Genetics University of Toronto Thrombophilia Study in Women (GUTTSI): genetic and other risk factors for venous thromboembolism in women

BACKGROUND: Women may be at increased risk for venous thromboembolism (VTE) as compared with men. We studied the effects of genetic and biochemical markers of thrombophilia in women, in conjunction with other established risk factors for VTE. METHOD: The present retrospective case-control study was conducted in a thrombosis treatment programme at a large Toronto hospital. The cases were 129 women aged 16-79 years with objectively confirmed VTE. Age-matched control individuals were women who were free of venous thrombosis. Neither cases nor control individuals had known cardiovascular disease. Participants were interviewed regarding personal risk factors for VTE, including smoking, history of malignancy, pregnancy, and oestrogen or oral contraceptive use. Blood specimens were analyzed for common single nucleotide polymorphisms of prothrombin, factor V and methylenetetrahydrofolate reductase (MTHFR; C677T, A1298C and T1317C), and the A66G polymorphism for methionine synthase reductase (MTRR).Fasting plasma homocysteine was also analyzed. RESULTS: Women with VTE were significantly more likely than female control individuals to carry the prothrombin polymorphism and the factor V polymorphism, or to have fasting hyperhomocysteinaemia. Homozygosity for the C677T MTHFR gene was not a significant risk factor for VTE, or were the A1298C or T1317C MTHFR homozygous variants. Also, the A66G MTRR homozygous state did not confer an increased risk for VTE. CONCLUSION: Prothrombin and factor V polymorphisms increased the risk for VTE in women, independent from other established risk factors. Although hyperhomocysteinaemia also heightens this risk, common polymorphisms in two genes that are responsible for homocysteine remethylation do not. These findings are consistent with previous studies that included both men and women

Defining the molecular role of gp91phox in the immune manifestation of acute allergic asthma using a preclinical murine model

<p>Abstract</p> <p>Objective</p> <p>The phenomena manifested during inflammation require interplay between circulating effector cells, local resident cells, soluble mediators and genetic host factors to establish, develop and maintain itself. Of the molecues involed in the initiation and perpetuation of acute allergic inflammation in asthma, the involvement of effector cells in redox reactions for producing O₂^-(superoxide anion) through the mediation of NADPH oxidase is a critical step. Prior data suggest that reactive oxygen species (ROS) produced by NADPH oxidase homologues in non-phagocytic cells play an important role in the regulation of signal transduction, while macrophages use a membrane-associated NADPH oxidase to generate an array of oxidizing intermediates which inactivate MMPs on or near them.</p> <p>Materials and Methods and Treatment</p> <p>To clarify the role of gp91phox subunit of NADPH oxidase in the development and progression of an acute allergic asthma phenotype, we induced allergen dependent inflammation in a gp91<it>^phox</it>-/- single knockout and a gp91phox-/-MMP-12-/- double knockout mouse models.</p> <p>Results</p> <p>In the knockout mice, both inflammation and airway hyperreactivity were more extensive than in wildtype mice post-OVA. Although OVA-specific IgE in plasma were comparable in wildtype and knockout mice, enhanced inflammatory cell recruitment from circulation and cytokine release in lung and BALf, accompanied by higher airway resistance as well as Penh in response to methacholine, indicate a regulatory role for NADPH oxidase in development of allergic asthma. While T cell mediated functions like Th2 cytokine secretion, and proliferation to OVA were upregulated synchronous with the overall robustness of the asthma phenotype, macrophage upregulation in functions such as proliferation, and mixed lymphocyte reaction indicate a regulatory role for gp91phox and an overall non-involvement or synergistic involvement of MMP12 in the response pathway (comparing data from gp91phox-/- and gp91phox-/-MMP-12-/- mice).</p

Metabolic Syndrome features and risk of neural tube defects

Research articl

A cluster randomized controlled trial of the effectiveness and cost-effectiveness of Intermediate Care Clinics for Diabetes (ICCD) : study protocol for a randomized controlled trial

