The immunological response to traumatic brain injury.

Traumatic brain injury (TBI) is the leading cause of death and disability in young adults in the developed world. The accuracy of early outcome-prediction remains poor even when all known prognostic factors are considered, suggesting important currently unidentified variables. In addition, whilst survival and neurological outcomes have improved markedly with the utilisation of therapies that optimise physiology, no treatments specifically modulate the underlying pathophysiology. The immunological response to TBI represents both a potential contributor to outcome heterogeneity and a therapeutically tractable component of the acute disease process. Furthermore, chronic inflammation has been linked with neurodegeneration, and may mark a bridge between acute brain injury and the subsequent neurodegenerative process seen in a proportion of patients following TBI. Given the complexity of the immune response and its varying functions ranging from repair of injury to bystander damage of healthy tissue, attempts at immunomodulatory intervention must necessarily be highly targeted towards the maladaptive facets of the inflammatory process. In this review we aim to provide an integrated description of the immunological processes triggered by TBI in both humans and animal models, in particular considering the interplay between the innate immune system, danger-associated molecular patterns and loss of self-tolerance leading to adaptive autoimmunity

Anthropometric indices of Gambian children after one or three annual rounds of mass drug administration with azithromycin for trachoma control.

BACKGROUND: Mass drug administration (MDA) with azithromycin, carried out for the control of blinding trachoma, has been linked to reduced mortality in children. While the mechanism behind this reduction is unclear, it may be due, in part, to improved nutritional status via a potential reduction in the community burden of infectious disease. To determine whether MDA with azithromycin improves anthropometric indices at the community level, we measured the heights and weights of children aged 1 to 4 years in communities where one (single MDA arm) or three annual rounds (annual MDA arm) of azithromycin had been distributed. METHODS: Data collection took place three years after treatment in the single MDA arm and one year after the final round of treatment in the annual MDA arm. Mean height-for-age, weight-for-age and weight-for-height z scores were compared between treatment arms. RESULTS: No significant differences in mean height-for-age, weight-for-age or weight-for-height z scores were found between the annual MDA and single MDA arms, nor was there a significant reduction in prevalence of stunting, wasting or underweight between arms. CONCLUSIONS: Our data do not provide evidence that community MDA with azithromycin improved anthropometric outcomes of children in The Gambia. This may suggest reductions in mortality associated with azithromycin MDA are due to a mechanism other than improved nutritional status

医師が患者から受ける暴力被害とその心理的影響

Objectives: To determine the incidence rate of work-related aggression and violence (WRAV) against doctors and investigate risk factors and psychological influences of WRAV doctors. Methods: We sent a self-administered questionnaire on WRAV committed by patients and their associates to 1,148 doctors in Nara Prefecture, Japan. We calculated the incidence rate of WRAV using the number of incidents encountered during the previous 12 mo and the doctor's average weekly working hours. Risk factors for the incidence WRAV were analyzed by Poisson regression, and the influence of WRAV on the symptoms of post-traumatic stress disorder (PTSD) was evaluated by multiple logistic regression analysis. Results: A total of 758 (66.0%) doctors returned the questionnaire. The incidence rate of WRAV was 0.20 [95% CI: 0.17-0.24]×10-3 per practice hour. Adjusted incidence rate ratios of WRAV were significantly increased among doctors 1) with a shorter career (11.0; 95% CI: 5.0-24.2), 2) working in a region with the lowest average taxable income (1.6; 1.1-2.4), and 3) whose specialties were dermatology (3.8; 2.3-6.3), psychiatry (2.7; 1.3-5.6) and ophthalmology (1.9; 1.2-3.2). Of 289 subjects who had encountered WRAV at least once during their career, 26 doctors (8.2%) had symptoms suggestive of PTSD due to the most severe incident. Conclusions: Doctors encountered WRAV at an incidence rate of 0.20×10-3 per practice hour, and some of them might develop PTSD. Countermeasures are required to maintain sound health and safe workplaces for doctors.博士（医学）・乙第1292号・平成24年5月28日Copyright © 2011 by the Japan Society for Occupational Healt

Preliminary evidence of reductive stress in human cytotoxic T-cells following exercise

