Telomere Length of Circulating Leukocyte Subpopulations and Buccal Cells in Patients with Ischemic Heart Failure and Their Offspring

BACKGROUND: We aimed to find support for the hypothesis that telomere length (TL) is causally involved in the pathogenesis of ischemic heart failure (IHF). We measured TL in IHF patients and their high-risk offspring and determined whether mean leukocyte TL reflects TL in CD34+ progenitor. We additionally measured TL of offspring of patients and controls to examine heritability throughout different cell types. METHODS AND RESULTS: TL was measured by qPCR in overall leukocytes, CD34+ progenitor cells, mononuclear cells (MNCs), and buccal cells in 27 IHF patients, 24 healthy controls and 60 offspring. TL in IHF patients was shorter than healthy controls in leukocytes (p = 0.002), but not in CD34+ cells (p = 0.39), MNCs (p = 0.31) or buccal cells (p = 0.19). Offspring of IHF patients had shorter TL in leukocytes than offspring of healthy subjects (p = 0.04) but not in other cell types. Controls and offspring showed a good within person correlation between leukocytes and CD34+ cells (r 0.562; p = 0.004 and r 0.602; p = 0.001, respectively). In IHF patients and offspring the correlation among cell types was blunted. Finally, we found strong correlations between parent and offspring TL in all four cell types. CONCLUSIONS: Reduced leukocyte TL in offspring of IHF subjects suggests a potential causal link of TL in ischemic heart disease. However, this causality is unlikely to originate from exhaustion of TL in CD34+ progenitor or MNC cells as their lengths are not well captured by overall leukocyte TL. Additionally, we found strong correlations between parent and offspring TL in all examined cell types, suggesting high heritability of TL among cell types

The Caenorhabditis elegans GATA Factor ELT-1 Works through the Cell Proliferation Regulator BRO-1 and the Fusogen EFF-1 to Maintain the Seam Stem-Like Fate

Seam cells in Caenorhabditis elegans provide a paradigm for the stem cell mode of division, with the ability to both self-renew and produce daughters that differentiate. The transcription factor RNT-1 and its DNA binding partner BRO-1 (homologues of the mammalian cancer-associated stem cell regulators RUNX and CBFβ, respectively) are known rate-limiting regulators of seam cell proliferation. Here, we show, using a combination of comparative genomics and DNA binding assays, that bro-1 expression is directly regulated by the GATA factor ELT-1. elt-1(RNAi) animals display similar seam cell lineage defects to bro-1 mutants, but have an additional phenotype in which seam cells lose their stem cell-like properties and differentiate inappropriately by fusing with the hyp7 epidermal syncytium. This phenotype is dependent on the fusogen EFF-1, which we show is repressed by ELT-1 in seam cells. Overall, our data suggest that ELT-1 has dual roles in the stem-like seam cells, acting both to promote proliferation and prevent differentiation

HMOX1 Gene Promoter Alleles and High HO-1 Levels Are Associated with Severe Malaria in Gambian Children

Heme oxygenase 1 (HO-1) is an essential enzyme induced by heme and multiple stimuli associated with critical illness. In humans, polymorphisms in the HMOX1 gene promoter may influence the magnitude of HO-1 expression. In many diseases including murine malaria, HO-1 induction produces protective anti-inflammatory effects, but observations from patients suggest these may be limited to a narrow range of HO-1 induction, prompting us to investigate the role of HO-1 in malaria infection. In 307 Gambian children with either severe or uncomplicated P. falciparum malaria, we characterized the associations of HMOX1 promoter polymorphisms, HMOX1 mRNA inducibility, HO-1 protein levels in leucocytes (flow cytometry), and plasma (ELISA) with disease severity. The (GT)n repeat polymorphism in the HMOX1 promoter was associated with HMOX1 mRNA expression in white blood cells in vitro, and with severe disease and death, while high HO-1 levels were associated with severe disease. Neutrophils were the main HO-1-expressing cells in peripheral blood, and HMOX1 mRNA expression was upregulated by heme-moieties of lysed erythrocytes. We provide mechanistic evidence that induction of HMOX1 expression in neutrophils potentiates the respiratory burst, and propose this may be part of the causal pathway explaining the association between short (GT)n repeats and increased disease severity in malaria and other critical illnesses. Our findings suggest a genetic predisposition to higher levels of HO-1 is associated with severe illness, and enhances the neutrophil burst leading to oxidative damage of endothelial cells. These add important information to the discussion about possible therapeutic manipulation of HO-1 in critically ill patients

Living Well with Diabetes: a randomized controlled trial of a telephone-delivered intervention for maintenance of weight loss, physical activity and glycaemic control in adults with type 2 diabetes

Background By 2025, it is estimated that approximately 1.8 million Australian adults (approximately 8.4% of the adult population) will have diabetes, with the majority having type 2 diabetes. Weight management via improved physical activity and diet is the cornerstone of type 2 diabetes management. However, the majority of weight loss trials in diabetes have evaluated short-term, intensive clinic-based interventions that, while producing short-term outcomes, have failed to address issues of maintenance and broad population reach. Telephone-delivered interventions have the potential to address these gaps. Methods/Design Using a two-arm randomised controlled design, this study will evaluate an 18-month, telephone-delivered, behavioural weight loss intervention focussing on physical activity, diet and behavioural therapy, versus usual care, with follow-up at 24 months. Three-hundred adult participants, aged 20-75 years, with type 2 diabetes, will be recruited from 10 general practices via electronic medical records search. The Social-Cognitive Theory driven intervention involves a six-month intensive phase (4 weekly calls and 11 fortnightly calls) and a 12-month maintenance phase (one call per month). Primary outcomes, assessed at 6, 18 and 24 months, are: weight loss, physical activity, and glycaemic control (HbA1c), with weight loss and physical activity also measured at 12 months. Incremental cost-effectiveness will also be examined. Study recruitment began in February 2009, with final data collection expected by February 2013. Discussion This is the first study to evaluate the telephone as the primary method of delivering a behavioural weight loss intervention in type 2 diabetes. The evaluation of maintenance outcomes (6 months following the end of intervention), the use of accelerometers to objectively measure physical activity, and the inclusion of a cost-effectiveness analysis will advance the science of broad reach approaches to weight control and health behaviour change, and will build the evidence base needed to advocate for the translation of this work into population health practice

The functions of Rab GTPases in plant membrane traffic.

Rab GTPases are important determinants of membrane identity and membrane targeting. Higher plants have evolved a unique set of Rab GTPases that presumably reflects the specific demands of plant cell trafficking. In recent years, significant progress has been made in identifying Rab GTPases involved in endosome organisation, cytokinesis and in post-Golgi traffic to the plasma membrane and vacuoles. These include members of the Rab-F1, Rab-F2, Rab-A1, Rab-A2 and Rab-A4 subclasses. Some important regulators or effectors have also been identified for Rab-F, Rab-A1 and Rab-A4 proteins. However, uncertainties remain about the trafficking pathways that connect the compartments in the trans-Golgi/prevacuolar/endosomal system and there is still little or no insight into the functions of several major subclasses within the Rab GTPase family