Global Methylation in Exposure Biology and Translational Medical Science

Background: Many groups are actively investigating how the epigenetic state relates to environmental exposures and development of disease, including cancer. There are myriad choices for capturing and measuring the epigenetic state of a tissue, ranging from assessing the total methyl-CpG content to array-based platforms that simultaneously probe hundreds of thousands of CpG loci. There is an emerging literature that uses CpG methylation at repetitive sequences, including LINE-1 (long interspersed nuclear element-1) elements, to capture the epigenomic state

The impact of low erythrocyte density in human blood on the fitness and energetic reserves of the African malaria vector Anopheles gambiae

Background Anaemia is a common health problem in the developing world. This condition is characterized by a reduction in erythrocyte density, primarily from malnutrition and/or infectious diseases such as malaria. As red blood cells are the primary source of protein for haematophagous mosquitoes, any reduction could impede the ability of mosquito vectors to transmit malaria by influencing their fitness or that of the parasites they transmit. The aim of this study was to determine the impact of differences in the density of red blood cells in human blood on malaria vector (Anopheles gambiae sensu stricto) fitness. The hypotheses tested are that mosquito vector energetic reserves and fitness are negatively influenced by reductions in the red cell density of host human blood meals commensurate with those expected from severe anaemia. Methods Mosquitoes (An. gambiae s.s.) were offered blood meals of different packed cell volume(PCV) of human blood consistent with those arising from severe anaemia (15%) and normalPCV (50%). Associations between mosquito energetic reserves (lipid, glucose and glycogen)and fitness measures (reproduction and survival) and blood meal PCV were investigated. Results The amount of protein that malaria vectors acquired from blood feeding (indexed by haematin excretion) was significantly reduced at low blood PCV. However, mosquitoes feeding on blood of low PCV had the same oviposition rates as those feeding on blood of normal PCV, and showed an increase in egg production of around 15%. The long-term survival of An. gambiae s.s was reduced after feeding on low PCV blood, but PCV had no significant impact on the proportion of mosquitoes surviving through the minimal period required to develop and transmit malaria parasites (estimated as 14 days post-blood feeding). The impact of blood PCV on the energetic reserves of mosquitoes was relatively minor. Conclusions These results suggest that feeding on human hosts whose PCV has been depleted due to severe anaemia does not significantly reduce the fitness or transmission potential of malaria vectors, and indicates that mosquitoes may be able exploit resources for reproduction more efficiently from blood of low rather than normal PCV

Bistability in Apoptosis by Receptor Clustering

Apoptosis is a highly regulated cell death mechanism involved in many physiological processes. A key component of extrinsically activated apoptosis is the death receptor Fas, which, on binding to its cognate ligand FasL, oligomerize to form the death-inducing signaling complex. Motivated by recent experimental data, we propose a mathematical model of death ligand-receptor dynamics where FasL acts as a clustering agent for Fas, which form locally stable signaling platforms through proximity-induced receptor interactions. Significantly, the model exhibits hysteresis, providing an upstream mechanism for bistability and robustness. At low receptor concentrations, the bistability is contingent on the trimerism of FasL. Moreover, irreversible bistability, representing a committed cell death decision, emerges at high concentrations, which may be achieved through receptor pre-association or localization onto membrane lipid rafts. Thus, our model provides a novel theory for these observed biological phenomena within the unified context of bistability. Importantly, as Fas interactions initiate the extrinsic apoptotic pathway, our model also suggests a mechanism by which cells may function as bistable life/death switches independently of any such dynamics in their downstream components. Our results highlight the role of death receptors in deciding cell fate and add to the signal processing capabilities attributed to receptor clustering.Comment: Accepted by PLoS Comput Bio

Ecology: a prerequisite for malaria elimination and eradication

* Existing front-line vector control measures, such as insecticide-treated nets and residual sprays, cannot break the transmission cycle of Plasmodium falciparum in the most intensely endemic parts of Africa and the Pacific * The goal of malaria eradication will require urgent strategic investment into understanding the ecology and evolution of the mosquito vectors that transmit malaria * Priority areas will include understanding aspects of the mosquito life cycle beyond the blood feeding processes which directly mediate malaria transmission * Global commitment to malaria eradication necessitates a corresponding long-term commitment to vector ecolog

