Regulation of Pancreatic Beta Cell Stimulus-Secretion Coupling by microRNAs.

Increased blood glucose after a meal is countered by the subsequent increased release of the hypoglycemic hormone insulin from the pancreatic beta cells. The cascade of molecular events encompassing the initial sensing and transport of glucose into the beta cell, culminating with the exocytosis of the insulin large dense core granules (LDCVs) is termed "stimulus-secretion coupling." Impairment in any of the relevant processes leads to insufficient insulin release, which contributes to the development of type 2 diabetes (T2D). The fate of the beta cell, when exposed to environmental triggers of the disease, is determined by the possibility to adapt to the new situation by regulation of gene expression. As established factors of post-transcriptional regulation, microRNAs (miRNAs) are well-recognized mediators of beta cell plasticity and adaptation. Here, we put focus on the importance of comprehending the transcriptional regulation of miRNAs, and how miRNAs are implicated in stimulus-secretion coupling, specifically those influencing the late stages of insulin secretion. We suggest that efficient beta cell adaptation requires an optimal balance between transcriptional regulation of miRNAs themselves, and miRNA-dependent gene regulation. The increased knowledge of the beta cell transcriptional network inclusive of non-coding RNAs such as miRNAs is essential in identifying novel targets for the treatment of T2D

What predicts mental health literacy among school teachers?

Objectives: The present study aimed at assessing high school teachers’ mental health literacy (MHL) and predictors related to study outcomes.Design: Cross-sectional studyMethods: We employed 460 high school teachers who engaged with adolescents for at least six hours per week with a minimum of five years of teaching experience in southern India. Semi-structured questionnaires were used to assess their MHL. Descriptive analysis and backward logistic regression analysis were performed. A p-value < 0.05 was set as significant.Results: Teachers’ MHL on depression was less than desirable; however, they identified 288 (62.6%) adolescents with mental health problems during their career, and 172(59.72%) were referred to mental health professionals. On logistic regression analysis, teachers’ educational status, their marital status, teaching a class with an average strength of 31-60 students per class, previous mental health training and having self-efficacy concerning seeking informationon mental health, perceived ability to spread awareness and to provide referrals were found to predict MHL among teachers.Conclusion: Sociodemographic factors including teachers’ educational status, average class strength and having had previous mental health training were predictors for MHL among high school teachers. Establishing training programs and referral networks may be key in early intervention among adolescents

Atrial Tachycardias Arising from Ablation of Atrial Fibrillation: A Proarrhythmic Bump or an Antiarrhythmic Turn?

The occurrence of atrial tachycardias (AT) is a direct function of the volume of atrial tissue ablated in the patients with atrial fibrillation (AF). Thus, the incidence of AT is highest in persistent AF patients undergoing stepwise ablation using the strategic combination of pulmonary vein isolation, electrogram based ablation and left atrial linear ablation. Using deductive mapping strategy, AT can be divided into three clinical categories viz. the macroreentry, the focal and the newly described localized reentry all of which are amenable to catheter ablation with success rate of 95%. Perimitral, roof dependent and cavotricuspid isthmus dependent AT involve large reentrant circuits which can be successfully ablated at the left mitral isthmus, left atrial roof and tricuspid isthmus respectively. Complete bidirectional block across the sites of linear ablation is a necessary endpoint. Focal and localized reentrant AT commonly originate from but are not limited to the septum, posteroinferior left atrium, venous ostia, base of the left atrial appendage and left mitral isthmus and they respond quickly to focal ablation. AT not only represents ablation-induced proarrhythmia but also forms a bridge between AF and sinus rhythm in longstanding AF patients treated successfully with catheter ablation

Wirkungsanalyse bestehender Klimaschutzmaßnahmen und -programme sowie Identifizierung möglicher weiterer Maßnahmen eines Energie- und Klimaschutzprogramms der Bundesregierung

Eine Analyse der deutschen Energie- und Klimapolitik hat ergeben: Nur im Maßnahmenfeld "Ausbau der Erneuerbaren Energien im Strombereich" wird voraussichtlich das Ziel ereicht. Dagegen wird in allen anderen Maßnahmenfeldern das Ziel verfehlt oder es bestehen Wirkungsdefizite der eingesetzten Politikinstrumente. Das betrifft insbesondere die Energieeffizienz auf der Nachfrageseite, aber auch die Kraft-Wärme-Kopplung und Erneuerbare Energien-Wärme. Für die Maßnahmenfelder "Fluorierte Treibhausgase", "Industrieprozesse" und "Landwirtschaft" müssen überhaupt erst verbindliche Reduktionsziele festgelegt und Politikinstrumente eingeführt werden

Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease

We identified rare coding variants associated with Alzheimer’s disease (AD) in a 3-stage case-control study of 85,133 subjects. In stage 1, 34,174 samples were genotyped using a whole-exome microarray. In stage 2, we tested associated variants (P<1×10-4) in 35,962 independent samples using de novo genotyping and imputed genotypes. In stage 3, an additional 14,997 samples were used to test the most significant stage 2 associations (P<5×10-8) using imputed genotypes. We observed 3 novel genome-wide significant (GWS) AD associated non-synonymous variants; a protective variant in PLCG2 (rs72824905/p.P522R, P=5.38×10-10, OR=0.68, MAFcases=0.0059, MAFcontrols=0.0093), a risk variant in ABI3 (rs616338/p.S209F, P=4.56×10-10, OR=1.43, MAFcases=0.011, MAFcontrols=0.008), and a novel GWS variant in TREM2 (rs143332484/p.R62H, P=1.55×10-14, OR=1.67, MAFcases=0.0143, MAFcontrols=0.0089), a known AD susceptibility gene. These protein-coding changes are in genes highly expressed in microglia and highlight an immune-related protein-protein interaction network enriched for previously identified AD risk genes. These genetic findings provide additional evidence that the microglia-mediated innate immune response contributes directly to AD development

