Is There a Causal Association between Genotoxicity and the Imposex Effect?

There is a growing body of evidence that indicates common environmental pollutants are capable of disrupting reproductive and developmental processes by interfering with the actions of endogenous hormones. Many reports of endocrine disruption describe changes in the normal development of organs and tissues that are consistent with genetic damage, and recent studies confirm that many chemicals classified to have hormone-modulating effects also possess carcinogenic and mutagenic potential. To date, however, there have been no conclusive examples linking genetic damage with perturbation of endocrine function and adverse effects in vivo. Here, we provide the first evidence of DNA damage associated with the development of imposex (the masculinization of female gastropods considered to be the result of alterations to endocrine-mediated pathways) in the dog-whelk Nucella lapillus. Animals (n = 257) that displayed various stages of tributyltin (TBT)-induced imposex were collected from sites in southwest England, and their imposex status was determined by physical examination. Linear regression analysis revealed a very strong relationship (correlation coefficient of 0.935, p < 0.0001) between the degree of imposex and the extent of DNA damage (micronucleus formation) in hemocytes. Moreover, histological examination of a larger number of dog-whelks collected from sites throughout Europe confirmed the presence of hyperplastic growths, primarily on the vas deferens and penis in both TBT-exposed male snails and in females that exhibited imposex. A strong association was found between TBT body burden and the prevalence of abnormal growths, thereby providing compelling evidence to support the hypothesis that environmental chemicals that affect reproductive processes do so partly through DNA damage pathways

Instability in a marginal coral reef: the shift from natural variability to a human-dominated seascape

As global climate change drives the demise of tropical reef ecosystems, attention is turning to the suitability o refuge habitat. For the Great Barrier Reef, are there historically stable southern refugia where corals from th north might migrate as climate changes? To address this question, we present a precise chronology of margina coral reef development from Moreton Bay, southeast Queensland, Australia. Our chronology shows that ree growth was episodic, responding to natural environmental variation throughout the Holocene, and tha Moreton Bay was inhospitable to corals for about half of the past 7000 years. The only significant change ii coral species composition occurred between similar to 200 and similar to 50 years ago, following anthropogenic alterations of th, bay and its catchments. Natural historical instability of reefs, coupled with environmental degradation sinc, European colonization, suggests that Moreton Bay offers limited potential as refuge habitat for reef species or human time scales

Selective Enhancement of Insulin Sensitivity in the Endothelium In Vivo Reveals a Novel Proatherosclerotic Signaling Loop

Rationale: In the endothelium, insulin stimulates endothelial NO synthase (eNOS) to generate the antiatherosclerotic signaling radical NO. Insulin-resistant type 2 diabetes mellitus is associated with reduced NO availability and accelerated atherosclerosis. The effect of enhancing endothelial insulin sensitivity on NO availability is unclear. Objective: To answer this question, we generated a mouse with endothelial cell (EC)–specific overexpression of the human insulin receptor (hIRECO) using the Tie2 promoter–enhancer. Methods and Results: hIRECO demonstrated significant endothelial dysfunction measured by blunted endothelium-dependent vasorelaxation to acetylcholine, which was normalized by a specific Nox2 NADPH oxidase inhibitor. Insulin-stimulated phosphorylation of protein kinase B was increased in hIRECO EC as was Nox2 NADPH oxidase–dependent generation of superoxide, whereas insulin-stimulated and shear stress–stimulated eNOS activations were blunted. Phosphorylation at the inhibitory residue Y657 of eNOS and expression of proline-rich tyrosine kinase 2 that phosphorylates this residue were significantly higher in hIRECO EC. Inhibition of proline-rich tyrosine kinase 2 improved insulin-induced and shear stress–induced eNOS activation in hIRECO EC. Conclusions: Enhancing insulin sensitivity specifically in EC leads to a paradoxical decline in endothelial function, mediated by increased tyrosine phosphorylation of eNOS and excess Nox2-derived superoxide. Increased EC insulin sensitivity leads to a proatherosclerotic imbalance between NO and superoxide. Inhibition of proline-rich tyrosine kinase 2 restores insulin-induced and shear stress–induced NO production. This study demonstrates for the first time that increased endothelial insulin sensitivity leads to a proatherosclerotic imbalance between NO and superoxide

Restoring Akt1 activity in outgrowth endothelial cells from south asian men rescues vascular reparative potential