Background World-wide healthcare systems are faced with an epidemic of type 2 diabetes. In the United Kingdom, clinical care is primarily provided by general practitioners (GPs) rather than hospital specialists. Intermediate care clinics for diabetes (ICCD) potentially provide a model for supporting GPs in their care of people with poorly controlled type 2 diabetes and in their management of cardiovascular risk factors. This study aims to (1) compare patients with type 2 diabetes registered with practices that have access to an ICCD service with those that have access only to usual hospital care; (2) assess the cost-effectiveness of the intervention; and (3) explore the views and experiences of patients, health professionals and other stakeholders. Methods/Design This two-arm cluster randomized controlled trial (with integral economic evaluation and qualitative study) is set in general practices in three UK Primary Care Trusts. Practices are randomized to one of two groups with patients referred to either an ICCD (intervention) or to hospital care (control). Intervention group: GP practices in the intervention arm have the opportunity to refer patients to an ICCD - a multidisciplinary team led by a specialist nurse and a diabetologist. Patients are reviewed and managed in the ICCD for a short period with a goal of improving diabetes and cardiovascular risk factor control and are then referred back to practice. or Control group: Standard GP care, with referral to secondary care as required, but no access to ICCD. Participants are adults aged 18 years or older who have type 2 diabetes that is difficult for their GPs to control. The primary outcome is the proportion of participants reaching three risk factor targets: HbA1c (≤7.0%); blood pressure (<140/80); and cholesterol (<4 mmol/l), at the end of the 18-month intervention period. The main secondary outcomes are the proportion of participants reaching individual risk factor targets and the overall 10-year risks for coronary heart disease(CHD) and stroke assessed by the United Kingdom Prospective Diabetes Study (UKPDS) risk engine. Other secondary outcomes include body mass index and waist circumference, use of medication, reported smoking, emotional adjustment, patient satisfaction and views on continuity, costs and health related quality of life. We aimed to randomize 50 practices and recruit 2,555 patients

向精神薬服用患者の突然死症例におけるカリウムイオンチャネルに関する分子生物学的解析：QT延長症候群関連遺伝子の多型が危険因子となり得るか？

Psychotropic drugs can pose the risk of acquired long QT syndrome (LQTS). Unexpected autopsy-negative sudden death in patients taking psychotropic drugs may be associated with prolonged QT intervals and life-threatening arrhythmias. We analyzed genes that encode for cardiac ion channels and potentially associated with LQTS, examining specifically the potassium channel genes KCNQ1 and KCNH2 in 10 cases of sudden death involving patients administered psychotropic medication in which autopsy findings identified no clear cause of death. We amplified and sequenced all exons of KCNQ1 and KCNH2, identifying G643S, missense polymorphism in KCNQ1, in 6 of the 10 cases. A study analysis indicated that only 11% of 381 healthy Japanese individuals carry this polymorphism. Reports of previous functional analyses indicate that the G643S polymorphism in the KCNQ1 potassium channel protein causes mild IKs channel dysfunction. Our present study suggests that administering psychotropic drug therapy to individuals carrying the G643S polymorphism may heighten the risk of prolonged QT intervals and life-threatening arrhythmias. Thus, screening for the G643S polymorphism before prescribing psychotropic drugs may help reduce the risk of unexpected sudden death2013博士（歯学）松本歯科大

A novel method to analyze leukocyte rolling behavior in vivo

Leukocyte endothelial cell interaction is a fundamentally important process in many disease states. Current methods to analyze such interactions include the parallel-plate flow chamber and intravital microscopy. Here, we present an improvement of the traditional intravital microscopy that allows leukocyte-endothelial cell interaction to be studied from the time the leukocyte makes its initial contact with the endothelium until it adheres to or detaches from the endothelium. The leukocyte is tracked throughout the venular tree with the aid of a motorized stage and the rolling and adhesive behavior is measured off-line. Because this method can involve human error, methods to automate the tracking procedure have been developed. This novel tracking method allows for a more detailed examination of leukocyte-endothelial cell interactions

Proton pump inhibitors and risk of gastric cancer: a population-based cohort study

Proton pump inhibitor (PPI) use leads to hypergastrinaemia, which has been associated with gastrointestinal neoplasia. We evaluated the association between PPI use and risk of gastric cancer using population-based health-care registers in North Jutland, Denmark, during 1990–2003. We compared incidence rates among new users of PPI (n=18 790) or histamine-2-antagonists (H2RAs) (n=17 478) and non-users of either drug. Poisson regression analysis was used to estimate incidence rate ratios (IRRs) adjusted for multiple confounders. We incorporated a 1-year lag time to address potential reverse causation. We identified 109 gastric cancer cases among PPI users and 52 cases among H2RA users. After incorporating the 1-year lag time, we observed IRRs for gastric cancer of 1.2 (95% CI: 0.8–2.0) among PPI users and 1.2 (95% CI: 0.8–1.8) among H2RA users compared with non-users. These estimates are in contrast to significant overall IRRs of 9.0 and 2.8, respectively, without the lag time. In lag time analyses, increased IRRs were observed among PPI users with the largest number of prescriptions or the longest follow-up compared with H2RA users or non-users. Although our results point to a major influence of reverse causation and confounding by indication on the association between PPI use and gastric cancer incidence, the finding of increased incidence among PPI users with most prescriptions and longest follow-up warrants further investigation

