Datasets:

reginaboateng

/

Bioasq7b

like 1

Association between sleep bruxism and gastroesophageal reflux disease. STATEMENT OF PROBLEM: Rhythmic masticatory muscle activity, including sleep bruxism (SB), can be induced in healthy individuals by experimental esophageal acidification, which plays an important role in the pathogenesis of gastroesophageal reflux disease (GERD). However, no robust evidence supports the association between SB and GERD. PURPOSE: The purpose of this study was to investigate the association between SB and GERD. MATERIAL AND METHODS: Forty-five individuals were eligible to participate in this observational transversal study at the Gastroenterology Service of the Clinical Hospital of Porto Alegre, Brazil. The participants were classified into 2 groups, those with and without GERD, according to the Montreal Criteria and pH-metry/endoscopy findings. The diagnosis of SB was not assessed in a sleep laboratory but was based on self-report plus clinical inspection, according to the minimal diagnostic criteria of the American Academy of Sleep Medicine. The Lipp Stress Symptom Inventory was used to evaluate self-perceived stress. Univariate and multiple logistic regression analyses were performed with SB as dependent variable and GERD, sex, age, body mass index, and stress as predictors (α=.05; 90% power). RESULTS: The study population included individuals with SB without GERD (13.3%) and individuals with SB with GERD (31.1%). In participants with GERD, the prevalence of SB was 73.7%. Only the variable GERD was significantly associated with SB (P=.017; odds ratio 6.58; 95% confidence interval 1.40-30.98), although adjusted for stress and age. CONCLUSIONS: Sleep bruxism is prevalent in GERD patients, and GERD is highly associated with SB.

Is there an association between bruxism and reflux?

530cefaaad0bf1360c00000f_003

yes

Magnesium sulfate in aneurysmal subarachnoid hemorrhage: a randomized controlled trial. BACKGROUND AND PURPOSE: Magnesium reverses cerebral vasospasm and reduces infarct volume after experimental subarachnoid hemorrhage (SAH) in rats. We aimed to assess whether magnesium reduces the frequency of delayed cerebral ischemia (DCI) in patients with aneurysmal SAH. METHODS: Patients were randomized within 4 days after SAH. Magnesium sulfate therapy consisted of a continuous intravenous dose of 64 mmol/L per day, to be started within 4 days after SAH and continued until 14 days after occlusion of the aneurysm. The primary outcome DCI (defined as the occurrence of a new hypodense lesion on computed tomography compatible with clinical features of DCI) was analyzed according to the "on-treatment" principle. For the secondary outcome measures "poor outcome" (Rankin >3) and "excellent outcome" (Rankin 0), we used the "intention-to-treat" principle. RESULTS: A total of 283 patients were randomized. Magnesium treatment reduced the risk of DCI by 34% (hazard ratio, 0.66; 95% CI, 0.38 to 1.14). After 3 months, the risk reduction for poor outcome was 23% (risk ratio, 0.77; 95% CI, 0.54 to 1.09). At that time, 18 patients in the treatment group and 6 in the placebo group had an excellent outcome (risk ratio, 3.4; 95% CI, 1.3 to 8.9). CONCLUSIONS: This study suggests that magnesium reduces DCI and subsequent poor outcome, but the results are not yet definitive. A next step should be a phase III trial to confirm the beneficial effect of magnesium therapy, with poor outcome as primary outcome.

Does magnesium sulfate improve outcomes of subarachnoid hemorrhage patients?

54d62ede3706e89528000002_012

no

The incidence of thyroid stimulating blocking antibodies during the hypothyroid phase in patients with subacute thyroiditis. The etiology of subacute (de Quervain's) thyroiditis (SAT) is uncertain, although it probably represents a nonspecific inflammatory response by the thyroid to a variety of viruses. It has been suggested that nonimmune processes are involved in SAT patients who have negative autoantibody titers. The disease has a variable course; although it is self-limited in most cases, some patients develop transient hypothyroidism, and others do not during the recovery period. The present study was performed to evaluate the occurrence of TSH receptor antibody (TRAb), measured by RRA (TSH binding inhibitor), TRAb measured by stimulation assay (thyroid-stimulating antibody), and TRAb measured by blocking assay [TSH-blocking antibody (TSH-BAb)] activity in 68 patients with SAT who had negative autoantibody titers. The patients were divided into 2 groups: group I, 31 patients who developed hypothyroidism during the recovery period; and group II, 37 patients who remained euthyroid during recovery. Positive immunoglobulin activity occurred in about 20% of group I patients during follow-up, but in only 3% of group II patients. About 20% of group I patients developed positive TSH-BAb activity and were hypothyroid, requiring exogenous hormone therapy for 1.2-3.5 yr, whereas hypothyroidism was relatively transient in group I patients who had negative TSH-BAb activity (2-6 months). Although increased TSH-BAb activity may account for hypothyroidism in some patients with SAT, the precise mechanism for the development of transient hypothyroidism in SAT remains enigmatic.

Are viruses involved in the etiology of human subacute thyroiditis?

513711055274a5fb0700000e_001

yes

Rate and polarity of gene fusion and fission in Oryza sativa and Arabidopsis thaliana. Eukaryotic gene fusion and fission events are mechanistically more complicated than in prokaryotes, and their quantitative contributions to genome evolution are still poorly understood. We have identified all differentially composite or split genes in 2 fully sequenced plant genomes, Oryza sativa and Arabidopsis thaliana. Out of 10,172 orthologous gene pairs, 60 (0.6% of the total) revealed a verified fusion or fission event in either lineage after the divergence of O. sativa and A. thaliana. Polarizing these events by outgroup comparison revealed differences in the rate of gene fission but not of gene fusion in the rice and Arabidopsis lineages. Gene fission occurred at a higher rate than gene fusion in the O. sativa lineage and was furthermore more common in rice than in Arabidopsis. Nucleotide insertion bias has promoted gene fission in the O. sativa lineage, consistent with its generally longer nucleotide sequences than A. thaliana in selectively neutral regions, and with the abundance of transposable elements in rice. The divergence time of monocots and dicots (140-200 Myr) indicates that gene fusion/fission events occur at an average rate of 1x10(-11) to 2x10(-11) events per gene per year, approximately 100-fold slower than the average per site nuclear nucleotide substitution rate in these lineages. Gene fusion and fission are thus rare and slow processes in higher plant genomes; they should be of utility to address deeper evolutionary relationships among plants--and the relationship of plants to other eukaryotic lineages--where sequence-based phylogenies provide equivocal or conflicting results.

Is there a difference in the rate between gene fusion and gene fission?

5149b575d24251bc05000047_004

yes

[Cannabis and cerebrovascular disease]. INTRODUCTION: Drug use is a well-kown risk factor for cerebrovascular disease in young people. Cannabis is the most widely consumed among the illicit drugs worldwide, but it has only exceptionally been associated to cerebrovascular disease. CLINICAL CASE: We here describe 2 young patients (26 and 29 years, respectively) who suffered from ischemic stroke in temporal relation with cannabis consumption. CONCLUSIONS: The review of the literature on this topic reveals another 18 patients with stroke in association to cannabis use. They all were young people with ischemic stroke. Although a causal relationship is difficult to establish due to the widespread use of cannabis, this drug may play an etiologic role in ischemic stroke.

Is marijuana use associated with increased risk for stroke?

5149e23dd24251bc0500004b_011

yes

Characterization of early autophagy signaling by quantitative phosphoproteomics. Under conditions of nutrient shortage autophagy is the primary cellular mechanism ensuring availability of substrates for continuous biosynthesis. Subjecting cells to starvation or rapamycin efficiently induces autophagy by inhibiting the MTOR signaling pathway triggering increased autophagic flux. To elucidate the regulation of early signaling events upon autophagy induction, we applied quantitative phosphoproteomics characterizing the temporal phosphorylation dynamics after starvation and rapamycin treatment. We obtained a comprehensive atlas of phosphorylation kinetics within the first 30 min upon induction of autophagy with both treatments affecting widely different cellular processes. The identification of dynamic phosphorylation already after 2 min demonstrates that the earliest events in autophagy signaling occur rapidly after induction. The data was subjected to extensive bioinformatics analysis revealing regulated phosphorylation sites on proteins involved in a wide range of cellular processes and an impact of the treatments on the kinome. To approach the potential function of the identified phosphorylation sites we performed a screen for MAP1LC3-interacting proteins and identified a group of binding partners exhibiting dynamic phosphorylation patterns. The data presented here provide a valuable resource on phosphorylation events underlying early autophagy induction.

Does the protein mTOR regulate autophagy?

5505ad7ff73303d458000007_003

yes

Inhibition of Plasmepsin V activity demonstrates its essential role in protein export, PfEMP1 display, and survival of malaria parasites. The malaria parasite Plasmodium falciparum exports several hundred proteins into the infected erythrocyte that are involved in cellular remodeling and severe virulence. The export mechanism involves the Plasmodium export element (PEXEL), which is a cleavage site for the parasite protease, Plasmepsin V (PMV). The PMV gene is refractory to deletion, suggesting it is essential, but definitive proof is lacking. Here, we generated a PEXEL-mimetic inhibitor that potently blocks the activity of PMV isolated from P. falciparum and Plasmodium vivax. Assessment of PMV activity in P. falciparum revealed PEXEL cleavage occurs cotranslationaly, similar to signal peptidase. Treatment of P. falciparum-infected erythrocytes with the inhibitor caused dose-dependent inhibition of PEXEL processing as well as protein export, including impaired display of the major virulence adhesin, PfEMP1, on the erythrocyte surface, and cytoadherence. The inhibitor killed parasites at the trophozoite stage and knockdown of PMV enhanced sensitivity to the inhibitor, while overexpression of PMV increased resistance. This provides the first direct evidence that PMV activity is essential for protein export in Plasmodium spp. and for parasite survival in human erythrocytes and validates PMV as an antimalarial drug target.

Could plasmepsins be used as targets for developing anti-malaria drugs?

58a6d89660087bc10a00002b_011

yes

Changes in gut hormone levels and negative energy balance during aerobic exercise in obese young males. We examined whether changes in gut hormone levels due to a single bout of aerobic exercise differ between obese young males and normal controls, and attempted to determine the involvement of hormonal changes during exercise in the regulation of energy balance (EB) in these obese subjects. Seven obese and seven age-matched subjects of normal weight participated in exercise and rest sessions. Subjects consumed a standardized breakfast that was followed by constant cycling exercise at 50% VO(2max) or rest for 60 min. At lunch, a test meal was presented, and energy intake (EI) and relative energy intake (REI) were calculated. Blood samples were obtained at 30 min intervals during both sessions for measurement of glucose, insulin, glucagon, ghrelin, peptide YY (PYY), and glucagon-like peptide-1 (GLP-1). Plasma levels of PYY and GLP-1 were increased by exercise, whereas plasma ghrelin levels were unaffected by exercise. The areas under the curve (AUC) of the time courses of PYY and GLP-1 levels did not significantly differ between the two groups. In contrast, EI and REI were decreased by exercise in both groups, and energy deficit was significantly larger in obese subjects than in normal controls. The present findings suggest that short-term EB during a single exercise session might be regulated not by increased amounts of these gut hormones per se.

Does physical activity influence gut hormones?

5158644cd24251bc0500008e_001

yes

Palmitoylation-dependent activation of MC1R prevents melanomagenesis. The melanocortin-1 receptor (MC1R), a G-protein-coupled receptor, has a crucial role in human and mouse pigmentation. Activation of MC1R in melanocytes by α-melanocyte-stimulating hormone (α-MSH) stimulates cAMP signalling and melanin production and enhances DNA repair after ultraviolet irradiation. Individuals carrying MC1R variants, especially those associated with red hair colour, fair skin and poor tanning ability (denoted as RHC variants), are associated with higher risk of melanoma. However, how MC1R activity is modulated by ultraviolet irradiation, why individuals with red hair are more prone to developing melanoma, and whether the activity of RHC variants might be restored for therapeutic benefit are unknown. Here we demonstrate a potential MC1R-targeted intervention strategy in mice to rescue loss-of-function MC1R in MC1R RHC variants for therapeutic benefit by activating MC1R protein palmitoylation. MC1R palmitoylation, primarily mediated by the protein-acyl transferase ZDHHC13, is essential for activating MC1R signalling, which triggers increased pigmentation, ultraviolet-B-induced G1-like cell cycle arrest and control of senescence and melanomagenesis in vitro and in vivo. Using C57BL/6J-Mc1rJ mice, in which endogenous MC1R is prematurely terminated, expressing Mc1r RHC variants, we show that pharmacological activation of palmitoylation rescues the defects of Mc1r RHC variants and prevents melanomagenesis. The results highlight a central role for MC1R palmitoylation in pigmentation and protection against melanoma.

Does MC1R palmitoylation reduce pigmentation?

5a9ac4161d1251d03b000010_000

no

Physical mapping of genetic markers on the short arm of chromosome 5. The deletion of the short arm of chromosome 5 is associated with the cri-du-chat syndrome. In addition, loss of this portion of a chromosome is a common cytogenetic marker in a number of malignancies. However, to date, no genes associated with these disorders have been identified. Physical maps are the first step in isolating causative genes, and genes involved in autosomal recessive disorders are now routinely mapped through the identification of linked markers. Extensive genetic maps based upon polymorphic short tandem repeats (STRs) have provided researchers with a large number of markers to which such disorders can be genetically mapped. However, the physical locations of many of these STRs have not been determined. Toward the goal of integrating the human genetic maps with the physical maps, a 5p somatic cell hybrid deletion mapping panel that was derived from patients with 5p deletions or translocations was used to physically map 47 STRs that have been used to construct genetic maps of 5p. These data will be useful in the localization of disease genes that map to 5p and may be involved in the etiology of the cri-du-chat syndrome.

Is Cri Du Chat associated with an expansion of a repeat with in the gene found on chromosome 5?

58dbba438acda3452900001c_015

no

Bowel obstruction in patients with Alpers-Huttenlocher syndrome. Alpers-Huttenlocher syndrome (AHS) is a very rare autosomal recessive disorder. AHS is caused by homozygous or compound heterozygous mutations in the nuclear gene encoding mitochondrial DNA polymerase gamma (POLG, chromosome 15q25). Most patients become symptomatic before the age of 2 years. We report 3 patients who were treated in our clinic between 2007 and 2010. All patients suffered from myoclonic seizures and had at least one refractory convulsive status which led to the diagnosis. All of them had varying degrees of developmental delay, 2 of them additionally ataxia. Gastrointestinal motility problems were severe in all patients despite only mildly deranged liver function. While in most aspects our patients present with typical AHS features, they also share intestinal problems, a feature that has not been recognized as typical for AHS before. AHS is a multisystem disorder that does affect all cell systems. Liver and brain are organs with the highest energy demand and are therefore usually affected early in the disease course of AHS. However, constipation and bowel obstruction should be regarded as typical complications in AHS and patients should be monitored and treated to improve quality of life. Regarding treatment options for epilepsy in AHS ketogenic diet as well as lacosamide might be considered.

Is Alpers disease inherited in an autosomal recessive mode?

5718a69e7de986d80d00000a_006

yes

Pregnancy and H1N1 influenza: lessons to learn. Pregnancy, with or without additional complications, constitutes a high-risk condition for complications of influenza infection and warrants early intervention with neuraminidase inhibitors such as oseltamivir, if influenza is suspected. Treatment should not be delayed for laboratory confirmation. In South Africa, the high burden of HIV infection is a further complication.

Is pregnancy an additional risk during during H1N1 infection?

531a3fe3b166e2b806000038_019

yes

Glucose-6-phosphate dehydrogenase (G6PD) deficiency among tribal populations of India - Country scenario. It is believed that the tribal people, who constitute 8.6 per cent of the total population (2011 census of India), are the original inhabitants of India. Glucose-6-phosphate-dehydrogenase (G6PD) deficiency is an X-linked genetic defect, affecting around 400 million people worldwide and is characterized by considerable biochemical and molecular heterogeneity. Deficiency of this enzyme is highly polymorphic in those areas where malaria is/has been endemic. G6PD deficiency was reported from India more than 50 years ago. t0 he prevalence varies from 2.3 to 27.0 per cent with an overall prevalence of 7.7 per cent in different tribal groups. Since the tribal populations live in remote areas where malaria is/has been endemic, irrational use of antimalarial drugs could result in an increased number of cases with drug induced haemolysis. Therefore, before giving antimalarial therapy, routine screening for G6PD deficiency should be undertaken in those tribal communities where its prevalence is high.

Has Glucose-6-phosphate dehydrogenase (G6PD) deficiency an X-linked inheritance?

58a2da4260087bc10a000005_015

yes

Extending preimplantation genetic diagnosis: the ethical debate. Ethical issues in new uses of preimplantation genetic diagnosis. The use of preimplantation genetic diagnosis (PGD) to screen embryos for aneuploidy and genetic disease is growing. New uses of PGD have been reported in the past year for screening embryos for susceptibility to cancer, for late-onset diseases, for HLA-matching for existing children, and for gender. These extensions have raised questions about their ethical acceptability and the adequacy of regulatory structures to review new uses. This article describes current and likely future uses of PGD, and then analyses the ethical issues posed by new uses of PGD to screen embryos for susceptibility and late-onset conditions, for HLA-matching for tissue donation to an existing child, and for gender selection. It also addresses ethical issues that would arise in more speculative scenarios of selecting embryos for hearing ability or sexual orientation. The article concludes that except for sex selection of the first child, most current extensions of PGD are ethically acceptable, and provides a framework for evaluating future extensions for nonmedical purposes that are still speculative.

Can Preimplantation Genetic Diagnosis (PGD) be used for gender selection?

