Ventricular divergence correlates with epicardial wavebreaks and predicts ventricular arrhythmia in isolated rabbit hearts during therapeutic hypothermia

INTRODUCTION: High beat-to-beat morphological variation (divergence) on the ventricular electrogram during programmed ventricular stimulation (PVS) is associated with increased risk of ventricular fibrillation (VF), with unclear mechanisms. We hypothesized that ventricular divergence is associated with epicardial wavebreaks during PVS, and that it predicts VF occurrence. METHOD AND RESULTS: Langendorff-perfused rabbit hearts (n = 10) underwent 30-min therapeutic hypothermia (TH, 30°C), followed by a 20-min treatment with rotigaptide (300 nM), a gap junction modifier. VF inducibility was tested using burst ventricular pacing at the shortest pacing cycle length achieving 1:1 ventricular capture. Pseudo-ECG (p-ECG) and epicardial activation maps were simultaneously recorded for divergence and wavebreaks analysis, respectively. A total of 112 optical and p-ECG recordings (62 at TH, 50 at TH treated with rotigaptide) were analyzed. Adding rotigaptide reduced ventricular divergence, from 0.13±0.10 at TH to 0.09±0.07 (p = 0.018). Similarly, rotigaptide reduced the number of epicardial wavebreaks, from 0.59±0.73 at TH to 0.30±0.49 (p = 0.036). VF inducibility decreased, from 48±31% at TH to 22±32% after rotigaptide infusion (p = 0.032). Linear regression models showed that ventricular divergence correlated with epicardial wavebreaks during TH (p<0.001). CONCLUSION: Ventricular divergence correlated with, and might be predictive of epicardial wavebreaks during PVS at TH. Rotigaptide decreased both the ventricular divergence and epicardial wavebreaks, and reduced the probability of pacing-induced VF during TH

Sustained Effects of Interleukin-1 Receptor Antagonist Treatment in Type 2 Diabetes

Objective: Interleukin (IL)-1 impairs insulin secretion and induces beta-cell apoptosis. Pancreatic beta-cell IL-1 expression is increased and interleukin-1-receptor antagonist (IL-1Ra) expression reduced in patients with type 2 diabetes mellitus. Treatment with recombinant IL-1Ra improves glycemia and beta-cell function and reduces inflammatory markers in patients with type 2 diabetes mellitus. Here we investigated the durability of these responses. Research Design and Methods: Among 70 ambulatory patients with type 2 diabetes and A1C and body mass index higher than 7.5% and 27, respectively, randomly assigned to receive 13 weeks of anakinra, a recombinant human IL-1Ra, or placebo, 67 completed treatment and were included in this double-blinded 39 week follow-up study. Primary outcome was change in betacell function following anakinra withdrawal. Analysis was done by intention-to-treat. Results: Thirty-nine weeks following anakinra withdrawal the proinsulin to insulin (PI/I) ratio but not stimulated C-peptide remained improved by -0.07 (95% CI -0.14 to -0.02, P=0.011) compared to placebo treated patients. Interestingly, a subgroup characterized by genetically determined low baseline IL-1Ra serum levels, maintained the improved stimulated C-peptide obtained by 13 weeks of IL-1Ra treatment. Reductions of C-reactive protein (-3.2 mg/l [95% CI -6.2 to -1.1, P=0.014]) and of IL-6 (-1.4 ng/l [95% CI -2.6 to -0.3, P=0.036]) were maintained until end of study. Conclusions: IL-1 blockade with anakinra induces improvement of the PI/I ratio and in markers of systemic inflammation lasting 39 weeks following treatment withdrawal

Atmospheric and oceanic stable isotope signatures of a cold-air outbreakin Iceland during YOPP SOP1 and IGP

Publisher's version (útgefin grein)North-Atlantic Cold-air outbreaks are weather events characterised by extensive fluxes of latent heat to theatmosphere. Understanding the water budget of these weather events is important for the weather impact indownstream coastal areas. We use here observations of the stable isotopic composition of water vapour andprecipitation, expressed by the quantities dD, d18O, d17O and the secondary parameters d-excess and 17O-excess,to extract information about the origin and condensation history of water vapour evaporating during a period ofcold-air outbreaks north of IcelandIcelandic research institute (RANNÍS 152229

