Studies of α-Helicity and Intersegmental Interactions in Voltage-Gated Na+ Channels: S2D4

Much data, including crystallographic, support structural models of sodium and potassium channels consisting of S1–S4 transmembrane segments (the “voltage-sensing domain”) clustered around a central pore-forming region (S5–S6 segments and the intervening loop). Voltage gated sodium channels have four non-identical domains which differentiates them from the homotetrameric potassium channels that form the basis for current structural models. Since potassium and sodium channels also exhibit many different functional characteristics and the fourth domain (D4) of sodium channels differs in function from other domains (D1–D3), we have explored its structure in order to determine whether segments in D4 of sodium channels differ significantly from that determined for potassium channels. We have probed the secondary and tertiary structure and the role of the individual amino acid residues of the S2D4) of Nav1.4 by employing cysteine-scanning mutagenesis (with tryptophan and glutamine substituted for native cysteine). A Fourier transform power spectrum of perturbations in free energy of steady-state inactivation gating (using midpoint potentials and slopes of Boltzmann equation fits of channel availability, h∞-V plots) indicates a substantial amount of α-helical structure in S2D4 (peak at 106°, α-Periodicity Index (α-PI) of 3.10), This conclusion is supported by α-PI values of 3.28 and 2.84 for the perturbations in rate constants of entry into (β) and exit from (α) fast inactivation at 0 mV for mutant channels relative to WT channels assuming a simple two-state model for transition from the open to inactivated state. The results of cysteine substitution at the two most sensitive sites of the S2D4 α-helix (N1382 and E1392C) support the existence of electrostatic network interactions between S2 and other transmembrane segments within Nav1.4D4 similar to but not identical to those proposed for K+ channels

Sirenomelia in a Nigerian triplet: a case report

<p>Abstract</p> <p>Introduction</p> <p>Sirenomelia, also known as mermaid syndrome, is a very rare fatal congenital abnormality in which the legs are fused together, giving them the appearance of a mermaid's tail. It is commonly associated with abnormal kidney development, genital and rectal abnormalities. A handful of cases have been reported in other parts of the world, however, no cases have previously been reported in a Nigerian neonate. To the best of our knowledge, we believe that this is the first case reported from West Africa and in a triplet.</p> <p>Case presentation</p> <p>A 16-hour-old baby boy, the second of a set of Nigerian triplets, presented to our facility with fusion of the entire lower limbs, imperforate anus, indiscernible genital structures, single umbilical artery and a neural tube defect. His parents were from the Hausa ethnic group and not related.</p> <p>Conclusion</p> <p>Sirenomelia has not been previously described in a set of triplets, and it is hoped that this report from West Africa will give information about the non-racial predilection of this condition.</p

Evaluation of Staphylococcus aureus Nasal Carriage Screening before Vascular Surgery

INTRODUCTION: Staphylococcus aureus is the most important pathogen in the development of surgical site infections (SSI). Patients who carry S. aureus in the nose are at increased risk for the development of SSI in cardiothoracic and orthopedic surgery. In these populations it has been shown that the risk for SSI can be substantially reduced by eradicating S. aureus carriage. For vascular surgery the relation between nasal carriage and surgical site infections has not been clearly investigated. For this reason we performed this study to analyze the relation between S. aureus nasal carriage and SSI in our vascular surgery population. METHODS: A prospective cohort study was undertaken, including all patients undergoing vascular surgery between January first 2010 and December 31th 2010. Before surgery patients were screened for S. aureus nasal carriage using a PCR technique. The presence of SSI was recorded based on criteria of the CDC. RESULTS: Screening was performed in 224. Of those, 55 (24.5%) were positive, 159 (71.0%) were negative and 10 (4.5%) were inconclusive. In the screened vascular population 4 S. aureus SSI occurred in the 55 carriers compared with 6 in 159 non-carriers (p=0.24). A stratified analysis revealed a 10-fold increased risk in nasal carriers undergoing central reconstruction surgery (3 S. aureus SSI in 20 procedures versus 1 in 65 procedures in non-carriers, p=0.039). DISCUSSION: In patients undergoing central reconstruction surgery nasals carriers are at increased risk for the development of S. aureus SSI. These patients will probably benefit from perioperative treatment to eradicate nasal carriage

Characterization of a new pathway that activates lumisterol <i>in vivo</i> to biologically active hydroxylumisterols

Abstract Using LC/qTOF-MS we detected lumisterol, 20-hydroxylumisterol, 22-hydroxylumisterol, 24-hydroxylumisterol, 20,22-dihydroxylumisterol, pregnalumisterol, 17-hydroxypregnalumisterol and 17,20-dihydroxypregnalumisterol in human serum and epidermis, and the porcine adrenal gland. The hydroxylumisterols inhibited proliferation of human skin cells in a cell type-dependent fashion with predominant effects on epidermal keratinocytes. They also inhibited melanoma proliferation in both monolayer and soft agar. 20-Hydroxylumisterol stimulated the expression of several genes, including those associated with keratinocyte differentiation and antioxidative responses, while inhibiting the expression of others including RORA and RORC. Molecular modeling and studies on VDRE-transcriptional activity excludes action through the genomic site of the VDR. However, their favorable interactions with the A-pocket in conjunction with VDR translocation studies suggest they may act on this non-genomic VDR site. Inhibition of RORα and RORγ transactivation activities in a Tet-on CHO cell reporter system, RORα co-activator assays and inhibition of (RORE)-LUC reporter activity in skin cells, in conjunction with molecular modeling, identified RORα and RORγ as excellent receptor candidates for the hydroxylumisterols. Thus, we have discovered a new biologically relevant, lumisterogenic pathway, the metabolites of which display biological activity. This opens a new area of endocrine research on the effects of the hydroxylumisterols on different pathways in different cells and the mechanisms involved

