Mendelian randomization supports causality between maternal hyperglycemia and epigenetic regulation of leptin gene in newborns.

Leptin is an adipokine that acts in the central nervous system and regulates energy balance. Animal models and human observational studies have suggested that leptin surge in the perinatal period has a critical role in programming long-term risk of obesity. In utero exposure to maternal hyperglycemia has been associated with increased risk of obesity later in life. Epigenetic mechanisms are suspected to be involved in fetal programming of long term metabolic diseases. We investigated whether DNA methylation levels near LEP locus mediate the relation between maternal glycemia and neonatal leptin levels using the 2-step epigenetic Mendelian randomization approach. We used data and samples from up to 485 mother-child dyads from Gen3G, a large prospective population-based cohort. First, we built a genetic risk score to capture maternal glycemia based on 10 known glycemic genetic variants (GRS10) and showed it was an adequate instrumental variable (ß = 0.046 mmol/L of maternal fasting glucose per additional risk allele; SE = 0.007; P = 7.8 × 10(-11); N = 467). A higher GRS10 was associated with lower methylation levels at cg12083122 located near LEP (ß = -0.072 unit per additional risk allele; SE = 0.04; P = 0.05; N = 166). Direction and effect size of association between the instrumental variable GRS10 and methylation at cg12083122 were consistent with the negative association we observed using measured maternal glycemia. Lower DNA methylation levels at cg12083122 were associated with higher cord blood leptin levels (ß = -0.17 log of cord blood leptin per unit; SE = 0.07; P = 0.01; N = 170). Our study supports that maternal glycemia is part of causal pathways influencing offspring leptin epigenetic regulation.

Review of a mock research protocol in functional neuroimaging by Canadian research ethics boards.

OBJECTIVE: To examine how research ethics boards (REBs) review research projects in emerging disciplines such as functional neuroimaging. DESIGN: To compare the criteria applied and the decisions reached by REBs that reviewed the same mock research protocol in functional neuroimaging. PARTICIPANTS: 44 Canadian biomedical REBs, mostly working in public university or hospital settings. MAIN MEASUREMENTS: The mock research protocol "The Neurobiology of Social Behavior" included several ethical issues operating at all three levels: personal, institutional and social. Data consisting of responses to closed questions were analysed quantitatively. Qualitative analysis of open-question responses used mixed classification. RESULTS: Similar criteria were used by most participating REBs. Yet the project was unconditionally approved by 3 REBs, approved conditionally by 10 and rejected by 30. CONCLUSIONS: The results point to the difficulty for REBs of reviewing all kinds of research projects, regardless of field, by relying on international and national norms framed in general terms and a possible variation between REBs in the interpretation of their mandate for the protection of research subjects.

Differences in diabetic co-morbidity between Aboriginal and non-Aboriginal people living in Bella Coola, Canada.

OBJECTIVES: (1) To identify which medical disorders are significantly associated with being a diabetic in the setting of an isolated, rural community; and (2) to determine if there are differences between Aboriginal and non-Aboriginal diabetics. DESIGN: population based retrospective chart review. STUDY POPULATION: people living in the Bella Coola Valley, Canada, and having a chart at the Bella Coola Medical Clinic as at September 2001. MAIN OUTCOME MEASURES: known diabetes related co-morbidity (retinopathy, nephropathy, coronary artery disease, peripheral vascular disease, neuropathy). RESULTS: There were 126 adult (>18 years old) diabetics living in the Bella Coola Valley. Prevalence rates for history of alcohol issues, retinopathy, coronary artery disease, cerebrovascular disease, peripheral vascular disease, peripheral neuropathy, hypertension, hypercholesterolemia, and nephropathy were 44%, 14%, 19%, 8%, 7%, 10%, 54%, 47%, and 7% respectively. For the 1597 non-diabetics living in the Bella Coola Valley, respective prevalence rates for these same co-morbidities were 20%, 0.3%, 2%, 1.5%, 1%, 1%, 10%, 6%, and 0.6%. The study did not demonstrate that Aboriginal people living in the Bella Coola Valley have an increased prevalence of diabetes associated co-morbidities over and above that found in the non-Aboriginal diabetic population. This was despite the fact the smoking rate was higher in the Aboriginal population. CONCLUSIONS: The development of diabetes in both Aboriginal and non-Aboriginal people living in the Bella Coola Valley was clearly associated with the presence of multiple co-morbidities, including hypertension, hypercholesterolemia, coronary artery disease, cerebrovascular disease, and neuropathy. Rates of diabetes associated co-morbidities were similar for both Aboriginal and non-Aboriginal diabetic populations. The authors speculate that a diet rich in fish oils (omega-3 fatty acids) accounted for the lower than expected rates of cardiovascular disease among this Aboriginal population.