Recent data suggest reduced indices of vascular repair in South Asian men, a group at increased risk of cardiovascular events. Outgrowth endothelial cells (OEC) represent an attractive tool to study vascular repair in humans and may offer potential in cell-based repair therapies. We aimed to define and manipulate potential mechanisms of impaired vascular repair in South Asian (SA) men. In vitro and in vivo assays of vascular repair and angiogenesis were performed using OEC derived from SA men and matched European controls, prior defining potentially causal molecular mechanisms. SA OEC exhibited impaired colony formation, migration, and in vitro angiogenesis, associated with decreased expression of the proangiogenic molecules Akt1 and endothelial nitric oxide synthase (eNOS). Transfusion of European OEC into immunodeficient mice after wire-induced femoral artery injury augmented reendothelialization, in contrast with SA OEC and vehicle; SA OEC also failed to promote angiogenesis after induction of hind limb ischemia. Expression of constitutively active Akt1 (E17KAkt), but not green fluorescent protein control, in SA OEC increased in vitro angiogenesis, which was abrogated by a NOS antagonist. Moreover, E17KAkt expressing SA OEC promoted re-endothelialization of wire-injured femoral arteries, and perfusion recovery of ischemic limbs, to a magnitude comparable with nonmanipulated European OEC. Silencing Akt1 in European OEC recapitulated the functional deficits noted in SA OEC. Reduced signaling via the Akt/eNOS axis is causally linked with impaired OEC-mediated vascular repair in South Asian men. These data prove the principle of rescuing marked reparative dysfunction in OEC derived from these men.This work was supported by the British Heart Foundation, London, UK, and the Diabetes Research and Wellness Foundation, Portsmouth, UK

Maternal feeding practices and fussy eating in toddlerhood: A discordant twin analysis

Background: Parental feeding practices are thought to play a causal role in shaping a child's fussiness; however, a child-responsive model suggests that feeding practices may develop in response to a child's emerging appetitive characteristics. We used a novel twin study design to test the hypothesis that mothers vary their feeding practices for twin children who differ in their 'food fussiness', in support of a child-responsive model. Methods: Participants were mothers and their 16 month old twin children (n=2026) from Gemini, a British twin birth cohort of children born in 2007. Standardized psychometric measures of maternal 'pressure to eat', 'restriction' and 'instrumental feeding', as well as child 'food fussiness', were completed by mothers. Within-family analyses examined if twin-pair differences in 'food fussiness' were associated with differences in feeding practices using linear regression models. In a subset of twins (n=247 pairs) who were the most discordant (highest quartile) on 'food fussiness' (difference score≥.50), Paired Samples T-test were used to explore the magnitude of differences in feeding practices between twins. Between-family analyses used Complex Samples General Linear Models to examine associations between feeding practices and 'food fussiness'. Results: Within-pair differences in 'food fussiness' were associated with differential 'pressure to eat' and 'instrumental feeding' (ps<.001), but not with 'restriction'. In the subset of twins most discordant on 'food fussiness', mothers used more pressure (p<.001) and food rewards (p<.05) with the fussier twin. Between-family analyses indicated that 'pressure to eat' and 'instrumental feeding' were positively associated with 'food fussiness', while 'restriction' was negatively associated with 'food fussiness' (ps<.001). Conclusions: Mothers appear to subtly adjust their feeding practices according to their perceptions of their toddler's emerging fussy eating behavior. Specifically, the fussier toddler is pressured more than their less fussy co-twin, and is more likely to be offered food rewards. Guiding parents on how to respond to fussy eating may be an important aspect of promoting feeding practices that encourage food acceptance

Preventing childhood obesity: what works?

Rates of overweight in North American children and adolescents have increased dramatically since the 1970s. Childhood obesity has reached epidemic proportions and calls for prevention and treatment programs to reverse this trend have been made. However, the evidence base needed for effective action is still incomplete, especially for childhood obesity prevention programs. This paper focuses on primary prevention of childhood obesity and has three aims: (1) to briefly describe current primary prevention approaches for childhood obesity and the evidence for their impact; (2) to elucidate promising, but untested intervention strategies using an ecological framework and evidence from experimental and epidemiological research on factors influencing children\u27s eating and weight status; and (3) to introduce a multiphase strategy for screening intervention components and building and evaluating potent interventions for childhood obesity. Most childhood obesity prevention programs have focused on school-aged children and have had little success. We suggest that, given these findings, prevention efforts should be expanded to explore other contexts in which children live as possible settings for intervention efforts, including the family and childcare settings. Given that 25% of preschool children are already overweight, intervening with children before school entry should be a priority. A review of experimental research on the developing controls of food intake in infancy and childhood suggests possible intervention strategies, focusing on parenting and aspects of the feeding environment. Epidemiological findings point to even earlier modifiable risk factors, including gestational weight gain, maternal prepregnancy weight, and formula feeding. However, the potential impact of altering these risk factors remains to be evaluated. In response to this problem, we suggest a new, multiphase method for accomplishing this, including screening intervention components, refining intervention designs and confirming component efficacy to build and evaluate potent, optimized interventions

Should public health interventions aimed at reducing childhood overweight and obesity be gender-focused?

