Screening for Familial APP Mutations in Sporadic Cerebral Amyloid Angiopathy

Background Advances in genetic technology have revealed that variation in the same gene can cause both rare familial and common sporadic forms of the same disease. Cerebral amyloid angiopathy (CAA), a common cause of symptomatic intracerebral hemorrhage (ICH) in the elderly, can also occur in families in an autosomal dominant pattern. The majority of affected families harbor mutations in the Beta amyloid Peptide (Aβ) coding region of the gene for amyloid precursor protein (APP) or have duplications of chromosomal segments containing APP. Methodology/Principal Findings A total of 58 subjects with a diagnosis of probable or definite CAA according to validated criteria were included in the present study. We sequenced the Aβ coding region of APP in 58 individuals and performed multiplex ligation-dependent probe amplification to determine APP gene dosage in 60. No patient harbored a known or novel APP mutation or gene duplication. The frequency of mutations investigated in the present study is estimated to range from 0% to 8% in individuals with probable CAA in the general population, based on the ascertained sample size. Conclusions/Significance We found no evidence that variants at loci associated with familial CAA play a role in sporadic CAA. Based on our findings, these rare highly-penetrant mutations are unlikely to be seen in sporadic CAA patients. Therefore, our results do not support systematic genetic screening of CAA patients who lack a strong family history of hemorrhage or dementia.National Institute of Neurological Disorders and Stroke (U.S.) (grant K23NS042695)American Heart AssociationAmerican Stroke Association (Bugher Foundation for Stroke Prevention Research

The use of Open Reading frame ESTs (ORESTES) for analysis of the honey bee transcriptome

BACKGROUND: The ongoing efforts to sequence the honey bee genome require additional initiatives to define its transcriptome. Towards this end, we employed the Open Reading frame ESTs (ORESTES) strategy to generate profiles for the life cycle of Apis mellifera workers. RESULTS: Of the 5,021 ORESTES, 35.2% matched with previously deposited Apis ESTs. The analysis of the remaining sequences defined a set of putative orthologs whose majority had their best-match hits with Anopheles and Drosophila genes. CAP3 assembly of the Apis ORESTES with the already existing 15,500 Apis ESTs generated 3,408 contigs. BLASTX comparison of these contigs with protein sets of organisms representing distinct phylogenetic clades revealed a total of 1,629 contigs that Apis mellifera shares with different taxa. Most (41%) represent genes that are in common to all taxa, another 21% are shared between metazoans (Bilateria), and 16% are shared only within the Insecta clade. A set of 23 putative genes presented a best match with human genes, many of which encode factors related to cell signaling/signal transduction. 1,779 contigs (52%) did not match any known sequence. Applying a correction factor deduced from a parallel analysis performed with Drosophila melanogaster ORESTES, we estimate that approximately half of these no-match ESTs contigs (22%) should represent Apis-specific genes. CONCLUSIONS: The versatile and cost-efficient ORESTES approach produced minilibraries for honey bee life cycle stages. Such information on central gene regions contributes to genome annotation and also lends itself to cross-transcriptome comparisons to reveal evolutionary trends in insect genomes

Observation of associated near-side and away-side long-range correlations in √sNN=5.02 TeV proton-lead collisions with the ATLAS detector

Two-particle correlations in relative azimuthal angle (Δϕ) and pseudorapidity (Δη) are measured in √sNN=5.02  TeV p+Pb collisions using the ATLAS detector at the LHC. The measurements are performed using approximately 1  μb-1 of data as a function of transverse momentum (pT) and the transverse energy (ΣETPb) summed over 3.1<η<4.9 in the direction of the Pb beam. The correlation function, constructed from charged particles, exhibits a long-range (2<|Δη|<5) “near-side” (Δϕ∼0) correlation that grows rapidly with increasing ΣETPb. A long-range “away-side” (Δϕ∼π) correlation, obtained by subtracting the expected contributions from recoiling dijets and other sources estimated using events with small ΣETPb, is found to match the near-side correlation in magnitude, shape (in Δη and Δϕ) and ΣETPb dependence. The resultant Δϕ correlation is approximately symmetric about π/2, and is consistent with a dominant cos⁡2Δϕ modulation for all ΣETPb ranges and particle pT