Investigating the dynamic nature of the ABC transporters: ABCB1 and MsbA as examples for the potential synergies of MD theory and EPR applications

ABC transporters are primary active transporters found in all kingdoms of life. Human multidrug resistance transporter ABCB1, or P-glycoprotein, has an extremely broad substrate spectrum and confers resistance against chemotherapy drug treatment in cancer cells. The bacterial ABC transporter MsbA is a lipid A flippase and a homolog to the human ABCB1 transporter, with which it partially shares its substrate spectrum. Crystal structures of MsbA and ABCB1 have been solved in multiple conformations, providing a glimpse into the possible conformational changes the transporter could be going through during the transport cycle. Crystal structures are inherently static, while a dynamic picture of the transporter in motion is needed for a complete understanding of transporter function. Molecular dynamics (MD) simulations and electron paramagnetic resonance (EPR) spectroscopy can provide structural information on ABC transporters, but the strength of these two methods lies in the potential to characterise the dynamic regime of these transporters. Information from the two methods is quite complementary. MD simulations provide an all atom dynamic picture of the time evolution of the molecular system, though with a narrow time window. EPR spectroscopy can probe structural, environmental and dynamic properties of the transporter in several time regimes, but only through the attachment sites of an exogenous spin label. In this review the synergistic effects that can be achieved by combining the two methods are highlighted, and a brief methodological background is also presented

Facing others’ misfortune: Personal distress mediates the association between maladaptive emotion regulation and social avoidance

Previous research has linked the use of certain emotion regulation strategies to the vicarious experience of personal distress (PD) and empathic concern (EC). However, it has not been tested yet whether (1) vicarious PD is positively associated with maladaptive emotion regulation strategies, (2) vicarious EC is positively associated with adaptive emotion regulation strategies and whether (3) PD and EC mediate the link between emotion regulation and reports of approach/avoidance in response to a person in distress. To that aim, we assessed people’s reports of PD (i.e., anxious, troubled, and upset) and EC (i.e., concerned, sympathetic, and soft-hearted) in response to a video depicting a person in a threatening situation (n = 78). Afterwards, we assessed participants’ reports of avoidance and approach in regards to the character and their disposition to use maladaptive and adaptive emotion regulation strategies. Results showed that PD as well as EC were positively related to maladaptive strategies and negatively related to adaptive strategies, and that the association between maladaptive regulation strategies (i.e., rumination) and the willingness to avoid the person in distress was mediated by greater reports of PD. This study thus expands previous evidence on the relationship between maladaptive regulation strategies and affective empathy and provides novel insights about the main role that personal distress played in the association between maladaptive strategies and social avoidance

Current understanding of the human microbiome

Author Posting. © The Author(s), 2018. This is the author's version of the work. It is posted here by permission of Nature Publishing Group for personal use, not for redistribution. The definitive version was published in Nature Medicine 24 (2018): 392–400, doi:10.1038/nm.4517.Our understanding of the link between the human microbiome and disease, including obesity, inflammatory bowel disease, arthritis and autism, is rapidly expanding. Improvements in the throughput and accuracy of DNA sequencing of the genomes of microbial communities associated with human samples, complemented by analysis of transcriptomes, proteomes, metabolomes and immunomes, and mechanistic experiments in model systems, have vastly improved our ability to understand the structure and function of the microbiome in both diseased and healthy states. However, many challenges remain. In this Review, we focus on studies in humans to describe these challenges, and propose strategies that leverage existing knowledge to move rapidly from correlation to causation, and ultimately to translation.Many of the studies described here in our laboratories were supported by the NIH, NSF, DOE, and the Alfred P. Sloan Foundation.2018-10-1

