A Metabolomic Signature of Acute Caloric Restriction

Context: The experimental paradigm of acute caloric restriction followed by refeeding can be used to study the homeostatic mechanisms that regulate energy homeostasis, which are relevant to understanding the adaptive response to weight loss. Objective: Metabolomics, the measurement of hundreds of small molecule metabolites, their precursors, derivatives, and degradation products, has emerged as a useful tool for the study of physiology and disease and was used here to study the metabolic response to acute caloric restriction. Participants, Design and Setting: We used four ultra high performance liquid chromatography-tandem mass spectrometry methods to characterize changes in carbohydrates, lipids, amino acids and steroids in eight normal weight men at baseline, after 48 hours of caloric restriction (CR; 10% of energy requirements) and after 48 hours of ad libitum refeeding in a tightly-controlled environment. Results: We identified a distinct metabolomic signature associated with acute CR characterized by the expected switch from carbohydrate to fat utilization with increased lipolysis and beta-fatty acid oxidation. We found an increase in omega-fatty acid oxidation and levels of endocannabinoids which are known to promote food intake. These changes were reversed with refeeding. Several plasmalogen phosphatidylethanolamines (endogenous anti-oxidants) significantly decreased with CR (all p≤0.0007). Additionally, 48 acute CR was associated with an increase in the branched chain amino acids (all p≤1.4x10-7) and dehydroepiandrosterone sulfate (p=0.0006). Conclusions We identified a distinct metabolomic signature associated with acute CR. Further studies are needed to characterise the mechanisms that mediate these changes and their potential contribution to the adaptive response to dietary restriction.This work was supported by the Wellcome Trust (to I.S.F.), the NIHR Cambridge Biomedical Research Centre, the European Research Council, the Bernard Wolfe Health Neuroscience Fund (all to I.S.F.), the Swiss National Science Foundation (P3SMP3-155318, PZ00P3-167826, to T.H.C.), and the Uehara Memorial Foundation (to T.S.). This work was supported by the NIHR Rare Diseases Translational Research Collaboration and the NeuroFAST consortium, which is funded by the European Union’s Seventh Framework Programme (FP7/2007-2013) under grant agreement no 245009

Adalimumab for Treating Moderate-to-Severe Hidradenitis Suppurativa: An Evidence Review Group Perspective of a NICE Single Technology Appraisal

As part of its single technology appraisal (STA) process, the UK National Institute for Health and Care Excellence (NICE) invited the manufacturer of adalimumab (AbbVie) to submit evidence on the clinical effectiveness and cost effectiveness of adalimumab for the treatment of moderate-to-severe hidradenitis suppurativa (HS). The appraisal assessed adalimumab as monotherapy in adult patients with an inadequate response to conventional systemic HS therapy. The School of Health and Related Research Technology Appraisal Group was commissioned to act as the independent Evidence Review Group (ERG). The ERG produced a critical review of the evidence for the clinical effectiveness and cost effectiveness of the technology based on the company’s submission to NICE. The evidence was mainly derived from three randomised controlled trials comparing adalimumab with placebo in adults with moderate-to-severe HS. The clinical-effectiveness review found that significantly more patients achieved a clinical response in the adalimumab groups than in the control groups but that the treatment effect varied between trials and there was uncertainty regarding its impact on a range of other relevant outcomes as well as long-term efficacy. The company’s submitted Markov model assessed the incremental cost effectiveness of adalimumab versus standard care for the treatment of HS from the perspective of the UK NHS and Personal Social Services (PSS) over a lifetime horizon. The original submitted model, including a patient access scheme (PAS), suggested that the incremental cost-effectiveness ratio (ICER) for adalimumab versus standard care was expected to be £16,162 per quality-adjusted life-year (QALY) gained. Following a critique of the model, the ERG’s preferred base case, which corrected programming errors and structural problems surrounding discontinuation rules and incorporated a lower unit cost for HS surgery, resulted in a probabilistic ICER of £29,725 per QALY gained. Based on additional analyses undertaken by the company and the ERG following the publication of the appraisal consultation document (ACD), the Appraisal Committee concluded that the maximum possible ICER for adalimumab compared with supportive care was between £28,500 and £33,200 per QALY gained but was likely to be lower. The Appraisal Committee recommended adalimumab (with the PAS) for the treatment of active moderate-to-severe HS in adults whose disease has not responded to conventional systemic therapy

Ignition of flammable atmospheres by mechanical stimuli

As readers of HazardEx will be well aware, following the introduction of the ATEX 95 and 137 directives, there are now requirements on both manufacturers of equipment and employers to consider the likelihood of ignition flammable atmospheres from mechanical impacts/sliding. The aim of this article is not to review legislative requirements, as these are well discussed else where, but to provide insight into the ignition mechanism and relevant research literature to assist those needing to make such assessments. It is certainly not the intention to advocate ignition source control as an appropriate hazard management strategy , particularly with easily ignited gases like hydrogen- this needs to be decided on a case by case basis. Guidance in the design standards i.e. [1] has improved from earlier versions, but still does not convey very well the likely influence of parameters such as material hardness, load, velocities and impact angle

Evidence for distinct coastal and offshore communities of bottlenose dolphins in the north east Atlantic.

