Autism as a disorder of neural information processing: directions for research and targets for therapy

The broad variation in phenotypes and severities within autism spectrum disorders suggests the involvement of multiple predisposing factors, interacting in complex ways with normal developmental courses and gradients. Identification of these factors, and the common developmental path into which theyfeed, is hampered bythe large degrees of convergence from causal factors to altered brain development, and divergence from abnormal brain development into altered cognition and behaviour. Genetic, neurochemical, neuroimaging and behavioural findings on autism, as well as studies of normal development and of genetic syndromes that share symptoms with autism, offer hypotheses as to the nature of causal factors and their possible effects on the structure and dynamics of neural systems. Such alterations in neural properties may in turn perturb activity-dependent development, giving rise to a complex behavioural syndrome many steps removed from the root causes. Animal models based on genetic, neurochemical, neurophysiological, and behavioural manipulations offer the possibility of exploring these developmental processes in detail, as do human studies addressing endophenotypes beyond the diagnosis itself

Age and sex-associated variation in the multi-site microbiome of an entire social group of free-ranging rhesus macaques

Background: An individual’s microbiome changes over the course of its lifetime, especially during infancy, and again in old age. Confounding factors such as diet and healthcare make it difficult to disentangle the interactions between age, health, and microbial changes in humans. Animal models present an excellent opportunity to study age- and sex-linked variation in the microbiome, but captivity is known to influence animal microbial abundance and composition, while studies of free-ranging animals are typically limited to studies of the fecal microbiome using samples collected non-invasively. Here, we analyze a large dataset of oral, rectal, and genital swabs collected from 105 free-ranging rhesus macaques (Macaca mulatta, aged 1 month-26 years), comprising one entire social group, from the island of Cayo Santiago, Puerto Rico. We sequenced 16S V4 rRNA amplicons for all samples. Results: Infant gut microbial communities had significantly higher relative abundances of Bifidobacterium and Bacteroides and lower abundances of Ruminococcus, Fibrobacter, and Treponema compared to older age groups, consistent with a diet high in milk rather than solid foods. The genital microbiome varied widely between males and females in beta-diversity, taxonomic composition, and predicted functional profiles. Interestingly, only penile, but not vaginal, microbiomes exhibited distinct age-related changes in microbial beta-diversity, taxonomic composition, and predicted functions. Oral microbiome composition was associated with age, and was most distinctive between infants and other age classes. Conclusions: Across all three body regions, with notable exceptions in the penile microbiome, while infants were distinctly different from other age groups, microbiomes of adults were relatively invariant, even in advanced age. While vaginal microbiomes were exceptionally stable, penile microbiomes were quite variable, especially at the onset of reproductive age. Relative invariance among adults, including elderly individuals, is contrary to findings in humans and mice. We discuss potential explanations for this observation, including that age-related microbiome variation seen in humans may be related to changes in diet and lifestyle. 4_dARqKdohA9mAZyu7q9YNVideo abstrac

Cross-sectional and prospective associations between sleep, screen time, active school travel, sports/exercise participation and physical activity in children and adolescents

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Теневой человек как социокультурный феномен

Background: Cardiorespiratory fitness (CRF) is a physical condition that is now well established as a predictor of numerous adverse health outcomes, independent of physical activity levels. In order to be able to improve CRF at the population level and to develop effective interventions and public health programmes, it is important to understand why some people are more fit than others. Therefore, the primary aim of the systematic review described in this protocol is to examine individual and interpersonal factors that are correlated with or determine CRF among adults. Methods: The review will focus on quantitative studies that investigate any personal and interpersonal correlates and/or determinants of objectively measured CRF among the general, non-symptomatic, non-institutionalized adult population (aged 18–65 years) worldwide. The databases MEDLINE, Embase, and Cochrane Library will be searched to identify all relevant published journal articles, and Google Scholar and Scopus will be searched for grey literature. Studies where CRF is not an outcome variable and experimental studies where participants specifically receive a fitness intervention that increases CRF will be excluded. For each study, data extracted will include, among other variables, study characteristics, methodology for selecting participants into the study as well as the participants’ demographic characteristics, types of correlates and determinants of CRF investigated and their measurement methods, the objective measure of CRF used and its measurement method and validity, and the main reported results on the association between the correlates or determinants and CRF. In addition, observational studies will be assessed for methodological quality and risk of bias using a customized version of the Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies by the National Heart, Lung, and Blood Institute. Experimental studies will be assessed using the 27-item Downs and Black “Checklist for Measuring Study Quality”. The final results will be presented as a narrative synthesis of the main findings of all included studies. Discussion: By consolidating and synthesizing the current research on possible individual and interpersonal correlates and determinants of CRF among adults worldwide, we aim to aid future public health actions, as well as identify gaps in our full understanding of what influences CRF

