Breastfeeding, the use of docosahexaenoic acid-fortified formulas in infancy and neuropsychological function in childhood

OBJECTIVE: To investigate the relation between breastfeeding, use of docosahexaenoic acid (DHA)-fortified formula and neuropsychological function in children. DESIGN: Prospective cohort study. SETTING: Southampton, UK. SUBJECTS: 241 children aged 4 years followed up from birth. MAIN OUTCOME MEASURES: IQ measured by the Wechsler Pre-School and Primary Scale of Intelligence (3rd edn), visual attention, visuomotor precision, sentence repetition and verbal fluency measured by the NEPSY, and visual form-constancy measured by the Test of Visual-Perceptual Skills (Non-Motor). RESULTS: In unadjusted analyses, children for whom breast milk or DHA-fortified formula was the main method of feeding throughout the first 6 months of life had higher mean full-scale and verbal IQ scores at age 4 years than those fed mainly unfortified formula. After adjustment for potential confounding factors, particularly maternal IQ and educational attainment, the differences in IQ between children in the breast milk and unfortified formula groups were severely attenuated, but children who were fed DHA-fortified formula had full-scale and verbal IQ scores that were respectively 5.62 (0.98 to 10.2) and 7.02 (1.56 to 12.4) points higher than children fed unfortified formula. However, estimated total intake of DHA in milk up to age 6 months was not associated with subsequent IQ or with score on any other test. CONCLUSIONS: Differences in children's intelligence according to type of milk fed in infancy may be due more to confounding by maternal or family characteristics than to the amount of long-chain polyunsaturated fatty acids they receive in milk

The proteasome controls ESCRT-III–mediated cell division in an archaeon

INTRODUCTION: Eukaryotes likely arose from a symbiotic partnership between an archaeal host and an alpha-proteobacterium, giving rise to the cell body and the mitochondria, respectively. Because of this, a number of proteins controlling key events in the eukaryotic cell division cycle have their origins in archaea. These include ESCRT-III proteins, which catalyze the final step of cytokinesis in many eukaryotes and in the archaeon Sulfolobus acidocaldarius. However, to date, no archaeon has been found that harbors homologs of cell cycle regulators, like cyclin-dependent kinases and cyclins, which order events in the cell cycle across all eukaryotes. Thus, it remains uncertain how key events in the archaeal cell cycle, including division, are regulated. RATIONALE: An exception to this is the 20S proteasome, which is conserved between archaea and eukaryotes and which regulates the eukaryotic cell cycle through the degradation of cyclins. To explore the function of the 20S proteasome in the archaeon S. acidocaldarius, we determined its structure by crystallography and carried out in vitro biochemical analyses of its activity with and without inhibition. The impact of proteasome inhibition on cell division and cell cycle progression was examined in vivo by flow cytometry and super-resolution microscopy. Following up with mass spectrometry, we identified proteins degraded by the proteasome during division. Finally, we used molecular dynamics simulations to model the mechanics of this process. RESULTS: Here, we present a structure of the 20S proteasome of S. acidocaldarius to a resolution of 3.7 Å, which we used to model its sensitivity to the eukaryotic inhibitor bortezomib. When this inhibitor was added to synchronous cultures, it was found to arrest cells mid-division, with a stable ESCRT-III division ring positioned at the cell center between the two separated and prereplicative nucleoids. Proteomics was then used to identify a single archaeal ESCRT-III homolog, CdvB, as a key target of the proteasome that must be degraded to enable division to proceed. Examining the localization patterns of CdvB and two other archaeal ESCRT-III homologs, CdvB1 and CdvB2, by flow cytometry and super-resolution microscopy revealed the sequence of events that leads to division. First, a CdvB ring is assembled. This CdvB ring then templates the assembly of the contractile ESCRT-III homologs, CdvB1 and CdvB2, to form a composite division ring. Cell division is then triggered by proteasome-mediated degradation of CdvB, which allows the CdvB1:CdvB2 copolymer to constrict, pulling the membrane with it. During constriction, the CdvB1:CdvB2 copolymer is disassembled, thus vacating the membrane neck to drive abscission, yielding two daughter cells with diffuse CdvB1 and CdvB2. CONCLUSION: This study reveals a role for the proteasome in driving structural changes in a composite ESCRT-III copolymer, enabling the stepwise assembly, disassembly, and contraction of an ESCRT-III–based division ring. Although it is not yet clear how proteasomal inhibition prevents S. acidocaldarius cells from resetting the cell cycle to initiate the next S phase, these data strengthen the case for the eukaryotic cell cycle regulation having its origins in archaea

