DNA methylation signatures in cord blood associated with birthweight are enriched for dmCpGs previously associated with maternal hypertension or pre-eclampsia, smoking and folic acid intake.

Many epidemiological studies have linked low birthweight to an increased risk of non-communicable diseases (NCDs) in later life, with epigenetic proceseses suggested as an underlying mechanism. Here, we sought to identify neonatal methylation changes associated with birthweight, at the individual CpG and genomic regional level, and whether the birthweight-associated methylation signatures were associated with specific maternal factors. Using the Illumina Human Methylation EPIC array, we assessed DNA methylation in the cord blood of 557 and 483 infants from the UK Pregnancies Better Eating and Activity Trial and Southampton Women's Survey, respectively. Adjusting for gestational age and other covariates, an epigenome-wide association study identified 2911 (FDR≤0.05) and 236 (Bonferroni corrected p ≤ 6.45×10-8) differentially methylated CpGs (dmCpGs), and 1230 differentially methylated regions (DMRs) (Stouffer ≤0.05) associated with birthweight. The top birthweight-associated dmCpG was located within the Homeobox Telomere-Binding Protein 1 (HMBOX1) gene with a 195 g (95%CI: -241, -149 g) decrease in birthweight per 10% increase in methylation, while the top DMR was located within the promoter of corticotropin-releasing hormone-binding protein (CRHBP). Furthermore, the birthweight-related dmCpGs were enriched for dmCpGs previously associated with gestational hypertension/pre-eclampsia (14.51%, p = 1.37×10-255), maternal smoking (7.71%, p = 1.50 x 10-57) and maternal plasma folate levels during pregnancy (0.33%, p = 0.029). The identification of birthweight-associated methylation markers, particularly those connected to specific pregnancy complications and exposures, may provide insights into the developmental pathways that affect birthweight and suggest surrogate markers to identify adverse prenatal exposures for stratifying for individuals at risk of later NCDs.

DNA methylation of Th2 lineage determination genes at birth is associated with allergic outcomes in childhood.

BACKGROUND: There is now increasing evidence that asthma and atopy originate in part in utero, with disease risk being associated with the altered epigenetic regulation of genes. OBJECTIVE AND METHODS: To determine the relationship between variations in DNA methylation at birth and the development of allergic disease, we examined the methylation status of CpG loci within the promoter regions of Th1/2 lineage commitment genes (GATA3, IL-4, IL-4R, STAT4 and TBET) in umbilical cord DNA at birth in a cohort of infants from the Southampton Women's Survey (n = 696) who were later assessed for asthma, atopic eczema and atopy. RESULTS: We found that higher methylation of GATA3 CpGs -2211/-2209 at birth was associated with a reduced risk of asthma at ages 3 (median ratio [median methylation in asthma group/median methylation in non-asthma group] = 0.74, P = .006) and 6-7 (median ratio 0.90, P = .048) years. Furthermore, we demonstrated that the GATA3 CpG loci associated with later risk of asthma lie within a NF-κB binding site and that methylation here blocks transcription factor binding to the GATA3 promoter in the human Jurkat T-cell line. Associations between umbilical cord methylation of CpG loci within IL-4R with atopic eczema at 12 months (median ratio 1.02, P = .028), and TBET with atopy (median ratio 0.98, P = .017) at 6-7 years of age were also observed. CONCLUSIONS AND CLINICAL RELEVANCE: Our findings provide further evidence of a developmental contribution to the risk of later allergic disorders and suggest that involvement of epigenetic mechanisms in childhood asthma is already demonstrable at birth.

Exercise training improves fat metabolism independent of total energy expenditure in sedentary overweight men, but does not restore lean metabolic phenotype.