No detrimental effect from chronic exposure to buprenorphine on corticosteroid-binding globulin and corticosensitive immune parameters.

Opioid drugs reportedly regulate the immune system via their effects on the hypothalamic- pituitary-adrenal (HPA) axis. The present study was carried out to assess the effects of chronic exposure to buprenorphine on HPA axis activation, corticosteroid-binding globulin (CBG), the main glucocorticoid (GC) carrier, and the immune system. Results show that buprenorphine, delivered by osmotic pump subcutaneously in C57BL/6 male mice during a 10-day period, caused a marked decrease in total corticosterone (CORT) levels at day 1 of exposure. CORT levels then increased with maximal values observed at day 5 of exposure. After day 5, total CORT levels gradually decreased and returned to control values. No significant changes were observed in CBG protein levels and mRNA expression in the liver. Since CBG levels remained unchanged, the percentage of free CORT values in buprenorphine mice did not differ from control values. Thus, the variations observed in the amount of free CORT were related only to changes measured in total CORT. These endocrine changes did not have a significant impact on the immune parameters measured. Total CD(4)+ and CD(8)+ splenic and thymic populations were not modulated by buprenorphine. However, splenocytes from mice exposed to buprenorphine after 5 days exhibited greater proliferation upon anti-TCR monoclonal antibody stimulation than saline-exposed mice. These results indicate that buprenorphine can be safely used because it did not have significant effects on GC availability for immune corticosensitive cells.

Changes in the components of moral reasoning during students' medical education: a pilot study.

INTRODUCTION: Many authors are concerned by students' moral reasoning not developing normally during medical education. AIM: This study is concerned with how the components of student' moral reasoning are affected by their medical studies. METHODS: Ninety-two medical students were tested on entry into first year and on finishing third year, to determine evolutionary changes in their moral reasoning. Changes in their use of arguments specific to each stage of moral development were measured. RESULTS: Significant changes were observed in the weighted global score (-18.14 +/- 59.17, P = 2.8%). Changes in global score correlated with changes in stages of moral reasoning. The multivariate structure of moral reasoning was reorganised into two principal components, which, respectively, explained almost 82% (first year) and 72% (third year) of the total variability in scores. Moral reasoning stages characterized by law-and-order and social-contract/legalistic orientations proved important for explaining the variability in students' moral reasoning at the start of medical training, while instrumental-relativist and interpersonal-concordance orientations explained variability post third year. CONCLUSIONS: Students restructure their handling of ethical questions by using arguments with more instrumental-relativist and interpersonal-concordance orientations, rather than those of the more desirable law-and-order or social-contract/legalistic type. To assess better the skills required for moral reasoning, a more sophisticated approach is needed than that of a simple measure of improvement/stagnation/deterioration.

Using clinical evaluation and lung scan to rule out suspected pulmonary embolism: Is it a valid option in patients with normal results of lower-limb venous compression ultrasonography?