This study investigated immunophenotypic differences in intracellular thiol redox state of peripheral blood mononuclear cells (PBMCs) isolated from trained (TR, n=9, mean {plus minus} SD: age 28 {plus minus} 5 years; BMI 23.2 {plus minus} 2.6 kg·m2; VO2max 56.9 {plus minus} 6.1 ml·kg-1·min-1) and recreationally active (RA, n=11, mean {plus minus} SD: age 27 {plus minus} 6 years; BMI 24.2 {plus minus} 3.7 kg·m2; VO2max 45.1 {plus minus} 6.4 ml·kg-1·min-1) participants before and after a maximal aerobic exercise tolerance test. Blood samples were taken before (PRE), during (sample acquired at 70% HRmax), immediately (POST+0) and 15 minutes post-exercise (POST+15). PBMCs were isolated and reduced thiol analysis (fluorescein-5 maleimide (F5M)) by immunophenotype (CD3+, CD4+ and CD8+) was performed using flow cytometry. A significant increase in cellular F5M fluorescence was observed in CD3+ T-cells at POST+0, with changes driven to a greater extent by CD8+ T-cells (fold change in both groups CD4: +2.3, CD8: +2.8; p<0.05). Further analysis revealed a population of highly reduced CD8+ T-cells (CD8+T-reduced+) that significantly increased from PRE to POST+0 in RA participants only (RA: +272 cell/µL, p<0.05). To further understand these results, CD8+T-reduced+ and CD8+T-reduced- cells were analysed for immunophenotype in response to the same exercise protocol (n=6, mean {plus minus} SD: age 24 {plus minus} 5 years; BMI 25.7 {plus minus} 4.1 kg·m-2; VO2max 41.33 {plus minus} 7.63 ml·kg-1·min-1). CD8+T-reduced+ had significantly less lymphoid homing potential (CCR7) POST+0 compared to PRE. This study is the first to demonstrate that lymphocyte populations become more reductive in response to acute exercise

Neurodegeneration progresses despite complete elimination of clinical relapses in a mouse model of multiple sclerosis.

BACKGROUND: [corrected] Multiple Sclerosis has two clinical phases reflecting distinct but inter-related pathological processes: focal inflammation drives the relapse-remitting stage and neurodegeneration represents the principal substrate of secondary progression. In contrast to the increasing number of effective anti-inflammatory disease modifying treatments for relapse-remitting disease, the absence of therapies for progressive disease represents a major unmet clinical need. This raises the unanswered question of whether elimination of clinical relapses will prevent subsequent progression and if so how early in the disease course should treatment be initiated. Experimental autoimmune encephalomyelitis in the Biozzi ABH mouse recapitulates the clinical and pathological features of multiple sclerosis including relapse-remitting episodes with inflammatory mediated demyelination and progressive disability with neurodegeneration. To address the relationship between inflammation and neurodegeneration we used an auto-immune tolerance strategy to eliminate clinical relapses in EAE in a manner analogous to the clinical effect of disease modifying treatments. RESULTS: By arresting clinical relapses in EAE at two distinct stages, early and late disease, we demonstrate that halting immune driven demyelination even after the first major clinical event is insufficient to prevent long-term neurodegeneration and associated gliosis. Nonetheless, early intervention is partially neuroprotective, whereas later interventions are not. Furthermore early tolerisation is also associated with increased remyelination. CONCLUSIONS: These findings are consistent with both a partial uncoupling of inflammation and neurodegeneration and that the regenerative response of remyelination is negatively correlated with inflammation. These findings strongly support the need for early combinatorial treatment of immunomodulatory therapies and neuroprotective treatments to prevent long-term neurodegeneration in multiple sclerosis

Detecting a conditional extrme value model

In classical extreme value theory probabilities of extreme events are estimated assuming all the components of a random vector to be in a domain of attraction of an extreme value distribution. In contrast, the conditional extreme value model assumes a domain of attraction condition on a sub-collection of the components of a multivariate random vector. This model has been studied in \cite{heffernan:tawn:2004,heffernan:resnick:2007,das:resnick:2008a}. In this paper we propose three statistics which act as tools to detect this model in a bivariate set-up. In addition, the proposed statistics also help to distinguish between two forms of the limit measure that is obtained in the model.Comment: 21 pages, 4 figure