The determinants of transverse tubular volume in resting skeletal muscle.

The transverse tubular (t)-system of skeletal muscle couples sarcolemmal electrical excitation with contraction deep within the fibre. Exercise, pathology and the composition of the extracellular fluid (ECF) can alter t-system volume (t-volume). T-volume changes are thought to contribute to fatigue, rhabdomyolysis and disruption of excitation-contraction coupling. However, mechanisms that underlie t-volume changes are poorly understood. A multicompartment, history-independent computer model of rat skeletal muscle was developed to define the minimum conditions for t-volume stability. It was found that the t-system tends to swell due to net ionic fluxes from the ECF across the access resistance. However, a stable t-volume is possible when this is offset by a net efflux from the t-system to the cell and thence to the ECF, forming a net ion cycle ECF→t-system→sarcoplasm→ECF that ultimately depends on Na(+)/K(+)-ATPase activity. Membrane properties that maximize this circuit flux decrease t-volume, including PNa(t) > PNa(s), PK(t) < PK(s) and N(t) < N(s) [P, permeability; N, Na(+)/K(+)-ATPase density; (t), t-system membrane; (s), sarcolemma]. Hydrostatic pressures, fixed charges and/or osmoles in the t-system can influence the magnitude of t-volume changes that result from alterations in this circuit flux. Using a parameter set derived from literature values where possible, this novel theory of t-volume was tested against data from previous experiments where t-volume was measured during manipulations of ECF composition. Predicted t-volume changes correlated satisfactorily. The present work provides a robust, unifying theoretical framework for understanding the determinants of t-volume.JAF was supported by a David Phillips Fellowship (BB/FO23863/1) awarded by the Biotechnology and Biological Sciences Research Council (UK). JS was supported by the Agency for Science, Technology and Research (Singapore) and a Caius Medical Association summer studentship from Gonville and Caius College, University of Cambridge.This is the final version. It was first published by Wiley at http://onlinelibrary.wiley.com/doi/10.1113/jphysiol.2014.281170/abstract

An evaluation of Social Impact Bonds in Health and Social Care: Interim Report

This interim report describes the progress of the nine ‘Trailblazer’ projects that received funds from the Social Enterprise Investment Fund in 2013 to investigate the feasibility of setting up Social Impact Bond (SIB) projects in health and social care in England. The findings discussed in this report are based on a literature review of the SIB literature and on documentary analysis and qualitative interviews with key informants involved in UK SIB development undertaken between May and November 2014

Effects of red blood cell transfusion on patients undergoing cardiac surgery in Queensland – a retrospective cohort study

Background: Packed red blood cell (pRBC) transfusion is a relatively safe and mainstay treatment commonly used in cardiac surgical patients. However, there is limited evidence on clinical effects of transfusing blood nearing end-of shelf life that has undergone biochemical changes during storage. Objective: To investigate evidence of associations between morbidity/mortality and transfusion of blood near end of shelf-life (> 35 days) in cardiac surgical patients. Methods: Data from the Queensland Health Admitted Patient Data Collection database 2007–2013 was retrospectively analysed. Coronary artery bypass graft and valvular repair patients were included. Multivariable logistic regression was used to examine the effect of pRBC age ( 4) were supported

Loss of NFIX transcription factor biases postnatal stem/progenitor cells towards oligodendrogenesis

Murine postnatal neural stem cells (NSCs) give rise to neurons, astrocytes, or oligodendrocytes (OLs); however, our knowledge of the genes that control this lineage specification is incomplete. In this study, we show that nuclear factor I X (NFIX), a transcription factor known to regulate NSC quiescence, also suppresses oligodendrogenesis (ODG) from NSCs. Immunostaining reveals little or no expression of NFIX in OL lineage cells both in vivo and in vitro. Loss of NFIX from subventricular zone (SVZ) NSCs results in enhanced ODG both in vivo and in vitro, while forced expression of NFIX blocks NSC differentiation into OLs in vitro. RNA-seq analysis shows that genes previously shown to be differentially expressed in OL progenitors are significantly enriched in RNA from Nfix(-/-) versus wild-type NSCs. These data indicate that NFIX influences the lineage specification of postnatal SVZ NSCs, specifically suppressing ODG

p38γ MAPK delays myelination and remyelination and is abundant in multiple sclerosis lesions