Permanent education in health: a review

OBJECTIVE : To undertake a meta-synthesis of the literature on the main concepts and practices related to permanent education in health. METHODS : A bibliographical search was conducted for original articles in the PubMed, Web of Science, LILACS, IBECS and SciELO databases, using the following search terms: “public health professional education”, “permanent education”, “continuing education”, “permanent education health”. Of the 590 articles identified, after applying inclusion and exclusion criteria, 48 were selected for further analysis, grouped according to the criteria of key elements, and then underwent meta-synthesis. RESULTS : The 48 original publications were classified according to four thematic units of key elements: 1) concepts, 2) strategies and difficulties, 3) public policies and 4) educational institutions. Three main conceptions of permanent education in health were found: problem-focused and team work, directly related to continuing education and education that takes place throughout life. The main strategies for executing permanent education in health are discussion, maintaining an open space for permanent education, and permanent education clusters. The most limiting factor is mainly related to directly or indirect management. Another highlight is the requirement for implementation and maintenance of public policies, and the availability of financial and human resources. The educational institutions need to combine education and service aiming to form critical-reflexive graduates. CONCLUSIONS : The coordination between health and education is based as much on the actions of health services as on management and educational institutions. Thus, it becomes a challenge to implement the teaching-learning processes that are supported by critical-reflexive actions. It is necessary to carry out proposals for permanent education in health involving the participation of health professionals, teachers and educational institutions.OBJETIVO : Realizar metasíntesis de la literatura sobre los principales conceptos y prácticas relacionados con la educación permanente en salud. MÉTODOS : Se realizó búsqueda bibliográfica de artículos originales en las bases de datos PubMed, Web of Science, Lilacs, IBECS y SciELO, utilizando los siguientes descriptores: “ public health professional education”, “permanent education”, “continuing education”, “permanent education health ”. De un total de 590 artículos identificados, posterior a los criterios de inclusión y exclusión, fueron seleccionados 48 para análisis, los cuales fueron sometidos al análisis individual, análisis comparativo, análisis con criterios de agrupamiento de elementos-clave y sometidos a metasíntesis. RESULTADOS : Los 48 artículos originales fueron clasificados como elementos-clave en cuatro unidades temáticas: 1) Concepciones; 2) Estrategias y dificultades; 3) Políticas públicas e 4) Instituciones formadoras. Se encontraron tres concepciones principales de educación permanente en salud: ubicación del problema y enfocarlo en el trabajo en equipo, directamente relacionado con la educación continua y educación que se da a lo largo de la vida. Las principales estrategias para efectivar la educación permanente fueron la ubicación del problema, mantenimiento de espacios para la educación permanente y polos de educación permanente. El mayor factor limitante estuvo relacionado con la gerencia directa o indirecta. Fueron mencionadas la necesidad de implementación y mantenimiento de políticas públicas, así como la disponibilidad de recursos financieros y humanos. Las instituciones formadoras tendrían la necesidad de articular educación y servicio para la formación de egresados críticos-reflexivos. CONCLUSIONES : La articulación educación y salud se encuentra pautada tanto en las acciones de los servicios de salud, cuanto en la gestión y de instituciones formadoras. Así, se torna un desafío implementar procesos de educación-aprendizaje que sean respaldados por acciones crítico-reflexivas. Es necesario realizar propuestas de educación permanente en salud con la participación de profesionales de los servicios, profesores y profesionales de las instituciones de educación.OBJETIVO : Realizar metassíntese da literatura sobre os principais conceitos e práticas relacionados à educação permanente em saúde. MÉTODOS : Foi realizada busca bibliográfica de artigos originais nas bases de dados PubMed, Web of Science, Lilacs, IBECS e SciELO, utilizando os seguintes descritores: “ public health professional education ”, “ permanent education”, “continuing education ”, “ permanent education health ”. De um total de 590 artigos identificados, após os critérios de inclusão e exclusão, foram selecionados 48 para análise, os quais foram submetidos à análise individual, análise comparativa, análise com critérios de agrupamentos de elementos-chave e submetidos à metassíntese. RESULTADOS : Os 48 artigos originais foram classificados como elementos-chave em quatro unidades temáticas: 1) Concepções; 2) Estratégias e dificuldades; 3) Políticas públicas; e 4) Instituições formadoras. Foram encontradas três concepções principais de educação permanente em saúde: problematizadora e focada no trabalho em equipe, diretamente relacionada à educação continuada e educação que se dá ao longo da vida. As principais estratégias para efetivação da educação permanente foram a problematização, manutenção de espaços para a educação permanente e polos de educação permanente. O maior fator limitante foi relacionado à gerência direta ou indireta. Foram indicadas a necessidade de implementação e manutenção de políticas públicas, além de disponibilidade de recursos financeiros e de recursos humanos. As instituições formadoras teriam necessidade de articular ensino e serviço para a formação de egressos críticos-reflexivos. CONCLUSÕES : A articulação educação e saúde encontra-se pautada tanto nas ações dos serviços de saúde, quanto de gestão e de instituições formadoras. Assim, torna-se um desafio implementar processos de ensino-aprendizagem que sejam respaldados por ações crítico-reflexivas. É necessário realizar propostas de educação permanente em saúde com a participação de profissionais dos serviços, professores e profissionais das instituições de ensino