Established Risk Factors Account for Most of the Racial Differences in Cardiovascular Disease Mortality

BACKGROUND: Cardiovascular disease (CVD) mortality varies across racial and ethnic groups in the U.S., and the extent that known risk factors can explain the differences has not been extensively explored. METHODS: We examined the risk of dying from acute myocardial infarction (AMI) and other heart disease (OHD) among 139,406 African-American (AA), Native Hawaiian (NH), Japanese-American (JA), Latino and White men and women initially free from cardiovascular disease followed prospectively between 1993–1996 and 2003 in the Multiethnic Cohort Study (MEC). During this period, 946 deaths from AMI and 2,323 deaths from OHD were observed. Relative risks of AMI and OHD mortality were calculated accounting for established CVD risk factors: body mass index (BMI), hypertension, diabetes, smoking, alcohol consumption, amount of vigorous physical activity, educational level, diet and, for women, type and age at menopause and hormone replacement therapy (HRT) use. RESULTS: Established CVD risk factors explained much of the observed racial and ethnic differences in risk of AMI and OHD mortality. After adjustment, NH men and women had greater risks of OHD than Whites (69% excess, P<0.001 and 62% excess, P = 0.003, respectively), and AA women had greater risks of AMI (48% excess, P = 0.01) and OHD (35% excess, P = 0.007). JA men had lower risks of AMI (51% deficit, P<0.001) and OHD (27% deficit, P = 0.001), as did JA women (AMI, 37% deficit, P = 0.03; OHD, 40% deficit, P = 0.001). Latinos had underlying lower risk of AMI death (26% deficit in men and 35% in women, P = 0.03). CONCLUSION: Known risk factors explain the majority of racial and ethnic differences in mortality due to AMI and OHD. The unexplained excess in NH and AA and the deficits in JA suggest the presence of unmeasured determinants for cardiovascular mortality that are distributed unequally across these populations

Immunospecific Responses to Bacterial Elongation Factor Tu during Burkholderia Infection and Immunization

Burkholderia pseudomallei is the etiological agent of melioidosis, a disease endemic in parts of Southeast Asia and Northern Australia. Currently there is no licensed vaccine against infection with this biological threat agent. In this study, we employed an immunoproteomic approach and identified bacterial Elongation factor-Tu (EF-Tu) as a potential vaccine antigen. EF-Tu is membrane-associated, secreted in outer membrane vesicles (OMVs), and immunogenic during Burkholderia infection in the murine model of melioidosis. Active immunization with EF-Tu induced antigen-specific antibody and cell-mediated immune responses in mice. Mucosal immunization with EF-Tu also reduced lung bacterial loads in mice challenged with aerosolized B. thailandensis. Our data support the utility of EF-Tu as a novel vaccine immunogen against bacterial infection

Cdk5 Is Required for Memory Function and Hippocampal Plasticity via the cAMP Signaling Pathway

