Longitudinal study of the effect of a 5-year exercise intervention on structural brain complexity in older adults. A Generation 100 substudy

Physical inactivity has been identified as an important risk factor for dementia. High levels of cardiorespiratory fitness (CRF) have been shown to reduce the risk of dementia. However, the mechanism by which exercise affects brain health is still debated. Fractal dimension (FD) is an index that quantifies the structural complexity of the brain. The purpose of this study was to investigate the effects of a 5-year exercise intervention on the structural complexity of the brain, measured through the FD, in a subset of 105 healthy older adults participating in the randomized controlled trial Generation 100 Study. The subjects were randomized into control, moderate intensity continuous training, and high intensity interval training groups. Both brain MRI and CRF were acquired at baseline and at 1-, 3- and 5-years follow-ups. Cortical thickness and volume data were extracted with FreeSurfer, and FD of the cortical lobes, cerebral and cerebellar gray and white matter were computed. CRF was measured as peak oxygen uptake (VO2peak) using ergospirometry during graded maximal exercise testing. Linear mixed models were used to investigate exercise group differences and possible CRF effects on the brain's structural complexity. Associations between change over time in CRF and FD were performed if there was a significant association between CRF and FD. There were no effects of group membership on the structural complexity. However, we found a positive association between CRF and the cerebral gray matter FD (p < 0.001) and the temporal lobe gray matter FD (p < 0.001). This effect was not present for cortical thickness, suggesting that FD is a more sensitive index of structural changes. The change over time in CRF was associated with the change in temporal lobe gray matter FD from baseline to 5-year follow-up (p < 0.05). No association of the change was found between CRF and cerebral gray matter FD. These results demonstrated that entering old age with high and preserved CRF levels protected against loss of structural complexity in areas sensitive to aging and age-related pathology

Household Tobacco Smoke and Admission Weight Predict Severe Bronchiolitis in Infants Independent of Deprivation: Prospective Cohort Study

To examine demographic, environmental and clinical factors associated with severe bronchiolitis in infants admitted to hospital and quantify the independent effects of these factors

Long-term cardiometabolic health in people born after assisted reproductive technology: a multi-cohort analysis

Aims To examine associations of assisted reproductive technology (ART) conception (vs. natural conception: NC) with offspring cardiometabolic health outcomes and whether these differ with age. Methods and results Differences in systolic (SBP) and diastolic blood pressure (DBP), heart rate (HR), lipids, and hyperglycaemic/insulin resistance markers were examined using multiple linear regression models in 14 population-based birth cohorts in Europe, Australia, and Singapore, and results were combined using meta-analysis. Change in cardiometabolic outcomes from 2 to 26 years was examined using trajectory modelling of four cohorts with repeated measures. 35 938 (654 ART) offspring were included in the meta-analysis. Mean age ranged from 13 months to 27.4 years but was <10 years in 11/14 cohorts. Meta-analysis found no statistical difference (ART minus NC) in SBP (-0.53 mmHg; 95% CI:-1.59 to 0.53), DBP (-0.24 mmHg; -0.83 to 0.35), or HR (0.02 beat/min; -0.91 to 0.94). Total cholesterol (2.59%; 0.10-5.07), HDL cholesterol (4.16%; 2.52-5.81), LDL cholesterol (4.95%; 0.47-9.43) were statistically significantly higher in ART-conceived vs. NC offspring. No statistical difference was seen for triglycerides (TG), glucose, insulin, and glycated haemoglobin. Long-term follow-up of 17 244 (244 ART) births identified statistically significant associations between ART and lower predicted SBP/DBP in childhood, and subtle trajectories to higher SBP and TG in young adulthood; however, most differences were not statistically significant. Conclusion These findings of small and statistically non-significant differences in offspring cardiometabolic outcomes should reassure people receiving ART. Longer-term follow-up is warranted to investigate changes over adulthood in the risks of hypertension, dyslipidaemia, and preclinical and clinical cardiovascular disease.Acknowledgements We thank all cohort members and researchers who participated in the study. Cohort-specific acknowledgments can be found in Supplementary material online, Text S2. Data used in this study are available to bone fide researchers upon request to each cohort. Details of how to access the data are provided in Supplementary material online, Text S2. Please contact Professor Deborah Lawlor ([email protected]) and Dr Ahmed Elhakeem ([email protected]) if you have relevant data and would like to join the ART-Health Cohort Collaboration and contribute to future collaborations

Folic acid supplementation before and during pregnancy in the Newborn Epigenetics STudy (NEST)

