Lipid peroxidation biomarkers for evaluating oxidative stress in equine neuroaxonal dystrophy.

BackgroundEquine neuroaxonal dystrophy/equine degenerative myeloencephalopathy (eNAD/EDM) is a neurodegenerative disorder affecting genetically predisposed foals maintained on an α-tocopherol (α-TOH) deficient diet. Currently no antemortem diagnostic test for eNAD/EDM is available.HypothesisBecause α-TOH deficiency is associated with increased lipid peroxidation, it was hypothesized that F2 -isoprostanes (F2 IsoP), F4 -neuroprostanes (F4 NP) and oxysterols derived from free radical oxidation would be increased in the cerebrospinal fluid (CSF) and neural tissue of eNAD/EDM affected horses and could serve as potential biomarkers for disease.AnimalsIsoprostane Study A: 14 Quarter horse foals (10 healthy foals and 4 eNAD/EDM affected foals) at 1 and 6 months of age. Isoprostane Study B: 17 eNAD/EDM affected and 10 unaffected horses ≥ 1-4 years of age. Oxysterol study: eNAD/EDM affected (n = 14, serum; n = 11, CSF; n = 10, spinal cord [SC]) and unaffected horses 1-4 years of age (n = 12, serum; n = 10, CSF; n = 7, SC).ProceduresCerebrospinal fluid [F2 IsoP] and [F4 NP] were assessed using gas chromatography-negative ion chemical ionization mass spectrometry. Serum, CSF, and cervical SC [oxysterols] were quantified using high performance liquid chromatography mass spectrometry. Results were compared with respective α-TOH concentrations.ResultsSpinal cord [7-ketocholesterol], [7-hydroxycholesterol], and [7-keto-27-hydrocholesterol] were higher in eNAD/EDM horses whereas [24-ketocholesterol] was lower. No significant difference was found in CSF [F2 IsoP] and [F4 NP], serum [oxysterols] and CSF [oxysterols] between eNAD/EDM affected and unaffected horses. No correlation was found between [F2 IsoP], [F4 NP], or [oxysterols] and respective [α-TOH].Conclusions and clinical importanceIn the SC, targeted markers of cholesterol oxidation were significantly increased in horses with eNAD/EDM

CXCR7 influences leukocyte entry into the CNS parenchyma by controlling abluminal CXCL12 abundance during autoimmunity

During CNS autoimmunity, brain endothelial cell CXCR7 internalizes CXCL12 from the perivascular space, thereby permitting leukocyte migration into the CNS parenchyma

A multidimensional platform for the purification of non-coding RNA species

A renewed interest in non-coding RNA (ncRNA) has led to the discovery of novel RNA species and post-transcriptional ribonucleoside modifications, and an emerging appreciation for the role of ncRNA in RNA epigenetics. Although much can be learned by amplification-based analysis of ncRNA sequence and quantity, there is a significant need for direct analysis of RNA, which has led to numerous methods for purification of specific ncRNA molecules. However, no single method allows purification of the full range of cellular ncRNA species. To this end, we developed a multidimensional chromatographic platform to resolve, isolate and quantify all canonical ncRNAs in a single sample of cells or tissue, as well as novel ncRNA species. The applicability of the platform is demonstrated in analyses of ncRNA from bacteria, human cells and plasmodium-infected reticulocytes, as well as a viral RNA genome. Among the many potential applications of this platform are a system-level analysis of the dozens of modified ribonucleosides in ncRNA, characterization of novel long ncRNA species, enhanced detection of rare transcript variants and analysis of viral genomes.Singapore-MIT Alliance for Research and TechnologyNational Institute of Environmental Health Sciences (ES017010)National Institute of Environmental Health Sciences (ES002109

Brief intervention to reduce risky drinking in pregnancy: study protocol for a randomized controlled trial