BACKGROUND: Obesity is a dietary fat storage disease. Although exercise prevents weight gain, effects of chronic training on dietary fat oxidation remains understudied in overweight adults. OBJECTIVE: We tested whether 2 months of training at current guidelines increase dietary fat oxidation in sedentary overweight adults like in sedentary lean adults. DESIGN: Sedentary lean (n=10) and overweight (n=9) men trained on a cycle ergometer at 50% VO2peak, 1 h day-1, four times per week, for 2 months while energy balance was clamped. Metabolic fate of [d31]palmitate and [1-13C]oleate mixed in standard meals, total substrate use, total energy expenditure (TEE), activity energy expenditure (AEE) and key muscle proteins/enzymes were measured before and at the end of the intervention. RESULTS: Conversely to lean subjects, TEE and AEE did not increase in overweight participants due to a spontaneous decrease in non-training AEE. Despite this compensatory behavior, aerobic fitness, insulin sensitivity and fat oxidation were improved by exercise training. The latter was not explained by changes in dietary fat trafficking but more likely by a coordinated response at the muscle level enhancing fat uptake, acylation and oxidation (FABPpm, CD36, FATP1, ACSL1, CPT1, mtGPAT). ACSL1 fold change positively correlated with total fasting (R2=0.59, P<0.0001) and post-prandial (R2=0.49, P=0.0006) fat oxidation whereas mtGPAT fold change negatively correlated with dietary palmitate oxidation (R2=0.40, P=0.009), suggesting modified fat trafficking between oxidation and storage within the muscle. However, for most of the measured parameters the post-training values observed in overweight adults remained lower than the pre-training values observed in the lean subjects. CONCLUSION: Independent of energy balance and TEE, exercise training at current recommendations improved fitness and fat oxidation in overweight adults. However the improved metabolic phenotype of overweight adults was not as healthy as the one of their lean counterparts before the 2-month training, likely due to the spontaneous reduction in non-training AEE.

Prevalence and correlates of metabolic syndrome in pre-crisis Syria: call for current relief efforts.

This study aimed to assess the prevalence, components and correlates of metabolic syndrome (MetS) in adults in pre-crisis Aleppo, Syrian Arab Republic. We used a population-based, 2-stage cluster sampling method in a population of 557 men and 611 women, randomly selected from 83 residential neighbourhoods including many rural settlers. Sociodemographic and lifestyle characteristics, comorbidity, anthropometry and biochemical indices were measured. Prevalence of MetS was estimated at 39.6%, with comparable rates in men and women. Hypertension was the most prevalent component (56.6%), followed by central obesity (51.4%). Among women, education (12 years) was inversely associated with risk of MetS, while family history of obesity and diabetes was associated with an increased risk. The high prevalence of MetS and its components emphasizes the burden of cardiovascular diseases among adults in pre-crisis Aleppo. A system of surveillance and management for cardiovascular diseases needs to be incorporated into the current humanitarian response.

Prevalence and correlates of metabolic syndrome in pre-crisis Syria: call for current relief efforts

This study aimed to assess the prevalence, components and correlates of metabolic syndrome [MetS] in adults in pre-crisis Aleppo, Syrian Arab Republic. We used a population-based, 2-stage cluster sampling method in a population of 557 men and 611 women, randomly selected from 83 residential neighbourhoods including many rural settlers. Sociodemographic and lifestyle characteristics, comorbidity, anthropometry and biochemical indices were measured. Prevalence of MetS was estimated at 39.6%, with comparable rates in men and women. Hypertension was the most prevalent component [56.6%], followed by central obesity [51.4%]. Among women, education [12 years] was inversely associated with risk of MetS, while family history of obesity and diabetes was associated with an increased risk. The high prevalence of MetS and its components emphasizes the burden of cardiovascular diseases among adults in pre-crisis Aleppo. A system of surveillance and management for cardiovascular diseases needs to be incorporated into the current humanitarian response

