Cardiovascular disease risk in the offspring of diabetic women: the impact of the intrauterine environment

The incidence of gestational diabetes is increasing worldwide, exposing large numbers of infants to hyperglycaemia whilst in utero. This exposure may have a long-term negative impact on the cardiovascular health of the offspring. Novel methods to assess cardiovascular status in the neonatal period are now available—including measuring arterial intima-media thickness and retinal photography. These measures will allow researchers to assess the relative impact of intrauterine exposures, distinguishing these from genetic or postnatal environmental factors. Understanding the long-term impact of the intrauterine environment should allow the development of more effective health policy and interventions to decrease the future burden of cardiovascular disease. Initiating disease prevention aimed at the developing fetus during the antenatal period may optimise community health outcomes

Mining Medical Data: Bridging the Knowledge Divide

Due to the signi¯cant amount of data generated by modern medicine there is a growing reliance on tools such as data mining and knowledge discovery to help make sense and comprehend such data. The success of this process requires collaboration and interaction between such methods and medical professionals. Therefore an important question is: How can we strengthen the relationship between two traditionally separate fields (technology and medicine) in order to work simultaneously towards enhancing knowledge in modern medicine. To address this question, this study examines the application of data mining techniques to a large asthma medical dataset. A discussion introducing various methods for a smooth approach, straying from the `jack of all trades, master of none' to a modular cooperative approach for a successful outcome is pro-posed. The results of this study support the use of data mining as a useful tool and highlight the advantages on a global scale of closer relations between the two distinct fields. The exploration of CRISP methodology suggests that a `one methodology fits all approach' is not appropriate, but rather combines to create a hybrid holistic approach to data mining

The maternal diet, gut bacteria, and bacterial metabolites during pregnancy influence offspring asthma

This review focuses on the current evidence that maternal dietary and gut bacterial exposures during pregnancy influence the developing fetal immune system and subsequent offspring asthma. Part 1 addresses exposure to a farm environment, antibiotics, and prebiotic and probiotic supplementation that together indicate the importance of bacterial experience in immune programming and offspring asthma. Part 2 outlines proposed mechanisms to explain these associations including bacterial exposure of the fetoplacental unit; immunoglobulin-related transplacental transport of gut bacterial components; cytokine signaling producing fetomaternal immune alignment; and immune programming via metabolites produced by gut bacteria. Part 3 focuses on the interplay between diet, gut bacteria, and bacterial metabolites. Maternal diet influences fecal bacterial composition, with dietary microbiota-accessible carbohydrates (MACs) selecting short-chain fatty acid (SCFA)-producing bacteria. Current evidence from mouse models indicates an association between increased maternal dietary MACs, SCFA exposure during pregnancy, and reduced offspring asthma that is, at least in part, mediated by the induction of regulatory T lymphocytes in the fetal lung. Part 4 discusses considerations for future studies investigating maternal diet-by-microbiome determinants of offspring asthma including the challenge of measuring dietary MAC intake; limitations of the existing measures of the gut microbiome composition and metabolic activity; measures of SCFA exposure; and the complexities of childhood respiratory health assessment

Dietary Fiber and Bacterial SCFA Enhance Oral Tolerance and Protect against Food Allergy through Diverse Cellular Pathways

The incidence of food allergies in western countries has increased dramatically in recent decades. Tolerance to food antigens relies on mucosal CD103+ dendritic cells (DCs), which promote differentiation of regulatory T (Treg) cells. We show that high-fiber feeding in mice improved oral tolerance and protected from food allergy. High-fiber feeding reshaped gut microbial ecology and increased the release of short-chain fatty acids (SCFAs), particularly acetate and butyrate. High-fiber feeding enhanced oral tolerance and protected against food allergy by enhancing retinal dehydrogenase activity in CD103+ DC. This protection depended on vitamin A in the diet. This feeding regimen also boosted IgA production and enhanced T follicular helper and mucosal germinal center responses. Mice lacking GPR43 or GPR109A, receptors for SCFAs, showed exacerbated food allergy and fewer CD103+ DCs. Dietary elements, including fiber and vitamin A, therefore regulate numerous protective pathways in the gastrointestinal tract, necessary for immune non-responsiveness to food antigens

The ontogeny of naïve and regulatory CD4(+) T-cell subsets during the first postnatal year: a cohort study

As there is limited knowledge regarding the longitudinal development and early ontogeny of naïve and regulatory CD4(+) T-cell subsets during the first postnatal year, we sought to evaluate the changes in proportion of naïve (thymic and central) and regulatory (resting and activated) CD4(+) T-cell populations during the first postnatal year. Blood samples were collected and analyzed at birth, 6 and 12 months of age from a population-derived sample of 130 infants. The proportion of naïve and regulatory CD4(+) T-cell populations was determined by flow cytometry, and the thymic and central naïve populations were sorted and their phenotype confirmed by relative expression of T cell-receptor excision circle DNA (TREC). At birth, the majority (94%) of CD4(+) T cells were naïve (CD45RA(+)), and of these, ~80% had a thymic naïve phenotype (CD31(+) and high TREC), with the remainder already central naïve cells (CD31(-) and low TREC). During the first year of life, the naïve CD4(+) T cells retained an overall thymic phenotype but decreased steadily. From birth to 6 months of age, the proportion of both resting naïve T regulatory cells (rTreg; CD4(+)CD45RA(+)FoxP3(+)) and activated Treg (aTreg, CD4(+)CD45RA(-)FoxP3(high)) increased markedly. The ratio of thymic to central naïve CD4(+) T cells was lower in males throughout the first postnatal year indicating early sexual dimorphism in immune development. This longitudinal study defines proportions of CD4(+) T-cell populations during the first year of postnatal life that provide a better understanding of normal immune development

