Enhanced production of IL-17A in patients with severe asthma is inhibited by 1α,25-dihydroxyvitamin D3 in a glucocorticoid-independent fashion

Background: TH17 cells are proposed to play a role in the pathology of asthma, including steroid-resistant (SR) disease. We previously identified a steroid-enhancing function of vitamin D in patients with SR asthma in restoring the impaired response to steroids for production of the anti-inflammatory cytokine IL-10. / Objective: We sought to investigate the production of the TH17-associated cytokines IL-17A and IL-22 in culture in patients with moderate-to-severe asthma defined on the basis of their clinical response to steroids and the susceptibility of this response to inhibition by steroids and the active form of vitamin D, 1α,25-dihydroxyvitamin D3 (1,25[OH]2D3). / Methods: PBMCs were stimulated in culture with or without dexamethasone and 1,25(OH)2D3. A cytometric bead array, ELISA, and intracellular cytokine staining were used to assess cytokine production. The role of CD39 in inhibition of the TH17 response was studied by using quantitative real-time PCR, flow cytometry, and addition of the antagonist POM-1 to culture. / Results: Asthmatic patients synthesized much higher levels of IL-17A and IL-22 than nonasthmatic control subjects, with patients with SR asthma expressing the highest levels of IL-17A. Glucocorticoids did not inhibit IL-17A cytokine expression in patients and enhanced production in cultures from control subjects. Treatment with 1,25(OH)2D3 with or without dexamethasone significantly reduced both IL-17A and IL-22 levels. An antagonist of the ectonucleotidase CD39 reversed 1,25(OH)2D3-mediated inhibition of the IL-17A response. / Conclusion: Patients with severe asthma exhibit increased levels of TH17 cytokines, which are not inhibited by steroids. 1,25(OH)2D3 inhibits TH17 cytokine production in all patients studied, irrespective of their clinical responsiveness to steroids, identifying novel steroid-enhancing properties of vitamin D in asthmatic patients

Incidence of self-reported brain injury and the relationship with substance abuse: findings from a longitudinal community survey

<p>Abstract</p> <p>Background</p> <p>Traumatic or serious brain injury (BI) has persistent and well documented adverse outcomes, yet 'mild' or 'moderate' BI, which often does not result in hospital treatment, accounts for half the total days of disability attributed to BI. There are currently few data available from community samples on the incidence and correlates of these injuries. Therefore, the study aimed to assess the 1) incidence of self-reported mild (not requiring hospital admission) and moderate (admitted to hospital)) brain injury (BI), 2) causes of injury 3) physical health scores and 4) relationship between BI and problematic alcohol or marijuana use.</p> <p>Methods</p> <p>An Australian community sequential-cohort study (cohorts aged 20-24, 40-44 and 60-64 years at wave one) used a survey methodology to assess BI and substance use at baseline and four years later.</p> <p>Results</p> <p>Of the 7485 wave one participants, 89.7% were re-interviewed at wave two. There were 56 mild (230.8/100000 person-years) and 44 moderate BI (180.5/100000 person-years) reported between waves one and two. Males and those in the 20-24 year cohort had increased risk of BI. Sports injury was the most frequent cause of BI (40/100) with traffic accidents being a greater proportion of moderate (27%) than mild (7%) BI. Neither alcohol nor marijuana problems at wave one were predictors of BI. BI was not a predictor of developing substance use problems by wave two.</p> <p>Conclusions</p> <p>BI were prevalent in this community sample, though the incidence declined with age. Factors associated with BI in community samples differ from those reported in clinical samples (e.g. typically traumatic brain injury with traffic accidents the predominate cause). Further, detailed evaluation of the health consequences of these injuries is warranted.</p

Effects of acute substance use and pre-injury substance abuse on traumatic brain injury severity in adults admitted to a trauma centre

