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Background: The early life environment may influence susceptibility to obesity and metabolic disease in later life through epigenetic processes. SLC6A4 is an important mediator of serotonin bioavailability, and has a key role in energy balance. We tested the hypothesis that methylation of the SLC6A4 gene predicts adiposity across the life course., Methods: DNA methylation at 5 CpGs within the SLC6A4 gene identified from a previous methyl binding domain array was measured by pyrosequencing. We measured DNA methylation in umbilical cord (UC) from children in the Southampton Women's Survey cohort (n = 680), in peripheral blood from adolescents in the Western Australian Pregnancy Cohort Study (n = 812), and in adipose tissue from lean and obese adults from the UK BIOCLAIMS cohort (n = 81). Real-time PCR was performed to assess whether there were corresponding alterations in gene expression in the adipose tissue., Results: Lower UC methylation of CpG5 was associated with higher total fat mass at 4 years (p = 0.031), total fat mass at 6-7 years (p = 0.0001) and % fat mass at 6-7 years (p = 0.004). Lower UC methylation of CpG5 was also associated with higher triceps skinfold thickness at birth (p = 0.013), 6 months (p = 0.038), 12 months (p = 0.062), 2 years (p = 0.0003), 3 years (p = 0.00004) and 6-7 years (p = 0.013). Higher maternal pregnancy weight gain (p = 0.046) and lower parity (p = 0.029) were both associated with lower SLC6A4 CpG5 methylation. In adolescents, lower methylation of CpG5 in peripheral blood was associated with greater concurrent measures of adiposity including BMI (p ≤ 0.001), waist circumference (p = 0.011), subcutaneous fat (p ≤ 0.001) and subscapular, abdominal and suprailiac skinfold thicknesses (p = 0.002, p = 0.008, p = 0.004, respectively). In adipose tissue, methylation of both SLC6A4 CpG5 (p = 0.019) and expression of SLC6A4 (p = 0.008) was lower in obese compared with lean adults., Conclusions: These data suggest that altered methylation of CpG loci within SLC6A4 may provide a robust marker of adiposity across the life course.

Background and Purpose: Pressures on hospital bed occupancy in the English National Health Service have focused attention on enhanced service delivery models and methods by which physical therapists might contribute to effective cost savings, while retaining a patient-centered approach. Earlier access to physical therapy may lead to better outcomes in frail older inpatients, but this has not been well studied in acute National Health Service hospitals. Our aim was to retrospectively study the associations between early physical therapy input and length of hospital stay (LOS), functional outcomes, and care needs on discharge., Methods: This was a retrospective observational study in a large tertiary university National Health Service hospital in the United Kingdom. We analyzed all admission episodes of people admitted to the department of medicine for the elderly wards for more than 3 months in 2016. Patients were categorized into 2 groups: those examined by a physical therapist within 24 hours of admission and those examined after 24 hours of admission.The outcome variables were as follows: LOS (days), functional measures on discharge (Elderly Mobility Scale and walking speed over 6 m), and the requirement of formal care on discharge. Characterization variables on admission were age, gender, existence of a formal care package, preadmission abode, the Clinical Frailty Scale, Charlson Comorbidity Index, the Emergency Department Modified Early Warning Score, C-reactive protein level on admission, and the 4-item version of the Abbreviated Mental Test.The association between the delay to physical therapy input and LOS before discharge home was evaluated using a Cox proportional hazards regression model., Results and Discussion: There were 1022 hospital episodes during the study period. We excluded 19 who were discharged without being examined by a physical therapist. Of the remaining 1003, 584 (58.2%) were examined within 24 hours of admission (early assessment) and 419 (41.8%) after 24 hours of admission (late assessment).The median (interquartile range) LOS of the early assessment group was 6.7 (3.1-13.7) versus 10.0 (4.2-20.1) days in the late assessment group, P < .001. The early assessment group was less likely to require formal care on discharge: n = 110 (20.3%) versus n = 105 (27.0%), P = .016. No other statistically significant differences were seen between the 2 groups.In the unadjusted Cox proportional hazards model, the hazard ratio for early assessment compared with late assessment was 1.29 (95% confidence interval: 1.12-1.48, P < .001). Early assessment was associated with a 29% higher probability of discharge to usual residence within the first 21 days after admission than the late assessment. Adjustment for possible confounding variables increased the hazard ratio: 1.34 (1.16-1.55), P < .001., Conclusions: Early physical therapy input was associated with a shorter LOS and lower odds of needing care on discharge. This may be due to the beneficial effect of early physical therapy in preventing hospital-related deconditioning in frail older adults. However, causality cannot be inferred and further research is needed to investigate causal mechanisms.