Screening and brief interventions for hazardous and harmful alcohol use among patients with active tuberculosis attending primary care clinics in South Africa: a cluster randomized controlled trial protocol

<p>Abstract</p> <p>Background</p> <p>In 2008 the World Health Organization (WHO) reported that South Africa had the highest tuberculosis (TB) incidence in the world. This high incidence rate is linked to a number of factors, including HIV co-infection and alcohol use disorders. The diagnosis and treatment package for TB and HIV co-infection is relatively well established in South Africa. However, because alcohol use disorders may present more insidiously, making it difficult to diagnose, those patients with active TB and misusing alcohol are not easily cured from TB. With this in mind, the primary purpose of this cluster randomized controlled trial is to provide screening for alcohol misuse and to test the efficacy of brief interventions in reducing alcohol intake in those patients with active TB found to be misusing alcohol in primary health care clinics in three provinces in South Africa.</p> <p>Methods/Design</p> <p>Within each of the three selected health districts with the highest TB burden in South Africa, 14 primary health care clinics with the highest TB caseloads will be selected. Those agreeing to participate will be stratified according to TB treatment caseload and the type of facility (clinic or community health centre). Within strata from 14 primary care facilities, 7 will be randomly selected into intervention and 7 to control study clinics (42 clinics, 21 intervention clinics and 21 control clinics). At the clinic level systematic sampling will be used to recruit newly diagnosed TB patients. Those consenting will be screened for alcohol misuse using the AUDIT. Patients who screen positive for alcohol misuse over a 6-month period will be given either a brief intervention based on the Information-Motivation-Behavioural Skills (IMB) Model or an alcohol use health education leaflet.</p> <p>A total sample size of 520 is expected.</p> <p>Discussion</p> <p>The trial will evaluate the impact of alcohol screening and brief interventions for patients with active TB in primary care settings in South Africa. The findings will impact public health and will enable the health ministry to formulate policy related to comprehensive treatment for TB and alcohol misuse, which will result in reduction in alcohol use and ultimately improve the TB cure rates.</p> <p>Trial registration number</p> <p>PACTR: <a href="http://apps.who.int/trialsearch/trial.aspx?trialid=PACTR201105000297151">PACTR201105000297151</a></p

Parent and child interactions with two contrasting anti-obesity advertising campaigns: A qualitative analysis

Background: Social marketing has been proposed as a framework that may be effectively used to encourage behaviour change relating to obesity. Social advertising (or mass media campaigning) is the most commonly used social marketing strategy to address the issue of obesity. While social advertising has the potential to effectively communicate information about obesity, some argue that the current framing and delivery of these campaigns are ineffective, and may cause more harm than good. Methods: We used a qualitative advertising reception study. 150 family groups (comprised of 159 parents and 184 children) were shown two Australian government anti-obesity advertisements: Measure Up (focused on problems associated with obesity) and Swap It (focused on solutions for obesity). Families were engaged in a discussion about the visual appeals, verbal messages and their perceptions about the impact of the advertisements on behavioural change. Open coding techniques and a constant comparative method of analysis was used to interpret the data.Results: Many parents had strong personal resonance with the visual imagery within the campaigns. While Swap It had strong ‘likeability’ with children, many children believed that the messages about overweight and obesity were less personally relevant because they did not perceive themselves to be overweight. The content and delivery style of the verbal messages (the serious risk focused message in Measure Up compared to the upbeat, fun practical message in Swap It) influenced how different audiences (parents and children) interpreted the information that was presented. Parents assimilated practical and instructive messages, while children assimilated messages about weight loss and weight gain. Parents and children recognised that the campaigns were asking individuals to take personal responsibility for their weight status, and were at times critical that the campaigns did not tackle the broader issues associated with the causes and consequences of obesity. The lack of practical tools to encourage behavioural change was a key barrier for obese parents. Conclusions: Well-funded, targeted social marketing campaigns will play an important role in the prevention and management of obesity. It is important that these campaigns are comprehensively evaluated and are backed up with structural supports to enable and encourage population subgroups to act upon messages