<p>Abstract</p> <p>Background</p> <p>Overweight in childhood is a major public health concern that calls for immediate preventative action. An increasing number of reports suggest that gender specific approaches to prevention may be more effective. However, there is a paucity of information to guide gender-sensitive health promotion and population health interventions for the prevention of overweight in childhood. In the present study, we sought to determine gender-differentials in overweight and underlying behaviors, nutrition and physical activity, among pre-adolescents in Alberta, Canada, to inform the discussion on gender-focused interventions for chronic disease prevention.</p> <p>Methods</p> <p>In 2008, we surveyed 3421 grade five students and their parents of 148 randomly selected schools. Students completed the Harvard food frequency questionnaire, questions on physical activities, and had their height and weight measured. Parents completed questions on socio-economic background and child's lifestyle. We applied multilevel regression methods to assess gender differentials in overweight, nutrition and physical activity.</p> <p>Results</p> <p>Overall, the prevalence of overweight was slightly higher among boys (29.1%) than girls (27.9%) with more pronounced differences in towns and urban geographies. Boys reported to be much more physically active relative to girls (OR = 2.12, 95% CI: 1.73-2.60). Diets of boys, relative to those of girls, reportedly constituted more fat and were less likely to meet the recommendation of 6 daily servings of vegetables and fruits (OR = 0.81, 95% CI: 0.71-0.93).</p> <p>Conclusion</p> <p>Our findings confirm the existence of gender differences in physical activity and nutrition, and support gender-focused health promotion whereby priority is given to physical activity among girls and to healthy eating among boys.</p

Does intensive management improve remission rates in patients with intermediate rheumatoid arthritis? (the TITRATE trial): study protocol for a randomised controlled trial.

BACKGROUND: Uncontrolled active rheumatoid arthritis can lead to increasing disability and reduced quality of life over time. 'Treating to target' has been shown to be effective in active established disease and also in early disease. However, there is a lack of nationally agreed treatment protocols for patients with established rheumatoid arthritis who have intermediate disease activity. This trial is designed to investigate whether intensive management of disease leads to a greater number of remissions at 12 months. Levels of disability and quality of life, and acceptability and cost-effectiveness of the intervention will also be examined. METHODS: The trial is a 12-month, pragmatic, randomised, open-label, two-arm, parallel-group, multicentre trial undertaken at specialist rheumatology centres across England. Three hundred and ninety-eight patients with established rheumatoid arthritis will be recruited. They will currently have intermediate disease activity (disease activity score for 28 joints assessed using an erythrocyte sedimentation rate of 3.2 to 5.1 with at least three active joints) and will be taking at least one disease-modifying anti-rheumatic drug. Participants will be randomly selected to receive intensive management or standard care. Intensive management will involve monthly clinical reviews with a specialist health practitioner, where drug treatment will be optimised and an individualised treatment support programme delivered based on several principles of motivational interviewing to address identified problem areas, such as pain, fatigue and adherence. Standard care will follow standard local pathways and will be in line with current English guidelines from the National Institute for Health and Clinical Excellence. Patients will be assessed initially and at 6 and 12 months through self-completed questionnaires and clinical evaluation. DISCUSSION: The trial will establish whether the known benefits of intensive treatment strategies in active rheumatoid arthritis are also seen in patients with established rheumatoid arthritis who have moderately active disease. It will evaluate both the clinical and cost-effectiveness of intensive treatment. TRIAL REGISTRATION: Current Controlled Trials, ID: ISRCTN70160382 . Registered on 16 January 2014.MRC Funding: MC_UP_1302/3 NIHR Funding: RP-PG-0610-1006

A Meta-Analysis of Local Adaptation in Plants

Local adaptation is of fundamental importance in evolutionary, population, conservation, and global-change biology. The generality of local adaptation in plants and whether and how it is influenced by specific species, population and habitat characteristics have, however, not been quantitatively reviewed. Therefore, we examined published data on the outcomes of reciprocal transplant experiments using two approaches. We conducted a meta-analysis to compare the performance of local and foreign plants at all transplant sites. In addition, we analysed frequencies of pairs of plant origin to examine whether local plants perform better than foreign plants at both compared transplant sites. In both approaches, we also examined the effects of population size, and of the habitat and species characteristics that are predicted to affect local adaptation. We show that, overall, local plants performed significantly better than foreign plants at their site of origin: this was found to be the case in 71.0% of the studied sites. However, local plants performed better than foreign plants at both sites of a pair-wise comparison (strict definition of local adaption) only in 45.3% of the 1032 compared population pairs. Furthermore, we found local adaptation much more common for large plant populations (>1000 flowering individuals) than for small populations (<1000 flowering individuals) for which local adaptation was very rare. The degree of local adaptation was independent of plant life history, spatial or temporal habitat heterogeneity, and geographic scale. Our results suggest that local adaptation is less common in plant populations than generally assumed. Moreover, our findings reinforce the fundamental importance of population size for evolutionary theory. The clear role of population size for the ability to evolve local adaptation raises considerable doubt on the ability of small plant populations to cope with changing environments

Milk feeding, solid feeding, and obesity risk:a review of the relationships between early life feeding practices and later adiposity

Childhood obesity is a major health issue with associated ill-health consequences during childhood and into later adolescence and adulthood. Given that eating behaviors are formed during early childhood, it is important to evaluate the relationships between early life feeding practices and later child adiposity. This review describes and evaluates recent literature exploring associations between child weight and the mode of milk feeding, the age of introducing solid foods and caregivers’ solid feeding practices. There are many inconsistencies in the literature linking early life feeding to later obesity risk and discrepancies may be related to inconsistent definitions, or a lack of control for confounding variables. This review summarizes the literature in this area and identifies the need for large scale longitudinal studies to effectively explore how early life feeding experiences may interact with each other and with nutritional provision during later childhood to predict obesity risk