Memory formation is modulated by pre- and post-synaptic signaling events in neurons. The neuronal protein kinase Cyclin-Dependent Kinase 5 (Cdk5) phosphorylates a variety of synaptic substrates and is implicated in memory formation. It has also been shown to play a role in homeostatic regulation of synaptic plasticity in cultured neurons. Surprisingly, we found that Cdk5 loss of function in hippocampal circuits results in severe impairments in memory formation and retrieval. Moreover, Cdk5 loss of function in the hippocampus disrupts cAMP signaling due to an aberrant increase in phosphodiesterase (PDE) proteins. Dysregulation of cAMP is associated with defective CREB phosphorylation and disrupted composition of synaptic proteins in Cdk5-deficient mice. Rolipram, a PDE4 inhibitor that prevents cAMP depletion, restores synaptic plasticity and memory formation in Cdk5-deficient mice. Collectively, our results demonstrate a critical role for Cdk5 in the regulation of cAMP-mediated hippocampal functions essential for synaptic plasticity and memory formation.Norman B. Leventhal FellowshipUnited States. National Institutes of Health (NIH T32 MH074249)United States. National Institutes of Health (NIH RO1 NS051874

Design of the Dutch Obesity Intervention in Teenagers (NRG-DOiT): systematic development, implementation and evaluation of a school-based intervention aimed at the prevention of excessive weight gain in adolescents

BACKGROUND: Only limited data are available on the development, implementation, and evaluation processes of weight gain prevention programs in adolescents. To be able to learn from successes and failures of such interventions, integral written and published reports are needed. METHODS: Applying the Intervention Mapping (IM) protocol, this paper describes the development, implementation, and evaluation of the Dutch Obesity Intervention in Teenagers (DOiT), a school-based intervention program aimed at the prevention of excessive weight gain. The intervention focussed on the following health behaviours: (1) reduction of the consumption of sugar-sweetened beverages, (2) reduction of energy intake derived from snacks, (3) decrease of levels of sedentary behaviour, and (4) increase of levels of physical activity (i.e. active transport behaviour and sports participation). The intervention program consisted of an individual classroom-based component (i.e. an educational program, covering 11 lessons of both biology and physical education classes), and an environmental component (i.e. encouraging and supporting changes at the school canteens, as well as offering additional physical education classes). We evaluated the effectiveness of the intervention program using a randomised controlled trial design. We assessed the effects of the intervention on body composition (primary outcome measure), as well as on behaviour, behavioural determinants, and aerobic fitness (secondary outcome measures). Furthermore, we conducted a process evaluation. DISCUSSION: The development of the DOiT-intervention resulted in a comprehensive school-based weight gain prevention program, tailored to the needs of Dutch adolescents from low socio-economic background

Mitochondrial Disease in Autism Spectrum Disorder Patients: A Cohort Analysis

Previous reports indicate an association between autism spectrum disorders (ASD) and disorders of mitochondrial oxidative phosphorylation. One study suggested that children with both diagnoses are clinically indistinguishable from children with idiopathic autism. There are, however, no detailed analyses of the clinical and laboratory findings in a large cohort of these children. Therefore, we undertook a comprehensive review of patients with ASD and a mitochondrial disorder.We reviewed medical records of 25 patients with a primary diagnosis of ASD by DSM-IV-TR criteria, later determined to have enzyme- or mutation-defined mitochondrial electron transport chain (ETC) dysfunction. Twenty-four of 25 patients had one or more major clinical abnormalities uncommon in idiopathic autism. Twenty-one patients had histories of significant non-neurological medical problems. Nineteen patients exhibited constitutional symptoms, especially excessive fatigability. Fifteen patients had abnormal neurological findings. Unusual developmental phenotypes included marked delay in early gross motor milestones (32%) and unusual patterns of regression (40%). Levels of blood lactate, plasma alanine, and serum ALT and/or AST were increased at least once in 76%, 36%, and 52% of patients, respectively. The most common ETC disorders were deficiencies of complex I (64%) and complex III (20%). Two patients had rare mtDNA mutations of likely pathogenicity.Although all patients' initial diagnosis was idiopathic autism, careful clinical and biochemical assessment identified clinical findings that differentiated them from children with idiopathic autism. These and prior data suggest a disturbance of mitochondrial energy production as an underlying pathophysiological mechanism in a subset of individuals with autism