Does self monitoring of blood glucose as opposed to urinalysis provide additional benefit in patients newly diagnosed with type 2 diabetes receiving structured education? The DESMOND SMBG randomised controlled trial protocol

BackgroundThe benefit of self-monitoring of blood glucose (SMBG) in people with type 2 diabetes on diet or oral agents other than sulphonylureas remains uncertain. Trials of interventions incorporating education about self-monitoring of blood glucose have reported mixed results. A recent systematic review concluded that SMBG was not cost-effective. However, what was unclear was whether a cheaper method of self-monitoring (such as urine glucose monitoring) could produce comparable benefit and patient acceptability for less cost.Methods/DesignThe DESMOND SMBG trial is comparing two monitoring strategies (blood glucose monitoring and urine testing) over 18 months when incorporated into a comprehensive self-management structured education programme. It is a multi-site cluster randomised controlled trial, conducted across 8 sites (7 primary care trusts) in England, UK involving individuals with newly diagnosed Type 2 diabetes.The trial has 80% power to demonstrate equivalence in mean HbA1c (the primary end-point) at 18 months of within &plusmn; 0.5% assuming 20% drop out and 20% non-consent. Secondary end-points include blood pressure, lipids, body weight and psychosocial measures as well as a qualitative sub-study.Practices were randomised to one of two arms: participants attend a DESMOND programme incorporating a module on self-monitoring of either urine or blood glucose. The programme is delivered by accredited educators who received specific training about equipoise. Biomedical data are collected and psychosocial scales completed at baseline, and 6, 12, and 18 months post programme. Qualitative research with participants and educators will explore views and experiences of the trial and preferences for methods of monitoring.DiscussionThe DESMOND SMBG trial is designed to provide evidence to inform the debate about the value of self-monitoring of blood glucose in people with newly diagnosed type 2 diabetes. Strengths include a setting in primary care, a cluster design, a health economic analysis, a comparison of different methods of monitoring while controlling for other components of training within the context of a quality assured structured education programme and a qualitative sub-study

The role of gonadotrophin-releasing hormone antagonists in the treatment of patients with advanced hormone-dependent prostate cancer in the UK.

PURPOSE: Comparing gonadotrophin-releasing hormone (GnRH) antagonists and agonists as androgen deprivation therapy for advanced prostate cancer (PC). METHODS: This article stems from a round-table meeting in December 2014 to compare the properties of GnRH agonists and antagonists in the published literature in order to identify the patient groups most likely to benefit from GnRH antagonist therapy. A broad PubMed and congress abstract search was carried out in preparation for the meeting to ensure that the latest data and opinion were available for the discussions. RESULTS: In randomised, controlled trials, GnRH antagonist therapy provides more rapid suppression of luteinising hormone, follicle-stimulating hormone and testosterone than GnRH agonist treatment. Compared with the GnRH agonist, there is evidence of improved disease control by a GnRH antagonist, with longer interval to prostate-specific antigen progression and greater reduction of serum alkaline phosphatase. In a post hoc analysis of six randomised trials, the risk of cardiac events within 1 year of initiating therapy was significantly lower among men receiving GnRH antagonist than agonist. Pre-clinical laboratory data suggest a number of mechanisms whereby GnRH antagonist therapy may benefit men with pre-existing cardiovascular disease (CVD), the most plausible hypothesis being that, unlike GnRH agonists, GnRH antagonists do not activate T lymphocytes, which act to increase atherosclerotic plaque rupture. CONCLUSION: When making treatment decisions, clinicians should consider comorbidities, particularly CVD, in addition to effects on PC. GnRH antagonists may be appropriate in patients with significant CV risk, existing osteopenia, lower urinary tract symptoms and significant metastatic disease