Report from the third international consensus meeting to harmonise core outcome measures for atopic eczema/dermatitis clinical trials (HOME).

This report provides a summary of the third meeting of the Harmonising Outcome Measures for Eczema (HOME) initiative held in San Diego, CA, U.S.A., 6-7 April 2013 (HOME III). The meeting addressed the four domains that had previously been agreed should be measured in every eczema clinical trial: clinical signs, patient-reported symptoms, long-term control and quality of life. Formal presentations and nominal group techniques were used at this working meeting, attended by 56 voting participants (31 of whom were dermatologists). Significant progress was made on the domain of clinical signs. Without reference to any named scales, it was agreed that the intensity and extent of erythema, excoriation, oedema/papulation and lichenification should be included in the core outcome measure for the scale to have content validity. The group then discussed a systematic review of all scales measuring the clinical signs of eczema and their measurement properties, followed by a consensus vote on which scale to recommend for inclusion in the core outcome set. Research into the remaining three domains was presented, followed by discussions. The symptoms group and quality of life groups need to systematically identify all available tools and rate the quality of the tools. A definition of long-term control is needed before progress can be made towards recommending a core outcome measure

Shape-induced force fields in optical trapping

Advances in optical tweezers, coupled with the proliferation of two-photon polymerization systems, mean that it is now becoming routine to fabricate and trap non-spherical particles. The shaping of both light beams and particles allows fine control over the flow of momentum from the optical to mechanical regimes. However, understanding and predicting the behaviour of such systems is highly complex in comparison with the traditional optically trapped microsphere. In this Article, we present a conceptually new and simple approach based on the nature of the optical force density. We illustrate the method through the design and fabrication of a shaped particle capable of acting as a passive force clamp, and we demonstrate its use as an optically trapped probe for imaging surface topography. Further applications of the design rules highlighted here may lead to new sensors for probing biomolecule mechanics, as well as to the development of optically actuated micromachines

How consistent are the transcriptome changes associated with cold acclimation in two species of the Drosophila virilis group?

This work was financially support by a Marie Curie Initial Training Network grant, “Understanding the evolutionary origin of biological diversity” (ITN-2008–213780 SPECIATION), grants from the Academy of Finland to A.H. (project 132619) and M.K. (projects 268214 and 272927), a grant from NERC, UK to M.G.R. (grant NE/J020818/1), and NERC, UK PhD studentship to D.J.P. (NE/I528634/1).For many organisms the ability to cold acclimate with the onset of seasonal cold has major implications for their fitness. In insects, where this ability is widespread, the physiological changes associated with increased cold tolerance have been well studied. Despite this, little work has been done to trace changes in gene expression during cold acclimation that lead to an increase in cold tolerance. We used an RNA-Seq approach to investigate this in two species of the Drosophila virilis group. We found that the majority of genes that are differentially expressed during cold acclimation differ between the two species. Despite this, the biological processes associated with the differentially expressed genes were broadly similar in the two species. These included: metabolism, cell membrane composition, and circadian rhythms, which are largely consistent with previous work on cold acclimation/cold tolerance. In addition, we also found evidence of the involvement of the rhodopsin pathway in cold acclimation, a pathway that has been recently linked to thermotaxis. Interestingly, we found no evidence of differential expression of stress genes implying that long-term cold acclimation and short-term stress response may have a different physiological basis.PostprintPeer reviewe

Microglial activation and chronic neurodegeneration

Microglia, the resident innate immune cells in the brain, have long been implicated in the pathology of neurode-generative diseases. Accumulating evidence points to activated microglia as a chronic source of multiple neurotoxic factors, including tumor necrosis factor-α, nitric oxide, interleukin-1β, and reactive oxygen species (ROS), driving progressive neuron damage. Microglia can become chronically activated by either a single stimulus (e.g., lipopolysaccharide or neuron damage) or multiple stimuli exposures to result in cumulative neuronal loss with time. Although the mechanisms driving these phenomena are just beginning to be understood, reactive microgliosis (the microglial response to neuron damage) and ROS have been implicated as key mechanisms of chronic and neurotoxic microglial activation, particularly in the case of Parkinson’s disease. We review the mechanisms of neurotoxicity associated with chronic microglial activation and discuss the role of neuronal death and microglial ROS driving the chronic and toxic microglial phenotype