Impact of comorbid psychiatric disorders on the outcome of substance abusers: a six year prospective follow-up in two Norwegian counties

BACKGROUND: Most help-seeking substance abusers have comorbid psychiatric disorders. The importance of such disorders for the long-term course of substance abuse is, however, still unclear. The aim of this paper is to describe six-year outcomes regarding death and relapse among alcoholics and poly-substance abusers and to analyse the predictive value of lifetime psychiatric disorders on relapse. METHODS: A consecutive sample of substance-dependent patients who received treatment in two counties in Norway (n = 287) was followed up after approximately six years. Information on socio-demographics, Axis I (CIDI) and II disorders (MCMI-II) and mental distress (HSCL-25) was gathered at baseline. At follow-up, detailed information regarding socio-demographics, use of substances (AUDIT and DUDIT) and mental distress (HSCL-25) was recorded (response rate: 63%). RESULTS: At six-year follow-up, 11% had died, most often male alcoholics (18%). Among the surviving patients, 70% had drug or alcohol related problems the year prior to follow-up. These patients were, classified as "relapsers". There were no significant differences in the relapse rate between women and men and among poly-substance abusers and alcoholics. The relapsers had an earlier onset of a substance use disorder, and more frequently major depression and agoraphobia. Multivariate analysis indicated that both psychiatric disorders (major depression) and substance use factors (early onset of a substance use disorder) were independent predictors of relapse. CONCLUSION: For reducing the risk of long-term relapse, assessment and treatment of major depression (and agoraphobia) are important. In addition, we are in need of a comprehensive treatment and rehabilitation program that also focuses on the addictive behaviour

A higher activation threshold of memory CD8+ T cells has a fitness cost that is modified by TCR affinity during Tuberculosis

All relevant data are within the paper and its Supporting Information files except for the primary TCR sequences. The data files for the primary TCR sequences are publicly deposited in the University of Massachusetts Medical School’s institutional repository, eScholarship@UMMS. The permanent link to the data is http://dx.doi.org/10.13028/M2CC70T cell vaccines against Mycobacterium tuberculosis (Mtb) and other pathogens are based on the principle that memory T cells rapidly generate effector responses upon challenge, leading to pathogen clearance. Despite eliciting a robust memory CD8+ T cell response to the immunodominant Mtb antigen TB10.4 (EsxH), we find the increased frequency of TB10.4-specific CD8+ T cells conferred by vaccination to be short-lived after Mtb challenge. To compare memory and naïve CD8+ T cell function during their response to Mtb, we track their expansions using TB10.4-specific retrogenic CD8+ T cells. We find that the primary (naïve) response outnumbers the secondary (memory) response during Mtb challenge, an effect moderated by increased TCR affinity. To determine whether the expansion of polyclonal memory T cells is restrained following Mtb challenge, we used TCRβ deep sequencing to track TB10.4-specific CD8+ T cells after vaccination and subsequent challenge in intact mice. Successful memory T cells, defined by their clonal expansion after Mtb challenge, express similar CDR3β sequences suggesting TCR selection by antigen. Thus, both TCR-dependent and -independent factors affect the fitness of memory CD8+ responses. The impaired expansion of the majority of memory T cell clonotypes may explain why some TB vaccines have not provided better protection.This work was supported by NIH R01 AI106725 as well as fellowship funding to SC from NIH AI T32 007061 and the UMass GSBS Millennium Program. The Small Animal Biocontainment Suite was supported in part by Center for AIDS Research Grant P30 AI 060354. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.info:eu-repo/semantics/publishedVersio