Basic science232. Certolizumab pegol prevents pro-inflammatory alterations in endothelial cell function

Background: Cardiovascular disease is a major comorbidity of rheumatoid arthritis (RA) and a leading cause of death. Chronic systemic inflammation involving tumour necrosis factor alpha (TNF) could contribute to endothelial activation and atherogenesis. A number of anti-TNF therapies are in current use for the treatment of RA, including certolizumab pegol (CZP), (Cimzia ®; UCB, Belgium). Anti-TNF therapy has been associated with reduced clinical cardiovascular disease risk and ameliorated vascular function in RA patients. However, the specific effects of TNF inhibitors on endothelial cell function are largely unknown. Our aim was to investigate the mechanisms underpinning CZP effects on TNF-activated human endothelial cells. Methods: Human aortic endothelial cells (HAoECs) were cultured in vitro and exposed to a) TNF alone, b) TNF plus CZP, or c) neither agent. Microarray analysis was used to examine the transcriptional profile of cells treated for 6 hrs and quantitative polymerase chain reaction (qPCR) analysed gene expression at 1, 3, 6 and 24 hrs. NF-κB localization and IκB degradation were investigated using immunocytochemistry, high content analysis and western blotting. Flow cytometry was conducted to detect microparticle release from HAoECs. Results: Transcriptional profiling revealed that while TNF alone had strong effects on endothelial gene expression, TNF and CZP in combination produced a global gene expression pattern similar to untreated control. The two most highly up-regulated genes in response to TNF treatment were adhesion molecules E-selectin and VCAM-1 (q 0.2 compared to control; p > 0.05 compared to TNF alone). The NF-κB pathway was confirmed as a downstream target of TNF-induced HAoEC activation, via nuclear translocation of NF-κB and degradation of IκB, effects which were abolished by treatment with CZP. In addition, flow cytometry detected an increased production of endothelial microparticles in TNF-activated HAoECs, which was prevented by treatment with CZP. Conclusions: We have found at a cellular level that a clinically available TNF inhibitor, CZP reduces the expression of adhesion molecule expression, and prevents TNF-induced activation of the NF-κB pathway. Furthermore, CZP prevents the production of microparticles by activated endothelial cells. This could be central to the prevention of inflammatory environments underlying these conditions and measurement of microparticles has potential as a novel prognostic marker for future cardiovascular events in this patient group. Disclosure statement: Y.A. received a research grant from UCB. I.B. received a research grant from UCB. S.H. received a research grant from UCB. All other authors have declared no conflicts of interes

Cut-off points for anthropometric indices of adiposity: differential classification in a large population of young women

Anthropometric indices of adiposity include BMI, waist circumference and waist:height ratio. In the recruitment phase of a prospective cohort study carried out between 1998 and 2002 we studied a population sample of 11 786 white Caucasian non-pregnant women in Southampton, UK aged 20-34 years, and explored the extent to which proposed cut-off points for the three indices identified the same or different women and how these indices related to adiposity. Height, weight and waist circumference were measured and fat mass was estimated from skinfold thicknesses; fat mass index was calculated as fat mass/height1.65. Of the subjects, 4869 (42 %) women were overweight (BMI >/= 25 kg/m2) and 1849 (16 %) were obese (BMI >/= 30 kg/m2). A total of 890 (8 %) subjects were not overweight but had a waist circumference >/= 80 cm and 748 (6 %) subjects were overweight but had a waist circumference /= 0.5. Of the variation in fat mass index, 85 % was explained by BMI, 76 % by waist circumference and 75 % by waist:height ratio. Our findings demonstrate that many women are differentially classified depending on which index of adiposity is used. As each index captures different aspects of size in terms of adiposity, there is the need to determine how the three indices relate to function and how they can be of use in defining risk of ill health in women

Influences on the quality of young children's diets: the importance of maternal food choices

It is recognised that eating habits established in early childhood may track into adult life. Developing effective interventions to promote healthier patterns of eating throughout the life course requires a greater understanding of the diets of young children and the factors that influence early dietary patterns. In a longitudinal UK cohort study, we assessed the diets of 1640 children at age 3 years using an interviewer-administered FFQ and examined the influence of maternal and family factors on the quality of the children's diets. To describe dietary quality, we used a principal components analysis-defined pattern of foods that is consistent with healthy eating recommendations. This was termed a ‘prudent’ diet pattern and was characterised by high intakes of fruit, vegetables and wholemeal bread, but by low intakes of white bread, confectionery, chips and roast potatoes. The key influence on the quality of the children's diets was the quality of their mother's diets; alone it accounted for almost a third of the variance in child's dietary quality. Mothers who had better-quality diets, which complied with dietary recommendations, were more likely to have children with comparable diets. This relationship remained strong even after adjustment for all other factors considered, including maternal educational attainment, BMI and smoking, and the child's birth order and the time spent watching television. Our data provide strong evidence of shared family patterns of diet and suggest that interventions to improve the quality of young women's diets could be effective in improving the quality of their children's diets