Bottlenose dolphin stock structure in the northeast Atlantic remains poorly understood. However, fine scale photo-id data have shown that populations can comprise multiple overlapping social communities. These social communities form structural elements of bottlenose dolphin (Tursiops truncatus) [corrected] populations, reflecting specific ecological and behavioural adaptations to local habitats. We investigated the social structure of bottlenose dolphins in the waters of northwest Ireland and present evidence for distinct inshore and offshore social communities. Individuals of the inshore community had a coastal distribution restricted to waters within 3 km from shore. These animals exhibited a cohesive, fission-fusion social organisation, with repeated resightings within the research area, within a larger coastal home range. The offshore community comprised one or more distinct groups, found significantly further offshore (>4 km) than the inshore animals. In addition, dorsal fin scarring patterns differed significantly between inshore and offshore communities with individuals of the offshore community having more distinctly marked dorsal fins. Specifically, almost half of the individuals in the offshore community (48%) had characteristic stereotyped damage to the tip of the dorsal fin, rarely recorded in the inshore community (7%). We propose that this characteristic is likely due to interactions with pelagic fisheries. Social segregation and scarring differences found here indicate that the distinct communities are likely to be spatially and behaviourally segregated. Together with recent genetic evidence of distinct offshore and coastal population structures, this provides evidence for bottlenose dolphin inshore/offshore community differentiation in the northeast Atlantic. We recommend that social communities should be considered as fundamental units for the management and conservation of bottlenose dolphins and their habitat specialisations

A comparison study into low leak rate buoyant gas dispersion in a small fuel cell enclosure using plain and louvre vent passive ventilation schemes

Hydrogen, producing electricity in fuel cells, is a versatile energy source, but with risks associated with flammability. Fuel cells use enclosures for protection which need ventilating to remove hydrogen emitted during normal operation or from supply system leaks. Passive ventilation, using buoyancy driven flow is preferred to mechanical systems. Performance depends upon vent design, size, shape, position and number. Vents are usually plain rectangular openings, but environmentally situated enclosures use louvres for protection. The effect of louvres on passive ventilation is not clear and has therefore been examined in this paper. Comparison ‘same opening area’ louvre and plain vent tests were undertaken using a 0.144 m3 enclosure with opposing upper and lower vents and helium leaking from a 4 mm nozzle on the base at rates from 1 to 10 lpm, simulating a hydrogen leak. Louvres increased stratified level helium concentrations by typically in excess of 15 %. The empirical data obtained was also used in a validation exercise with a SolidWorks: Flow Simulation CFD model, which provided a good qualitative representation of flow behaviour and close empirical data correlations

Individual differences in explicit and implicit visuomotor learning and working memory capacity

The theoretical basis for the association between high working memory capacity (WMC) and enhanced visuomotor adaptation is unknown. Visuomotor adaptation involves interplay between explicit and implicit systems. We examined whether the positive association between adaptation and WMC is specific to the explicit component of adaptation. Experiment 1 replicated the positive correlation between WMC and adaptation, but revealed this was specific to the explicit component of adaptation, and apparently driven by a sub-group of participants who did not show any explicit adaptation in the correct direction. A negative correlation was observed between WMC and implicit learning. Experiments 2 and 3 showed that when the task restricted the development of an explicit strategy, high WMC was no longer associated with enhanced adaptation. This work reveals that the benefit of high WMC is specifically linked to an individual’s capacity to use an explicit strategy. It also reveals an important contribution of individual differences in determining how adaptation is performed

Domestic Refrigerator Design -Safety Issues and Opportunities

There are around 300 house fires in Great Britain each year involving a fridge or freezer. This paper describes the examination of evidence of domestic fires in London between 2005 and 2015 where fridges or freezers have been cited as a fire source. It describes the generic reasons for the cause and spread of the fire and potential ways of constructing and using fridges and freezers to significantly reduce risk and spread

Phase transitions in biological membranes

Native membranes of biological cells display melting transitions of their lipids at a temperature of 10-20 degrees below body temperature. Such transitions can be observed in various bacterial cells, in nerves, in cancer cells, but also in lung surfactant. It seems as if the presence of transitions slightly below physiological temperature is a generic property of most cells. They are important because they influence many physical properties of the membranes. At the transition temperature, membranes display a larger permeability that is accompanied by ion-channel-like phenomena even in the complete absence of proteins. Membranes are softer, which implies that phenomena such as endocytosis and exocytosis are facilitated. Mechanical signal propagation phenomena related to nerve pulses are strongly enhanced. The position of transitions can be affected by changes in temperature, pressure, pH and salt concentration or by the presence of anesthetics. Thus, even at physiological temperature, these transitions are of relevance. There position and thereby the physical properties of the membrane can be controlled by changes in the intensive thermodynamic variables. Here, we review some of the experimental findings and the thermodynamics that describes the control of the membrane function.Comment: 23 pages, 15 figure

Complement is activated in progressive multiple sclerosis cortical grey matter lesions

The symptoms of multiple sclerosis (MS) are caused by damage to myelin and nerve cells in the brain and spinal cord. Inflammation is tightly linked with neurodegeneration, and it is the accumulation of neurodegeneration that underlies increasing neurological disability in progressive MS. Determining pathological mechanisms at play in MS grey matter is therefore a key to our understanding of disease progression