It is now widely recognized that the environment in early life can have important effects on human growth and development, including the 'programming' of far-reaching effects on the risk of developing common metabolic and other noncommunicable diseases in later life. We have shown that greater childhood adiposity is associated with higher maternal adiposity, low maternal vitamin D status, excessive gestational weight gain and short duration of breast-feeding; maternal dietary patterns in pregnancy and vitamin D status have been linked with childhood bone mineral content and muscle function. Human studies have identified fetal liver blood flow adaptations and epigenetic changes as potential mechanisms that could link maternal influences with offspring body composition. In experimental studies, there is now substantial evidence that the environment during early life induces altered phenotypes through epigenetic mechanisms. Epigenetic processes, such as DNA methylation, covalent modifications of histones and non-coding RNAs, can induce changes in gene expression without a change in DNA base sequence. Such processes are involved in cell differentiation and genomic imprinting, as well as the phenomenon of developmental plasticity in response to environmental influences. Elucidation of such epigenetic processes may enable early intervention strategies to improve early development and growth., (© 2016 Nestec Ltd., Vevey/S. Karger AG, Basel.)

Evidence from both human and animal studies has shown that the prenatal and early postnatal environments influence susceptibility to chronic disease in later life and suggests that epigenetic processes are an important mechanism by which the environment alters long-term disease risk. Epigenetic processes, including DNA methylation, histone modification and non-coding RNAs, play a central role in regulating gene expression. The epigenome is highly sensitive to environmental factors in early life, such as nutrition, stress, endocrine disruption and pollution, and changes in the epigenome can induce long-term changes in gene expression and phenotype. In this review we focus on how the early life nutritional environment can alter the epigenome leading to an altered susceptibility to disease in later life.

Background: Early life environments induce long-term changes in neurocognitive development and behaviour. In animal models, early environmental cues affect neuropsychological phenotypes via epigenetic processes but, as yet, there is little direct evidence for such mechanisms in humans., Method: We examined the relation between DNA methylation at birth and child neuropsychological outcomes in two culturally diverse populations using a genome-wide methylation analysis and validation by pyrosequencing., Results: Within the UK Southampton Women's Survey (SWS) we first identified 41 differentially methylated regions of interest (DMROI) at birth associated with child's full-scale IQ at age 4 years. Associations between HES1 DMROI methylation and later cognitive function were confirmed by pyrosequencing in 175 SWS children. Consistent with these findings, higher HES1 methylation was associated with higher executive memory function in a second independent group of 200 SWS 7-year-olds. Finally, we examined a pathway for this relationship within a Singaporean cohort (n = 108). Here, HES1 DMROI methylation predicted differences in early infant behaviour, known to be associated with academic success. In vitro, methylation of HES1 inhibited ETS transcription factor binding, suggesting a functional role of this site., Conclusions: Thus, our findings suggest that perinatal epigenetic processes mark later neurocognitive function and behaviour, providing support for a role of epigenetic processes in mediating the long-term consequences of early life environment on cognitive development., (© The Author 2015. Published by Oxford University Press on behalf of the International Epidemiological Association.)

Suboptimal maternal nutrition and body composition are implicated in metabolic disease risk in adult offspring. We hypothesized that modest disruption of glucose homeostasis previously observed in young adult sheep offspring from ewes of a lower body condition score (BCS) would deteriorate with age, due to changes in skeletal muscle structure and insulin signaling mechanisms. Ewes were fed to achieve a lower (LBCS, n = 10) or higher (HBCS, n = 14) BCS before and during pregnancy. Baseline plasma glucose, glucose tolerance and basal glucose uptake into isolated muscle strips were similar in male offspring at 210 ± 4 weeks. Vastus total myofiber density (HBCS, 343 ± 15; LBCS, 294 ± 14 fibers/mm(2), P < .05) and fast myofiber density (HBCS, 226 ± 10; LBCS 194 ± 10 fibers/mm(2), P < .05), capillary to myofiber ratio (HBCS, 1.5 ± 0.1; LBCS 1.2 ± 0.1 capillary:myofiber, P < .05) were lower in LBCS offspring. Vastus protein levels of Akt1 were lower (83% ± 7% of HBCS, P < .05), and total glucose transporter 4 was increased (157% ± 6% of HBCS, P < .001) in LBCS offspring, Despite the reduction in total myofiber density in LBCS offspring, glucose tolerance was normal in mature adult life. However, such adaptations may lead to complications in metabolic control in an overabundant postnatal nutrient environment.