<p>Abstract</p> <p>Background</p> <p>Folic acid (FA) added to foods during fortification is 70-85% bioavailable compared to 50% of folate occurring naturally in foods. Thus, if FA supplements also are taken during pregnancy, both mother and fetus can be exposed to FA exceeding the Institute of Medicine's recommended tolerable upper limit (TUL) of 1,000 micrograms per day (μg/d) for adult pregnant women. The primary objective is to estimate the proportion of women taking folic acid (FA) doses exceeding the TUL before and during pregnancy, and to identify correlates of high FA use.</p> <p>Methods</p> <p>During 2005-2008, pre-pregnancy and pregnancy-related data on dietary supplementation were obtained by interviewing 539 pregnant women enrolled at two obstetrics-care facilities in Durham County, North Carolina.</p> <p>Results</p> <p>Before pregnancy, 51% of women reported FA supplementation and 66% reported this supplementation during pregnancy. Before pregnancy, 11.9% (95% CI = 9.2%-14.6%) of women reported supplementation with FA doses above the TUL of 1,000 μg/day, and a similar proportion reported this intake prenatally. Before pregnancy, Caucasian women were more likely to take FA doses above the TUL (OR = 2.99; 95% = 1.28-7.00), compared to African American women, while women with chronic conditions were less likely to take FA doses above the TUL (OR = 0.48; 95%CI = 0.21-0.97). Compared to African American women, Caucasian women were also more likely to report FA intake in doses exceeding the TUL during pregnancy (OR = 5.09; 95%CI = 2.07-12.49).</p> <p>Conclusions</p> <p>Fifty-one percent of women reported some FA intake before and 66% during pregnancy, respectively, and more than one in ten women took FA supplements in doses that exceeded the TUL. Caucasian women were more likely to report high FA intake. A study is ongoing to identify possible genetic and non-genotoxic effects of these high doses.</p

SNX12 Role in Endosome Membrane Transport

In this paper, we investigated the role of sorting nexin 12 (SNX12) in the endocytic pathway. SNX12 is a member of the PX domain-containing sorting nexin family and shares high homology with SNX3, which plays a central role in the formation of intralumenal vesicles within multivesicular endosomes. We found that SNX12 is expressed at very low levels compared to SNX3. SNX12 is primarily associated with early endosomes and this endosomal localization depends on the binding to 3-phosphoinositides. We find that overexpression of SNX12 prevents the detachment (or maturation) of multivesicular endosomes from early endosomes. This in turn inhibits the degradative pathway from early to late endosomes/lysosomes, much like SNX3 overexpression, without affecting endocytosis, recycling and retrograde transport. In addition, while previous studies showed that Hrs knockdown prevents EGF receptor sorting into multivesicular endosomes, we find that overexpression of SNX12 restores the sorting process in an Hrs knockdown background. Altogether, our data show that despite lower expression level, SNX12 shares redundant functions with SNX3 in the biogenesis of multivesicular endosomes

Fetal and infant origins of asthma

Previous studies have suggested that asthma, like other common diseases, has at least part of its origin early in life. Low birth weight has been shown to be associated with increased risks of asthma, chronic obstructive airway disease, and impaired lung function in adults, and increased risks of respiratory symptoms in early childhood. The developmental plasticity hypothesis suggests that the associations between low birth weight and diseases in later life are explained by adaptation mechanisms in fetal life and infancy in response to various adverse exposures. Various pathways leading from adverse fetal and infant exposures to growth adaptations and respiratory health outcomes have been studied, including fetal and early infant growth patterns, maternal smoking and diet, children’s diet, respiratory tract infections and acetaminophen use, and genetic susceptibility. Still, the specific adverse exposures in fetal and early postnatal life leading to respiratory disease in adult life are not yet fully understood. Current studies suggest that both environmental and genetic factors in various periods of life, and their epigenetic mechanisms may underlie the complex associations of low birth weight with respiratory disease in later life. New well-designed epidemiological studies are needed to identify the specific underlying mechanisms. This review is focused on specific adverse fetal and infant growth patterns and exposures, genetic susceptibility, possible respiratory adaptations and perspectives for new studies

Purinergic Receptor Stimulation Reduces Cytotoxic Edema and Brain Infarcts in Mouse Induced by Photothrombosis by Energizing Glial Mitochondria