52b2ed144003448f55000004_000

yes

Is an estimated glomerular filtration rate better than creatinine to be incorporated into the end-stage liver disease score? AIM: To incorporate estimated glomerular filtration rate (eGFR) into the model for end-stage liver disease (MELD) score to evaluate the predictive value. METHODS: From January 2004 to October 2008, the records of 4127 admitted cirrhotic patients were reviewed. Patients who survived and were followed up as outpatients were defined as survivors and their most recent available laboratory data were collected. Patients whose records indicated death at any time during the hospital stay were defined as non-survivors (in-hospital mortality). Patients with incomplete data or with cirrhosis due to a congenital abnormality such as primary biliary cirrhosis were excluded; thus, a total of 3857 patients were enrolled in the present study. The eGFR, which was calculated by using either the modification of diet in renal disease (MDRD) equation or the chronic kidney disease epidemiology collaboration (CKD-EPI) equation, was incorporated into the MELD score after adjustment with the original MELD equation by logistic regression analysis [bilirubin and international normalized ratio (INR) were set at 1.0 for values less than 1.0]. RESULTS: Patients defined as survivors were significantly younger, had a lower incidence of hepatoma, lower Child-Pugh and MELD scores, and better renal function. The underlying causes of cirrhosis were very different from those in Western countries. In Taiwan, most cirrhotic patients were associated with the hepatitis virus, especially hepatitis B. There were 16 parameters included in univariate logistic regression analysis to predict in-hospital mortality and those with significant predicting values were included in further multivariate analysis. Both 4-variable MDRD eGFR and 6-variable MDRD eGFR, rather than creatinine, were significant predictors of in-hospital mortality. Three new equations were constructed (MELD-MDRD-4, MELD-MDRD-6, MELD-CKD-EPI). As expected, original MELD score was a significant predictor of in-hospital mortality (odds ratio = 1.25, P < 0.001). MELD-MDRD-4 excluded serum creatinine, with the coefficients refit among the remaining 3 variables, i.e., total bilirubin, INR and 4-variable MDRD eGFR. This model represented an exacerbated outcome over MELD score, as suggested by a decrease in chi-square (2161.45 vs 2198.32) and an increase in -2 log (likelihood) (2810.77 vs 2773.90). MELD-MDRD-6 included 6-variable MDRD eGFR as one of the variables and showed an improvement over MELD score, as suggested by an increase in chi-square (2293.82 vs 2198.32) and a decrease in -2 log (likelihood) (2810.77 vs 2664.79). Finally, when serum creatinine was replaced by CKD-EPI eGFR, it showed a slight improvement compared to the original MELD score (chi-square: 2199.16, -2 log (likelihood): 2773.07). In the receiver-operating characteristic curve, the MELD-MDRD-6 score showed a marginal improvement in area under the curve (0.909 vs 0.902), sensitivity (0.854 vs 0.819) and specificity (0.818 vs 0.839) compared to the original MELD equation. In patients with a different eGFR, the MELD-MDRD-6 equation showed a better predictive value in patients with eGFR > 90, 60-89, 30-59 and 15-29. CONCLUSION: Incorporating eGFR obtained by the 6-variable MDRD equation into the MELD score showed an equal predictive performance in in-hospital mortality compared to a creatinine-based MELD score.

Is creatinine assessment included in the MELD score?

5a68f633b750ff4455000019_006

yes

ACH-806, an NS4A antagonist, inhibits hepatitis C virus replication by altering the composition of viral replication complexes. Treatment of hepatitis C patients with direct-acting antiviral drugs involves the combination of multiple small-molecule inhibitors of distinctive mechanisms of action. ACH-806 (or GS-9132) is a novel, small-molecule inhibitor specific for hepatitis C virus (HCV). It inhibits viral RNA replication in HCV replicon cells and was active in genotype 1 HCV-infected patients in a proof-of-concept clinical trial (1). Here, we describe a potential mechanism of action (MoA) wherein ACH-806 alters viral replication complex (RC) composition and function. We found that ACH-806 did not affect HCV polyprotein translation and processing, the early events of the formation of HCV RC. Instead, ACH-806 triggered the formation of a homodimeric form of NS4A with a size of 14 kDa (p14) both in replicon cells and in Huh-7 cells where NS4A was expressed alone. p14 production was negatively regulated by NS3, and its appearance in turn was associated with reductions in NS3 and, especially, NS4A content in RCs due to their accelerated degradation. A previously described resistance substitution near the N terminus of NS3, where NS3 interacts with NS4A, attenuated the reduction of NS3 and NS4A conferred by ACH-806 treatment. Taken together, we show that the compositional changes in viral RCs are associated with the antiviral activity of ACH-806. Small molecules, including ACH-806, with this novel MoA hold promise for further development and provide unique tools for clarifying the functions of NS4A in HCV replication.

Are there any HCV replication inhibitors available?

53353927d6d3ac6a34000043_005

yes

MicroRNA-223 regulates cyclin E activity by modulating expression of F-box and WD-40 domain protein 7. F-box and WD-40 domain protein 7 (Fbw7) provides substrate specificity for the Skp1-Cullin1-F-box protein (SCF) ubiquitin ligase complex that targets multiple oncoproteins for degradation, including cyclin E, c-Myc, c-Jun, Notch, and mammalian target of rapamycin (mTOR). Fbw7 is a bona fide tumor suppressor, and loss-of-function mutations in FBXW7 have been identified in diverse human tumors. Although much is known about targets of the Fbw7 ubiquitin ligase pathway, relatively little is known about the regulation of Fbw7 expression. We identified a panel of candidate microRNA regulators of Fbw7 expression within a study of gene expression alterations in primary erythroblasts obtained from cyclin E(T74A T393A) knock-in mice, which have markedly dysregulated cyclin E expression. We found that overexpression of miR-223, in particular, significantly reduces FBXW7 mRNA levels, increases endogenous cyclin E protein and activity levels, and increases genomic instability. We next confirmed that miR-223 targets the FBXW7 3'-untranslated region. We then found that reduced miR-223 expression in primary mouse embryonic fibroblasts leads to increased Fbw7 expression and decreased cyclin E activity. Finally, we found that miR-223 expression is responsive to acute alterations in cyclin E regulation by the Fbw7 pathway. Together, our data indicate that miR-223 regulates Fbw7 expression and provide the first evidence that activity of the SCF(Fbw7) ubiquitin ligase can be modulated directly by the microRNA pathway.

Is protein Fbw7 a SCF type of E3 ubiquitin ligase?

550ae16bc2af5d5b70000009_012

yes

Abnormal changes in NKT cells, the IGF-1 axis, and liver pathology in an animal model of ALS. Amyotrophic lateral sclerosis (ALS) is a rapidly progressing fatal neurodegenerative disorder characterized by the selective death of motor neurons (MN) in the spinal cord, and is associated with local neuroinflammation. Circulating CD4(+) T cells are required for controlling the local detrimental inflammation in neurodegenerative diseases, and for supporting neuronal survival, including that of MN. T-cell deficiency increases neuronal loss, while boosting T cell levels reduces it. Here, we show that in the mutant superoxide dismutase 1 G93A (mSOD1) mouse model of ALS, the levels of natural killer T (NKT) cells increased dramatically, and T-cell distribution was altered both in lymphoid organs and in the spinal cord relative to wild-type mice. The most significant elevation of NKT cells was observed in the liver, concomitant with organ atrophy. Hepatic expression levels of insulin-like growth factor (IGF)-1 decreased, while the expression of IGF binding protein (IGFBP)-1 was augmented by more than 20-fold in mSOD1 mice relative to wild-type animals. Moreover, hepatic lymphocytes of pre-symptomatic mSOD1 mice were found to secrete significantly higher levels of cytokines when stimulated with an NKT ligand, ex-vivo. Immunomodulation of NKT cells using an analogue of α-galactosyl ceramide (α-GalCer), in a specific regimen, diminished the number of these cells in the periphery, and induced recruitment of T cells into the affected spinal cord, leading to a modest but significant prolongation of life span of mSOD1 mice. These results identify NKT cells as potential players in ALS, and the liver as an additional site of major pathology in this disease, thereby emphasizing that ALS is not only a non-cell autonomous, but a non-tissue autonomous disease, as well. Moreover, the results suggest potential new therapeutic targets such as the liver for immunomodulatory intervention for modifying the disease, in addition to MN-based neuroprotection and systemic treatments aimed at reducing oxidative stress.

Are immune cells affected in Amyotrophic Lateral Sclerosis?

56cae51f5795f9a73e000025_001

yes

The circadian clock coordinates ribosome biogenesis. Biological rhythms play a fundamental role in the physiology and behavior of most living organisms. Rhythmic circadian expression of clock-controlled genes is orchestrated by a molecular clock that relies on interconnected negative feedback loops of transcription regulators. Here we show that the circadian clock exerts its function also through the regulation of mRNA translation. Namely, the circadian clock influences the temporal translation of a subset of mRNAs involved in ribosome biogenesis by controlling the transcription of translation initiation factors as well as the clock-dependent rhythmic activation of signaling pathways involved in their regulation. Moreover, the circadian oscillator directly regulates the transcription of ribosomal protein mRNAs and ribosomal RNAs. Thus the circadian clock exerts a major role in coordinating transcription and translation steps underlying ribosome biogenesis.

Is the circadian clock involved in ribosome biogenesis?

56bf7d90ef6e394741000015_000

yes

Miller fisher syndrome: a hospital-based retrospective study. Miller Fisher syndrome (MFS), characterized as ataxia, areflexia and ophthalmoplegia, is generally considered as a variant of Guillain-Barré syndrome (GBS). However, some investigators believed that the syndrome could be explained by a central origin. To obtain more information about MFS for comparison with GBS, we conducted a retrospective study by analyzing the clinical data of MFS patients admitted to our hospital over a period of 11 years. The calibrated male/female ratio was 1.65. A seasonal clustering in winter was noted. The percentage of MFS among GBS was especially high (18%, 11/60) in Taiwan when compared with other series. Involvement of limb muscle strength, autonomic function and cranial nerves, except ocular motor nerves, was rarely found in our patients. When MFS is accompanied by limb weakness, it might represent a transitional form between MFS and GBS. Bulbar palsy and dysautonomia might predict a relatively poor prognosis. To obtain more reliable information, lumbar puncture should be done 1 week after disease onset, and electrophysiological tests should be done serially in every MFS patient. Eighty percent (80%, 4/5) of our patients were positive for IgG anti-GQ(1b) antibody activity. In our study, there is more evidence indicating that MFS is a peripheral nervous system disorder; however, no definite conclusion could be made as to whether MFS is exclusively a peripheral or central nervous system disorder. We think MFS is an immune-mediated clinical entity which mainly involves the peripheral nervous system with rare involvement of other parts of the central nervous system.

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

571f59cd0fd6f91b68000008_007

yes

Phospholamban interacts with HAX-1, a mitochondrial protein with anti-apoptotic function. Phospholamban (PLN) is a key regulator of Ca(2+) homeostasis and contractility in the heart. Its regulatory effects are mediated through its interaction with the sarcoplasmic reticulum Ca(2+)-ATPase, (SERCA2a), resulting in alterations of its Ca(2+)-affinity. To identify additional proteins that may interact with PLN, we used the yeast-two-hybrid system to screen an adult human cardiac cDNA library. HS-1 associated protein X-1 (HAX-1) was identified as a PLN-binding partner. The minimal binding regions were mapped to amino acid residues 203-245 for HAX-1 and residues 16-22 for PLN. The interaction between the two proteins was confirmed using GST-HAX-1, bound to the glutathione-matrix, which specifically adsorbed native PLN from human or mouse cardiac homogenates, while in reciprocal binding studies, recombinant His-HAX-1 bound GST-PLN. Kinetic studies using surface plasmon resonance yielded a K(D) of approximately 1 muM as the binding affinity for the PLN/HAX-1 complex. Phosphorylation of PLN by cAMP-dependent protein kinase reduced binding to HAX-1, while increasing concentrations of Ca(2+) diminished the PLN/HAX-1 interaction in a dose-dependent manner. HAX-1 concentrated to mitochondria, but upon transient co-transfection of HEK 293 cells with PLN, HAX-1 redistributed and co-localized with PLN at the endoplasmic reticulum. Analysis of the anti-apoptotic function of HAX-1 revealed that the presence of PLN enhanced the HAX-1 protective effects from hypoxia/reoxygenation-induced cell death. These findings suggest a possible link between the Ca(2+) handling by the sarcoplasmic reticulum and cell survival mediated by the PLN/HAX-1 interaction.

Does Serca2a bind PLN in the heart?

51680b05298dcd4e51000064_008

yes

Spectrum of NSD1 mutations in Sotos and Weaver syndromes. Sotos syndrome is an overgrowth syndrome characterised by pre- and postnatal overgrowth, macrocephaly, advanced bone age, and typical facial features. Weaver syndrome is a closely related condition characterised by a distinctive craniofacial appearance, advanced carpal maturation, widened distal long bones, and camptodactyly. Haploinsufficiency of the NSD1 gene has recently been reported as the major cause of Sotos syndrome while point mutations accounted for a minority of cases. We looked for NSD1 deletions or mutations in 39 patients with childhood overgrowth. The series included typical Sotos patients (23/39), Sotos-like patients (lacking one major criteria, 10/39), and Weaver patients (6/39). We identified NSD1 deletions (6/33) and intragenic mutations (16/33) in Sotos syndrome patients. We also identified NSD1 intragenic mutations in 3/6 Weaver patients. We conclude therefore that NSD1 mutations account for most cases of Sotos syndrome and a significant number of Weaver syndrome cases in our series. Interestingly, mental retardation was consistently more severe in patients with NSD1 deletions. Macrocephaly and facial gestalt but not overgrowth and advanced bone age were consistently observed in Sotos syndrome patients. We suggest therefore considering macrocephaly and facial gestalt as mandatory criteria for the diagnosis of Sotos syndrome and overgrowth and advanced bone age as minor criteria.

Is Weaver syndrome similar to Sotos?

571f34ac0fd6f91b68000005_000

yes

Fbxw7-dependent degradation of Notch is required for control of "stemness" and neuronal-glial differentiation in neural stem cells. Control of the growth and differentiation of neural stem cells is fundamental to brain development and is largely dependent on the Notch signaling pathway. The mechanism by which the activity of Notch is regulated during brain development has remained unclear, however. Fbxw7 (also known as Fbw7, SEL-10, hCdc4, or hAgo) is the F-box protein subunit of an Skp1-Cul1-F-box protein (SCF)-type ubiquitin ligase complex that plays a central role in the degradation of Notch family members. We now show that mice with brain-specific deletion of Fbxw7 (Nestin-Cre/Fbxw7(F/F) mice) die shortly after birth with morphological abnormalities of the brain and the absence of suckling behavior. The maintenance of neural stem cells was sustained in association with the accumulation of Notch1 and Notch3, as well as up-regulation of Notch target genes in the mutant mice. Astrogenesis was also enhanced in the mutant mice in vivo, and the differentiation of neural progenitor cells was skewed toward astrocytes rather than neurons in vitro, with the latter effect being reversed by treatment of the cells with a pharmacological inhibitor of the Notch signaling pathway. Our results thus implicate Fbxw7 as a key regulator of the maintenance and differentiation of neural stem cells in the brain.

Is protein Fbw7 a SCF type of E3 ubiquitin ligase?

550ae16bc2af5d5b70000009_004

yes

Beyond genetics: epigenetic code in chronic kidney disease. Epigenetics refers to a heritable change in the pattern of gene expression that is mediated by a mechanism specifically not due to alterations in the primary nucleotide sequence. Well-known epigenetic mechanisms encompass DNA methylation, chromatin remodeling (histone modifications), and RNA interference. Functionally, epigenetics provides an extra layer of transcriptional control and plays a crucial role in normal physiological development, as well as in pathological conditions. Aberrant DNA methylation is implicated in immune dysfunction, inflammation, and insulin resistance. Epigenetic changes may be responsible for 'metabolic memory' and development of micro- and macrovascular complications of diabetes. MicroRNAs are critical in the maintenance of glomerular homeostasis and hence RNA interference may be important in the progression of renal disease. Recent studies have shown that epigenetic modifications orchestrate the epithelial-mesenchymal transition and eventually fibrosis of the renal tissue. Oxidative stress, inflammation, hyperhomocysteinemia, and uremic toxins could induce epimutations in chronic kidney disease. Epigenetic alterations are associated with inflammation and cardiovascular disease in patients with chronic kidney disease. Reversible nature of the epigenetic changes gives a unique opportunity to halt or even reverse the disease process through targeted therapeutic strategies.

Are epigenetic modifications implicated in cardiovascular development and disease?

54f7291630767eb92e000002_014

yes

The use of a computer-based decision support system facilitates primary care physicians' management of chronic pain. We tested whether computer-based decision support (CBDS) could enhance the ability of primary care physicians (PCPs) to manage chronic pain. Structured summaries were generated for 50 chronic pain patients referred by PCPs to a pain clinic. A pain specialist used a decision support system to determine appropriate pain therapy and sent letters to the referring physicians outlining these recommendations. Separately, five board-certified PCPs used a CBDS system to "treat" the 50 cases. A successful outcome was defined as one in which new or adjusted therapies recommended by the software were acceptable to the PCPs (i.e., they would have prescribed it to the patient in actual practice). Two pain specialists reviewed the PCPs' outcomes and assigned medical appropriateness scores (0 = totally inappropriate to 10 = totally appropriate). One year later, the hospital database provided information on how the actual patients' pain was managed and the number of patients re-referred by their PCP to the pain clinic. On the basis of CBDS recommendations, the PCP subjects "prescribed" additional pain therapy in 213 of 250 evaluations (85%), with a medical appropriateness score of 5.5 +/- 0.1. Only 25% of these chronic pain patients were subsequently re-referred to the pain clinic within 1 yr. The use of a CBDS system may improve the ability of PCPs to manage chronic pain and may also facilitate screening of consults to optimize specialist utilization.