The relevance of stretch intensity and position-a systematic review

Stretching exercises to increase the range of motion (ROM) of joints have been used by sports coaches and medical professionals for improving performance and rehabilitation. The ability of connective and muscular tissues to change their architecture in response to stretching is important for their proper function, repair, and performance. Given the dearth of relevant data in the literature, this review examined two key elements of stretching: stretch intensity and stretch position; and their significance to ROM, delayed onset muscle soreness (DOMS), and inflammation in different populations. A search of three databases, Pub-Med, Google Scholar, and Cochrane Reviews, identified 152 articles, which were subsequently categorized into four groups: athletes (24), clinical (29), elderly (12), and general population (87). The use of different populations facilitated a wider examination of the stretching components and their effects. All 152 articles incorporated information regarding duration, frequency and stretch position, whereas only 79 referred to the intensity of stretching and 22 of these 79 studies were deemed high quality. It appears that the intensity of stretching is relatively under-researched, and the importance of body position and its influence on stretch intensity, is largely unknown. In conclusion, this review has highlighted areas for future research, including stretch intensity and position and their effect on musculo-tendinous tissue, in relation to the sensation of pain, delayed onset muscle soreness, inflammation, as well as muscle health and performance

The Glycosyltransferase Repertoire of the Spikemoss Selaginella moellendorffii and a Comparative Study of Its Cell Wall

Spike mosses are among the most basal vascular plants, and one species, Selaginella moellendorffii, was recently selected for full genome sequencing by the Joint Genome Institute (JGI). Glycosyltransferases (GTs) are involved in many aspects of a plant life, including cell wall biosynthesis, protein glycosylation, primary and secondary metabolism. Here, we present a comparative study of the S. moellendorffii genome across 92 GT families and an additional family (DUF266) likely to include GTs. The study encompasses the moss Physcomitrella patens, a non-vascular land plant, while rice and Arabidopsis represent commelinid and non-commelinid seed plants. Analysis of the subset of GT-families particularly relevant to cell wall polysaccharide biosynthesis was complemented by a detailed analysis of S. moellendorffii cell walls. The S. moellendorffii cell wall contains many of the same components as seed plant cell walls, but appears to differ somewhat in its detailed architecture. The S. moellendorffii genome encodes fewer GTs (287 GTs including DUF266s) than the reference genomes. In a few families, notably GT51 and GT78, S. moellendorffii GTs have no higher plant orthologs, but in most families S. moellendorffii GTs have clear orthologies with Arabidopsis and rice. A gene naming convention of GTs is proposed which takes orthologies and GT-family membership into account. The evolutionary significance of apparently modern and ancient traits in S. moellendorffii is discussed, as is its use as a reference organism for functional annotation of GTs

HMOX1 Gene Promoter Alleles and High HO-1 Levels Are Associated with Severe Malaria in Gambian Children

Heme oxygenase 1 (HO-1) is an essential enzyme induced by heme and multiple stimuli associated with critical illness. In humans, polymorphisms in the HMOX1 gene promoter may influence the magnitude of HO-1 expression. In many diseases including murine malaria, HO-1 induction produces protective anti-inflammatory effects, but observations from patients suggest these may be limited to a narrow range of HO-1 induction, prompting us to investigate the role of HO-1 in malaria infection. In 307 Gambian children with either severe or uncomplicated P. falciparum malaria, we characterized the associations of HMOX1 promoter polymorphisms, HMOX1 mRNA inducibility, HO-1 protein levels in leucocytes (flow cytometry), and plasma (ELISA) with disease severity. The (GT)n repeat polymorphism in the HMOX1 promoter was associated with HMOX1 mRNA expression in white blood cells in vitro, and with severe disease and death, while high HO-1 levels were associated with severe disease. Neutrophils were the main HO-1-expressing cells in peripheral blood, and HMOX1 mRNA expression was upregulated by heme-moieties of lysed erythrocytes. We provide mechanistic evidence that induction of HMOX1 expression in neutrophils potentiates the respiratory burst, and propose this may be part of the causal pathway explaining the association between short (GT)n repeats and increased disease severity in malaria and other critical illnesses. Our findings suggest a genetic predisposition to higher levels of HO-1 is associated with severe illness, and enhances the neutrophil burst leading to oxidative damage of endothelial cells. These add important information to the discussion about possible therapeutic manipulation of HO-1 in critically ill patients