An outbreak of severe infections among Australian infants caused by a novel recombinant strain of human parechovirus type 3

Human parechovirus types 1-16 (HPeV1-16) are positive strand RNA viruses in the family Picornaviridae. We investigated a 2015 outbreak of HPeV3 causing illness in infants in Victoria, Australia. Virus genome was extracted from clinical material and isolates and sequenced using a combination of next generation and Sanger sequencing. The HPeV3 outbreak genome was 98.7% similar to the HPeV3 Yamagata 2011 lineage for the region encoding the structural proteins up to nucleotide position 3115, but downstream of that the genome varied from known HPeV sequences with a similarity of 85% or less. Analysis indicated that recombination had occurred, may have involved multiple types of HPeV and that the recombination event/s occurred between March 2012 and November 2013. However the origin of the genome downstream of the recombination site is unknown. Overall, the capsid of this virus is highly conserved, but recombination provided a different non-structural protein coding region that may convey an evolutionary advantage. The indication that the capsid encoding region is highly conserved at the amino acid level may be helpful in directing energy towards the development of a preventive vaccine for expecting mothers or antibody treatment of young infants with severe disease

HIF3A cord blood methylation and systolic blood pressure at 4 years - a population-based cohort study

Methylation levels at the hypoxia-inducible factor 3 alpha gene (HIF3A) in blood have been linked to body mass index (BMI) in adults. Despite evidence implicating HIF3A in angiogenesis and metabolism, no studies have examined links between HIF3A methylation in early life and cardiovascular health. Here, we investigated the relationship between HIF3A methylation in blood at birth and 12 months of age with cardiovascular measures at 4 years. We also examined influences of prenatal exposures, birth outcomes, and genetic variation. Methylation of two HIF3A promoter regions in cord blood was measured using Sequenom EpiTYPER mass-spectrometry. The first promoter region was also measured in 12-month blood. Four-year cardiovascular measures included blood pressure, pulse wave velocity, and aortic and carotid intima-media thickness. Associations were tested using partial correlation tests and linear regression modelling. Methylation of the first HIF3A promoter in cord and 12-month blood was not associated with four-year measures. There was modest evidence of an association between DNA methylation at the second HIF3A promoter in cord blood and four-year systolic blood pressure (n = 353, r = 0.12, p = 0.03). In sex-stratified analysis, methylation of the second promoter was modestly associated with systolic and diastolic blood pressure (r = 0.16, p = 0.03 for both) in males only. In conclusion, HIF3A methylation at birth shows some evidence of an association with later blood pressure in childhood. Further work should determine whether this relationship persists into later childhood, and should assess potential functional links between HIF3A methylation and cardiovascular health more generally

VITALITY trial: protocol for a randomised controlled trial to establish the role of postnatal vitamin D supplementation in infant immune health

Introduction Postnatal vitamin D supplementation may be associated with a reduction in IgE-mediated food allergy, lower respiratory tract infections and improved bone health. Countries in the Northern hemisphere recommend universal infant vitamin D supplementation to optimise early vitamin D levels, despite the absence of large trials proving safety or efficacy for any disease outcome. With the aim of determining the clinical and cost-effectiveness of daily vitamin D supplementation in breastfed infants from age 6–8 weeks to 12 months of age, we have started a double-blind, randomised, placebo-controlled trial of daily 400 IU vitamin D supplementation during the first year of life, VITALITY. Methods nd analysis Infants (n=3012) who are fully breastfed and not receiving vitamin D supplementation will be recruited at the time of their first immunisation, from council-led immunisation clinics throughout metropolitan Melbourne, Australia. The primary outcome is challenge-proven food allergy at 12 months of age. Secondary outcomes are food sensitisation (positive skin prick test), number of lower respiratory infections (through hospital linkage), moderately-severe and persistent eczema (by history and examination) and vitamin D deficiency (serum vitamin D <50 nmol/L) at age 12 months. The trial is underway and the first 130 participants have been recruited

Epigenetic dysregulation of naive CD4+ T-cell activation genes in childhood food allergy

Food allergy poses a significant clinical and public health burden affecting 2–10% of infants. Using integrated DNA methylation and transcriptomic profiling, we found that polyclonal activation of naive CD4+ T cells through the T cell receptor results in poorer lymphoproliferative responses in children with immunoglobulin E (IgE)-mediated food allergy. Reduced expression of cell cycle-related targets of the E2F and MYC transcription factor networks, and remodeling of DNA methylation at metabolic (RPTOR, PIK3D, MAPK1, FOXO1) and inflammatory genes (IL1R, IL18RAP, CD82) underpins this suboptimal response. Infants who fail to resolve food allergy in later childhood exhibit cumulative increases in epigenetic disruption at T cell activation genes and poorer lymphoproliferative responses compared to children who resolved food allergy. Our data indicate epigenetic dysregulation in the early stages of signal transduction through the T cell receptor complex, and likely reflects pathways modified by gene–environment interactions in food allergy