Are there any Decision support systems for chronic pain management ?

54fefbbc6ad7dcbc1200000a_003

yes

Assignment of the gene for beta 2-microglobulin (B2m) to mouse chromosome 2. We have assigned the gene (B2m) coding for murine beta 2-microglobulin (B2M) to mouse chromosome 2 by using a novel panel of Chinese hamster-mouse somatic cell hybrid clones. Because of 35 independent primary hybrids used in this study were derived from two types of feral mice, each with a different combination of Robertsonian translocation chromosomes, as well as from mice with a normal complement of acrocentric chromosomes, analysis of 16 selected mouse enzyme markers provided data on the segregation of all 20 mouse chromosomes in these hybrids. Mouse B2M was identified in cell hybrids by immunoprecipitation with a species-specific anti-mouse B2M antiserum followed by two-dimensional polyacrylamide gel electrophoresis of the immunoprecipitated polypeptides. Enzyme analysis of the segregant clones excluded all chromosomes for B2m assignment except mouse chromosome 2, and karyotype analysis of nine informative hybrid clones confirmed the assignment of B2m to this chromosome. These results demonstrate that, in the mouse, as in man, B2m is not linked to the major histocompatibility or immunoglobulin loci.

Are mouse chromosomes acrocentric?

5a89537cfcd1d6a10c000002_007

yes

Structure and function of the histone chaperone CIA/ASF1 complexed with histones H3 and H4. CIA (CCG1-interacting factor A)/ASF1, which is the most conserved histone chaperone among the eukaryotes, was genetically identified as a factor for an anti-silencing function (Asf1) by yeast genetic screening. Shortly after that, the CIA-histone-H3-H4 complex was isolated from Drosophila as a histone chaperone CAF-1 stimulator. Human CIA-I/II (ASF1a/b) was identified as a histone chaperone that interacts with the bromodomain-an acetylated-histone-recognizing domain-of CCG1, in the general transcription initiation factor TFIID. Intensive studies have revealed that CIA/ASF1 mediates nucleosome assembly by forming a complex with another histone chaperone in human cells and yeast, and is involved in DNA replication, transcription, DNA repair and silencing/anti-silencing in yeast. CIA/ASF1 was shown as a major storage chaperone for soluble histones in proliferating human cells. Despite all these biochemical and biological functional analyses, the structure-function relationship of the nucleosome assembly/disassembly activity of CIA/ASF1 has remained elusive. Here we report the crystal structure, at 2.7 A resolution, of CIA-I in complex with histones H3 and H4. The structure shows the histone H3-H4 dimer's mutually exclusive interactions with another histone H3-H4 dimer and CIA-I. The carboxy-terminal beta-strand of histone H4 changes its partner from the beta-strand in histone H2A to that of CIA-I through large conformational change. In vitro functional analysis demonstrated that CIA-I has a histone H3-H4 tetramer-disrupting activity. Mutants with weak histone H3-H4 dimer binding activity showed critical functional effects on cellular processes related to transcription. The histone H3-H4 tetramer-disrupting activity of CIA/ASF1 and the crystal structure of the CIA/ASF1-histone-H3-H4 dimer complex should give insights into mechanisms of both nucleosome assembly/disassembly and nucleosome semi-conservative replication.

Does the histone chaperone ASF1 interact with histones H1/H2?

58dcbb8c8acda34529000021_000

no

Dual EGFR/HER2 inhibition sensitizes prostate cancer cells to androgen withdrawal by suppressing ErbB3. PURPOSE: Patients with recurrent prostate cancer are commonly treated with androgen withdrawal therapy (AWT); however, almost all patients eventually progress to castration resistant prostate cancer (CRPC), indicating failure of AWT to eliminate androgen-sensitive prostate cancer. The overall goal of these studies is to determine whether dual inhibition of the receptor tyrosine kinases epidermal growth factor receptor (EGFR) and HER2 would prolong the effectiveness of this treatment in prostate cancer. EXPERIMENTAL DESIGN: We used androgen-dependent LNCaP cells and its CRPC sublines LNCaP-AI and C4-2. Additional data were collected in pRNS-1-1 cells stably expressing a mutant androgen receptor (AR-T877A), and in nude mice harboring CWR22 tumors. Studies utilized EGFR inhibitors erlotinib and AG1478, and HER2 inhibitors trastuzumab and AG879. RESULTS: Dual EGFR/HER2 inhibition induced apoptosis selectively in androgen-sensitive prostate cancer cells undergoing AWT, but not in the presence of androgens, or in CRPC cells. We show that AWT alone failed to induce significant apoptosis in androgen-dependent cells, due to AWT-induced increase in HER2 and ErbB3, which promoted survival by increasing Akt phosphorylation. AWT-induced ErbB3 stabilized the AR and stimulated PSA, while it was inactivated only by inhibition of both its dimerization partners EGFR and HER2 (prostate cancer cells do not express ErbB4); but not the inhibition of any one receptor alone, explaining the success of dual EGFR/HER2 inhibition in sensitizing androgen-dependent cells to AWT. The effectiveness of the inhibitors in suppressing growth correlated with its ability to prevent Akt phosphorylation. CONCLUSION: These studies indicate that dual EGFR/HER2 inhibition, administered together with AWT, sensitize prostate cancer cells to apoptosis during AWT.

Is the monoclonal antibody Trastuzumab (Herceptin) of potential use in the treatment of prostate cancer?

5313b049e3eabad021000013_027

yes

Defining the intramembrane binding mechanism of sarcolipin to calcium ATPase using solution NMR spectroscopy. Sarcolipin (SLN) is an integral membrane protein that is expressed in both skeletal and cardiac muscle, where it inhibits SERCA (calcium ATPase) by lowering its apparent Ca2+ affinity in a manner similar to that of its homologue phospholamban (PLN). We use solution NMR to map the structural changes occurring within SLN upon interaction with the regulatory target, SERCA, co-reconstituting the two proteins in dodecylphosphocholine (DPC) detergent micelles, a system that preserves the native structure of SLN and the activity of SERCA, with the goal of comparing these interactions with those of the previously studied PLN-SERCA complex. Our analysis of the structural dynamics of SLN in DPC micelles shows this polypeptide to be partitioned into four subdomains: a short unstructured N terminus (residues 1-6), a short dynamic helix (residues 7-14), a more rigid helix (residues 15-26), and an unstructured C terminus (residues 27-31). Upon addition of SERCA, the different domains behave according to their dynamics, molding onto the surface of the enzyme. Remarkably, each domain of SLN behaves in a manner similar to that of the corresponding domains in PLN, supporting the hypothesis that both SLN and PLN bind SERCA in the same groove and with similar mechanisms.

Is Sarcolipin a regulatory/inhibitory protein of the Calcium ATPase SERCA?

55016397e9bde69634000006_001

yes

Phase 3 solanezumab trials: Secondary outcomes in mild Alzheimer's disease patients. INTRODUCTION: EXPEDITION and EXPEDITION2 were identically designed placebo-controlled phase 3 studies assessing effects of solanezumab, an antiamyloid monoclonal antibody binding soluble amyloid-β peptide, on cognitive and functional decline over 80 weeks in patients with mild-to-moderate Alzheimer's disease (AD). Primary findings for both studies have been published. METHODS: Secondary analyses of efficacy, biomarker, and safety endpoints in the pooled (EXPEDTION + EXPEDITION2) mild AD population were performed. RESULTS: In the mild AD population, less cognitive and functional decline was observed with solanezumab (n = 659) versus placebo (n = 663), measured by Alzheimer's Disease Assessment Scale Cognitive subscale, Mini-Mental State Examination, and Alzheimer's Disease Cooperative Study-Activities of Daily Living functional scale Instrumental ADLs. Baseline-to-endpoint changes did not differ between treatment groups for Alzheimer's Disease Cooperative Study-Activities of Daily Living functional scale, basic items of the ADCS-ADL, and Clinical Dementia Rating Sum of Boxes. Plasma/cerebrospinal fluid biomarker findings indicated target engagement by solanezumab. Solanezumab demonstrated acceptable safety. Efficacy findings for the moderate AD population are also provided. DISCUSSION: These findings describe solanezumab effects on efficacy/safety measures in a mild AD population. Another phase 3 study, EXPEDITION3, will investigate solanezumab's effects in a mild AD population.

Is Solanezumab effective for Alzheimer's Disease?

5a70e1d999e2c3af26000007_004

no

Poliovirus-mediated disruption of cytoplasmic processing bodies. Metazoan cells form cytoplasmic mRNA granules such as stress granules (SG) and processing bodies (P bodies) that are proposed to be sites of aggregated, translationally silenced mRNAs and mRNA degradation. Poliovirus (PV) is a plus-strand RNA virus containing a genome that is a functional mRNA; thus, we investigated if PV antagonizes the processes that lead to formation of these structures. We have previously shown that PV infection inhibits the ability of cells to form stress granules by cleaving RasGAP-SH3-binding protein (G3BP). Here, we show that P bodies are also disrupted during PV infection in cells by 4 h postinfection. The disruption of P bodies is more rapid and more complete than disruption of stress granules. The kinetics of P body disruption correlated with production of viral proteinases and required substantial viral gene product expression. The organizing mechanism that forms P body foci in cells is unknown; however, potential scaffolding, aggregating, or other regulatory proteins found in P bodies were investigated for degradation. Two factors involved in 5'-end mRNA decapping and degradation, Xrn1 and Dcp1a, and the 3' deadenylase complex component Pan3 underwent accelerated degradation during infection, and Dcp1a may be a direct substrate of PV 3C proteinase. Several other key factors proposed to be essential for P body formation, GW182, Edc3, and Edc4, were unaffected by poliovirus infection. Since deadenylation has been reported to be required for P body formation, viral inhibition of deadenylation, through Pan3 degradation, is a potential mechanism of P body disruption.

Is exonuclease Xrn1 a component of the P-bodies?

56c9e9d15795f9a73e00001d_010

yes

[Adynamia, finger paresthesias]. A 40-year-old woman was admitted for investigation of weakness and angina pectoris. She had generalised weakness of muscles, cold intolerance and a reduced physical performance. A previous neurological examination had already revealed a carpal-tunnel syndrome of the right hand. This syndrome, combined with a rough, cool skin and a periorbital edema, lead to the assumption of hypothyroidism. The diagnosis was confirmed by a combination of very high concentrations of TSH and decreased concentrations of the thyroid hormones. Replacement therapy by oral administration of L-thyroxin resulted in a gradual improvement of the patient's state.

Is physical performance influenced by thyroid hormone metabolism?

5151b8efd24251bc0500007a_001

yes

Targeting Mutant BRAF in Relapsed or Refractory Hairy-Cell Leukemia. BACKGROUND: BRAF V600E is the genetic lesion underlying hairy-cell leukemia. We assessed the safety and activity of the oral BRAF inhibitor vemurafenib in patients with hairy-cell leukemia that had relapsed after treatment with a purine analogue or who had disease that was refractory to purine analogues. METHODS: We conducted two phase 2, single-group, multicenter studies of vemurafenib (at a dose of 960 mg twice daily)--one in Italy and one in the United States. The therapy was administered for a median of 16 weeks in the Italian study and 18 weeks in the U.S. study. Primary end points were the complete response rate (in the Italian trial) and the overall response rate (in the U.S. trial). Enrollment was completed (28 patients) in the Italian trial in April 2013 and is still open (26 of 36 planned patients) in the U.S. trial. RESULTS: The overall response rates were 96% (25 of 26 patients who could be evaluated) after a median of 8 weeks in the Italian study and 100% (24 of 24) after a median of 12 weeks in the U.S. study. The rates of complete response were 35% (9 of 26 patients) and 42% (10 of 24) in the two trials, respectively. In the Italian trial, after a median follow-up of 23 months, the median relapse-free survival was 19 months among patients with a complete response and 6 months among those with a partial response; the median treatment-free survival was 25 months and 18 months, respectively. In the U.S. trial, at 1 year, the progression-free survival rate was 73% and the overall survival rate was 91%. Drug-related adverse events were usually of grade 1 or 2, and the events most frequently leading to dose reductions were rash and arthralgia or arthritis. Secondary cutaneous tumors (treated with simple excision) developed in 7 of 50 patients. The frequent persistence of phosphorylated ERK-positive leukemic cells in bone marrow at the end of treatment suggests bypass reactivation of MEK and ERK as a resistance mechanism. CONCLUSIONS: A short oral course of vemurafenib was highly effective in patients with relapsed or refractory hairy-cell leukemia. (Funded by the Associazione Italiana per la Ricerca sul Cancro and others; EudraCT number, 2011-005487-13; ClinicalTrials.gov number NCT01711632.).

Is vemurafenib effective for hairy-cell leukemia?

56c02bc3ef6e394741000018_004

yes

TREM2 in Alzheimer's disease. Recent works have demonstrated a rare functional variant (R47H) in triggering receptor expressed on myeloid cells (TREM) 2 gene, encoding TREM2 protein, increase susceptibility to late-onset Alzheimer's disease (AD), with an odds ratio similar to that of the apolipoprotein E ε4 allele. The reduced function of TREM2 was speculated to be the main cause in the pathogenic effects of this risk variant, and TREM2 is highly expressed in white matter, as well as in the hippocampus and neocortex, which is partly consistent with the pathological features reported in AD brain, indicating the possible involvement of TREM2 in AD pathogenesis. Emerging evidence has demonstrated that TREM2 could suppress inflammatory response by repression of microglia-mediated cytokine production and secretion, which may prevent inflammation-induced bystander damage of neurons. TREM2 also participates in the regulation of phagocytic pathways that are responsible for the removal of neuronal debris. In this article, we review the recent epidemiological findings of TREM2 that related with late-onset AD and speculate the possible roles of TREM2 in progression of this disease. Based on the potential protective actions of TREM2 in AD pathogenesis, targeting TREM2 might provide new opportunities for AD treatment.

Is TREM2 associated with Alzheimer's disease?

531a31a1b166e2b806000035_008

yes

Sudden death: ethical and legal problems of post-mortem forensic genetic testing for hereditary cardiac diseases. Hereditary non-structural diseases such as catecholaminergic polymorphic ventricular tachycardia (CPVT), long QT, and the Brugada syndrome as well as structural disease such as hypertrophic cardiomyopathy (HCM) and arrhythmogenic right ventricular cardiomyopathy (ARVC) cause a significant percentage of sudden cardiac deaths in the young. In these cases, genetic testing can be useful and does not require proxy consent if it is carried out at the request of judicial authorities as part of a forensic death investigation. Mutations in several genes are implicated in arrhythmic syndromes, including SCN5A, KCNQ1, KCNH2, RyR2, and genes causing HCM. If the victim's test is positive, this information is important for relatives who might be themselves at risk of carrying the disease-causing mutation. There is no consensus about how professionals should proceed in this context. This article discusses the ethical and legal arguments in favour of and against three options: genetic testing of the deceased victim only; counselling of relatives before testing the victim; counselling restricted to relatives of victims who tested positive for mutations of serious and preventable diseases. Legal cases are mentioned that pertain to the duty of geneticists and other physicians to warn relatives. Although the claim for a legal duty is tenuous, recent publications and guidelines suggest that geneticists and others involved in the multidisciplinary approach of sudden death (SD) cases may, nevertheless, have an ethical duty to inform relatives of SD victims. Several practical problems remain pertaining to the costs of testing, the counselling and to the need to obtain permission of judicial authorities.

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

530cf4fe960c95ad0c000003_017

yes

Overexpression of microRNAs-155 and 21 targeting mismatch repair proteins in inflammatory bowel diseases. Microsatellite instability (MSI) due to mismatch repair (MMR) deficiency is reported in 5-10% of colorectal cancers (CRCs) complicating inflammatory bowel diseases (IBD). The molecular mechanisms underlying MMR deficiency may be different in IBD CRCs, and in sporadic and hereditary MSI tumors. Here, we hypothesize that overexpression of miR-155 and miR-21, two inflammation-related microRNAs that target core MMR proteins, may constitute a pre-neoplastic event for the development of MSI IBD CRCs. We studied miR-155 and miR-21 expression using real-time quantitative PCR in MSI (n = 10) and microsatellite stable (n = 10) IBD CRCs, and in MSI (n = 32) and microsatellite stable (n = 30) non-IBD CRCs. We also screened colonic samples from IBD patients without cancer (n = 18) and used healthy colonic mucosa as controls (n = 20). MiR-155 and miR-21 appeared significantly overexpressed not only in the colonic mucosa of IBD subjects without CRC but also in neoplastic tissues of IBD patients compared with non-IBD controls (P < 0.001). Importantly, in patients with IBD CRCs, miR-155 and miR-21 overexpression extended to the distant non-neoplastic mucosa (P < 0.001). Ratios of expressions in tumors versus matched distant mucosa revealed a nearly significant association between miR-155 overexpression and MSI in IBDs (P = 0.057). These results show a strong deregulation of both MMR-targeting microRNAs in IBD subjects with or without cancer. MiR-155 overexpression being particularly associated to MSI IBD CRCs and extending to distant non-neoplastic mucosa, strongly suggests that a pre-neoplastic miR-155 field defect may promote MSI-driven transformation of the colonic mucosa. The detection and monitoring of miR-155 field defect may, therefore, have implications for the prevention and treatment of MSI IBD CRCs.

Is miR-21 related to carcinogenesis?