Work, life and time in the new economy: an introduction

International audienc

Comorbidades físicas e psicológicas antes e depois da cirurgia bariátrica : um estudo longitudinal

Introduction: Morbid obesity has multiple implications for psychological and physical health. Bariatric surgery has been selected as the treatment of choice for this chronic disease, despite the controversial impact of the surgery on psychosocial health. The objective of this study was to describe candidates for bariatric surgery and analyze changes in weight, psychopathology, personality, and health problems and complaints at 6- and 12- month follow-up assessments. Methods: Thirty obese patients (20 women and 10 men) with a mean age of 39.17±8.81 years were evaluated in different dimensions before surgery and 6 and 12 months after the procedure. Results: Six and 12 months after bariatric surgery, patients reported significant weight loss and a significant reduction in the number of health problems and complaints. The rates of self-reported psychopathology were low before surgery, and there were no statistically significant changes over time. The conscientiousness, extraversion, and agreeableness dimensions increased, but neuroticism and openness remained unchanged. All changes had a medium effect size. Conclusions: Our results suggest that patients experience significant health improvements and some positive personality changes after bariatric surgery. Even though these findings underscore the role of bariatric surgery as a relevant treatment for morbid obesity, more in-depth longitudinal studies are needed to elucidate the evolution of patients after the procedure.Introdução: A obesidade mórbida tem várias implicações para a saúde psicológica e física. A cirurgia bariátrica tem sido o tratamento de escolha para essa doença crônica, apesar da controvérsia sobre o impacto da cirurgia na saúde psicossocial. O objetivo deste estudo foi descrever candidatos a cirurgia bariátrica e analisar mudanças no peso, psicopatologia personalidade, problemas e queixas de saúde desses pacientes em avaliações realizadas 6 e 12 meses após a cirurgia. Métodos: Trinta pacientes obesos (20 mulheres e 10 homens) com idade média de 39,17±8,81 anos foram avaliados em diferentes dimensões antes da cirurgia e 6 e 12 meses após. Resultados: Aos 6 e 12 meses após a cirurgia bariátrica, os pacientes relataram significativa perda de peso e significativa redução no número de problemas e queixas de saúde. As taxas de psicopatologia autorrelatada foram baixas antes da cirurgia e não sofreram mudanças significativas com o tempo. As dimensões conscienciosidade, extroversão e agradabilidade aumentaram, mas o neuroticismo e a abertura permaneceram inalteradas. Todas as mudanças apresentaram um tamanho de efeito médio. Conclusões: Os nossos resultados sugerem que os pacientes experimentam melhoras significativas em saúde e algumas mudanças positivas de personalidade após a cirurgia bariátrica. Embora esses achados reforcem o papel da cirurgia bariátrica como um tratamento relevante para a obesidade mórbida, mais estudos longitudinais e aprofundados são necessários para elucidar a evolução dos pacientes após a realização do procedimento.(undefined

Speciation of common Gram-negative pathogens using a highly multiplexed high resolution melt curve assay

The identification of the bacterial species responsible for an infection remains an important step for the selection of antimicrobial therapy. Gram-negative bacteria are an important source of hospital and community acquired infections and frequently antimicrobial resistant. Speciation of bacteria is typically carried out by biochemical profiling of organisms isolated from clinical specimens, which is time consuming and delays the initiation of tailored treatment. Whilst molecular methods such as PCR have been used, they often struggle with the challenge of detecting and discriminating a wide range of targets. High resolution melt analysis is an end-point qPCR detection method that provides greater multiplexing capability than probe based methods. Here we report the design of a high resolution melt analysis assay for the identification of six common Gram-negative pathogens; Escherichia coli, Klebsiella pneumoniae, Klebsiella oxytoca, Pseudomonas aeruginosa, Salmonella Sp, and Acinetobacter baumannii, and a generic Gram-negative specific 16S rRNA control. The assay was evaluated using a well characterised collection of 113 clinically isolated Gram-negative bacteria. The agreement between the HRM assay and the reference test of PCR and sequencing was 98.2% (Kappa 0.96); the overall sensitivity and specificity of the assay was 97.1% (95% CI: 90.1–99.7%) and 100% (95% CI: 91.78–100%) respectively