<p>Abstract</p> <p>Background</p> <p>The aims of this study were to describe the occurrence of substance use at the time of injury and pre-injury substance abuse in patients with moderate-to-severe traumatic brain injury (TBI). Effects of acute substance use and pre-injury substance abuse on TBI severity were also investigated.</p> <p>Methods</p> <p>A prospective study of 111 patients, aged 16-55 years, injured from May 2005 to May 2007 and hospitalised at the Trauma Referral Centre in Eastern Norway with acute TBI (Glasgow Coma Scale 3-12). Based on structural brain damages shown on a computed tomography (CT) scan, TBI severity was defined by modified Marshall classification as less severe (score <3) and more severe (score ≥3). Clinical definition of substance use (alcohol and/or other psychoactive substances) was applied when hospital admission records reflected blood alcohol levels or a positive drug screen, or when a physician verified influence by examining the patient. Pre-injury substance abuse (alcohol and drug problems) was screened by using the CAGE questionnaire.</p> <p>Results</p> <p>Forty-seven percent of patients were positive for substance use on admission to hospital. Significant pre-injury substance abuse was reported by 26% of patients. Substance use at the time of injury was more frequent in the less severe group (p = 0.01). The frequency of pre-injury substance abuse was higher in the more severe group (30% vs. 23%). In a logistic regression model, acute substance use at time of injury tended to decrease the probability of more severe intracranial injury, but the effect was not statistically significant after adjusting for age, gender, education, cause of injury and substance abuse, OR = 0.39; 95% CI 0.11-1.35, p = 0.14. Patients with positive screens for pre-injury substance abuse (CAGE ≥2) were more likely to have more severe TBI in the adjusted regression analyses, OR = 4.05; 95% CI 1.10-15.64, p = 0.04.</p> <p>Conclusions</p> <p>Acute <b>s</b>ubstance use was more frequent in patients with less severe TBI caused by low-energy events such as falls, violence and sport accidents. Pre-injury substance abuse increased the probability of more severe TBI caused by high-energy trauma such as motor vehicle accidents and falls from higher levels. Preventive efforts to reduce substance consumption and abuse in at-risk populations are needed.</p

Search for new phenomena in final states with an energetic jet and large missing transverse momentum in pp collisions at √ s = 8 TeV with the ATLAS detector

Results of a search for new phenomena in final states with an energetic jet and large missing transverse momentum are reported. The search uses 20.3 fb−1 of √ s = 8 TeV data collected in 2012 with the ATLAS detector at the LHC. Events are required to have at least one jet with pT > 120 GeV and no leptons. Nine signal regions are considered with increasing missing transverse momentum requirements between Emiss T > 150 GeV and Emiss T > 700 GeV. Good agreement is observed between the number of events in data and Standard Model expectations. The results are translated into exclusion limits on models with either large extra spatial dimensions, pair production of weakly interacting dark matter candidates, or production of very light gravitinos in a gauge-mediated supersymmetric model. In addition, limits on the production of an invisibly decaying Higgs-like boson leading to similar topologies in the final state are presente

Cognition based bTBI mechanistic criteria; a tool for preventive and therapeutic innovations

Blast-induced traumatic brain injury has been associated with neurodegenerative and neuropsychiatric disorders. To date, although damage due to oxidative stress appears to be important, the specific mechanistic causes of such disorders remain elusive. Here, to determine the mechanical variables governing the tissue damage eventually cascading into cognitive deficits, we performed a study on the mechanics of rat brain under blast conditions. To this end, experiments were carried out to analyse and correlate post-injury oxidative stress distribution with cognitive deficits on a live rat exposed to blast. A computational model of the rat head was developed from imaging data and validated against in vivo brain displacement measurements. The blast event was reconstructed in silico to provide mechanistic thresholds that best correlate with cognitive damage at the regional neuronal tissue level, irrespectively of the shape or size of the brain tissue types. This approach was leveraged on a human head model where the prediction of cognitive deficits was shown to correlate with literature findings. The mechanistic insights from this work were finally used to propose a novel helmet design roadmap and potential avenues for therapeutic innovations against blast traumatic brain injury

Development and psychometric properties the Barriers to Access to Care Evaluation scale (BACE) related to people with mental ill health

Many people with mental illness do not seek or delay seeking care. This study aimed to develop, and provide an initial validation of, a comprehensive measure for assessing barriers to access to mental health care including a 'treatment stigma' subscale, and to present preliminary evidence about the prevalence of barriers experienced by adults currently or recently using secondary mental health services in the UK

Age-related change in brain metabolite abnormalities in autism: a meta-analysis of proton magnetic resonance spectroscopy studies