511a4ec01159fa8212000004_067

yes

Resistance mutations against HCV protease inhibitors and antiviral drug design. The treatment for hepatitis C virus (HCV) infection has been significantly improved with the approval of the first two HCV NS3/4A protease inhibitors, telaprevir (Incivek) and boceprevir (Victrelis). These two direct acting antivirals (DAAs) are used clinically in combination with pegylated interferon-alpha (PEG-IFNα) and ribavirin (RBV). The sustained virologic response (SVR) rates are increased to ~70% and the duration of the treatment is ~50% shorter among treatment-naïve patients with genotype 1 HCV. Variants (quasi species) are almost constantly introduced during HCV replication due to its rapid replication rate and the low fidelity of its polymerase. Drug resistant variants carrying mutations that affect the binding of DAAs have the growth advantage over wild-type virus and could become the dominant viral quasi species during treatment with DAAs. Mutations at a number of key positions of the NS3/4A protease have been reported to be associated with drug resistance. This review summarizes the mutations that are responsible for resistance against the two approved protease inhibitors and several compounds in advanced clinical trials. The impacts of the resistance mutations on the binding of the inhibitors as well as the design of next-generation protease inhibitors are discussed from the perspective of medicinal chemistry.

Are there any HCV replication inhibitors available?

53353927d6d3ac6a34000043_010

yes

[Familiar case of granular dystrophy and oculocutaneous albinism]. CLINICAL CASE: A 35-year-old female patient with blurred vision since childhood, for which no treatment had been given, presented with poor visual acuity. She had white skin and fair yellow hair. There were several well circumscribed deposits in the central and anterior corneal stroma, and iris transillumination and foveal hypoplasia were evident. The clinical diagnosis was oculo-cutaneous albinism and granular corneal dystrophy. We found oculo-cutaneous albinism in two brothers and granular dystrophy in three brothers, the mother and a son. DISCUSSION: Corneal dystrophy is an autosomal dominant disorder inherited independently of oculocutaneous albinism, which is inherited as an autosomal recessive condition. This is the first case report of granular dystrophy concurrent with oculocutaneous albinism.

Does oculocutaneous albinism show an autosomal recessive inheritance?

58cbb55402b8c60953000033_004

yes

In vivo and in vitro antitumor activity of butyroyloxymethyl-diethyl phosphate (AN-7), a histone deacetylase inhibitor, in human prostate cancer. AN-7, a prodrug of butyric acid, induced histone hyperacetylation and differentiation and inhibited proliferation of human prostate 22Rv1 cancer cells in vitro and in vivo. In nude mice implanted with these cells, 50 mg/kg AN-7 given orally thrice a week led to inhibition of tumor growth and metastasis, tumor regression in >25% of animals and increased survival. Median time to the experimental end point (tumor volume 2 cm3 or death) in the untreated was 52 days, and average tumor volume was 0.8 +/- 0.18 cm3. At the same time, 94.4% of AN-7-treated mice survived and had average tumor volumes of 0.37 +/- 0.1 cm3. PSA expression was a useful marker for 22Rv1 lung metastasis detection. Sizeable metastases positively stained for PSA and limited air gaps were found in lungs of untreated mice. In animals treated with AN-7, lung morphology appeared normal. Primary tumors of treated animals were highly positive for PSA and had an elevated level of p21 and the proapoptotic protein Bax. Sections taken from AN-7-treated animals, examined under an electron microscope, exhibited condensed chromatin and apoptotic bodies. PSA serum levels were higher in untreated compared to treated animals and correlated with tumor volume. Since prolonged oral administration with 50 mg/kg or a single oral dose of 1.2 g/kg AN-7 did not cause adverse effects and the former exhibited significant anticancer activity, AN-7 is likely to display a high therapeutic index and may be beneficial for prostate cancer patients.

Are histone deacetylase (HDAC) inhibitors good candidates to control metastasis of solid tumors?

517404878ed59a060a000023_007

yes

[Restless-legs syndrome]. Restless-legs syndrome (RLS) is a sensorimotor disorder, characterized by an irresistible urge to move the legs usually accompanied or caused by uncomfortable and unpleasant sensations. It begins or worsens during periods of rest or inactivity, is partially or totally relieved by movements and is exacerbated or occurs at night and in the evening. RLS sufferers represent 2 to 3% of the general population in Western countries. Supportive criteria include a family history, the presence of periodic-leg movements (PLM) when awake or asleep and a positive response to dopaminergic treatment. The RLS phenotypes include an early onset form, usually idiopathic with a familial history and a late onset form, usually secondary to peripheral neuropathy. Recently, an atypical RLS phenotype without PLM and l-DOPA resistant has been characterized. RLS can occur in childhood and should be distinguished from attention deficit/hyperactivity disorder, growing pains and sleep complaints in childhood. RLS should be included in the diagnosis of all patients consulting for sleep complaints or discomfort in the lower limbs. It should be differentiated from akathisia, that is, an urge to move the whole body without uncomfortable sensations. Polysomnographic studies and the suggested immobilization test can detect PLM. Furthermore, an l-DOPA challenge has recently been validated to support the diagnosis of RLS. RLS may cause severe-sleep disturbances, poor quality of life, depressive and anxious symptoms and may be a risk factor for cardiovascular disease. In most cases, RLS is idiopathic. It may also be secondary to iron deficiency, end-stage renal disease, pregnancy, peripheral neuropathy and drugs, such as antipsychotics and antidepressants. The small-fiber neuropathy can mimic RLS or even trigger it. RLS is associated with many neurological and sleep disorders including Parkinson's disease, but does not predispose to these diseases. The pathophysiology of RLS includes an altered brain-iron metabolism, a dopaminergic dysfunction, a probable role of pain control systems and a genetic susceptibility with nine loci and three polymorphisms in genes serving developmental functions. RLS treatment begins with the elimination of triggering factors and iron supplementation when deficient. Mild or intermittent RLS is usually treated with low doses of l-DOPA or codeine; the first-line treatment for moderate to severe RLS is dopaminergic agonists (pramipexole, ropinirole, rotigotine). In severe, refractory or neuropathy-associated RLS, antiepileptic (gabapentin, pregabalin) or opioid (oxycodone, tramadol) drugs can be used.

Is pregabalin effective for treatment of patients with restless leg syndrome?

54cf4a0ef693c3b16b00000c_006

yes

Nitric oxide and acid induce double-strand DNA breaks in Barrett's esophagus carcinogenesis via distinct mechanisms. BACKGROUND & AIMS: The luminal microenvironment including acid and nitric oxide (NO) has been implicated in Barrett's esophagus carcinogenesis. We investigated the ability of acid and NO to induce DNA damage in esophageal cells. METHODS: Transformed and primary Barrett's esophagus and adenocarcinoma cells were exposed to either acid, (pH 3.5), +/- antioxidant or NO from a donor or generated by acidification of nitrite in the presence of ascorbate +/- NO scavenger. Phosphorylation of histone H2AX and the neutral comet assay were used to detect DNA double-strand breaks (DSBs). Intracellular levels of reactive oxygen species and NO were detected with fluorescent dyes. Mitochondrial viability was measured with a rhodamine dye. Long-term survival was assessed by clonogenic assay. RESULTS: Exposure to acid (pH 3.5) for > or =15 minutes induced DSBs in all cell lines (P < .05). There was a concomitant increase in intracellular reactive oxygen species in the absence of mitochondrial damage, and pretreatment with antioxidants inhibited DNA damage. Exposure to physiologic concentrations of NO produced from the NO donor or acidification of salivary nitrite induced DSBs in a dose- (>25 micromol/L) and cell-dependent manner (adenocarcinoma >Barrett's esophagus, P < .05). This occurred preferentially in S-phase cells consistent with stalled replication forks and was blocked with a NO scavenger. NO also induced DSBs in primary Barrett's esophagus cells treated ex vivo. Cells were able to survive when exposed to acid and NO. CONCLUSIONS: Both acid and NO have the potential to generate DSBs in the esophagus and via distinct mechanisms.

Do DNA double-strand breaks play a causal role in carcinogenesis?

5162f5b6298dcd4e5100004c_002

yes

Experience with bladder training in 65 patients. The results of in-patient bladder training in 65 women with frequency, urgency and urge incontinence are reported. There was a good initial response in 88%. By 6 months the response rate had fallen to 38%. Patients with sensory urgency appeared to do better than those with detrusor instability and it is suggested that bladder training may be indicated as primary treatment in sensory urgency. Eysenck Personality Inventory testing was carried out in 43 patients. The mean neuroticism score was high, with non-responders having a higher neuroticism score than responders. Patients with detrusor instability had a higher mean neuroticism score than those with sensory urgency. Introverted patients appeared to do better than extraverts with bladder training.

Is Bladder training an effective method to treat urge incontinence ?

515df98f298dcd4e51000030_009

yes

A phase II study of carboplatin and chronic high-dose tamoxifen in patients with recurrent malignant glioma. PURPOSE: To determine the response rate, time to disease progression, survival, and toxicity of intravenous carboplatin and chronic oral high-dose tamoxifen in patients with recurrent malignant gliomas. PATIENTS AND METHODS: Patients with histological confirmation of recurrent malignant gliomas were eligible for this multicenter phase II trial. Treatment consisted of 400 mg/m2 carboplatin intravenously every 4 weeks and oral high dose chronic tamoxifen (80 mg bid in women and 100 mg bid in men). RESULTS: Twenty seven patients met the eligibility criteria and were evaluable for response. The histological subtypes were: 16 (59%) glioblastoma multiforme (GBM), malignant astrocytoma (5 patients), malignant mixed glioma (5 patients), and glioblastoma/gliosarcoma (1 patient). Twenty-two patients (82%) had an ECOG performance status of 0 or 1. No complete responses were observed, 4 patients (15%) achieved a partial response, and 14 patients (52%) had stable disease. Median time to progression was 3.65 months (95%CI 2.56, 4.83). Median overall survival was 14.09 months (95%CI 7.06, 19.91). One patient with a recurrent GBM had a sustained partial response and is progression free 81 months since starting treatment. Another patient with mixed malignant oligoastrocytoma also had a prolonged partial response (lasting 63 months) and is alive 84 months after treatment for recurrence. The most frequently reported grade 3 or 4 toxicities were fatigue (19%), nausea (11%) and anorexia (11%). CONCLUSIONS: Carboplatin and high dose tamoxifen has similar response rates to other regimens for recurrent malignant gliomas and are probably equivalent to those found using tamoxifen as monotherapy. Long-lasting periods of disease free survival in some patients (particularly those with malignant mixed oligo astrocytomas) were found.

Was tamoxifen tested for treatment of glioma patients?

56c0968def6e394741000026_001

yes

Cutaneous cancers in Calabar, Southern Nigeria. Globally, cutaneous cancers are among the most common form of cancer. Among Africans, there are significant differences in the types of skin cancer compared to those documented in patients from other countries. We evaluated all the patients with a histological diagnosis of skin cancer presenting to the University of Calabar Teaching Hospital from January 2005 through December 2006. Twenty-nine patients (18 males and 11 females) with skin cancer were identified and these accounted for 8.0 percent of total malignancies. Their ages ranged from 16 to 70 years (mean 43.5 years). Kaposi sarcoma (KS) was the most common skin cancer. Kaposi sarcoma associated with HIV represented 81.8 percent of KS cases found. Squamous cell carcinoma (SCC) ranked second and malignant melanoma third. Of the skin cancers in our series, the most common site was the lower limb (55.2%), followed by the head and neck (24%). The 4 albinos accounted for 13.8 percent of the skin cancers found. Immunosuppression (KS), chronic ulcer, inflammation, albinism, and solar radiation were identified risk factors. Public education strategies on prevention, with an emphasis on early identification and surgical treatment of skin cancers are urged. In addition, treatment of and close observation of chronic ulcers are recommended.

Does melanoma occur in people of African origin ?

515df6f2298dcd4e5100002d_008

yes

High frequency of potentially pathogenic SORL1 mutations in autosomal dominant early-onset Alzheimer disease. Performing exome sequencing in 14 autosomal dominant early-onset Alzheimer disease (ADEOAD) index cases without mutation on known genes (amyloid precursor protein (APP), presenilin1 (PSEN1) and presenilin2 (PSEN2)), we found that in five patients, the SORL1 gene harbored unknown nonsense (n=1) or missense (n=4) mutations. These mutations were not retrieved in 1500 controls of same ethnic origin. In a replication sample, including 15 ADEOAD cases, 2 unknown non-synonymous mutations (1 missense, 1 nonsense) were retrieved, thus yielding to a total of 7/29 unknown mutations in the combined sample. Using in silico predictions, we conclude that these seven private mutations are likely to have a pathogenic effect. SORL1 encodes the Sortilin-related receptor LR11/SorLA, a protein involved in the control of amyloid beta peptide production. Our results suggest that besides the involvement of the APP and PSEN genes, further genetic heterogeneity, involving another gene of the same pathway is present in ADEOAD.

Has whole exome sequencing been performed in Alzheimer patients?

58bbb8ae22d3005309000018_001

yes

Combining PCI-24781, a novel histone deacetylase inhibitor, with chemotherapy for the treatment of soft tissue sarcoma. PURPOSE: Histone deactylase inhibitors (HDACi) are a promising new class of anticancer therapeutics; however, little is known about HDACi activity in soft tissue sarcoma (STS), a heterogeneous cohort of mesenchymal origin malignancies. Consequently, we investigated the novel HDACi PCI-24781, alone/in combination with conventional chemotherapy, to determine its potential anti-STS-related effects and the underlying mechanisms involved. EXPERIMENTAL DESIGN: Immunoblotting was used to evaluate the effects of PCI-24781 on histone and nonhistone protein acetylation and expression of potential downstream targets. Cell culture-based assays were utilized to assess the effects of PCI-24781 on STS cell growth, cell cycle progression, apoptosis, and chemosensitivity. Quantitative reverse transcription-PCR, chromatin immunoprecipitation, and reporter assays helped elucidate molecular mechanisms resulting in PCI-24781-induced Rad51 repression. The effect of PCI-24781, alone or with chemotherapy, on tumor and metastatic growth was tested in vivo using human STS xenograft models. RESULTS: PCI-24781 exhibited significant anti-STS proliferative activity in vitro, inducing S phase depletion, G(2)/M cell cycle arrest, and increasing apoptosis. Superior effects were seen when combined with chemotherapy. A PCI-24781-induced reduction in Rad51, a major mediator of DNA double-strand break homologous recombination repair, was shown and may be a mechanism underlying PCI-24781 chemosensitization. We showed that PCI-24781 transcriptionally represses Rad51 through an E2F binding-site on the Rad51 proximal promoter. Although single-agent PCI-24781 had modest effects on STS growth and metastasis, marked inhibition was observed when combined with chemotherapy. CONCLUSIONS: In light of these findings, this novel molecular-based combination may be applicable to multiple STS histologic subtypes, and potentially merits rigorous evaluation in human STS clinical trials.

Are histone deacetylase (HDAC) inhibitors good candidates to control metastasis of solid tumors?

517404878ed59a060a000023_000

yes

Sonidegib, a novel smoothened inhibitor for the treatment of advanced basal cell carcinoma. Basal cell carcinoma (BCC) is the most common nonmelanoma skin cancer. If left untreated, BCCs can become locally aggressive or even metastasize. Currently available treatments include local destruction, surgery, and radiation. Systemic options for advanced disease are limited. The Hedgehog (Hh) pathway is aberrantly activated in a majority of BCCs and in other cancers. Hh pathway inhibitors are targeted agents that inhibit the aberrant activation of the Hh pathway, with smoothened being a targeted component. Sonidegib is a novel smoothened inhibitor that was recently approved by the US Food and Drug Administration. This review focuses on BCC pathogenesis and the clinical efficacy of sonidegib for the treatment of advanced BCC.

Is sonidegib effective for basal cell carcinoma?

589a246f78275d0c4a000034_006

yes

Preincubation of T antigen with DNA overcomes repression of SV40 DNA replication by nucleosome assembly. Circular duplex DNA containing the SV40 replication origin was assembled into chromosomes in vitro with core histones and nucleosome assembly factor from HeLa cells. Their ability to serve as a template for replication was examined by incubating them with SV40 T antigen and HeLa cell extract. Nucleosome assembly of the template prevented DNA replication. Replication of chromosomes was severely inhibited at more than two-thirds of physiological nucleosome density. When the DNA was preincubated with T antigen and then assembled into chromosomes, however, inhibition of DNA replication was greatly reduced. These results suggest that nucleosome assembly of the template inhibits initiation of SV40 DNA replication and that the inhibition can be overcome by formation of an initiation complex before nucleosome assembly.

Are nucleosomes positioned at DNA replication origins?

513596225274a5fb0700000d_002

no

The interactomes of POU5F1 and SOX2 enhancers in human embryonic stem cells. The genes POU5F1 and SOX2 are critical for pluripotency and reprogramming, yet the chromosomal organization around these genes remains poorly understood. We assayed long-range chromosomal interactions on putative enhancers of POU5F1 and SOX2 genes in human embryonic stem cells (hESCs) using 4C-Seq technique. We discovered that their frequent interacting regions mainly overlap with early DNA replication domains. The interactomes are associated with active histone marks and enriched with 5-hydroxymethylcytosine sites. In hESCs, genes within the interactomes have elevated expression. Additionally, some genes associated with the POU5F1 enhancer contribute to pluripotency. Binding sites for multiple DNA binding proteins, including ATF3, CTCF, GABPA, JUND, NANOG, RAD21 and YY1, are enriched in both interactomes. The RARG locus, frequently interacting with the POU5F1 locus, has abundant RAD21 binding sites co-localized with other protein binding sites. Thus the interactomes of these two pluripotency genes could be an important part of the regulatory network in hESCs.

Are there interactomes available for POU5F1 and SOX2?