On the Ethics of Trade Credit: Understanding Good Payment Practice in the Supply Chain

In spite of its commercial importance and signs of clear concern in public policy arenas, trade credit has not been subjected to systematic, extended analysis in the business ethics literature, even where suppliers as a stakeholder group have been considered. This paper makes the case for serious consideration of the ethics of trade credit and explores the issues surrounding slow payment of debts. It discusses trade debt as a kind of promise, but— noting that not all promises are good ones—goes on to develop an analysis of the ethics of trade credit grounded in an understanding of its fundamental purpose. Making a distinction between ‘‘operating’’ trade credit and ‘‘financial’’ trade credit, the paper provides an account of the maximum period for which it is appropriate for one company to delay payment to another from which it has purchased goods or services. The concern of commentators and policy makers that companies should not take too long to pay their debts is affirmed, but the understanding of what timely payment means is significantly finessed, with one conclusion being that, if debts have not already been settled according to acceptable standard terms of trade, cash should pass quickly back along the supply chain once the customer in the final product market has paid. The analysis has implications not only for companies that take credit but also for external parties that seek to rate companies or set regulations according to speed of payment—an approach that is shown to be misleadingly simplistic, albeit well intentioned. A corresponding important responsibility for suppliers, not to extend excessive credit (and thus act as a quasi-bank), also follows from the analysis developed. Having provided a novel analysis of an important business problem, the paper then discusses some of the related practical issues and makes suggestions for further research

Interactions between obstructive sleep apnea syndrome and insulin resistance

Previous studies have shown Obstructive Sleep Apnea (OSA) as a risk factor for development of cardiovascular and cerebrovascular disease. However, controversies remain as to whether these changes are consequences of the associated obesity or OSA itself results in endocrine and metabolic changes, including impairment of insulin sensitivity, growth hormone, secretion inflammatory cytokines alterations, activation of peripheral sympathetic activity, and hipothalamic-pituitary-adrenal (HPA) axis, that may predispose to vascular disease. Furthermore many cardiovascular risk factors, such as hypertension, obesity, insulin resistance and type 2 diabetes, are strongly associated with OSA. In this article, we will review the evidence and discuss possible mechanisms underlying these links and the pathophysiology of OSA morbidities.Estudos anteriores mostraram que pacientes com Apnéia Obstrutiva do Sono (AOS) apresentam maior risco para doenças cardiovasculares. Entretanto, permanece controverso se essa associação depende da obesidade ou se ocorre devido a alterações fisiológicas decorrentes da desordem do sono, como ativação do sistema nervoso simpático, da inflamação e desordens do eixo corticotrófico e somatotrófico, que predispõem a danos vasculares. Além disso, muitos fatores de risco para doenças cardiovasculares (DCV) estão fortemente associados ao distúrbio respiratório, entre eles hipertensão, obesidade, resistência à insulina e diabetes tipo 2 (DM2). Neste artigo, vamos discutir a interação entre resistência à insulina e AOS e os possíveis mecanismos fisiopatológicos que contribuem para suas co-morbidades.Universidade Federal de São Paulo (UNIFESP) Escola Paulista de Medicina Departamento de Clínica MédicaUniversidade Federal de São Paulo (UNIFESP) Escola Paulista de Medicina Departamento de PsicobiologiaUNIFESP, EPM, Depto. de Clínica MédicaUNIFESP, EPM, Depto. de PsicobiologiaSciEL

Mechanisms Underlying Interferon-γ-Induced Priming of Microglial Reactive Oxygen Species Production.

