of perinatal mortality (female cases) and 54 of their male partners (male cases). Seventy-one healthy unrelated women after uneventful pregnancies only and 66 of their male partners were used as controls. SETTING: Obstetric outpatient clinic in a regional hospital (Remierde Graaf Group, Deflt). METHODS: Presence of various coagulation abnormalities, hyperhomocysteinaemia and anticardiolipins was investigated. RESULTS: The frequency of antithrombin deficiency (12% vs 0%), increased activated protein C (APC) resistance (32% vs 6%), total protein S deficiency (11% vs 1%) and elevated factor VIII:C activity (43% vs 17%) was significantly higher in female cases compared with controls. In male cases, the frequency of increased APC resistance was significantly higher compared with controls (22% vs 0%). In 30 of the 54 couples with a history of perinatal mortality, more than one thrombophilic abnormality was found (55%) compared with 10 of the 62 control couples (17%). CONCLUSION: The risk of having thrombophilia is doubled in men who have fathered pregnancies which ended in perinatal death as well as in the mothers of such pregnancies.

Is thrombophilia related to increased risk of miscarriage?

513cdc38bee46bd34c000007_001

yes