Multiple sclerosis is a chronic inflammatory disease in which disability results from the disruption of myelin and axons. During the initial stages of the disease, injured myelin is replaced by mature myelinating oligodendrocytes that differentiate from oligodendrocyte precursor cells. However, myelin repair fails in secondary and chronic progressive stages of the disease and with ageing, as the environment becomes progressively more hostile. This may be attributable to inhibitory molecules in the multiple sclerosis environment including activation of the p38MAPK family of kinases. We explored oligodendrocyte precursor cell differentiation and myelin repair using animals with conditional ablation of p38MAPKγ from oligodendrocyte precursors. We found that p38γMAPK ablation accelerated oligodendrocyte precursor cell differentiation and myelination. This resulted in an increase in both the total number of oligodendrocytes and the migration of progenitors ex vivo and faster remyelination in the cuprizone model of demyelination/remyelination. Consistent with its role as an inhibitor of myelination, p38γMAPK was significantly downregulated as oligodendrocyte precursor cells matured into oligodendrocytes. Notably, p38γMAPK was enriched in multiple sclerosis lesions from patients. Oligodendrocyte progenitors expressed high levels of p38γMAPK in areas of failed remyelination but did not express detectable levels of p38γMAPK in areas where remyelination was apparent. Our data suggest that p38γ could be targeted to improve myelin repair in multiple sclerosis.Peer reviewe

A progenitor candidate for the type II-P supernova SN 2018aoq in NGC 4151

We present our findings based on pre-and post-explosion data of the type II-Plateau SN 2018aoq that exploded in NGC 4151. As distance estimates to NGC 4151 vary by an order of magnitude, we utilised the well-known correlation between ejecta velocity and plateau brightness, i.e. the standard candle method, to obtain a distance of 18.2 ± 1.2 Mpc, which is in very good agreement with measurements based on geometric methods. The above distance implies a mid-plateau absolute magnitude of MV 50 = 15.76 ± 0.14 suggesting that it is of intermediate brightness when compared to IIP SNe such as SN 2005cs at the faint end, and more typical events such as SN 1999em. This is further supported by relatively low expansion velocities (Fe IIλ5169 ∼ 3000 km s-1 at +42 d). Using archival HST/WFC3 imaging data, we find a point source coincident with the supernova position in the F350LP, F555W, F814W, and F160W filters. This source shows no significant variability over the ∼2 month time span of the data. From fits to the spectral energy distribution of the candidate progenitor, we find log L/L4.7 and T3.5 kK, implying an M-type red supergiant progenitor. From comparisons to single and binary star models, we find that both favour the explosion of a star with a zero-age main sequence mass of ∼10M.</p

A progenitor candidate for the type II-P supernova SN 2018aoq in NGC 4151

We present our findings based on pre- and post-explosion data of the type II-Plateau SN 2018aoq that exploded in NGC 4151. As distance estimates to NGC 4151 vary by an order of magnitude, we utilised the well-known correlation between ejecta velocity and plateau brightness, i.e. the standard candle method, to obtain a distance of 18.2 ± 1.2 Mpc, which is in very good agreement with measurements based on geometric methods. The above distance implies a mid-plateau absolute magnitude of MV50 = - 15.76 ± 0.14 suggesting that it is of intermediate brightness when compared to IIP SNe such as SN 2005cs at the faint end, and more typical events such as SN 1999em. This is further supported by relatively low expansion velocities (Fe IIλ5169 ˜ 3000 km s-1 at +42 d). Using archival HST/WFC3 imaging data, we find a point source coincident with the supernova position in the F350LP, F555W, F814W, and F160W filters. This source shows no significant variability over the ˜2 month time span of the data. From fits to the spectral energy distribution of the candidate progenitor, we find log(L/L⊙) ˜ 4.7 and Teff ˜ 3.5 kK, implying an M-type red supergiant progenitor. From comparisons to single and binary star models, we find that both favour the explosion of a star with a zero-age main sequence mass of ˜10 M⊙.</p

OGLE-2013-SN-079: A LONELY SUPERNOVA CONSISTENT WITH A HELIUM SHELL DETONATION

We present observational data for a peculiar supernova discovered by the OGLE-IV survey and followed by the Public ESO Spectroscopic Survey for Transient Objects. The inferred redshift of z = 0.07 implies an absolute magnitude in the rest-frame I-band of MI ~ –17.6 mag. This places it in the luminosity range between normal Type Ia SNe and novae. Optical and near infrared spectroscopy reveal mostly Ti and Ca lines, and an unusually red color arising from strong depression of flux at rest wavelengths <5000 Å. To date, this is the only reported SN showing Ti-dominated spectra. The data are broadly consistent with existing models for the pure detonation of a helium shell around a low-mass CO white dwarf and "double-detonation" models that include a secondary detonation of a CO core following a primary detonation in an overlying helium shell