Modifiable early-life risk factors for childhood adiposity and overweight: an analysis of their combined impact and potential for prevention

Background: early life may be a “critical period” when appetite and regulation of energy balance are programmed, with lifelong consequences for obesity risk. Insight into the potential impact of modifying early-life risk factors on later obesity can be gained by evaluating their combined effects.Objective: the objective was to examine the relation between the number of early-life risk factors and obesity outcomes among children in a prospective birth cohort (Southampton Women's Survey).Design: five risk factors were defined: maternal obesity [prepregnant body mass index (BMI; in kg/m2) >30], excess gestational weight gain (Institute of Medicine, 2009), smoking during pregnancy, low maternal vitamin D status (<64 nmol/L), and short duration of breastfeeding (none or <1 mo). Obesity outcomes examined when the children were aged 4 and 6 y were BMI, dual-energy X-ray absorptiometry–assessed fat mass, overweight, or obesity (International Obesity Task Force). Data were available for 991 mother-child pairs, with children born between 1998 and 2003.Results: of the children, 148 (15%) had no early-life risk factors, 330 (33%) had 1, 296 (30%) had 2, 160 (16%) had 3, and 57 (6%) had 4 or 5. At both 4 and 6 y, there were positive graded associations between number of early-life risk factors and each obesity outcome (all P < 0.001). After taking account of confounders, the relative risk of being overweight or obese for children who had 4 or 5 risk factors was 3.99 (95% CI: 1.83, 8.67) at 4 y and 4.65 (95% CI: 2.29, 9.43) at 6 y compared with children who had none (both P < 0.001).Conclusions: having a greater number of early-life risk factors was associated with large differences in adiposity and risk of overweight and obesity in later childhood. These findings suggest that early intervention to change these modifiable risk factors could make a significant contribution to the prevention of childhood obesity

Cohort profile: The Southampton Women's Survey

Inverse associations between birthweight and later risk of major chronic diseases, notably cardiovascular disease, diabetes, and osteoporosis, have been found in various studies.1 Birthweight is determined by length of gestation and the combination of the early trajectory of fetal growth and the capacity of the fetal supply line to maintain this trajectory in late gestation. Studies in early pregnancy, assisted reproductive technology, and animal experiments indicate that both genetic and environmental factors are important in establishing the fetal growth trajectory and the fetal supply line; environmental factors include transgenerational influences and the mother's body composition, endocrine profile, diet, and physical activity around the time of conception.2 As these influences may change during early pregnancy, there is a need to characterize women before conception

Clustering of lifestyle risk factors and poor physical function in older adults: the Hertfordshire cohort study

OBJECTIVES: To examine the relationship between number of lifestyle risk factors (out of low physical activity, poor diet, obesity, smoking) and physical function in older community-dwelling men and women. DESIGN: Cross-sectional study, Hertfordshire, United Kingdom. PARTICIPANTS: Men (n = 1,682) and women (n = 1,540) aged 59 to 73. MEASUREMENTS: Physical activity was assessed using an administered questionnaire with a score from 0 to 100; low activity was defined as a score of 50 or less. Diet was assessed using a food frequency questionnaire; diet quality was assessed according to a score for a principal component analysis-defined "healthy" dietary pattern. Poor diet was categorized as a dietary pattern score in the lowest quarter of the distribution. Obesity was defined as a body mass index of 30.0 kg/m(2) or more. Physical function was assessed according to self-report (SF-36); poor function was defined as a score in lowest quarter of the distribution. A subgroup of participants had objective assessments of physical function (Timed Up-and-Go Test, timed 3-m walk, chair rises, one-legged standing balance). RESULTS: There was a graded increase in prevalence of poor self-reported physical function in men and women with increasing number of risk factors (men, adjusted odds ratio (AOR) for 3 or 4 risk factors vs none = 3.79, 95% confidence interval (CI) = 2.31-6.21; women, AOR = 5.37, 95% CI = 2.66-10.84). With the exception of balance, the objective assessments also showed graded relationships with number of risk factors, such that more risk factors was associated with poorer physical function. CONCLUSION: These modifiable lifestyle risk factors are linked to marked differences in risk of poorer physical function in older adults. Efforts to encourage healthy lifestyles have the potential to improve physical function and to promote healthier ageing