Microglial priming and enhanced reactivity to secondary insults cause substantial neuronal damage and are hallmarks of brain aging, traumatic brain injury and neurodegenerative diseases. It is, thus, of particular interest to identify mechanisms involved in microglial priming. Here, we demonstrate that priming of microglia with interferon-γ (IFN γ) substantially enhanced production of reactive oxygen species (ROS) following stimulation of microglia with ATP. Priming of microglial ROS production was substantially reduced by inhibition of p38 MAPK activity with SB203580, by increases in intracellular glutathione levels with N-Acetyl-L-cysteine, by blockade of NADPH oxidase subunit NOX2 activity with gp91ds-tat or by inhibition of nitric oxide production with L-NAME. Together, our data indicate that priming of microglial ROS production involves reduction of intracellular glutathione levels, upregulation of NADPH oxidase subunit NOX2 and increases in nitric oxide production, and suggest that these simultaneously occurring processes result in enhanced production of neurotoxic peroxynitrite. Furthermore, IFNγ-induced priming of microglial ROS production was reduced upon blockade of Kir2.1 inward rectifier K+ channels with ML133. Inhibitory effects of ML133 on microglial priming were mediated via regulation of intracellular glutathione levels and nitric oxide production. These data suggest that microglial Kir2.1 channels may represent novel therapeutic targets to inhibit excessive ROS production by primed microglia in brain pathology

Tension, Free Space, and Cell Damage in a Microfluidic Wound Healing Assay

We use a novel, microfluidics-based technique to deconstruct the classical wound healing scratch assay, decoupling the contribution of free space and cell damage on the migratory dynamics of an epithelial sheet. This method utilizes multiple laminar flows to selectively cleave cells enzymatically, and allows us to present a 'damage free' denudation. We therefore isolate the influence of free space on the onset of sheet migration. First, we observe denudation directly to measure the retraction in the cell sheet that occurs after cell-cell contact is broken, providing direct and quantitative evidence of strong tension within the sheet. We further probe the mechanical integrity of the sheet without denudation, instead using laminar flows to selectively inactivate actomyosin contractility. In both cases, retraction is observed over many cell diameters. We then extend this method and complement the enzymatic denudation with analogies to wounding, including gradients in signals associated with cell damage, such as reactive oxygen species, suspected to play a role in the induction of movement after wounding. These chemical factors are evaluated in combination with the enzymatic cleavage of cells, and are assessed for their influence on the collective migration of a non-abrasively denuded epithelial sheet. We conclude that free space alone is sufficient to induce movement, but this movement is predominantly limited to the leading edge, leaving cells further from the edge less able to move towards the wound. Surprisingly, when coupled with a gradient in ROS to simulate the chemical effects of abrasion however, motility was not restored, but further inhibited.Massachusetts Institute of Technology. Presidential FellowshipNational Institutes of Health (U.S.). Biotechnology Training FellowshipSingapore-MIT Alliance for Research and TechnologyMassachusetts Institute of Biotechnology Training GrantMassachusetts Institute of Technology (Open-source Funding

A qualitative study of the understanding and use of ‘compassion focused coping strategies’ in people who suffer from serious weight difficulties.

Abstract Background The physical and psychological health problems associated with obesity are now well documented, as is the urgency for addressing them. In addition, associations between quality of life, depression, self-esteem, self-criticism, and obesity are now established indicating a need for a better understanding of the links between self-evaluation, affect-regulation and eating behaviours. Methods Compassion has now been identified as a major source of resilience, helpful self-relating and affect regulation. Thus this study used semi-structured interviews to explore the understanding and experiences of compassion in 2 overweight men and 10 women seeking help for weight problems. The interviews examined people's understandings of compassion, their recall of experiences of compassion in childhood, their current experiences of receiving compassion from others, being compassionate to others, being self-compassionate, and whether they would be compassionate or self-critical for relapses in overeating. Interviews were transcribed and analysed using thematic analysis (Qual Res Psychol, 3: 77-101, 2006). Results Participants saw compassion as related to ‘caring’ and being ‘listened to’. However, their recall of earlier experiences of compassion was of primarily practical help rather than emotional engagement. Typically their response to their own relapse and setbacks were self-criticism, self-disgust and even self-hatred rather than self-caring or understanding. Self-critical/hating responses tend to be associated with poor weight regulation. Conclusions When people with weight problems relapse, or struggle to control their eating, they can become quite self-critical, even self-hating, which may increase difficulties with emotionally coping and maintaining healthy lifestyles and eating habits. Although turning to others for support and compassion, and becoming self-compassionate are antidotes to self-criticism, and are associated with better coping and mental health, many participants did not utilise compassionate strategies – often the opposite. It is possible that interventions that include mindfulness and compassion training could be helpful for these difficulties.N/