Identification of genetic variants associated with Huntington's disease progression: a genome-wide association study

Background Huntington's disease is caused by a CAG repeat expansion in the huntingtin gene, HTT. Age at onset has been used as a quantitative phenotype in genetic analysis looking for Huntington's disease modifiers, but is hard to define and not always available. Therefore, we aimed to generate a novel measure of disease progression and to identify genetic markers associated with this progression measure. Methods We generated a progression score on the basis of principal component analysis of prospectively acquired longitudinal changes in motor, cognitive, and imaging measures in the 218 indivduals in the TRACK-HD cohort of Huntington's disease gene mutation carriers (data collected 2008–11). We generated a parallel progression score using data from 1773 previously genotyped participants from the European Huntington's Disease Network REGISTRY study of Huntington's disease mutation carriers (data collected 2003–13). We did a genome-wide association analyses in terms of progression for 216 TRACK-HD participants and 1773 REGISTRY participants, then a meta-analysis of these results was undertaken. Findings Longitudinal motor, cognitive, and imaging scores were correlated with each other in TRACK-HD participants, justifying use of a single, cross-domain measure of disease progression in both studies. The TRACK-HD and REGISTRY progression measures were correlated with each other (r=0·674), and with age at onset (TRACK-HD, r=0·315; REGISTRY, r=0·234). The meta-analysis of progression in TRACK-HD and REGISTRY gave a genome-wide significant signal (p=1·12 × 10−10) on chromosome 5 spanning three genes: MSH3, DHFR, and MTRNR2L2. The genes in this locus were associated with progression in TRACK-HD (MSH3 p=2·94 × 10−8 DHFR p=8·37 × 10−7 MTRNR2L2 p=2·15 × 10−9) and to a lesser extent in REGISTRY (MSH3 p=9·36 × 10−4 DHFR p=8·45 × 10−4 MTRNR2L2 p=1·20 × 10−3). The lead single nucleotide polymorphism (SNP) in TRACK-HD (rs557874766) was genome-wide significant in the meta-analysis (p=1·58 × 10−8), and encodes an aminoacid change (Pro67Ala) in MSH3. In TRACK-HD, each copy of the minor allele at this SNP was associated with a 0·4 units per year (95% CI 0·16–0·66) reduction in the rate of change of the Unified Huntington's Disease Rating Scale (UHDRS) Total Motor Score, and a reduction of 0·12 units per year (95% CI 0·06–0·18) in the rate of change of UHDRS Total Functional Capacity score. These associations remained significant after adjusting for age of onset. Interpretation The multidomain progression measure in TRACK-HD was associated with a functional variant that was genome-wide significant in our meta-analysis. The association in only 216 participants implies that the progression measure is a sensitive reflection of disease burden, that the effect size at this locus is large, or both. Knockout of Msh3 reduces somatic expansion in Huntington's disease mouse models, suggesting this mechanism as an area for future therapeutic investigation

Prevalence, associated factors and outcomes of pressure injuries in adult intensive care unit patients: the DecubICUs study

Funder: European Society of Intensive Care Medicine; doi: http://dx.doi.org/10.13039/501100013347Funder: Flemish Society for Critical Care NursesAbstract: Purpose: Intensive care unit (ICU) patients are particularly susceptible to developing pressure injuries. Epidemiologic data is however unavailable. We aimed to provide an international picture of the extent of pressure injuries and factors associated with ICU-acquired pressure injuries in adult ICU patients. Methods: International 1-day point-prevalence study; follow-up for outcome assessment until hospital discharge (maximum 12 weeks). Factors associated with ICU-acquired pressure injury and hospital mortality were assessed by generalised linear mixed-effects regression analysis. Results: Data from 13,254 patients in 1117 ICUs (90 countries) revealed 6747 pressure injuries; 3997 (59.2%) were ICU-acquired. Overall prevalence was 26.6% (95% confidence interval [CI] 25.9–27.3). ICU-acquired prevalence was 16.2% (95% CI 15.6–16.8). Sacrum (37%) and heels (19.5%) were most affected. Factors independently associated with ICU-acquired pressure injuries were older age, male sex, being underweight, emergency surgery, higher Simplified Acute Physiology Score II, Braden score 3 days, comorbidities (chronic obstructive pulmonary disease, immunodeficiency), organ support (renal replacement, mechanical ventilation on ICU admission), and being in a low or lower-middle income-economy. Gradually increasing associations with mortality were identified for increasing severity of pressure injury: stage I (odds ratio [OR] 1.5; 95% CI 1.2–1.8), stage II (OR 1.6; 95% CI 1.4–1.9), and stage III or worse (OR 2.8; 95% CI 2.3–3.3). Conclusion: Pressure injuries are common in adult ICU patients. ICU-acquired pressure injuries are associated with mainly intrinsic factors and mortality. Optimal care standards, increased awareness, appropriate resource allocation, and further research into optimal prevention are pivotal to tackle this important patient safety threat