<p>Abstract</p> <p>Background</p> <p>Risky drinking in pregnancy by UK women is likely to result in many alcohol-exposed pregnancies. Studies from the USA suggest that brief intervention has promise for alcohol risk reduction in antenatal care. However, further research is needed to establish whether this evidence from the USA is applicable to the UK. This pilot study aims to investigate whether pregnant women can be recruited and retained in a randomized controlled trial of brief intervention aimed at reducing risky drinking in women receiving antenatal care.</p> <p>Methods</p> <p>The trial will rehearse the parallel-group, non-blinded design and procedures of a subsequent definitive trial. Over 8 months, women aged 18 years and over (target number 2,742) attending their booking appointment with a community midwife (n = 31) in north-east England will be screened for alcohol consumption using the consumption questions of the Alcohol Use Disorders Identification Test (AUDIT-C). Those screening positive, without a history of substance use or alcohol dependence, with no pregnancy complication, and able to give informed consent, will be invited to participate in the trial (target number 120). Midwives will be randomized in a 1:1 ratio to deliver either treatment as usual (control) or structured brief advice and referral for a 20-minute motivational interviewing session with an alcohol health worker (intervention). As well as demographic and health information, baseline measures will include two 7-day time line follow-back questionnaires and the EuroQoL EQ-5D-3 L questionnaire. Measures will be repeated in telephone follow-ups in the third trimester and at 6 months post-partum, when a questionnaire on use of National Health Service and social care resources will also be completed. Information on pregnancy outcomes and stillbirths will be accessed from central health service records before the follow-ups. Primary outcomes will be rates of eligibility, recruitment, intervention delivery, and retention in the study population, to inform power calculations for a definitive trial. The health-economics component will establish how cost-effectiveness will be assessed, and examine which data on health service resource use should be collected in a main trial. Participants’ views on instruments and procedures will be sought to confirm their acceptability.</p> <p>Discussion</p> <p>The study will produce a full trial protocol with robust sample-size calculations to extend evidence on effectiveness of screening and brief intervention.</p> <p>Trial Registration</p> <p>Current Controlled Trials ISRCTN43218782</p

Diffusion tensor imaging of frontal lobe white matter tracts in schizophrenia

We acquired diffusion tensor and structural MRI images on 103 patients with schizophrenia and 41 age-matched normal controls. The vector data was used to trace tracts from a region of interest in the anterior limb of the internal capsule to the prefrontal cortex. Patients with schizophrenia had tract paths that were significantly shorter in length from the center of internal capsule to prefrontal white matter. These tracts, the anterior thalamic radiations, are important in frontal-striatal-thalamic pathways. These results are consistent with findings of smaller size of the anterior limb of the internal capsule in patients with schizophrenia, diffusion tensor anisotropy decreases in frontal white matter in schizophrenia and hypothesized disruption of the frontal-striatal-thalamic pathway system

Preparedness for Pediatric Office Emergencies: A Multicenter, Simulation-Based Study

OBJECTIVES Pediatric emergencies can occur in pediatric primary care offices. However, few studies have measured emergency preparedness, or the processes of emergency care, provided in the pediatric office setting. In this study, we aimed to measure emergency preparedness and care in a national cohort of pediatric offices. METHODS This was a multicenter study conducted over 15 months. Emergency preparedness scores were calculated as a percentage adherence to 2 checklists on the basis of the American Academy of Pediatrics guidelines (essential equipment and supplies and policies and protocols checklists). To measure the quality of emergency care, we recruited office teams for simulation sessions consisting of 2 patients: a child with respiratory distress and a child with a seizure. An unweighted percentage of adherence to checklists for each case was calculated. RESULTS Forty-eight teams from 42 offices across 9 states participated. The mean emergency preparedness score was 74.7% (SD: 12.9). The mean essential equipment and supplies subscore was 82.2% (SD: 15.1), and the mean policies and protocols subscore was 57.1% (SD: 25.6). Multivariable analyses revealed that independent practices and smaller total staff size were associated with lower preparedness. The median asthma case performance score was 63.6% (interquartile range: 43.2–81.2), whereas the median seizure case score was 69.2% (interquartile range: 46.2–80.8). Offices that had a standardized process of contacting emergency medical services (EMS) had a higher rate of activating EMS during the simulations. CONCLUSIONS Pediatric office preparedness remains suboptimal in a multicenter cohort, especially in smaller, independent practices. Academic and community partnerships using simulation can help address gaps and implement important processes like contacting EMS

A randomised controlled feasibility trial for an educational school-based mental health intervention: study protocol

Background: With the burden of mental illness estimated to be costing the English economy alone around £22.5 billion a year [1], coupled with growing evidence that many mental disorders have their origins in adolescence, there is increasing pressure for schools to address the emotional well-being of their students, alongside the stigma and discrimination of mental illness. A number of prior educational interventions have been developed and evaluated for this purpose, but inconsistency of findings, reporting standards, and methodologies have led the majority of reviewers to conclude that the evidence for the efficacy of these programmes remains inconclusive. Methods/Design: A cluster randomised controlled trial design has been employed to enable a feasibility study of 'SchoolSpace', an intervention in 7 UK secondary schools addressing stigma of mental illness, mental health literacy, and promotion of mental health. A central aspect of the intervention involves students in the experimental condition interacting with a young person with lived experience of mental illness, a stigma reducing technique designed to facilitate students' engagement in the project. The primary outcome is the level of stigma related to mental illness. Secondary outcomes include mental health literacy, resilience to mental illness, and emotional well-being. Outcomes will be measured pre and post intervention, as well as at 6 month follow-up. Discussion: The proposed intervention presents the potential for increased engagement due to its combination of education and contact with a young person with lived experience of mental illness. Contact as a technique to reduce discrimination has been evaluated previously in research with adults, but has been employed in only a minority of research trials investigating the impact on youth. Prior to this study, the effect of contact on mental health literacy, resilience, and emotional well-being has not been evaluated to the authors' knowledge. If efficacious the intervention could provide a reliable and cost-effective method to reduce stigma in young people, whilst increasing mental health literacy, and emotional well-being. Trial registration: ISRCTN: ISRCTN0740602