Abnormal trajectory of brain development has been suggested by previous structural magnetic resonance imaging and head circumference findings in autism spectrum disorders (ASDs); however, the neurochemical backgrounds remain unclear. To elucidate neurochemical processes underlying aberrant brain growth in ASD, we conducted a comprehensive literature search and a meta-analysis of 1H-magnetic resonance spectroscopy (1H-MRS) studies in ASD. From the 22 articles identified as satisfying the criteria, means and s.d. of measure of N-acetylaspartate (NAA), creatine, choline-containing compounds, myo-Inositol and glutamate+glutamine in frontal, temporal, parietal, amygdala-hippocampus complex, thalamus and cerebellum were extracted. Random effect model analyses showed significantly lower NAA levels in all the examined brain regions but cerebellum in ASD children compared with typically developed children (n=1295 at the maximum in frontal, P<0.05 Bonferroni-corrected), although there was no significant difference in metabolite levels in adulthood. Meta-regression analysis further revealed that the effect size of lower frontal NAA levels linearly declined with older mean age in ASD (n=844, P<0.05 Bonferroni-corrected). The significance of all frontal NAA findings was preserved after considering between-study heterogeneities (P<0.05 Bonferroni-corrected). This first meta-analysis of 1H-MRS studies in ASD demonstrated robust developmental changes in the degree of abnormality in NAA levels, especially in frontal lobes of ASD. Previously reported larger-than-normal brain size in ASD children and the coincident lower-than-normal NAA levels suggest that early transient brain expansion in ASD is mainly caused by an increase in non-neuron tissues, such as glial cell proliferation

Effects of traumatic brain injury and posttraumatic stress disorder on Alzheimer's disease in veterans, using the Alzheimer's Disease Neuroimaging Initiative

Both traumatic brain injury (TBI) and posttraumatic stress disorder (PTSD) are common problems resulting from military service, and both have been associated with increased risk of cognitive decline and dementia resulting from Alzheimer's disease (AD) or other causes. This study aims to use imaging techniques and biomarker analysis to determine whether traumatic brain injury (TBI) and/or PTSD resulting from combat or other traumas increase the risk for AD and decrease cognitive reserve in Veteran subjects, after accounting for age. Using military and Department of Veterans Affairs records, 65 Vietnam War veterans with a history of moderate or severe TBI with or without PTSD, 65 with ongoing PTSD without TBI, and 65 control subjects are being enrolled in this study at 19 sites. The study aims to select subject groups that are comparable in age, gender, ethnicity, and education. Subjects with mild cognitive impairment (MCI) or dementia are being excluded. However, a new study just beginning, and similar in size, will study subjects with TBI, subjects with PTSD, and control subjects with MCI. Baseline measurements of cognition, function, blood, and cerebrospinal fluid biomarkers; magnetic resonance images (structural, diffusion tensor, and resting state blood-level oxygen dependent (BOLD) functional magnetic resonance imaging); and amyloid positron emission tomographic (PET) images with florbetapir are being obtained. One-year follow-up measurements will be collected for most of the baseline procedures, with the exception of the lumbar puncture, the PET imaging, and apolipoprotein E genotyping. To date, 19 subjects with TBI only, 46 with PTSD only, and 15 with TBI and PTSD have been recruited and referred to 13 clinics to undergo the study protocol. It is expected that cohorts will be fully recruited by October 2014. This study is a first step toward the design and statistical powering of an AD prevention trial using at-risk veterans as subjects, and provides the basis for a larger, more comprehensive study of dementia risk factors in veterans

Psychometric Properties of the Parent and Teacher Versions of the Strengths and Difficulties Questionnaire for 4- to 12-Year-Olds: A Review

Since its development, the Strengths and Difficulties Questionnaire (SDQ) has been widely used in both research and practice. The SDQ screens for positive and negative psychological attributes. This review aims to provide an overview of the psychometric properties of the SDQ for 4- to 12-year-olds. Results from 48 studies (N = 131,223) on reliability and validity of the parent and teacher SDQ are summarized quantitatively and descriptively. Internal consistency, test–retest reliability, and inter-rater agreement are satisfactory for the parent and teacher versions. At subscale level, the reliability of the teacher version seemed stronger compared to that of the parent version. Concerning validity, 15 out of 18 studies confirmed the five-factor structure. Correlations with other measures of psychopathology as well as the screening ability of the SDQ are sufficient. This review shows that the psychometric properties of the SDQ are strong, particularly for the teacher version. For practice, this implies that the use of the SDQ as a screening instrument should be continued. Longitudinal research studies should investigate predictive validity. For both practice and research, we emphasize the use of a multi-informant approach