BACKGROUND: In patients with a low clinical probability of pulmonary embolism (PE) and a nondiagnostic lung scan, the prevalence of PE is theoretically very low. We assessed the safety and usefulness of this association for ruling out PE. METHODS: We analyzed data from 2 consecutive cohort management studies performed in 2 university hospitals (Geneva University Hospital, Geneva, Switzerland, and Hospital Saint-Luc, Montreal, Quebec), which enrolled 1034 consecutive patients who came to the emergency department with clinically suspected PE. All patients were submitted to a sequential diagnostic protocol of lung scan, D-dimer testing, lower-limb venous compression ultrasonography (US), and pulmonary angiography in case of inconclusive results of noninvasive workup. RESULTS: The prevalence of PE was 27.6%. Empirical assessment was accurate for identifying patients with a low likelihood of PE (8.2% prevalence of PE in the low clinical probability category). One hundred eighty patients had a low clinical probability of PE and a nondiagnostic lung scan. Among these patients, US showed deep vein thrombosis in 5. Hence, PE could be ruled out by a low clinical probability, a nondiagnostic lung scan, and a normal US in 175 patients (21.5%). The 3-month thromboembolic risk in these patients was low (1.7%; 95% confidence interval, 0.4%-4.9%). CONCLUSIONS: Anticoagulant treatment could be safely withheld in patients with a low clinical probability of PE and a nondiagnostic lung scan, provided that the US is normal. This combination of findings avoided pulmonary angiography in 21.5% of patients with suspected PE in this series.

Non-invasive diagnosis of venous thromboembolism in outpatients.

BACKGROUND: We designed a simple and integrated diagnostic algorithm for acute venous thromboembolism based on clinical probability assessment of deep-vein thrombosis (DVT) or pulmonary embolism (PE), plasma D-dimer measurement, lower-limb venous compression ultrasonography, and lung scan to reduce the need for phlebography and pulmonary angiography. METHODS: 918 consecutive patients presenting at the emergency ward of the Geneva University Hospital, Geneva, Switzerland, and Hôpital Saint-Luc, Montreal, Canada, with clinically suspected venous thromboembolism were entered into a sequential diagnostic protocol. Patients in whom venous thromboembolism was deemed absent were not given anticoagulants and were followed up for 3 months. FINDINGS: A normal D-dimer concentration (<500 microg/L by a rapid ELISA) ruled out venous thromboembolism in 286 (31%) members of the study cohort, whereas DVT by ultrasonography established the diagnosis in 157 (17%). Lung scan was diagnostic in 80 (9%) of the remaining patients. Venous thromboembolism was also deemed absent in patients with low to intermediate clinical probability of DVT and a normal venous ultrasonography (236 [26%] patients), and in patients with a low clinical probability of PE and a non-diagnostic result on lung scan (107 [12%] patients). Pulmonary angiography and phlebography were done in only 50 (5%) and 2 (<1%) of the patients, respectively. Hence, a non-invasive diagnosis was possible in 866 (94%) members of the entire cohort. The 3-month thromboembolic risk in patients not given anticoagulants, based on the results of the diagnostic protocol, was 1.8% (95% CI 0.9-3.1). INTERPRETATION: A diagnostic strategy combining clinical assessment, D-dimer, ultrasonography, and lung scan gave a non-invasive diagnosis in the vast majority of outpatients with suspected venous thromboembolism, and appeared to be safe.

Clinical usefulness of intravenous human immunoglobulins in invasive group A Streptococcal infections: case report and review.

The spectrum of invasive Streptococcus pyogenes (group A streptococcus) infections includes bacteremia, toxic shock syndrome, and necrotizing fasciitis or myositis. We report the successful use of intravenous immunoglobulins in conjunction with antibiotics and surgery in a case of necrotizing myositis, toxic shock, and bacteremia. A literature review revealed that three other patients with invasive group A streptococcal infections had been treated with immunoglobulins: one adult patient had toxic shock syndrome, one had necrotizing fasciitis, and one child had septic arthritis. On the basis of this report and the review, we suggest that intravenous immunoglobulins may be useful in the treatment of all forms of invasive group A streptococcal infections associated with toxic shock syndrome.

[A new case of Urbach-Wiethe disease. Electron-microscopy study]. / Un nouveau cas de maladie d'Urbach Wiethe. Etude en microscopie électronique.

A new case of Urbach Wiethe disease is reported. The diagnosis of this disorder, despite the existence of typical histological connective tissue deposits, was recognized late. The authors review the morphological characteristics of the disease, emphasizing that atypical clinical presentations may occur which underline the importance of the histological examination.