56c85f675795f9a73e000013_000

yes

Modeling the dyadic effects of parenting, stress, and coping on parent-child communication in families tested for hereditary breast-ovarian cancer risk. Genetic testing for BRCA genes, associated with hereditary breast-ovarian cancer risk, is an accepted cancer control strategy. BRCA genetic testing has both medical and psychosocial implications for individuals seeking testing and their family members. However, promoting open and adaptive communication about cancer risk in the family is challenging for parents of minor children. Using prospective data collected from mothers undergoing BRCA genetic testing and their untested co-parents (N = 102 parenting dyads), we examined how maternal and co-parent characteristics independently and conjointly influenced the overall quality of parent-child communication with minor children. Statistical associations were tested in accordance with the Actor-Partner Interdependence Model. Significant Actor effects were observed among mothers, such that open parent-child communication prior to genetic testing was positively associated with open communication 6 months following receipt of genetic test results; and among co-parents, more open parent-child communication at baseline and greater perceived quality of the parenting relationship were associated with more open parent-child communication at follow-up. Partner effects were also observed: co-parents' baseline communication and confidence in their ability to communicate with their minor children about genetic testing was positively associated with open maternal parent-child communication at follow-up. These results demonstrate that for families facing the prospect of cancer genetic testing, perceptions and behaviors of both members of child-rearing couples have important implications for the overall quality of communication with their minor children, including communication about cancer risk.

Could BRCA gene test used for breast and ovarian cancer risk?

58a6bce660087bc10a000029_022

yes

Phospholamban modulates the functional coupling between nucleotide domains in Ca-ATPase oligomeric complexes in cardiac sarcoplasmic reticulum. Oligomeric interactions between Ca-ATPase polypeptide chains and their modulation by phospholamban (PLB) were measured in native cardiac sarcoplasmic reticulum (SR) microsomes. Progressive modification of Lys(514) with fluorescein 5-isothiocyanate (FITC), which physically blocks access to the nucleotide binding site by ATP, demonstrates that Ca-ATPase active sites function independently of one another prior to the phosphorylation of PLB. However, upon cAMP-dependent protein kinase (PKA) phosphorylation of PLB, a second-order dependence between residual enzyme activity and the fraction of active sites is observed, consistent with a dimeric functional complex. Complementary distance measurements were made using FITC or 5-iodoacetamidofluorescein (IAF) bound to Cys(674) within the N- or P-domains, respectively, to detect structural coupling within oligomeric complexes. Accompanying the phosphorylation of PLB, neighboring Ca-ATPase polypeptide chains exhibit a 4 +/- 2 A decrease in the proximity between FITC sites within the N-domain and a 9 +/- 3 A increase in the proximity between IAF sites within P-domains. Thus, the phosphorylation of PLB induces spatial rearrangements between the N- and P-domain elements of proximal Ca-ATPase polypeptide chains which restore functional interactions between neighboring polypeptide chains and, in turn, result in increased rates of catalytic turnover. These results are interpreted in terms of a structural model, calculated through optimization of shape complementarity, desolvation, and electrostatic energies, which suggests a dimeric arrangement of Ca-ATPase polypeptide chains through the proximal association of N-domains that accommodates interaction with PLB. We suggest that the phosphorylation of PLB acts to release constraints involving interdomain subunit interactions that enhance catalytically important N-domain motions.

Is phospholamban phosphorylated by Protein kinase A?

54da0c524b1fd0d33c00000b_004

yes

Monoubiquitylation in the Fanconi anemia DNA damage response pathway. The hereditary genetic disorder Fanconi anemia (FA) belongs to the heterogeneous group of diseases associated with defective DNA damage repair. Recently, several reviews have discussed the FA pathway and its molecular players in the context of genome maintenance and tumor suppression mechanisms [H. Joenje, K.J. Patel, The emerging genetic and molecular basis of Fanconi anaemia, Nat. Rev. Genet. 2 (2001) 446-457; W. Wang, Emergence of a DNA-damage response network consisting of Fanconi anaemia and BRCA proteins, Nat. Rev. Genet. 8 (2007) 735-748; L.J. Niedernhofer, A.S. Lalai, J.H. Hoeijmakers, Fanconi anemia (cross)linked to DNA repair, Cell 123 (2005) 1191-1198; K.J. Patel, Fanconi anemia and breast cancer susceptibility, Nat. Genet. 39 (2007) 142-143]. This review assesses the influence of post-translational modification by ubiquitin. We review and extract the key features of the enzymatic cascade required for the monoubiquitylation of the FANCD2/FANCI complex and attempt to include recent findings into a coherent mechanism. As this part of the FA pathway is still far from fully understood, we raise several points that must be addressed in future studies.

Is Fanconi anemia presented as a genetically and clinically heterogeneous disease entity?

54ede5c394afd61504000006_010

yes

[Pendred syndrome as a cause of familial deafness]. Pendred syndrome is an autosomal recessive disorder characterized by congenital deafness and goiter. The gene responsible for this syndrome is located on chromosome 7q31. The disorder is related to a defect in iodine organification, but the molecular basis of the defect remains unknown. We report two cases of Pendred syndrome, a young woman and her brother. The patients presented deafness, goiter that appeared in the prepubertal years, and a positive perchloriate discharge test. The genetic factors, clinical features, and diagnosis are reviewed.

Do patients with Pendred syndrome present congenital deafness?

56d8b27651531f7e33000003_019

yes

Simultaneous determination of 5-hydroxytryptophan and 3,4-dihydroxyphenylalanine in rat brain by HPLC with electrochemical detection following electrical stimulation of the dorsal raphe nucleus. HPLC coupled with electrochemical detection was used to make concurrent measurements of the rate of accumulation of 5-hydroxytryptophan and 3,4-dihydroxyphenylalanine in selected brain regions (striatum, nucleus accumbens, septum, medial periventricular hypothalamus) and thoracic spinal cords of rats treated with NSD 1015, an inhibitor of aromatic-L-amino-acid decarboxylase. 5-Hydroxytryptophan and 3,4-dihydroxyphenylalanine accumulated in all brain regions 30 min after the intravenous infusion of various doses of NSD 1015; there were no significant differences in the responses to 12.5, 25, 50, and 100 mg/kg. After the intravenous administration of 25 mg/kg NSD 1015 the concentrations of 5-hydroxytryptophan and 3,4-dihydroxyphenylalanine increased linearly with time in all brain regions for at least 30 min. Electrical stimulation of 5-hydroxytryptamine neurons in the dorsal raphe nucleus for 30 min at 5 or 10 Hz increased 5-hydroxytryptophan accumulation in all brain regions but not in the spinal cord. Unexpectedly, this stimulation also increased the accumulation of 3,4-dihydroxyphenylalanine in the hypothalamus and spinal cord. These results suggest that 5-hydroxytryptophan accumulation following the administration of NSD 1015 is a valid index of 5-hydroxytryptamine neuronal activity in the brain.

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

589c334e78275d0c4a00003d_017

yes

Relationship of thyroid stimulating hormone with coronary atherosclerosis in angina patients. BACKGROUND: In the previous recent reports, subclinical hypothyroidism is an independent risk factor for acute myocardial infarction in elderly women. It was not established whether a normal range of thyroid stimulating hormone (TSH) influences the presence of coronary atherosclerosis. We postulated that the level of TSH is risk factor of coronary atherosclerosis in angina patients who have normal thyroid function. METHODS: We studied 344 angina patients (62.5+/-9.72 years, male 50%) who underwent elective coronary angiography. TSH, free thyroxine, serum lipid levels and high-sensitivity C-reactive protein levels were measured and compared to the severity of coronary artery disease. RESULTS: In patients with high level of TSH (> or =2.1 microIU/mL), age (p=0.016), the levels of serum creatinine (p=0.004) and Gensini's score (p=0.016) were significantly higher than those in patients with low TSH levels. The incidence of multi-vessel disease was higher in patients with high TSH level (p=0.026). TSH level showed a significant correlation with age (r=0.109, p=0.044) and Gensini's score (r=0.117, p=0.045). The multivariate analysis revealed that age (OR 2.39, p=0.001), diabetes (OR 3.74, p=0.001), creatinine (OR 2.06, p=0.008), and smoking (OR 1.85, p=0.045) were independent predictors for significant coronary artery disease, but TSH level did not predict coronary artery stenosis. CONCLUSIONS: Although the high level of serum TSH is associated with multi-vessel disease, it was not the determinant of coronary artery disease in patients with normal range of thyroid function.

Is there a relationship between thyroid hormone altered metabolism and coronary artery disease?

531d1279b166e2b806000042_001

yes

Disomy 21 in spermatozoa and the paternal origin of trisomy 21 Down syndrome. BACKGROUND: Trisomy 21 Down syndrome is the most common genetic cause for congenital malformations and intellectual disability. It is well known that in the outstanding majority of cases the extra chromosome 21 originates from the mother but only in less than 10 % from the father. The mechanism underlying this striking difference in parental origin of Trisomy 21 Down syndrome is still unknown. However, it seems likely that the main reason is a much higher stringency in the elimination of any trisomy 21 cells during fetal testicular than ovarian development. We have here focussed attention on the paternal gametic output, i.e. the incidence of disomy 21 in spermatozoa. RESULTS: We have used fluorescence in situ hybridisation (FISH) to determine the copy number of chromosome 21 in spermatozoa from 11 men with normal spermiograms. Due to the well-known risk of false positive and false negative signals using a single FISH probe, we have applied two chromosome 21q probes, and we have added a chromosome 18-specific probe to allow differentiation between disomy 21 and diploidy. Analysing a total number of 2000 spermatozoa per case, we documented an average incidence of disomy 21 at 0.13 %, with a range of 0.00-0.25 % and a SD of 0.08. There was no indication of diploidy in this cohort of 22,000 sperm. CONCLUSION: Numerous previous studies on the incidence of disomy 21 in sperm have been published, using FISH. As far as we are aware, none of these have applied more than a single chromosome 21-specific probe. Accepting our mean of 0.13 % of disomy 21, and providing there is no selective fertilisation capability of disomy 21 sperm in relation to the normal, we conclude that around 1 in 800 conceptions is expected to be trisomic for chromosome 21 of paternal origin. Bearing in mind that the maternal origin likely is at least 10 times more common, we tentatively propose that around 1 in 80 oocytes in the maternal ovarian reserve may be disomy 21. One reason for this discrepancy may be a more stringent selection against aberrant chromosome numbers during spermatogenesis than oogenesis. Further work is required to determine the relevant stages of spermatogenesis at which such a selection may take place.

Down's syndrome occurs when an individual has an extra copy or part of a copy of chromosome 21, yes or no?

5a76016683b0d9ea6600000d_010

yes

Apremilast (Otezla). No progress in plaque psoriasis or psoriatic arthritis. When PUVA therapy and immunosuppressants such as methotrexate are ineffective, TNF alpha antagonists are an option for patients with severe plaque psoriasis, in the absence of a better alternative. This is also the case for patients with psoriatic arthritis after failure of a "disease-modifying" antirheumatic drug. Apremilast, an oral immunosuppressant that inhibits phosphodiesterase type 4, has been authorised in the European Union for use in these settings. In patients with plaque psoriasis, oral apremilast was compared with subcutaneous etanercept, aTNF alpha antagonist, in a randomised, doubleblind, placebo-controlled trial lasting 16 weeks and involving 250 patients in whom other treatments had failed or were inappropriate. This trial failed to show that apremilast was more effective than etanercept. And about one-quarter more patients experienced symptom relief compared with placebo. In patients with psoriatic arthritis, there are no clinical trials comparing apremilast with TNF alpha antagonists, and no interpretable trials of apremilast after failure of a TNF alpha antagonist. In three randomised, double-blind trials including a total of 1493 patients treated for 16 weeks, at least a modest improvement in joint status was reported in about 35% of patients treated with apremilast versus 19% with placebo. This would suggest that apremilast is less effective than a TNF alpha antagonist. In the trial versus etanercept, serious adverse events occurred in 3.6% of patients treated with apremilast versus 1.2% of those treated with the TNF alpha antagonist. The main adverse effects of apremilast are diarrhoea, nausea and vomiting, headache, sometimes marked weight loss, and infections. A risk of depression and cardiac arrhythmia must also be taken into account. A risk of cancer in the long-term is likely, given the immunosuppressive action of apremilast. Apremilast is a substrate of cytochrome P450 isoenzyme 3A4 and accumulates in patients with renal failure. This creates a risk of multiple pharmacokinetic interactions.

Is apremilast effective for psoriatic arthritis?

5896e22078275d0c4a000014_010

yes

Deep brain stimulation and ablation for obsessive compulsive disorder: evolution of contemporary indications, targets and techniques. Surgical therapy for treatment-resistant obsessive compulsive disorder (OCD) remains an effective option for well-selected patients managed within a multidisciplinary setting. Historically, lesions within the limbic system have been used to control both obsessive thoughts and repetitive compulsions associated with this disease. We discuss classical targets as well as contemporary neuromodulatory approaches that have been shown to provide symptomatic relief. Recently, deep brain stimulation (DBS) of the anterior limb of the internal capsule/ventral striatum received Conformité Européene (CE) mark and Food and Drug Administration (FDA) approvals for treatment of intractable OCD. Remarkably, this is the first such approval for neurosurgical intervention in a strictly psychiatric indication in modern times. This target is discussed in detail along with alternative targets currently being proposed. We close with a discussion of gamma knife capsulotomy, a modality with deep historical roots. Further directions in the surgical treatment of OCD will require better preoperative predictors of postoperative responses, optimal selection of individualized targets, and rigorous reporting of adverse events and standardized outcomes. To meet these challenges, centers must be equipped with a multidisciplinary team and patient-centered approach to ensure adequate screening and follow up of patients with this difficult-to-treat condition.

Is there a role for gamma knife in treatment of Obsessive-Compulsive Disorder?

5898500478275d0c4a000017_003

yes

Prospective study of carmustine wafers in combination with 6-month metronomic temozolomide and radiation therapy in newly diagnosed glioblastoma: preliminary results. OBJECT: Locoregional chemotherapy with carmustine wafers, positioned at surgery and followed by radiation therapy, has been shown to prolong survival in patients with newly diagnosed glioblastoma, as has concomitant radiochemotherapy with temozolomide. A combination of carmustine wafers with the Stupp treatment regimen has only been investigated in retrospective studies. METHODS: In a single-institution prospective study, the authors assessed 12-month progression-free survival (PFS), toxicity, and overall survival in patients with glioblastoma treated with surgery, carmustine wafers, radiotherapy, and 6-month metronomic temozolomide chemotherapy. Thirty-five patients with de novo glioblastoma, between the ages of 18 and 70 years, and with Karnofsky Performance Scale scores of at least 70, were included in the study. Patients were followed monthly and assessed using MRI every 2 months. RESULTS: After a median follow-up of 15 months, the median time to tumor progression was 12.5 months and median survival was 17.8 months. Due to toxicity (mostly hematological), 7 patients had to prematurely stop temozolomide treatment. Twenty-two patients developed Grade 3 CD4(+) lymphocytopenia. Three patients developed oral-esophageal candidiasis, 2 developed pneumonia, and 1 developed a dorsolumbar zoster. Early intracranial hypertension was observed in 1 patient, and 1 was treated empirically for suspected brain abscess. One patient died of Legionella pneumonia soon after repeat surgery. CONCLUSIONS: Overall, this treatment schedule produced promising results in terms of PFS without a marked increase in toxicities as compared with the Stupp regimen. However, the gain in median survival using this schedule was less clear. Only prospective comparative trials will determine whether these preliminary results will translate into a long-term survival advantage with an acceptable toxicity profile.

Do carmustine wafers improve survival of glioblastoma patients?

54d630283706e89528000004_022

yes

Iodine and tri-iodo-thyronine reduce the incidence of type 1 diabetes mellitus in the autoimmune prone BB rats. Thyroid hormones modulate the immune system and metabolism, influence insulin secretion, and cause decreased glucose tolerance. Thyroid hormones have been described to change the incidence of spontaneous autoimmune thyroiditis in Bio-Breeding/Worcester (BB) rats but it is unknown how these hormones affect the development of type 1 diabetes mellitus (T1DM). The aim was to investigate the influence of changes in thyroid function during postnatal development on the prevalence of T1DM in BB rats and the influence of T3 on the beta cell mass in non-diabetic Wistar rats. BB rats were treated with sodium iodine (NaI) or thyroid stimulating hormone (TSH) neonatally or with tri-iodo-thyronine (T3) during adolescence. At the age of 19 weeks the incidence of T1DM and the degree of insulitis were evaluated. The influence of T3 treatment on the beta cell mass was evaluated in Wistar rats by unbiased stereological methods. The incidence of T1DM in control BB rats was 68% at the age of 19 weeks. NaI and T3 reduced the incidence, whereas TSH had no effect. In Wistar rats T3 treatment increased the beta cell mass per bodyweight. The modulation of thyroid function during postnatal development may thus affect the precipitation of T1DM in genetically susceptible individuals.

Does triiodothyronine play a regulatory role in insulin secretion from pancreas?

51682382298dcd4e51000066_008

yes

Monoclonal antibody to desmin purified from cow Purkinje fibers reveals a cell-type specific determinant. We have raised monoclonal antibodies (Mab) to the Mr 55,000 desmin polypeptide, electrophoretically purified from cytoskeletal preparations of isolated bovine heart Purkinje fibers. One of the Mabs, 39AB6, revealed desmin only in cow Purkinje fibers and did not react with desmins from other muscle cells, including ventricular cardiac muscle, striated muscle and smooth muscle, as revealed by both immunoblotting and immunocytochemistry. Desphosphorylation of electrophoretically separated polypeptides on nitrocellulose with alkaline phosphatase did not affect the binding of the Mab. The present results show that there are cell-type specific antigenic determinants in intermediate proteins of the desmin type.

Are there any desmins present in plants?