La présente étude avait pour objectif d'évaluer la prévalence, les composantes et les corrélats du syndrome métabolique chez l'adulte à Alep avant la crise, en République arabe syrienne. Nous avons utilisé une méthode d'échantillonnage en grappe à deux degrés basée sur une population de 557 hommes et 611 femmes, choisis de manière aléatoire dans 83 zones résidentielles, comprenant de nombreux habitants de zones rurales. Les caractéristiques socio-démographiques et relatives au mode de vie, les comorbidités, l'anthropométrie et les indices biochimiques ont été évaluées. La prévalence du syndrome métabolique a été estimée à 39,6%, avec des taux comparables entre hommes et femmes. L'hypertension était la composante la plus prévalente [56,6%], suivie par l'obésité centrale [51,4%]. Parmi les femmes, l'éducation était inversement associée au risque de syndrome métabolique, alors que des antécédents familiaux d'obésité et de diabète étaient associés à un risque accru. La forte prévalence du syndrome métabolique et de ses composantes met en évidence la charge des maladies cardio-vasculaires chez l'adulte à Alep avant la crise. Un système de surveillance et de prise en charge des maladies cardio-vasculaires doit être incorporé à la riposte humanitaire actuelle

Validity of combining heart rate and uniaxial acceleration to measure free-living physical activity energy expenditure in young men.

Combining accelerometry (ACC) with heart rate (HR) monitoring is thought to improve activity energy expenditure (AEE) estimations compared with ACC alone to evaluate the validity of ACC and HR used alone or combined. The purpose of this study was to estimate AEE in free-living conditions compared with doubly labeled water (DLW). Ten-day free-living AEE was measured by a DLW protocol in 35 18- to 55-yr-old men (11 lean active; 12 lean sedentary; 12 overweight sedentary) wearing an Actiheart (combining ACC and HR) and a RT3 accelerometer. AEE was estimated using group or individual calibration of the HR/AEE relationship, based on an exercise-tolerance test. In a subset (n = 21), AEE changes (ΔAEE) were measured after 1 mo of detraining (active subjects) or an 8-wk training (sedentary subjects). Actiheart-combined ACC/HR estimates were more accurate than estimates from HR or ACC alone. Accuracy of the Actiheart group-calibrated ACC/HR estimates was modest [intraclass correlation coefficient (ICC) = 0.62], with no bias but high root mean square error (RMSE) and limits of agreement (LOA). The mean bias of the estimates was reduced by one-third, like RMSE and LOA, by individual calibration (ICC = 0.81). Contrasting with group-calibrated estimates, the Actiheart individual-calibrated ACC/HR estimates explained 40% of the variance of the DLW-ΔAEE (ICC = 0.63). This study supports a good level of agreement between the Actiheart ACC/HR estimates and DLW-measured AEE in lean and overweight men with varying fitness levels. Individual calibration of the HR/AEE relationship is necessary for AEE estimations at an individual level rather than at group scale and for ΔAEE evaluation.

Molecular regulation and pharmacology of pacemaker channels.

The spontaneous activity of cardiac tissue originates in specialized pacemaker cells in the sino-atrial node that generate autonomous rhythmic electrical impulses. A number of regions in the brain are also able to generate spontaneous rhythmic activity to control and regulate important physiological functions. The generation of pacemaker potentials relies on a complex interplay between different types of currents carried by cation channels. Among these currents, the hyperpolarization-activated current (termed I(f), cardiac pacemaker "funny" current, and I(h) in neurons) is the major component contributing to the initiation of cardiac and neuronal excitability and to the modulation of this excitability by neurotransmitters and hormones. I(f) is an inward current activated by hyperpolarization of the membrane potential and by intracellular cyclic nucleotides such as cAMP. The identification at the end of the 1990s of a family of mammalian genes that encode for four Hyperpolarization-activated Cyclic Nucleotide-gated channels, HCN1-4, has made analysis of the location of these channels and the study of their biophysical properties an obtainable goal. As a result, specific agents have been developed for their ability to selectively reduce heart rate by lowering cardiac pacemaker activity where f-channels are their main natural target. These drugs include alinidine, zatebradine, cilobradine, ZD-7288 and ivabradine. Recent data indicate that pharmacological tools such as W7 and genistein, which have been used to identify some intracellular pathways involved in ionic channel modulation, also have the ability to inhibit I(f) directly. This opens new perspectives for the future development of other specific rhythm-lowering agents.