Reduced fetal growth associates with endothelial dysfunction and cardiovascular risk in both young and adult offspring and the nitric oxide (NO) system has been implicated in these effects. Epigenetic processes are likely to underlie such effects, but there is to date no evidence that endothelial dysfunction in early life results from epigenetic processes on key genes in the NO system, such as NOS3 (eNOS) and ARG2 (arginase-2). We determined basal DNA methylation status in NOS3 and ARG2 promoters, and DNA methyltransferase 1 (DNMT1) effect on eNOS and arginase-2 expression using human endothelial cells isolated from umbilical arteries (HUAEC) and veins (HUVEC) from control and intrauterine growth restricted (IUGR) fetuses. Compared with cells from control pregnancies, eNOS protein and mRNA levels were increased in HUAEC, but decreased in HUVEC, from IUGR, while arginase-2 levels were increased in IUGR-HUVEC. The NOS3 promoter showed a decrease in DNA methylation at CpG -352 in IUGR-HUAEC, and an increase in IUGR-HUVEC, when compared with control cells. Methylation in the hypoxia response element of the NOS3 promoter was increased in IUGR-HUAEC and decreased in HUVEC. Methylation in the AGR2 promoter in IUGR-HUVEC was decreased in a putative HRE, and without changes in IUGR-HUAEC. Silencing of DNMT1 expression normalized eNOS expression in IUGR endothelial cells, and restored the normal response to hypoxia in HUVEC, without effects on arginase-2. This data suggest that eNOS expression in IUGR-derived endothelial cells is programmed by altered DNA methylation, and can be reversed by transient silencing of the DNA methylation machinery.

Poor nutrition during fetal development can permanently alter growth, cardiovascular physiology and metabolic function. Animal studies have shown that prenatal undernutrition followed by balanced postnatal nutrition alters deoxyribonucleic acid (DNA) methylation of gene promoter regions of candidate metabolic control genes in the liver. The aim of this study was to investigate whether methylation status of the proximal promoter regions of four candidate genes differed between individuals exposed to the Dutch famine in utero. In addition, we determined whether methylation status of these genes was associated with markers of metabolic and cardiovascular disease and adult lifestyle. Methylation status of the GR1-C (glucocorticoid receptor), PPARγ (peroxisome proliferator-activated receptor gamma), lipoprotein lipase and phosphatidylinositol 3 kinase p85 proximal promoters was investigated in DNA isolated from peripheral blood samples of 759 58-year-old subjects born around the time of the 1944-45 Dutch famine. We observed no differences in methylation levels of the promoters between exposed and unexposed men and women. Methylation status of PPARγ was associated with levels of high-density lipoprotein cholesterol and triglycerides as well as with exercise and smoking. Hypomethylation of the GR promoter was associated with adverse adult lifestyle factors, including higher body mass index, less exercise and more smoking. The previously reported increased risk of cardiovascular and metabolic disease after prenatal famine exposure was not associated with differences in methylation status across the promoter regions of these candidate genes measured in peripheral blood. The adult environment seems to affect GR and PPARγ promoter methylation.