Treatments to improve the neurological outcome of edema and cerebral ischemic stroke are severely limited. Here, we present the first in vivo single cell images of cortical mouse astrocytes documenting the impact of single vessel photothrombosis on cytotoxic edema and cerebral infarcts. The volume of astrocytes expressing green fluorescent protein (GFP) increased by over 600% within 3 hours of ischemia. The subsequent growth of cerebral infarcts was easily followed as the loss of GFP fluorescence as astrocytes lysed. Cytotoxic edema and the magnitude of ischemic lesions were significantly reduced by treatment with the purinergic ligand 2-methylthioladenosine 5′ diphosphate (2-MeSADP), an agonist with high specificity for the purinergic receptor type 1 isoform (P2Y1R). At 24 hours, cytotoxic edema in astrocytes was still apparent at the penumbra and preceded the cell lysis that defined the infarct. Delayed 2MeSADP treatment, 24 hours after the initial thrombosis, also significantly reduced cytotoxic edema and the continued growth of the brain infarction. Pharmacological and genetic evidence are presented indicating that 2MeSADP protection is mediated by enhanced astrocyte mitochondrial metabolism via increased inositol trisphosphate (IP3)-dependent Ca2+ release. We suggest that mitochondria play a critical role in astrocyte energy metabolism in the penumbra of ischemic lesions, where low ATP levels are widely accepted to be responsible for cytotoxic edema. Enhancement of this energy source could have similar protective benefits for a wide range of brain injuries

Predictors of children's secondhand smoke exposure at home: a systematic review and narrative synthesis of the evidence

BACKGROUND: Children's exposure to secondhand smoke (SHS) has been causally linked to a number of childhood morbidities and mortalities. Over 50% of UK children whose parents are smokers are regularly exposed to SHS at home. No previous review has identified the factors associated with children's SHS exposure in the home. AIM: To identify by systematic review, the factors which are associated with children's SHS exposure in the home, determined by parent or child reports and/or biochemically validated measures including cotinine, carbon monoxide or home air particulate matter. METHODS: Electronic searches of MEDLINE, EMBASE, PsychINFO, CINAHL and Web of Knowledge to July 2014, and hand searches of reference lists from publications included in the review were conducted. FINDINGS: Forty one studies were included in the review. Parental smoking, low socioeconomic status and being less educated were all frequently and consistently found to be independently associated with children's SHS exposure in the home. Children whose parents held more negative attitudes towards SHS were less likely to be exposed. Associations were strongest for parental cigarette smoking status; compared to children of non-smokers, those whose mothers or both parents smoked were between two and 13 times more likely to be exposed to SHS. CONCLUSION: Multiple factors are associated with child SHS exposure in the home; the best way to reduce child SHS exposure in the home is for smoking parents to quit. If parents are unable or unwilling to stop smoking, they should instigate smoke-free homes. Interventions targeted towards the socially disadvantaged parents aiming to change attitudes to smoking in the presence of children and providing practical support to help parents smoke outside the home may be beneficial

Parental and household smoking and the increased risk of bronchitis, bronchiolitis and other lower respiratory infections in infancy: systematic review and meta-analysis

<p>Abstract</p> <p>Background</p> <p>Passive smoke exposure increases the risk of lower respiratory infection (LRI) in infants, but the extensive literature on this association has not been systematically reviewed for nearly ten years. The aim of this paper is to provide an updated systematic review and meta-analysis of studies of the association between passive smoking and LRI, and with diagnostic subcategories including bronchiolitis, in infants aged two years and under.</p> <p>Methods</p> <p>We searched MEDLINE and EMBASE (to November 2010), reference lists from publications and abstracts from major conference proceedings to identify all relevant publications. Random effect pooled odds ratios (OR) with 95% confidence intervals (CI) were estimated.</p> <p>Results</p> <p>We identified 60 studies suitable for inclusion in the meta-analysis. Smoking by either parent or other household members significantly increased the risk of LRI; odds ratios (OR) were 1.22 (95% CI 1.10 to 1.35) for paternal smoking, 1.62 (95% CI 1.38 to 1.89) if both parents smoked, and 1.54 (95% CI 1.40 to 1.69) for any household member smoking. Pre-natal maternal smoking (OR 1.24, 95% CI 1.11 to 1.38) had a weaker effect than post-natal smoking (OR 1.58, 95% CI 1.45 to 1.73). The strongest effect was on bronchiolitis, where the risk of any household smoking was increased by an OR of 2.51 (95% CI 1.96 to 3.21).</p> <p>Conclusions</p> <p>Passive smoking in the family home is a major influence on the risk of LRI in infants, and especially on bronchiolitis. Risk is particularly strong in relation to post-natal maternal smoking. Strategies to prevent passive smoke exposure in young children are an urgent public and child health priority.</p