Predicting Hospital-Acquired Infections by Scoring System with Simple Parameters

BACKGROUND: Hospital-acquired infections (HAI) are associated with increased attributable morbidity, mortality, prolonged hospitalization, and economic costs. A simple, reliable prediction model for HAI has great clinical relevance. The objective of this study is to develop a scoring system to predict HAI that was derived from Logistic Regression (LR) and validated by Artificial Neural Networks (ANN) simultaneously. METHODOLOGY/PRINCIPAL FINDINGS: A total of 476 patients from all the 806 HAI inpatients were included for the study between 2004 and 2005. A sample of 1,376 non-HAI inpatients was randomly drawn from all the admitted patients in the same period of time as the control group. External validation of 2,500 patients was abstracted from another academic teaching center. Sixteen variables were extracted from the Electronic Health Records (EHR) and fed into ANN and LR models. With stepwise selection, the following seven variables were identified by LR models as statistically significant: Foley catheterization, central venous catheterization, arterial line, nasogastric tube, hemodialysis, stress ulcer prophylaxes and systemic glucocorticosteroids. Both ANN and LR models displayed excellent discrimination (area under the receiver operating characteristic curve [AUC]: 0.964 versus 0.969, p = 0.507) to identify infection in internal validation. During external validation, high AUC was obtained from both models (AUC: 0.850 versus 0.870, p = 0.447). The scoring system also performed extremely well in the internal (AUC: 0.965) and external (AUC: 0.871) validations. CONCLUSIONS: We developed a scoring system to predict HAI with simple parameters validated with ANN and LR models. Armed with this scoring system, infectious disease specialists can more efficiently identify patients at high risk for HAI during hospitalization. Further, using parameters either by observation of medical devices used or data obtained from EHR also provided good prediction outcome that can be utilized in different clinical settings

Epidemiology of nausea and vomiting of pregnancy: prevalence, severity, determinants, and the importance of race/ethnicity

<p>Abstract</p> <p>Background</p> <p>Studies that contributed to the epidemiology of nausea and vomiting of pregnancy have reported conflicting findings, and often failed to account for all possible co-variables necessary to evaluate the multidimensional associations. The objectives of this study were to: 1) Estimate the prevalence and the severity of nausea and vomiting of pregnancy during the 1^stand the 2^ndtrimester of pregnancy, and 2) Identify determinants of presence and severity of nausea and vomiting of pregnancy during the 1^stand 2^ndtrimesters separately, with a special emphasis on the impact of race/ethnicity.</p> <p>Methods</p> <p>A prospective study including pregnant women attending the Centre Hospitalier Universitaire (CHU) Sainte-Justine or René-Laennec clinics for their prenatal care was conducted from 2004 to 2006. Women were eligible if they were ≥ 18 years of age, and ≤ 16 weeks of gestation. Women were asked to fill out a 1^sttrimester self-administered questionnaire and were interviewed over the telephone during their 2^ndtrimester of pregnancy. Presence of nausea and vomiting of pregnancy was based on the reporting of pregnant women (yes/no); severity of symptoms was measured by the validated modified-PUQE index.</p> <p>Results</p> <p>Of the 367 women included in the study, 81.2% were Caucasians, 10.1% Blacks, 4.6% Hispanics, and 4.1% Asians. Multivariate analyses showed that race/ethnicity was significantly associated with a decreased likelihood of reporting nausea and vomiting of pregnancy (Asians vs. Caucasians OR: 0.13; 95%CI 0.02–0.73; and Blacks vs. Caucasians OR: 0.29; 95%CI 0.09–0.99).</p> <p>Conclusion</p> <p>Our study showed that race/ethnicity was associated with the reporting of nausea and vomiting of pregnancy in the 1^sttrimester of pregnancy.</p

Recent Advances in the Diagnosis and Treatment of Influenza Pneumonia

A potentially fatal complication of influenza infection is the development of pneumonia, caused either directly by the influenza virus, or by secondary bacterial infection. Pneumonia related to the 2009 influenza A pandemic was found to be underestimated by commonly used pneumonia severity scores in many cases, and to be rapidly progressive, leading to respiratory failure. Confirmation of etiology by laboratory testing is warranted in such cases. Rapid antigen and immunofluorescence testing are useful screening tests, but have limited sensitivity. Confirmation of pandemic H1N1 influenza A infection can only be made by real-time reverse-transcriptase polymerase chain reaction (rRT-PCR) or viral culture. The most effective preventive measure is annual influenza vaccination in selected individuals. Decisions to administer antiviral medications for influenza treatment or chemoprophylaxis should be based upon clinical and epidemiological factors, and should not be delayed by confirmatory laboratory testing results. Neuraminidase inhibitors (NI) are the agents of choice