Comprehensive Research Synopsis and Systematic Meta-Analyses in Parkinson's Disease Genetics: The PDGene Database

More than 800 published genetic association studies have implicated dozens of potential risk loci in Parkinson's disease (PD). To facilitate the interpretation of these findings, we have created a dedicated online resource, PDGene, that comprehensively collects and meta-analyzes all published studies in the field. A systematic literature screen of ∼27,000 articles yielded 828 eligible articles from which relevant data were extracted. In addition, individual-level data from three publicly available genome-wide association studies (GWAS) were obtained and subjected to genotype imputation and analysis. Overall, we performed meta-analyses on more than seven million polymorphisms originating either from GWAS datasets and/or from smaller scale PD association studies. Meta-analyses on 147 SNPs were supplemented by unpublished GWAS data from up to 16,452 PD cases and 48,810 controls. Eleven loci showed genome-wide significant (P<5×10−8) association with disease risk: BST1, CCDC62/HIP1R, DGKQ/GAK, GBA, LRRK2, MAPT, MCCC1/LAMP3, PARK16, SNCA, STK39, and SYT11/RAB25. In addition, we identified novel evidence for genome-wide significant association with a polymorphism in ITGA8 (rs7077361, OR 0.88, P = 1.3×10−8). All meta-analysis results are freely available on a dedicated online database (www.pdgene.org), which is cross-linked with a customized track on the UCSC Genome Browser. Our study provides an exhaustive and up-to-date summary of the status of PD genetics research that can be readily scaled to include the results of future large-scale genetics projects, including next-generation sequencing studies

Genome-Wide Gene-Environment Study Identifies Glutamate Receptor Gene GRIN2A as a Parkinson's Disease Modifier Gene via Interaction with Coffee

Our aim was to identify genes that influence the inverse association of coffee with the risk of developing Parkinson's disease (PD). We used genome-wide genotype data and lifetime caffeinated-coffee-consumption data on 1,458 persons with PD and 931 without PD from the NeuroGenetics Research Consortium (NGRC), and we performed a genome-wide association and interaction study (GWAIS), testing each SNP's main-effect plus its interaction with coffee, adjusting for sex, age, and two principal components. We then stratified subjects as heavy or light coffee-drinkers and performed genome-wide association study (GWAS) in each group. We replicated the most significant SNP. Finally, we imputed the NGRC dataset, increasing genomic coverage to examine the region of interest in detail. The primary analyses (GWAIS, GWAS, Replication) were performed using genotyped data. In GWAIS, the most significant signal came from rs4998386 and the neighboring SNPs in GRIN2A. GRIN2A encodes an NMDA-glutamate-receptor subunit and regulates excitatory neurotransmission in the brain. Achieving P2df = 10−6, GRIN2A surpassed all known PD susceptibility genes in significance in the GWAIS. In stratified GWAS, the GRIN2A signal was present in heavy coffee-drinkers (OR = 0.43; P = 6×10−7) but not in light coffee-drinkers. The a priori Replication hypothesis that “Among heavy coffee-drinkers, rs4998386_T carriers have lower PD risk than rs4998386_CC carriers” was confirmed: ORReplication = 0.59, PReplication = 10−3; ORPooled = 0.51, PPooled = 7×10−8. Compared to light coffee-drinkers with rs4998386_CC genotype, heavy coffee-drinkers with rs4998386_CC genotype had 18% lower risk (P = 3×10−3), whereas heavy coffee-drinkers with rs4998386_TC genotype had 59% lower risk (P = 6×10−13). Imputation revealed a block of SNPs that achieved P2df<5×10−8 in GWAIS, and OR = 0.41, P = 3×10−8 in heavy coffee-drinkers. This study is proof of concept that inclusion of environmental factors can help identify genes that are missed in GWAS. Both adenosine antagonists (caffeine-like) and glutamate antagonists (GRIN2A-related) are being tested in clinical trials for treatment of PD. GRIN2A may be a useful pharmacogenetic marker for subdividing individuals in clinical trials to determine which medications might work best for which patients