5162e011298dcd4e51000049_001

no

Escherichia coli RecG and RecA proteins in R-loop formation. Escherichia coli rnhA mutants devoid of RNase HI exhibit constitutive stable DNA replication, cSDR, which is thought to be initiated from R-loops stabilized in the absence of RNase HI. We found that a combination of an rnhA and a recG mutation is lethal to the cell. recG mutations that inactivate the helicase activity of RecG protein and inhibit reverse branch migration of Holliday junctions impart phenotypes resembling those of rnhA mutants. Thus, recG mutants display cSDR activity, and recG polA double mutants are inviable as are rnhA polA double mutants. These results suggest that the RecG helicase has a role in preventing R-loop formation. A model that R-loops are formed by assimilation of RNA transcripts into the duplex DNA is discussed. The model further postulates that RecA protein catalyzes this assimilation reaction and that RecG protein counteracts RecA in this reaction, resolves R-loops by its helicase activity, or does both.

Do R-loops tend to form at sites of DNA replication?

56e2985951531f7e33000013_004

yes

A DOG's View of Fanconi Anemia: Insights from C. elegans. C. elegans provides an excellent model system for the study of the Fanconi Anemia (FA), one of the hallmarks of which is sensitivity to interstrand crosslinking agents. Central to our understanding of FA has been the investigation of DOG-1, the functional ortholog of the deadbox helicase FANCJ. Here we review the current understanding of the unique role of DOG-1 in maintaining stability of G-rich DNA in C. elegans and explore the question of why DOG-1 animals are crosslink sensitive. We propose a dynamic model in which noncovalently linked G-rich structures form and un-form in the presence of DOG-1. When DOG-1 is absent but crosslinking agents are present the G-rich structures are readily covalently crosslinked, resulting in increased crosslinks formation and thus giving increased crosslink sensitivity. In this interpretation DOG-1 is neither upstream nor downstream in the FA pathway, but works alongside it to limit the availability of crosslink substrates. This model reconciles the crosslink sensitivity observed in the absence of DOG-1 function with its unique role in maintaining G-Rich DNA and will help to formulate experiments to test this hypothesis.

Is hypersensitivity to DNA crosslinking agents a hallmark of Fanconi anemia?

54ecb66d445c3b5a5f000002_013

yes

Biology of PIWI-interacting RNAs: new insights into biogenesis and function inside and outside of germlines. PIWI-interacting RNAs (piRNAs) are endogenous small noncoding RNAs that act as guardians of the genome, protecting it from invasive transposable elements in the germline. Animals lacking piRNA functions show defects in gametogenesis and exhibit sterility. Their descendants are also predisposed to inheriting mutations. Thus, the piRNA pathway has evolved to repress transposons post-transcriptionally and/or transcriptionally. A growing number of studies on piRNAs have investigated piRNA-mediated gene silencing, including piRNA biogenesis. However, piRNAs remain the most enigmatic among all of the silencing-inducing small RNAs because of their complexity and uniqueness. Although piRNAs have been previously suggested to be germline-specific, recent studies have shown that piRNAs also play crucial roles in nongonadal cells. Furthermore, piRNAs have also recently been shown to have roles in multigenerational epigenetic phenomena in worms. The purpose of this review is to highlight new piRNA factors and novel insights in the piRNA world.

Are piRNAs involved in gene silencing?

56c6f6005795f9a73e000009_004

yes

Efficacy of perioperative oral triiodothyronine replacement therapy in patients undergoing off-pump coronary artery bypass grafting. OBJECTIVE: The aim of this study was to assess the effects of oral triiodothyronine (T3) therapy on postoperative thyroid hormone concentrations, hemodynamic variables, and outcomes. DESIGN: A prospective, randomized, controlled, double-blind study. SETTING: Cardiac operating room at a single institution. PARTICIPANTS: One hundred patients undergoing elective off-pump coronary artery bypass graft surgery. INTERVENTIONS: Patients received either 20 μg of oral T3 or placebo every 12 hours starting 20 minutes before anesthetic induction, for a total of 4 doses. MEASUREMENTS AND MAIN RESULTS: Plasma concentrations of thyroid hormones were measured serially before surgery, upon arrival in the intensive care unit, and 12, 24, and 36 hours after surgery. Hemodynamic variables also were recorded serially. Postoperative inotrope requirement and major morbidity endpoints were assessed. Serum T3 concentrations were significantly higher with fewer patients having T3 concentrations below the normal range in the T3 group than the placebo group throughout the postoperative period. Hemodynamic variables, postoperative inotrope requirement, and outcome variables showed no differences between the groups. CONCLUSIONS: Oral T3 therapy significantly attenuated the postoperative decline in T3 concentrations in patients undergoing off-pump coronary artery bypass graft surgery. The lack of apparent clinical benefit merits further investigations in patients with reduced cardiac performance.

Does administration of triiodothyronine improve outcome following coronary artery bypass grafting?

532673c4d6d3ac6a34000009_008

no

Comparison of Ewing's sarcoma of bone and peripheral neuroepithelioma. An immunocytochemical and ultrastructural analysis of two primitive neuroectodermal neoplasms. Ewing's sarcoma of bone (ESB) and peripheral neuroepithelioma (PN) are frequently considered to be different tumors. Some researchers have suggested that PN is morphologically a neuroectodermal Ewing's sarcoma. We sought to determine the extent of neuroectodermal features in conventional ESB on direct patient material (25 cases) and to compare these tumors with a similar group of readily diagnosed PNs (10 cases). Light microscopic, ultrastructural, and immunophenotypic parameters were assessed and compared for both groups. The avidin-biotin complex method was used. All tumors were antigenically intact since all stained for vimentin or at least one marker. Neuroectodermal antigens (neuron-specific enolase, Leu-7 [HNK-1], neurofilament 200 kd, and S100) were found in nine of 10 cases of PN and in 17 of 25 cases of ESB. In ESB, an atypical light microscopic appearance correlated with the presence of neuroectodermal features in most cases, but neuroectodermal phenotype was more frequent (68%) than morphological evidence of neuroectodermal differentiation (36%). These data support the concept that ESB and PN are both peripheral primitive neuroectodermal neoplasms, differing only in extent of neuroectodermal phenotype and morphological differentiation.

Is peripheral neuroepithelioma related to Ewing sarcoma?

552fa6f5bc4f83e828000002_005

yes

[Miller-Fisher syndrome: clinical features, associated infections and clinical course in 8 cases]. BACKGROUND AND OBJECTIVE: Miller-Fisher syndrome (MFS) is considered the most common variant of Guillain-Barré syndrome (GBS) and is characterized by the clinical triad of ophthalmoplegia, ataxia and areflexia. Respiratory involvement and relapses are unusual. Patients with MFS usually have a good recovery and no residual deficits. We describe the clinical features, associated infections and evolution in eight patients with MFS. PATIENTS AND METHOD: Eight cases of MFS and sixty-one of GBS were studied between 1994 and 2003. All cases showed the clinical triad of MFS without major limb weakness or other signs suggestive of CNS involvement. RESULTS: The proportion of MFS with respect to GBS during the same period was 13.1%. Four had a positive serology for Epstein-Barr virus, Salmonella enteritidis, Chlamydia pneumoniae and Mycoplasma pneumoniae. Our cases showed facial palsy (75%), dysphagia (75%), pupillary abnormalities (37.5%) and ventilation support (37.5%). Antiganglioside antibodies, determined in three cases (4 episodes), were positive [GQ1b (50%) and GD1b (50%)]. In all cases, there was a markedly reduced amplitude of the distal sensory as well as frequent axonal degeneration signs. The oldest three patients relapsed and required ventilation support. CONCLUSIONS: We report for the first time an association between S. enteritidis and C. pneumoniae and MFS. Older patients in our series suffered a faster disease progression with need of ventilation support. We conclude that an older age correlates with poor prognosis and relapses.

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

571f59cd0fd6f91b68000008_004

yes

Signaling pathway involved in cyclooxygenase-2 up-regulation by hepatocyte growth factor in endometrial cancer cells. Hepatocyte growth factor (HGF) is up-regulated in tissue repair and has been implicated in playing a role in this process through its anti-apoptotic and proliferative activities. Cyclooxygenase-2 (COX-2) is an inducible enzyme in the biosynthetic pathway of prostaglandins, and its activation has been shown to play an important role in cell growth. We previously reported that HGF significantly inhibited anoikis, possibly through the up-regulation of COX-2 expression in the endometrial RL95-2 cancer cell line. Here, we report that i) treatment of RL95-2 cells with HGF resulted in phosphorylation of the HGF receptor c-Met, activation of Akt and IκB, translocation of NF-κB into the nucleus, and up-regulation of COX-2 mRNA; ii) the IκB-α phosphorylation inhibitor BAY11-7082 and the selective COX-2 inhibitor CAY10452 blocked HGF-mediated anoikis resistance in RL95-2 cells; and iii) HGF induced migration and invasion in RL95-2 cells, while the phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 and CAY10452 blocked these effects of HGF stimulation. Our data suggest that HGF possesses chemotactic ability, has anti-apoptosis action, and induces cellular infiltration via the PI3K/Akt pathway; it also triggers NF-κB activation and up-regulates COX-2 gene expression in endometrial cancer cells.

Is c-met involved in the activation of the Akt pathway?

5318a955b166e2b806000020_017

yes

Metabolic ketoacidosis with normal blood glucose: A rare complication of sodium-glucose cotransporter 2 inhibitors. Ketoacidosis is a significant and often a life-threatening complication of diabetes mellitus seen mostly in type 1 diabetes mellitus as well as occasionally in type 2 diabetes mellitus. Diabetic ketoacidosis usually manifests with high blood glucose more than 250 mg/dL, but euglycemic diabetic ketoacidosis is defined as ketoacidosis associated with blood glucose level less than 250 mg/dL. Normal blood glucose in such patients results in significant delay in diagnosis and management of diabetic ketoacidosis, thus increasing mortality and morbidity. We present a case of euglycemic diabetic ketoacidosis secondary to canagliflozin in a type 2 diabetic patient.

Can canagliflozin cause euglycemic diabetic ketoacidosis?

5a6f922fb750ff4455000059_004

yes

Effect of Dark Chocolate Extracts on Phorbol 12-Myristate 13-Acetate-Induced Oxidative Burst in Leukocytes Isolated by Normo-Weight and Overweight/Obese Subjects. Oxidative and inflammatory stress represents a major risk factor for cardiovascular disease (CVD) in overweight and obese subjects. Between the different plant foods, chocolate has been shown to decrease CVD risk due to its antioxidant and anti-inflammatory properties. However, as we recently showed in epidemiological studies, meta-analyses, and human trials, dietary antioxidants resulted more effective in subjects characterized by an ongoing oxidative stress, than in healthy people. Aim of this work was to investigate the effect of different concentrations of chocolate phenolic extract (CPE) on in vitro free radical production, stimulated by phorbol 12-myristate 13-acetate (PMA), in leukocytes extracted from blood of normo-weight and overweight/obese subjects. Neutrophils from overweight/obese group had a significantly higher free radical production compared to the normo-weight group. In neutrophils, the lowest CPE concentration significantly reduced free radical production in overweight/obese group only, and higher CPE concentrations were effective in both groups. In monocytes, the CPE concentration that was significantly effective in reducing free radical production was lower in overweight/obese subjects than in normo-weight subjects. Chocolate polyphenol extracts inhibit oxidative burst in human neutrophils and monocytes with a higher efficiency in subjects characterized by an unphysiological oxidative/inflammatory stress, such as overweight and obese. Results of this study provide further evidence about a differential role of dietary antioxidant strictly related to the "stress" condition of the subjects.

Is the consumption of chocolate associated with an increase in cardiovascular disease?

5aa304f1d6d6b54f79000004_013

no

Genome sequence of a novel HIV-1 circulating recombinant form (CRF64_BC) identified from Yunnan, China. We report a novel HIV-1 circulating recombinant form (CRF64_BC) that was isolated from five epidemiologically unlinked HIV-infected persons in Yunnan province. CRF64_BC was composed of subtype B and subtype C, with five short subtype B segments inserted into the subtype C backbone. Phylogenetic analysis demonstrated that the C subregion was correlated with the India C lineage, which was transmitted into China in the early 1990s. The evolutionary history of the B subregion was not as clear as the C subregion, as the short length of this region yielded poor phylogenetic results. Dehong is considered the epicenter of HIV-1 in China, and recombinant strains such as CRF07_BC and CRF08_BC, which also originated from this region, have spread widely in China. The newly emerged CRF64_BC increases the complexity of the HIV epidemic in China and complicates the development of subtype-specific tools against HIV transmission.

Is there a phylogenetic analysis for HIV?

53354eafd6d3ac6a34000044_001

yes

A pilot study of an exercise & cognitive behavioral therapy intervention for epithelial ovarian cancer patients. BACKGROUND: Ovarian cancer has the highest mortality rate of all gynaecologic cancers. Faced with poor prognoses, stressful treatment effects and a high likelihood of recurrence, survivors must confront significant physical and psychological morbidities that negatively impact health-related quality of life. Frequently reported side effects include cancer-related fatigue, peripheral neuropathy, and psychological distress. Exercise and cognitive behavioral therapy interventions have counteracted such adverse effects in other cancer populations. OBJECTIVE: To investigate the feasibility and benefits of a 24-week home-based exercise intervention, coordinated with 12 weeks of cognitive behavioral therapy (two sessions per month), developed for two types of patients diagnosed with epithelial ovarian cancer: 1) those undergoing primary treatment with adjuvant chemotherapy after primary surgery; 2) those on surveillance after completing treatment within the last 2 years. METHODS: Participants were recruited from the Gynaecologic Oncology Clinic. Eligible participants completed baseline assessments and were provided with home-based exercise equipment. Cognitive behavioral therapy was provided every other week for patients via telephone. Assessments were completed at baseline (T1), 3 months (T2) and 6 months (T3). RESULTS: 19 of the 46 eligible patients approached were enrolled, with 7 patients in the treatment group and 12 in the surveillance group. There was a significant within group increase in peak VO2 from baseline to 6 months: F(2,16) = 5.531, p = 0.015, partial η2 = 0.409. CONCLUSION: The combined 6-month exercise-cognitive behavioral therapy intervention was associated with significant increases in aerobic fitness in epithelial ovarian cancer patients assessed. These improvements were similar regardless of whether the patient was receiving chemotherapy or under surveillance.

Can cognitive behavioral therapy improve fatigue in cancer patients?

54d762653706e89528000014_003

yes

[Cocaine and cerebrovascular disease in young adults]. INTRODUCTION AND OBJECTIVE: The use of cocaine has been increasingly associated with cerebrovascular disease specially in young adults. We review the cases of stroke related to cocaine abuse in this group. PATIENTS AND METHODS: We performed a retrospective study between 1989-1998. Data were obtained from the Young Adults Stroke Registry. To investigate the etiology of stroke all patients underwent cardiologic examination, coagulation and neuroimaging tests. RESULTS: We identified 13 patients under 45 years of age with stroke related to cocaine abuse (0.39% of all strokes and 7.60% of the ones in young adults). Mean age in this group was 28.30 years. Eight developed ischemic manifestations (5 infarcts, 2 TIAs and 1 encephalopathy with multiple ischemic lesions), 4 had intraparenchymal hemorrhages and 1 had a subarachnoid hemorrhage. The principal route of administration was intranasal and the time course from cocaine use to stroke ranged from several hours to several years. 61.53% had history of other drug abuse and in 84.61% other risk factors were identified. Angiographic studies demonstrated: arterial occlusions (3 cases), changes consistent with vasospasm (1), segmental narrowing (1) and arterial wall irregularities (1). No aneurysms or arterio-venous malformations were found. The frequency of cocaine-related stroke in young adults has decreased from 8.33% in 1989 to 5% in 1998. CONCLUSIONS: Cocaine is a well known cause of stroke, specially in young adults. In most cases other risk factors can be identified. Multiple overlapping mechanisms may be involved (vasospasm-thrombosis, high blood pressure, embolism.

Is cocaine use associated with increased risk for intracerebral hemorrhage?

5159b990d24251bc050000a3_004

yes

Intranasal clonidine as a premedicant: three cases with unique indications. Clonidine is experiencing increasing use in the pediatric population as a sedative and analgesic because of its central alpha2-adrenergic agonism. We report three cases of preoperative use of intranasal clonidine in pediatric patients, all for different indications. One patient was treated for preoperative agitation and hallucinations associated with oral midazolam. One patient was given clonidine as a premedicant. The third patient was treated for preoperative agitation and hypertension. All three patients had subjective resolution of indicated symptoms and none experienced adverse outcomes.

Can clonidine be used to reduce agitation in children.

515df89e298dcd4e5100002f_001

yes

Denosumab: recent update in postmenopausal osteoporosis. Postmenopausal osteoporosis is a major concern to public health. Fractures are the major clinical consequence of osteoporosis and are associated with substantial morbidity, mortality and health care costs. Bone strength determinants such as bone mineral density and bone quality parameters are determined by life-long remodeling of skeletal tissue. Receptor activator of nuclear factor-kB ligand (RANKL) is a cytokine essential for osteoclast differentiation, activation and survival. Denosumab (Prolia®) is a fully human monoclonal antibody for RANKL, which selectively inhibits osteoclastogenesis, being recently approved for the treatment of postmenopausal osteoporosis in women at a high or increased risk of fracture by the FDA in the United States and by the European Medicines Agency in Europe since June 2010. FREEDOM, DECIDE and STAND are the phase 3 trials comparing denosumab with placebo and alendronate in postmenopausal osteoporosis. The authors aim to update denosumab role in postmenopausal osteoporosis with a physiopathological review.

Has Denosumab (Prolia) been approved by FDA?