Background: Glucocorticoids are the key regulators of the biological stress response and act by binding to glucocorticoid receptors (GR). Expression of GR is altered by DNA methylation. Methylation patterns in GR promoters have been shown to be highly variable between individuals, but little is known about the functional consequences of this variation for the acute stress response. The present study investigated associations between methylation status of the GR 1-C promoter and cortisol, cardiovascular and perceived stress responses to a psychosocial stress protocol in a large healthy adult population., Methods: A total of 725 overall healthy men and women, aged 55-60 years, participated in a standardized psychosocial stress protocol consisting of three different stressors. At different stages during the stress protocol, salivary cortisol levels, continuous blood pressure and heart rate (HR) levels as well as perceived stress were measured. Stress reactivity was calculated as the increase between basal and peak measurements. Methylation status of the GR 1-C promoter was assessed in DNA isolated from peripheral blood samples using a methylation sensitive PCR assay for 675 of the 725 participants., Results: A decrease in methylation of the GR 1-C promoter was associated with a decrease in stress reactivity as indicated by lower cortisol and lower HR reactivity. A 1% decrease in GR 1-C methylation corresponded with a cortisol decrease by 0.14% (95% CI: 0.03-0.25, p=0.02) and an HR decrease by 0.10 bpm (0.03-0.16, p=0.003). Adjusting for sex, lifestyle and education largely abolished these associations. A decrease in methylation of the GR 1-C promoter was also associated with an increase in stress perception as indicated by higher perceived stress (0.03 points [0.00-0.06, p=0.05]), lower perceived performance (-0.03 points [-0.05 to -0.01], p=0.02), and lower perceived control (-0.03 points [-0.05 to 0.00], p=0.04). After adjusting for sex and educational level the associations were no longer statistically significant. GR 1-C methylation status was not associated with blood pressure responses to the stress protocol., Discussion: Although effects were small, variation in methylation status in the GR 1-C promoter was associated with physical and perceived acute stress responses. Interestingly, these associations could largely be explained by differences in lifestyle and education., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Poor prenatal nutrition is associated with a greater risk of adult glucose intolerance and insulin insensitivity in the offspring. Skeletal muscle is the primary tissue for glucose utilization, and insulin resistance in muscle is the earliest identifiable abnormality in the pre-diabetic patient. We investigated the effect of early and late gestation undernutrition on structure and markers of growth and glucose metabolism regulation in the fetal triceps brachii (TB, slow- and fast-twitch myofibres) and soleus (slow-twitch myofibres) muscles. Pregnant sheep were fed 100% nutrient requirements (C, n = 8) or a restricted diet peri-implantation (PI, n = 9; 40%, 1-31 days gestation (dGA) (term approximately 147)) or in late gestation (L, n = 6; 50%, 104-127 dGA). At 127 +/- 1 dGA we measured myofibre and capillary density in the fetal TB and soleus muscles, and mRNA levels in the TB of insulin receptor (InsR), glucose transporter-4 (GLUT-4) and type 1 insulin-like growth factor receptor (IGF-1R). Total myofibre and capillary densities were lower in the TB, but not the soleus, of PI and L fetuses. The predominant effect in the L group was on slow-twitch myofibres. In TB, InsR, GLUT-4 and IGF-1R mRNA levels were greater in L group fetuses. Our finding of reduced myofibre density is consistent with a redistribution of resources at the expense of specific peripheral tissues by early and late gestation undernutrition which may be mediated by a decrease in capillary density. The increase in key regulatory components of glucose uptake following late gestation undernutrition may constitute a short-term compensation to maintain glucose homeostasis in the face of fewer type I (insulin-sensitive) myofibres. However, together these adaptations may influence the risk of later metabolic disease and thus our findings have implications for future strategies aimed at improving maternal diet.

Birth weight in a total of 1886 British infants with phenylketonuria (PKU) born between 1964 and 1992 was examined in relation to sex, social class, gestational age, disease severity and birth year. Comparisons were made with two national surveys (British births 1970 and Office of Population Censuses and Surveys 1981). In contrast to a recent Dutch study, birth weight in British infants with PKU (mean 3307 g, median 3337 g) showed a similar distribution to population norms. Birth weight showed no temporal trends and no trends with disease severity. CONCLUSION. Birth weight is not reduced in British infants with PKU.

In 82 children with mild phenylketonuria (PKU) (blood phenylalanine (Phe) concentrations consistently below 900 mumol/l throughout follow up) the relationship between intelligence at age 4 (IQ by Stanford-Binet) and average blood Phe concentrations from birth to 4 years was examined. Of the 82 children 24 had received no treatment. In the group as a whole, and in the 24 untreated subjects alone, mean IQs were significantly below population norms, with deficits of approximately 4.5 points and 9 points respectively. After allowing for social class IQ fell progressively by approximately 6 points for each 100 mumol/l rise in mean Phe concentrations in both the treated and untreated subjects. This relationship resembled that previously reported in early treated children with more severe forms of PKU, except that the scale of the relationship was even greater. We conclude that all children whose blood Phe concentrations reach 400 mumol/l or above should receive a low Phe diet, at least during the preschool years, and that the aim should be to control blood Phe levels below 400 mumol/l throughout early childhood in all forms of PKU.

Intellectual status at 18 years is reported in 192 patients with phenylketonuria born in the UK between 1964 and 1971, together with their school progress. Mean IQs expressed as standard deviation scores (IQ-SDS) were significantly below estimated population norms, and showed a small decrease from 14 to 18 years of age (mean IQ-SDS -1.06 +/- 1.3 at 14 years and -1.28 +/- 1.07 at 18 years, t = 5.7, p < 0.0001). At 18 years, 27% of subjects had IQs over 2 SDs below the estimated population mean. IQ-SDS at 18 years, although significantly related to average phenylalanine control both between birth and 14 years, and between 14 and 18 years, was not independently related to either variable after allowing for IQ-SDS at 14 years. We conclude that general ability in young adults with early treated phenylketonuria, although reduced in comparison with their peers and closely related to phenylalanine control in early childhood, is not directly influenced by phenylalanine control in the four years preceding the 18th birthday. The apparent fall in IQ-SDS between 14 and 18 years may be due to methodological problems in the analysis of longitudinal IQ data without a control group, rather than providing evidence of intellectual decline.