Dual effect of CTCF loss on neuroprogenitor differentiation and survival

An increasing number of proteins involved in genome organization have been implicated in neurodevelopmental disorders, highlighting the importance of chromatin architecture in the developing CNS. The CCCTC-binding factor (CTCF) is a zinc finger DNA binding protein involved in higher-order chromatin organization, and mutations in the human CTCF gene cause an intellectual disability syndrome associated with microcephaly. However, information on CTCF function in vivo in the developing brain is lacking. To address this gap, we conditionally inactivated the Ctcf gene at early stages of mouse brain development. Cre-mediated Ctcf deletion in the telencephalon and anterior retina at embryonic day 8.5 triggered upregulation of the p53 effector PUMA (p53 upregulated modulator of apoptosis), resulting in massive apoptosis and profound ablation of telencephalic structures. Inactivation of Ctcf several days later at E11 also resulted in PUMA upregulation and increased apoptotic cell death, and the Ctcf-null forebrain was hypocellular and disorganized at birth. Although deletion of both Ctcf and Puma in the embryonic brain efficiently rescued Ctcf-null progenitor cell apoptosis, it failed to improve neonatal hypocellularity due to decreased proliferative capacity of rescued apical and outer radial glia progenitor cells. This was exacerbated by an independent effect of CTCF loss that resulted in depletion of the progenitor pool due to premature neurogenesis earlier in development. Our findings demonstrate that CTCF activities are required for two distinct events in early cortex formation: first, to correctly regulate the balance between neuroprogenitor cell proliferation and differentiation, and second, for the survival of neuroprogenitor cells, providing new clues regarding the contributions of CTCF in microcephaly/intellectual disability syndrome pathologies

Allergenic food introduction and risk of childhood atopic diseases

Background: The role of timing and diversity of allergenic food introduction in the development of childhood allergic sensitization and atopic diseases is controversial. Objective: To examine whether timing and diversity of allergenic food introduction are associated with allergic sensitization, allergy and eczema in children until age 10 years. Materials and methods: This study among 5,202 children was performed in a population-based prospective cohort. Timing (age 6 months vs. >6 months) and diversity (0, 1, 2 and 3 foods) of allergenic food (cow’s milk, hen’s egg, peanut, tree nuts, soy and gluten) introduction were assessed by questionnaires at ages 6 and 12 months. At age 10 years, inhalant and food allergic sensitization were measured by skin prick tests, and physician-diagnosed inhalant and food allergy by questionnaire. Data on parental-reported physician-diagnosed eczema were obtained from birth until age 10 years. Results: Children introduced to gluten at age 6 months had a decreased risk of eczema (aOR (95% CI): 0.84 (0.72, 0.99)), compared with children introduced to gluten at age >6 months. However, timing of allergenic food introduction was not associated with allergic sensitization or physician-diagnosed allergy. Children introduced to 3 allergenic foods at age 6 months had a decreased risk of physician-diagnosed inhalant allergy (0.64 (0.42, 0.98)), compared with children not introduced to any allergenic food at age 6 months. However, diversity of allergenic food introduction was not associated with allergic sensitization, physician-diagnosed food allergy or eczema. Conclusion: Neither timing nor diversity of allergenic food introduction was consistently associate

Diet quality throughout early life in relation to allergic sensitization and atopic diseases in childhood

Early-life nutrition is an important modifiable determinant in the development of a child’s immune system, and may thereby influence the risk of allergic sensitization and atopic diseases. However, associations between overall dietary patterns and atopic diseases in childhood remain unclear. We examined associations of diet quality in early life with allergic sensitization, self-reported physician-diagnosed inhalant and food allergies, eczema, and asthma among 5225 children participating in a population-based cohort in the Netherlands. Diet was assessed during pregnancy, infancy, and childhood using validated food-frequency questionnaires. We calculated food-based diet quality scores (0–10 or 0–15), reflecting adherence to dietary guidelines. At age 10 years, allergic sensitization was assessed with skin prick tests. Information on physician-diagnosed inhalant and food allergies, eczema, and asthma was obtained with questionnaires. We observed no associations between diet quality during pregnancy and allergic sensitization (odds ratio (OR) = 1.05 per point in the diet score, 95% confidence interval (CI): 0.99, 1.13), allergies (0.96, 95% CI: 0.88, 1.04), eczema (0.99, 95% CI: 0.93, 1.06), or asthma (0.93, 95% CI: 0.85, 1.03) in childhood. Also, diet quality in infancy or childhood were not associated with atopic outcomes in childhood. Our findings do not support our hypothesis that a healthy dietary pattern in early life is associated with a lower risk of allergic sensitization or atopic diseases in childhood

Effectiveness and cost-effectiveness of ehealth interventions in somatic diseases: A systematic review of systematic reviews and meta-analyses

EHealth potentially enhances quality of care and may reduce health care costs. However, a review of systematic reviews published in 2010 concluded that high-quality evidence on the benefits of eHealth interventions was still lacking. Objective: We conducted a systematic review of systematic reviews and meta-analyses on the effectiveness/cost-effectiveness of eHealth interventions in patients with somatic diseases to analyze whether, and to what possible extent, the outcome of recent research supports or differs from previous conclusions. Methods: Literature searches were performed in PubMed, EMBASE, The Cochrane Library, and Scopus for systematic reviews and meta-analyses on eHealth interventions published between August 2009 and December 2012. Articles were screened for relevance based on preset inclusion and exclusion criteria. Citations of residual articles were screened for additional literature. Included papers were critically appraised using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Statement before data were extracted. Based on conclusions drawn by the authors of the included articles, reviews and meta-analyses were divided into 1 of 3 groups: suitable, promising, or limited evidence on effectiveness/cost-effectiveness. Cases of uncertainty were resolved by consensus discussion. Effect sizes were extracted from papers that included a meta-analysis. To compare our results with previous findings, a trend analysis was performed. Results: Our literature searches yielded 31 eligible reviews, of which 20 (65%) reported on costs. Seven papers (23%) concluded that eHealth is effective/cost-effective, 13 (42%) underlined that evidence is promising, and others found limited or inconsistent proof. Methodological quality of the included reviews and meta-analyses was generally considered high. Trend analysis showed a considerable accumulation of literature on eHealth. However, a similar percentage of papers concluded that eHealth is effective/cost-effective or evidence is at least promising (65% vs 62%). Reviews focusing primarily on children or family caregivers still remained scarce. Although a pooled (subgroup) analysis of aggregate data from randomized studies was performed in a higher percentage of more recently published reviews (45% vs 27%), data on economic outcome measures were less frequently reported (65% vs 85%). Conclusions: The number of reviews and meta-analyses on eHealth interventions in patients with somatic diseases has increased considerably in recent years. Most articles show eHealth is effective/cost-effective or at least suggest evidence is promising, which is consistent with previous findings. Although many researchers advocate larger, well-designed, controlled studies, we believe attention should be given to the development and evaluation of strategies to implement effective/cost-effective eHealth initiatives in daily practice, rather than to further strengthen current evidence

Parental and child factors associated with inhalant and food allergy in a population-based prospective cohort study: the Generation R Study

The prevalence of allergic diseases in children is markedly increasing to epidemic proportions. The aim of this study is to describe the presence and examine associated parental and child characteristics of allergic sensitization an