52bf1db603868f1b06000011_003

yes

Rucaparib: A Poly(ADP-Ribose) Polymerase Inhibitor for BRCA-Mutated Relapsed Ovarian Cancer. OBJECTIVE: To review the pharmacology, safety, efficacy, and the role of rucaparib in the treatment of relapsed, advanced ovarian cancer. SUMMARY: A total of 2 phase I/II trials and 1 phase II trial have evaluated the safety and efficacy of oral rucaparib in ovarian cancer. In patients with deleterious BRCA1/2 mutation, an overall response rate of 80% was achieved in the phase II trial Assessment of Rucaparib in Ovarian CancEr Trial 2 (ARIEL2). In the same trial, progression-free survival was higher in patients with BRCA1/2 mutation and BRCA wild types with high loss of heterozygosity (LOH) than BRCA wild types with low LOH. Rucaparib was found to be relatively well tolerated in clinical trials, with the most common adverse events being anemia, fatigue, and nausea. CONCLUSION: Rucaparib appears to be a safe and effective new option in the treatment of relapsed, advanced BRCA1/2 mutant ovarian cancer. The role of rucaparib in this setting will likely expand and be further elucidated as results from several ongoing studies become available.

Is Rucaparib effective for ovarian cancer?

5a7379a83b9d13c70800000a_006

yes

Polyadenylation of ribosomal RNA in human cells. The addition of poly(A)-tails to RNA is a process common to almost all organisms. In eukaryotes, stable poly(A)-tails, important for mRNA stability and translation initiation, are added to the 3' ends of most nuclear-encoded mRNAs, but not to rRNAs. Contrarily, in prokaryotes and organelles, polyadenylation stimulates RNA degradation. Recently, polyadenylation of nuclear-encoded transcripts in yeast was reported to promote RNA degradation, demonstrating that polyadenylation can play a double-edged role for RNA of nuclear origin. Here we asked whether in human cells ribosomal RNA can undergo polyadenylation. Using both molecular and bioinformatic approaches, we detected non-abundant polyadenylated transcripts of the 18S and 28S rRNAs. Interestingly, many of the post-transcriptionally added tails were composed of heteropolymeric poly(A)-rich sequences containing the other nucleotides in addition to adenosine. These polyadenylated RNA fragments are most likely degradation intermediates, as primer extension (PE) analysis revealed the presence of distal fragmented molecules, some of which matched the polyadenylation sites of the proximal cleavage products revealed by oligo(dT) and circled RT-PCR. These results suggest the presence of a mechanism to degrade ribosomal RNAs in human cells, that possibly initiates with endonucleolytic cleavages and involves the addition of poly(A) or poly(A)-rich tails to truncated transcripts, similar to that which operates in prokaryotes and organelles.

Is polyadenylation a process that stabilizes a protein by adding a string of Adenosine residues to the end of the molecule?

5a8714e261bb38fb24000005_006

no

[Normal pressure hydrocephalus in an elderly patient]. INTRODUCTION: Idiopathic normal pressure hydrocephalus is a disease that most frequently concerns subjects of an advanced age. It is not easy to establish a definitive diagnosis, and the practitioner frequently encounters decision-making problems regarding the following question: should a shunt be performed, or not? Opinions remain contradictory, even though the available scientific data is increasingly precise. The aim of this review is to analyze the physiopathogenic, clinical, paraclinical and therapeutic data associated with this type of hydrocephalus. CURRENT KNOWLEDGE AND KEY POINTS: If the clinical triad is determinant, no other investigation is in fact necessary to confirm the diagnosis, although it should always be questioned in the case of ventricular enlargement determined by tomodensitometry. The decision to perform the only efficient procedure, i.e., a ventricular shunt operation, depends upon a number of established arguments in favor of that procedure. Clinical improvement, which is often spectacular, can then confirm the diagnosis. FUTURE PROSPECTS AND PROJECTS: The efficacy of surgical treatment has been confirmed by clinical studies, and there is a reduced tendency as regards post-operative complications. However, each case should be considered individually and with the cooperation of and coordination between the family, the physician and the neurosurgeon.

Does ventriculoperitoneal shunt improve normal pressure hydrocephalus?

532627d0d6d3ac6a34000001_000

yes

Acute mitral regurgitation due to chordal rupture in a patient with neonatal Marfan syndrome caused by a deletion in exon 29 of the FBN1 gene. The neonatal Marfan syndrome is an autosomal dominantly inherited disease with an extremely poor prognosis. This report gives a clinical and echocardiographic description of an infant with a mutation in exon 29 of the fibrillin-1 gene (FBN1), a region in which this severe form of Marfan syndrome seems to cluster. The infant died at the age of 3 months due to severe acute mitral regurgitation leading to intractable heart failure.

Is Marfan syndrome associated with chordal rupture?

5a722a052dc08e987e000002_004

yes

[Molecular genetics of MTHFR: polymorphisms are not all benign]. Methylenetetrahydrofolate reductase (MTHFR) is a key regulatory enzyme in folate and homocysteine metabolism. Research performed during the past decade has clarified our understanding of MTHFR deficiencies that cause homocystinuria or mild hyperhomocysteinemia. Our cloning of the MTHFR coding sequence was initially followed by the identification of the first deleterious mutations in MTHFR, in patients with homocystinuria and marked hyperhomocysteinemia. Shortly thereafter, we identified the 677C-->T variant and showed that it encoded a thermolabile enzyme with reduced activity. Currently, a total of 41 rare but deleterious mutations in MTHFR, as well as about 60 polymorphisms have been reported. The 677C-->T (Ala222Val) variant has been particularly noteworthy since it has become recognized as the most common genetic cause of hyperhomocysteinemia. The disruption of homocysteine metabolism by this polymorphism influences risk for several complex disorders, including cardiovascular disease, neural tube defects and some cancers. We describe here the complex structure of the MTHFR gene, summarize the current state of knowledge on rare and common mutations in MTHFR and discuss some relevant findings in a mouse model for MTHFR deficiency.

Can methylenetetrahydrofolate reductase (MTHFR) gene mutations cause homocystinuria?

58d8d0cc8acda34529000008_014

yes

Pharmacogenetic risk for adverse reactions to irinotecan in the major ethnic populations of Singapore: regulatory evaluation by the health sciences authority. BACKGROUND: For genetic polymorphisms known to alter drug effect or safety, regulatory authorities can tap into population genomic databases and other sources of allele and genotype distribution data to make a more informed decision about the anticipated impact of such variants on the main ethnic groups in a country's population. OBJECTIVE: The aim of this short communication is to describe how the Singapore Health Sciences Authority (HSA) made use of allele and genotype distributions in the main ethnic groups in Singapore (Chinese, Malay, Indian) and population genetic tools to compare with North American Caucasians and Japanese. METHODS: Published papers and publicly accessible genomic databases were searched up to August 2009 to obtain allele and genotype frequencies for UGT1A1*6 and *28, two common variants of UGT1A1, a gene that encodes for a key enzyme in the pathway of irinotecan metabolism. These variants are associated with greater risk of serious toxicity. RESULTS: In Singapore, the combined prevalence of three high-risk genotypes, UGT1A1*6/*6, *6/*28 and *28/*28, is 9.7% in Chinese, 5.0% in Malays and 18.7% in Indians, compared with 11.5% in North American Caucasians and 8.1% in Japanese. Indians are at an elevated risk of irinotecan-induced neutropenia associated with UGT1A1*28 compared with Chinese and Japanese, and at an even higher risk compared with North American Caucasians. On the other hand, Chinese and Japanese are at an elevated risk of irinotecan-induced neutropenia associated with UGT1A1*6 relative to Indians in Singapore or North American Caucasians. Population genotype data were the basis for the HSA to request revision of the package insert from manufacturers of irinotecan products. Moreover, the data provided the impetus for the HSA to publicize the availability of UGT1A1 genetic testing at the National Cancer Centre. CONCLUSION: With the growing volume of genomic data and pharmacogenomic associations, a regulatory authority is now able to more readily utilize population genetic information and tools to supplement evaluations of drug products pertinent to the country's ethnic demography.

Is the UGT1A1*28 polymorphism associated with irinotecan response in Caucasians?

51680b0e298dcd4e51000065_000

yes

Malignant lymphomas in autoimmunity and inflammation: a review of risks, risk factors, and lymphoma characteristics. Certain autoimmune and chronic inflammatory conditions, such as Sjögren's syndrome and rheumatoid arthritis (RA), have consistently been associated with an increased risk of malignant lymphomas, but it is unclear whether elevated lymphoma risk is a phenomenon that accompanies inflammatory conditions in general. Likewise, it is debated whether the increased risk identified in association with some disorders pertains equally to all individuals or whether it varies among groups of patients with different phenotypic or treatment-related characteristics. It is similarly unclear to what extent the increased lymphoma occurrence is mediated through specific lymphoma subtypes. This update reviews the many findings on risks, risk levels, and lymphoma characteristics that have been presented recently in relation to a broad range of chronic inflammatory, including autoimmune, conditions. Recent results clearly indicate an association between severity of chronic inflammation and lymphoma risk in RA and Sjögren's syndrome. Thus, the average risk of lymphoma in RA may be composed of a markedly increased risk in those with most severe disease and little or no increase in those with mild or moderate disease. The roles of immunosuppressive therapy and EBV infection seem to be limited. Furthermore, RA, Sjögren's syndrome, systemic lupus erythematosus, and possibly celiac disease may share an association with risk of diffuse large B-cell lymphoma, in addition to well-established links of Sjögren's syndrome with risk of mucosa-associated lymphoid tissue lymphoma and of celiac disease with risk of small intestinal lymphoma. However, there is also obvious heterogeneity in risk and risk mediators among different inflammatory diseases.

Are patients with Sjogren syndrome at increased risk for lymphoma?

5a6f87c5b750ff4455000056_014

yes

TRPM2 contributes to antigen-stimulated Ca²⁺ influx in mucosal mast cells. Food allergy (FA) is a common allergic disease without any currently available effective drug therapies. Mucosal mast cells (MMCs) play a particularly important role in FA, and the increase in their cytosolic Ca(2+) concentration ([Ca(2+)]cyt) is considered to be a principal component of the degranulation process. However, the mechanisms governing Ca(2+) influx remain poorly understood in MMCs. Recent reports have highlighted the functions of the transient receptor potential melastatin 2 (TRPM2) channel in immunocytes, including its role in monocyte chemokine production and macrophage phagocytic activity. Although TRPM2 gene expression has been demonstrated in mast cells, the significance of such expression remains virtually unknown. In this study, we found that antigen-stimulated degranulation was significantly reduced in mucosal-type bone marrow-derived mast cells (mBMMCs) prepared from TRPM2-knockout (TRPM2-KO) mice (TRPM2-KO mBMMCs) and was suppressed following the administration of three TRPM2 inhibitors with different chemical structures, including econazole, flufenamic acid (FFA), and 2-aminoethoxydiphenyl borate. Furthermore, the antigen-stimulated increase in [Ca(2+)]cyt was significantly decreased in TRPM2-KO mBMMCs and was also suppressed by the TRPM2 inhibitors econazole and FFA. In addition, thapsigargin-induced increase in [Ca(2+)]cyt was significantly decreased in TRPM2-KO mBMMCs. These results suggest that TRPM2 may participate in antigen-induced extracellular Ca(2+) influx and subsequent degranulation. In addition, TRPM2 inhibitors were shown to improve food allergic reactions in a mouse model. Together, these results suggest that TRPM2 inhibitors suppress MMC degranulation via regulation of the increase in [Ca(2+)]cyt. Thus, TRPM2 may play a key role in degranulation by modulating intracellular Ca(2+) in MMCs.

The TRPM2 gene is associated with development of spontaneous thromboembolism?

5ab144fefcf4565872000012_000

no

[Trisomy 21 in visual art]. In 1866, J. Langdon Down published a paper on "an ethnic classification of idiots" and noted their facial resemblance with individuals of the Mongolian people. In 1959, J. Lejeune, M. Gautier, and R. Turpin demonstrated that the children with Down syndrome had an extra copy of chromosome 21. There is now a debate within the medical literature on the age of trisomy 21 as a disease affecting mankind. Since it was not described before 1866, some authors questioned whether this disease is an old or new condition in humans. Three methods of investigation are useful for demonstrating that trisomy 21 has been present in humans for a long time: the figuration of this condition in historical paintings, figurines, and pottery; its presence in old skeletal remains; and the origin of human chromosome 21 during primate phylogeny. Figurines strongly suggestive of trisomy 21 have been found in the Greco-Roman world, in many Central and South American pre-Columbian cultures, and in Khmer temples. In Europe, during the Renaissance, Italian and Flemish artists represented trisomy 21 in paintings of religious inspiration. Studies on the origin and pathology of chromosome 21 have shown that the ancestral human chromosome 21 arose 30-50 million years ago and that trisomy 21 has existed since time immemorial.

Down's syndrome occurs when an individual has an extra copy or part of a copy of chromosome 21, yes or no?

5a76016683b0d9ea6600000d_002

yes

Mechanisms coordinating ELAV/Hu mRNA regulons. The 5' and 3' untranslated regions (UTRs) of messenger RNAs (mRNAs) function as platforms that can determine the fate of each mRNA individually and in aggregate. Multiple mRNAs that encode proteins that are functionally related often interact with RNA-binding proteins (RBPs) and noncoding RNAs (ncRNAs) that coordinate their expression in time and space as RNA regulons within the ribonucleoprotein (RNP) infrastructure we term the ribonome. Recent ribonomic methods have emerged that can determine which mRNAs are bound and regulated by RBPs and ncRNAs, some of which act in combination to determine global outcomes. ELAV/Hu proteins bind to AU-rich elements (ARE) in mRNAs and regulate their stability from splicing to translation, and the ubiquitous HuR protein has been implicated in cancerous cell growth. Recent work is focused on mechanistic models of how ELAV/Hu proteins increase mRNA stability and translation by repressing microRNAs (miRs) and the RNA induced silencing complex (RISC) via ARE-based ribonucleosomes that may affect global functions of mRNA regulons.

Does HuR bind to the untranslated regions (UTRs) of mRNAs?

58ce69cd1f5fb2b734000003_003

yes

Effectiveness of antiangiogenic drugs in glioblastoma patients: A systematic review and meta-analysis of randomized clinical trials. BACKGROUND: glioblastomas are highly vascularized tumors and various antiangiogenic drugs have been investigated in clinical trials showing unclear results. We performed a systematic review and a meta-analysis to clarify and evaluate their effectiveness in glioblastoma patients. PATIENTS AND METHODS: we searched relevant published and unpublished randomized clinical trials analyzing antiangiogenic drugs versus chemotherapy in glioblastoma patients from January 2006 to January 2016 in MEDLINE, WEB of SCIENCE, ASCO, ESMO and SNO databases. RESULTS: fourteen randomized clinical trials were identified (7 with bevacizumab, 2 cilengitide, 1 enzastaurin, 1 dasatinib, 1 vandetanib, 1 temsirolimus, 1 cediranib) including 4330 patients. Antiangiogenic drugs showed no improvement in overall survival with a pooled HR of 1.00, a trend for an inferior outcome, in terms of overall survival, was observed in the group of patients receiving antiangiogenic drug alone compared to cytotoxic drug alone (HR=1.24, p=0.056). Bevacizumab did not improve overall survival. Twelve trials (4113 patients) were analyzed for progression-free survival. Among antiangiogenic drugs, only bevacizumab demonstrated an improvement of progression-free survival (HR=0.63, p<0.001), both alone (HR=0.60, p=0.003) or in combination to chemotherapy (HR=0.63; p<0.001), both as first-line treatment (HR=0.70, p<0.001) or in recurrent disease (HR=0.52, p<0.001). CONCLUSIONS: antiangiogenic drugs did not improve overall survival in glioblastoma patients, either as first or second-line treatment, and either as single agent or in combination with chemotherapy. Among antiangiogenic drugs, only bevacizumab improved progression-free survival regardless of treatment line, both as single agent or in combination with chemotherapy.

Is enzastaurin effective treatment of glioblastoma?

5a7612b483b0d9ea6600001d_002

no

γ-Secretase inhibitors and modulators for Alzheimer's disease. γ-Secretase is a membrane embedded aspartyl protease complex with presenilin as the catalytic component. Along with β-secretase, this enzyme produces the amyloid β-protein of Alzheimer's disease (AD) from the amyloid β-protein precursor. Because of its key role in the pathogenesis of AD, γ-secretase has been a prime target for drug discovery, and many inhibitors of this protease have been developed. The therapeutic potential of these inhibitors is virtually negated by the fact that γ-secretase is an essential part of the Notch signaling pathway, rendering the compounds unacceptably toxic upon chronic exposure. However, these compounds have served as useful chemical tools for biological investigations. In contrast, γ-secretase modulators continue to be of keen interest as possible AD therapeutics. These modulators either shift amyloid β-protein production to shorter, less pathogenic peptides or inhibit the proteolysis of amyloid β-protein precursor selectively compared to that of Notch. The various chemical types of inhibitors and modulators will be discussed, along with their use as probes for basic biology and their potential as AD therapeutics.

Is there any research that relates the function of Notch Signaling with Alzheimer Disease?