ABJ theory in the higher spin limit

This article is distributed under the terms of the Creative Commons Attribution License (CC-BY 4.0), which permits any use, distribution and reproduction in any medium, provided the original author(s) and source are creditedArticle funded by SCOAP3 .Article funded by SCOAP3 .The work of SH was supported in part by the National Research Foundation of South Africa and DSTNRF Centre of Excellence in Mathematical and Statistical Sciences (CoE-MaSS). Opinions expressed and conclusions arrived at are those of the author and are not necessarily to be attributed to the NRF or the CoE-MaSS. The work of KO was supported in part by JSPS Grant-in-Aid for Young Scientists (B) 23740178. MS is grateful to the Weizmann Institute for the stimulating environment at the “Black Holes and Quantum Information” workshop. The work of MS was supported in part by Grant-in-Aid for Young Scientists (B) 24740159 from the Japan Society for the Promotion of Science (JSPS)

Comparing methods to estimate treatment effects on a continuous outcome in multicentre randomized controlled trials: A simulation study

<p>Abstract</p> <p>Background</p> <p>Multicentre randomized controlled trials (RCTs) routinely use randomization and analysis stratified by centre to control for differences between centres and to improve precision. No consensus has been reached on how to best analyze correlated continuous outcomes in such settings. Our objective was to investigate the properties of commonly used statistical models at various levels of clustering in the context of multicentre RCTs.</p> <p>Methods</p> <p>Assuming no treatment by centre interaction, we compared six methods (ignoring centre effects, including centres as fixed effects, including centres as random effects, generalized estimating equation (GEE), and fixed- and random-effects centre-level analysis) to analyze continuous outcomes in multicentre RCTs using simulations over a wide spectrum of intraclass correlation (ICC) values, and varying numbers of centres and centre size. The performance of models was evaluated in terms of bias, precision, mean squared error of the point estimator of treatment effect, empirical coverage of the 95% confidence interval, and statistical power of the procedure.</p> <p>Results</p> <p>While all methods yielded unbiased estimates of treatment effect, ignoring centres led to inflation of standard error and loss of statistical power when within centre correlation was present. Mixed-effects model was most efficient and attained nominal coverage of 95% and 90% power in almost all scenarios. Fixed-effects model was less precise when the number of centres was large and treatment allocation was subject to chance imbalance within centre. GEE approach underestimated standard error of the treatment effect when the number of centres was small. The two centre-level models led to more variable point estimates and relatively low interval coverage or statistical power depending on whether or not heterogeneity of treatment contrasts was considered in the analysis.</p> <p>Conclusions</p> <p>All six models produced unbiased estimates of treatment effect in the context of multicentre trials. Adjusting for centre as a random intercept led to the most efficient treatment effect estimation across all simulations under the normality assumption, when there was no treatment by centre interaction.</p

The association of hyperglycaemia and insulin resistance with incident depressive symptoms over 4 years of follow-up: The Maastricht Study.

AIMS/HYPOTHESIS: Depression is twice as common in individuals with type 2 diabetes as in the general population. However, it remains unclear whether hyperglycaemia and insulin resistance are directly involved in the aetiology of depression. Therefore, we investigated the association of markers of hyperglycaemia and insulin resistance, measured as continuous variables, with incident depressive symptoms over 4 years of follow-up. METHODS: We used data from the longitudinal population-based Maastricht Study (n = 2848; mean age 59.9 ± 8.1 years, 48.8% women, 265 incident depression cases, 10,932 person-years of follow-up). We assessed hyperglycaemia by fasting and 2 h post-load OGTT glucose levels, HbA1c and skin autofluorescence (reflecting AGEs) at baseline. We used the Matsuda insulin sensitivity index and HOMA-IR to calculate insulin resistance at baseline. Depressive symptoms (nine-item Patient Health Questionnaire score ≥10) were assessed at baseline and annually over 4 years. We used Cox regression analyses, and adjusted for demographic, cardiovascular and lifestyle risk factors. RESULTS: Fasting plasma glucose, 2 h post-load glucose and HbA1c levels were associated with an increased risk for incident depressive symptoms after full adjustment (HR 1.20 [95% CI 1.08, 1.33]; HR 1.25 [1.08, 1.44]; and HR 1.22 [1.09, 1.37] per SD, respectively), while skin autofluorescence, insulin sensitivity index and HOMA-IR were not (HR 0.99 [0.86, 1.13]; HR 1.02 [0.85, 1.25]; and HR 0.93 [0.81, 1.08], per SD, respectively). CONCLUSIONS/INTERPRETATION: The observed temporal association between hyperglycaemia and incident depressive symptoms in this study supports the presence of a mechanistic link between hyperglycaemia and the development of depressive symptoms. Graphical abstract