532bf6f2d6d3ac6a34000015_003

yes

Emerging treatments for ulcerative colitis: a systematic review. OBJECTIVES: Various investigational medicinal products have been developed for ulcerative colitis (UC). Our aim was to systematically evaluate novel pharmacological therapeutic agents for the treatment of UC. MATERIAL AND METHODS: Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) recommendations were followed. A search of the medical literature was conducted in the MEDLINE database for original research papers published between 01 January 2010 and 31 October 2014. RESULTS: Twenty one studies, including 11,524 adults were analyzed. Thirteen different novel therapeutic drug options were identified. Vedolizumab and golimumab were superior to placebo as induction and maintenance therapy. Tofacitinib showed dose related efficacy for induction therapy. Etrolizumab showed higher clinical remission rates compared to placebo. Phosphatidylcholine led to an improved clinical activity index. HMPL-004 may become a mesalamine alternative for mild to moderate UC. PF00547,659 was well tolerated. Statins were not beneficial for acute exacerbations of UC. Abatacept, rituximab and visilizumab did not lead to improved outcomes compared to placebo. Higher concentration of BMS 936557 was associated with improved efficacy compared to placebo. Basiliximab did not enhance corticosteroid efficacy. CONCLUSIONS: Patients with UC might achieve clinical response or remission by utilizing some of these agents with a favorable side effect profile. Further studies are needed to evaluate their short- and long-term efficacy and safety.

Is Tofacitinib effective for Ulcerative Colitis?

5a723edd2dc08e987e00000c_008

yes

Work performance of employees with depression: the impact of work stressors. PURPOSE: Depressed employees are vulnerable to adverse work outcomes. We hypothesized that work performance is impaired by depression and is worsened by exposure to psychosocial work stressors. DESIGN: Longitudinal cohort study with surveys administered at baseline, 6, 12, and 18 months. SETTING: Recruitment in primary care offices. SUBJECTS: A total of 14,268 were screened; 286 depressed, employed adults (18-62 years) and 193 controls were enrolled. MEASURES: At-work limitations (presenteeism) and absenteeism were measured with the Work Limitations Questionnaire (WLQ) and WLQ Work Absence Module, respectively. Work stressors were assessed using a modified version of the Job Content Questionnaire. ANALYSIS: Univariate and multivariate tests assessed the degree to which at-work limitations were related to depression and/or stressful work. RESULTS: Presenteeism and absenteeism were significantly worse for the depression group at each time point (p < or = .001). In cross-sectional models, presenteeism was associated with more severe depression symptoms, poorer general physical health, psychologically demanding work, the interaction ofpsychologically demanding work with depression, and less job control (r2 range = .33-.54). Absences were explained by depression symptom severity and poorer general physical health but not work stressors (r2 = .19). Because of minimal change in the work stressors, their longitudinal effects on outcomes were mostly nonsignificant. CONCLUSION: This study found that depression symptoms are related to work absences and impaired work performance, and results partly confirmed that work stressors add to this impact. Results suggest that workers with depression may benefit from care involving medical and vocational interventions.

Is there an association between presenteeism and depression?

54f49e56d0d681a040000004_009

yes

Acute effect of thyroid hormone on insulin secretion in rats. To elucidate the mechanism of thyroid hormone-induced hyperinsulinemia, the acute and direct effect of thyroid hormone administration on insulin secretion was investigated in rats in vivo and in vitro. In the perfused rat pancreas, the addition of thyroxine (10 micrograms/dL) or 3,5,3'-triiodothyronine (150 ng/dL) to the perfusing medium did not affect insulin secretion. The administration of thyroxine (40 micrograms/kg, s.c.) in vivo increased the plasma insulin level from 11 +/- 2 microUnits/mL (mean +/- SD) to 30 +/- 7 microUnits/mL, while blood glucose and plasma glucagon were unchanged. This phenomenon was inhibited completely by the preadministration of oxprenolol hydrochloride (2 mg/kg, s.c.), and inhibited partly by the preadministration of metoprolol tartrate (35 mg/kg, s.c.). These results suggest that thyroid hormone induces hyperinsulinemia via beta-adrenergic stimulation in the rat.

Does triiodothyronine play a regulatory role in insulin secretion from pancreas?

51682382298dcd4e51000066_004

yes

Resveratrol inhibits LXRα-dependent hepatic lipogenesis through novel antioxidant Sestrin2 gene induction. Liver X receptor-α (LXRα), a member of the nuclear receptor superfamily of ligand-activated transcription factors, regulates de novo fatty acid synthesis that leads to stimulate hepatic steatosis. Although, resveratrol has beneficial effects on metabolic disease, it is not known whether resveratrol affects LXRα-dependent lipogenic gene expression. This study investigated the effect of resveratrol in LXRα-mediated lipogenesis and the underlying molecular mechanism. Resveratrol inhibited the ability of LXRα to activate sterol regulatory element binding protein-1c (SREBP-1c) and thereby inhibited target gene expression in hepatocytes. Moreover, resveratrol decreased LXRα-RXRα DNA binding activity and LXRE-luciferase transactivation. Resveratrol is known to activate Sirtuin 1 (Sirt1) and AMP-activated protein kinase (AMPK), although its precise mechanism of action remains controversial. We found that the ability of resveratrol to repress T0901317-induced SREBP-1c expression was not dependent on AMPK and Sirt1. It is well established that hepatic steatosis is associated with antioxidant and redox signaling. Our data showing that expression of Sestrin2 (Sesn2), which is a novel antioxidant gene, was significantly down-regulated in the livers of high-fat diet-fed mice. Moreover, resveratrol up-regulated Sesn2 expression, but not Sesn1 and Sesn3. Sesn2 overexpression repressed LXRα-activated SREBP-1c expression and LXRE-luciferase activity. Finally, Sesn2 knockdown using siRNA abolished the effect of resveratrol in LXRα-induced FAS luciferase gene transactivation. We conclude that resveratrol affects Sesn2 gene induction and contributes to the inhibition of LXRα-mediated hepatic lipogenesis.

Is farnesoid X receptor (FXR) a nuclear receptor?

55263a1898daae017c000001_013

yes

Progesterone for acute traumatic brain injury. BACKGROUND: Traumatic brain injury is a leading cause of death and disability. Progesterone is a potential neuroprotective drug to treat patients with traumatic brain injury. OBJECTIVES: To assess the effectiveness and safety of progesterone in people with acute traumatic brain injury (TBI). SEARCH STRATEGY: We searched: the Cochrane Injuries Group's Specialised Register (to April 2010), Cochrane Central Register of Controlled Trials 2010, Issue 1 (The Cochrane Library), MEDLINE (Ovid) (1950 to April week 1 2010), EMBASE (Ovid) (1980 to week 14 2010), LILACS (to 17 April 2010 ), Zetoc (to 21 April 2010), Clinicaltrials.gov (17 April 2010 ), Controlled-trials.com (17 April 2010). SELECTION CRITERIA: We included published and unpublished randomised controlled trials (RCTs) of progesterone versus no progesterone (or placebo) for the treatment of acute TBI. DATA COLLECTION AND ANALYSIS: Two authors independently screened search results to identify the full texts of potentially relevant studies for inclusion. From the results of the screened searches two authors independently selected trials meeting the inclusion criteria, with no disagreement. MAIN RESULTS: Three studies were included with 315 patients. All three studies reported the effects of progesterone on mortality. The pooled relative risk (RR) for mortality at end of follow-up is 0.61, 95% confidence interval (CI) 0.40 to 0.93. Three studies measured disability and found the RR of death or severe disability in patients treated with progesterone was 0.77, 95% confidence interval (CI) 0.62 to 0.96. Two studies presented data on intracranial pressure and adverse events. One study presented blood pressure and temperature data. There was no substantial evidence for the presence of heterogeneity. AUTHORS' CONCLUSIONS: Current clinical evidence from three small RCTs indicates progesterone may improve the neurologic outcome of patients suffering TBI. This evidence is still insufficient and further multicentre randomised controlled trials are required.

Is progesterone effective for treatment of patients with traumatic brain injury based on clinical trial data?

54cf48acf693c3b16b00000b_000

no

Obstructive sleep apnea and its relationship to cardiac arrhythmias. Obstructive sleep apnea (OSA) affects approximately 4% of middle-aged men and 2% of middle-aged women. Cardiac arrhythmias are common problems in patients with OSA, even though the true prevalence and clinical relevance of cardiac arrhythmias remains to be determined. The presence and complexity of both tachyarrhythmias and bradyarrhythmias may influence morbidity, mortality, and the quality of life for OSA patients. Although the exact mechanisms underlying the link between OSA and cardiac arrhythmias are not well established, they could be partially the same proposed mechanisms relating OSA to different cardiovascular diseases. OSA is characterized by repetitive pharyngeal collapse during sleep that leads to markedly reduced or absent airflow, followed by oxyhemoglobin desaturation, persistent inspiratory efforts against an occluded airway, and termination by arousal from sleep. These mechanisms elicit a variety of autonomic, hemodynamic, humoral, and neuroendocrine responses that by themselves evoke acute and chronic changes in cardiovascular function. These effects may lead to the development of cardiac arrhythmias and any other form of cardiovascular disease linked to OSA. The aims of this review are to describe the essential cardiovascular pathophysiological aspects of OSA, to outline the relationship between OSA and both tachyarrhythmias and bradyarrhythmias and their possible influence in the natural history of OSA patients, and to assess the effects of OSA treatment on the presence of cardiac arrhythmias.

Are sleep apnea and snoring associated with cardiac arrhythmias?

5a981dd0fcd1d6a10c00002e_002

yes

Achondroplasia. Achondroplasia (MIM 100800) is the most common non-lethal skeletal dysplasia. Its incidence is between one in 10,000 and one in 30,000. The phenotype is characterized by rhizomelic disproportionate short stature, enlarged head, midface hypoplasia, short hands and lordotic lumbar spine, associated with normal cognitive development. This autosomal-dominant disorder is caused by a gain-of-function mutation in the gene encoding the type 3 receptor for fibroblast growth factor (FGFR3); in more than 95% of cases, the mutation is G380R. The diagnosis is suspected on physical examination and confirmed by different age-related radiological features. Anticipatory and management care by a multidisciplinary team will prevent and treat complications, including cervical cord compression, conductive hearing loss and thoracolumbar gibbosity. Weight counselling, psychosocial guidance and professional integration programmes play an important role in the global quality of life of these patients and their families.

Is Achondroplasia associated with hearing loss?

52b2efcb4003448f55000005_007

yes

ChIPnorm: a statistical method for normalizing and identifying differential regions in histone modification ChIP-seq libraries. The advent of high-throughput technologies such as ChIP-seq has made possible the study of histone modifications. A problem of particular interest is the identification of regions of the genome where different cell types from the same organism exhibit different patterns of histone enrichment. This problem turns out to be surprisingly difficult, even in simple pairwise comparisons, because of the significant level of noise in ChIP-seq data. In this paper we propose a two-stage statistical method, called ChIPnorm, to normalize ChIP-seq data, and to find differential regions in the genome, given two libraries of histone modifications of different cell types. We show that the ChIPnorm method removes most of the noise and bias in the data and outperforms other normalization methods. We correlate the histone marks with gene expression data and confirm that histone modifications H3K27me3 and H3K4me3 act as respectively a repressor and an activator of genes. Compared to what was previously reported in the literature, we find that a substantially higher fraction of bivalent marks in ES cells for H3K27me3 and H3K4me3 move into a K27-only state. We find that most of the promoter regions in protein-coding genes have differential histone-modification sites. The software for this work can be downloaded from http://lcbb.epfl.ch/software.html.

Does Chromatin Immunoprecipitation (ChIP) show a bias for highly expressed loci?

52ef6da1c8da898910000011_003

yes

Siltuximab: a new option for the management of Castleman's disease. Castleman's disease is a rare lymphoproliferative disorder the underlying mechanism of which remains unclear. However, interleukin-6 (IL-6) may play a role in the pathogenesis of the disease. Blockade of the IL-6 pathway has been explored in multiple preclinical and clinical studies with promising results for the treatment of different types of cancer and Castleman's disease. Siltuximab is a human/murine chimeric immunoglobulin G1kappa (IgG1kappa) monoclonal antibody against human IL-6. It binds to IL-6 neutralizing its biological activity. Recent phase II clinical studies in patients with multicentric Castleman's disease have shown the efficacy and safety of siltuximab in patients with this condition. Results from this study led to the recent approval of siltuximab for the treatment of Castleman's disease by the FDA and EMA.

Is siltuximab effective for Castleman disease?

5896d3e278275d0c4a000012_009

yes

Expression and function of Uc.160+, a transcribed ultraconserved region, in gastric cancer. BACKGROUND: Transcribed ultraconserved regions (T-UCRs) are a novel class of noncoding RNAs that are highly conserved among the orthologous regions in most vertebrates. It has been reported that T-UCRs have distinct signatures in human cancers. We previously discovered the downregulation of T-UCR expression in gastric cancer (GC), indicating that T-UCRs could play an important role in GC biology. Uc.160+, a T-UCR reported to be downregulated in human cancer, has not been examined in GC. METHODS: We analyzed the expression pattern of Uc.160+ in nonneoplastic and tumor tissues of the stomach by using uantitative reverse transcription polymerase chain reaction (qRT-PCR) and in situ hybridization (ISH), specifically focusing on the mechanism of transcriptional regulation and target genes that are regulated by T-UCRs. We also attempted to determine the effect of Uc.160+ expression on biological features of GC cell lines by Western blotting. RESULTS: On the basis of the qRT-PCR and ISH results, Uc.160+ expression in adenoma and GC tissues was clearly downregulated compared with that in nonneoplastic mucosa tissues of the stomach. Cancer-specific DNA methylation in the promoter region of Uc.160 was observed by bisulfite genomic DNA sequencing analysis. The effect of DNA methylation on Uc.160+ expression was further confirmed by reporter gene assay. We also revealed that Uc.160+ inhibited the phosphorylation of Akt by regulating phosphatase and tensin homolog (PTEN) expression. CONCLUSIONS: These results indicate that Uc.160+ could possibly have a tumor suppressive role in GC.

Does Uc.160 promote cancer?

5a6d2558b750ff4455000036_000

no

RNA-induced silencing complex (RISC) Proteins PACT, TRBP, and Dicer are SRA binding nuclear receptor coregulators. The cytoplasmic RNA-induced silencing complex (RISC) contains dsRNA binding proteins, including protein kinase RNA activator (PACT), transactivation response RNA binding protein (TRBP), and Dicer, that process pre-microRNAs into mature microRNAs (miRNAs) that target specific mRNA species for regulation. There is increasing evidence for important functional interactions between the miRNA and nuclear receptor (NR) signaling networks, with recent data showing that estrogen, acting through the estrogen receptor, can modulate initial aspects of nuclear miRNA processing. Here, we show that the cytoplasmic RISC proteins PACT, TRBP, and Dicer are steroid receptor RNA activator (SRA) binding NR coregulators that target steroid-responsive promoters and regulate NR activity and downstream gene expression. Furthermore, each of the RISC proteins, together with Argonaute 2, associates with SRA and specific pre-microRNAs in both the nucleus and cytoplasm, providing evidence for links between NR-mediated transcription and some of the factors involved in miRNA processing.

Is Dicer part of the RISC loading complex?

5516fc8832767d0305000002_003

yes

Sarcolipin overexpression in rat slow twitch muscle inhibits sarcoplasmic reticulum Ca2+ uptake and impairs contractile function. Sarcolipin (SLN) is an inhibitor of sarco(endo)plasmic reticulum Ca(2+)-ATPases (SERCAs) in vitro, but its function in vivo has not been defined. NF-SLN cDNA (SLN tagged N-terminally with a FLAG epitope) was introduced into rat soleus muscle in one hindlimb by plasmid injection and electrotransfer. Western blotting showed expression and co-immunoprecipitation showed physical interaction between NF-SLN and SERCA2a. Contractile properties and SERCA2a function were assessed and compared with vector-injected contralateral soleus muscles. NF-SLN reduced both peak twitch force (P(t)) (123.9 +/- 12.5 versus 69.8 +/- 8.9 millinewtons) and tetanic force (P(o)) (562.3 +/- 51.0 versus 300.7 +/- 56.9 millinewtons) and reduced both twitch and tetanic rates of contraction (+dF/dt) and relaxation (-dF/dt) significantly. Repetitive stimulation (750-ms trains at 50 Hz once every 2 s for 3 min) showed that NF-SLN increased susceptibility to fatigue. These changes in contractile function were observed in the absence of endogenous phospholamban, and NF-SLN had no effect on either SERCA2a or SERCA1a expression levels. NF-SLN also decreased maximal Ca(2+) transport activity at pCa 5 by 31% with no significant change in apparent Ca(2+) affinity (6.36 +/- 0.07 versus 6.39 +/- 0.08 pCa units). These results show that NF-SLN expression impairs muscle contractile function by inhibiting SERCA function and diminishing sarcoplasmic reticulum Ca(2+) stores.

Is Sarcolipin a regulatory/inhibitory protein of the Calcium ATPase SERCA?

55016397e9bde69634000006_017

yes

Ultraviolet-A and -B differentially modify the tyrosine-kinase profile of human keratinocytes and induce the expression of Arg+. To investigate the expression profile of protein tyrosine kinases (PTKs) in normal human epidermal keratinocytes (NHEK) in response to UVA and UVB we employed a reversed transcriptase polymerase chain reaction (PCR) approach using degenerate primers derived from the conserved catalytic domain of PTKs. Quantitative real-time PCR with specific primers was used to confirm the influence of UV on the expression of the identified PTKs. Arg (Abelson-related gene, Abl2) was the PTK with the highest prevalence (30% of all PTKs) and UVA led to a further induction of Arg expression reaching nine-fold mRNA baseline expression at 17 h after irradiation. UVB was followed by an initial downregulation and a subsequent increase in Arg mRNA reaching five-fold baseline levels after 24 h. We conclude that UVA and UVB differentially modify the expression of PTKs in NHEK, and that Arg appears to have a major role in the response of keratinocytes to UV. These results provide a basis for further studies of PTK in UV-induced signaling that regulates protective responses, cell growth and carcinogenesis in the skin.

Does the Abelson-related gene (ARG) gene encode for a serine kinase?

58db94948acda34529000017_001

no