Impact of metabolic perturbation on ovarian function

Metabolic perturbations including hyperinsulinemia that are induced during obesity and heat stress in humans and production animals are allied with several health hallmarks and impaired fertility. This dissertation research focused on charactering the impact of changes to central metabolism on ovarian function. We hypothesized that hyperinsulinemia induced during central metabolic perturbations, alters ovarian insulin-mediated PI3K signaling, negatively impacting ovarian folliculogenesis, steroidogenesis and xenobiotic biotransformation. To test this hypothesis, mRNA and protein expression profiles of insulin, PI3K, steroidogenic, inflammatory and chemical metabolism members were quantified using qRT-PCR, Western blotting or immunohistochemistry techniques using three models of hyperinsulinemia: 1) high fat diet (HFD)-induced obesity, 2) a transgenic mouse model of progressive obesity and 3) a porcine model of hyperinsulinemia. Overall, our data demonstrates that the ovarian insulin-KITLG-KIT-AKT signaling pathway is active and upregulated during central metabolic alterations. Perturbations to ovarian insulin-KITLG-KIT-AKT signaling pathway are likely to impact 1) follicle activation, oocyte viability and recruitment, 2) steroid hormone biosynthesis, and 3) xenobiotic biotransformation, potentially accelerating susceptibility to chemical exposure. All of these scenarios could lead to impairment of ovarian function, and may at least partially explain why female fecundity is compromised during altered metabolic states

Venous thromboembolism prevention in intracerebral hemorrhage: A systematic review and network meta-analysis

IntroductionTo summarize and compare the effectiveness of pharmacological thromboprophylaxis to pneumatic compression devices (PCD) for the prevention of venous thromboembolism in patients with acute intracerebral hemorrhage.MethodsMEDLINE, PUBMED, EMBASE, and CENTRAL were systematically searched to identify randomized and non-randomized studies that compared each intervention directly to each other or against a common control (hydration, anti-platelet agents, stockings) in adults with acute spontaneous intracerebral hemorrhage. Two investigators independently screened the studies, extracted data, and appraised risk of bias. Studies with a high risk of bias were excluded from our final analysis. The primary outcome was the occurrence of venous thromboembolism (proximal deep vein thrombosis or pulmonary embolism) in the first 30 days.Results8,739 articles were screened; four articles, all randomized control trials, met eligibility criteria. Bayesian network meta-analysis was performed to calculate risk estimates using both fixed and random effects analyses. 607 patients were included in the network analysis. PCD were associated with a significant decrease in venous thromboembolism compared to control (OR: 0.43, 95% Credible Limits [CrI]: 0.23-0.80). We did not find evidence of statistically significant differences between pharmacological thromboprophylaxis and control (OR: 0.93, 95% CrI: 0.19-4.37) or between PCD and pharmacological thromboprophylaxis (OR: 0.47, 95% CrI: 0.09-2.54).ConclusionPCDs are superior to control interventions, but meaningful comparisons with pharmacotherapy are not possible due to a lack of data. This requires further exploration via large pragmatic clinical trials.Trial registrationPROSPERO: CRD42018090960

Association between antipsychotic drugs, antidepressant drugs, and venous thromboembolism.

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[Mechanical prophylaxis of venous thromboembolism].

International audienceMechanical devices for the prevention of venous thromboembolism (VTE) act on venous stasis and include static systems: the graduated compression stockings (or elastic stockings or anti-embolism stockings) and dynamical systems: intermittent pneumatic compression and venous foot pump. The main advantage of these devices is that they have no risk of bleeding. If the prevention of VTE is based primarily on drug prophylaxis, mechanical devices are recommended primarily for patients with high risk of bleeding, if there is contraindication to anticoagulants. Alone or in combination with drug prophylaxis, their efficacy on deep vein thrombosis prevention is well documented in surgery, but the evidence is insufficient for the prevention of pulmonary embolism and in other settings. Their interest in stroke is called into question after the results of the CLOTS 1 and 2 studies. These results, beyond the context of stroke, have raised numerous questions about the real benefit/risk ratio of mechanical devices for the prevention of VTE. They highlight the need to assess or re-evaluate mechanical devices by rigorous clinical trials

[Hormone therapy and risk for venous thromboembolism in postmenopausal women].

International audienceOral estrogens are associated with a two-fold to three-fold increased risk of venous thromboembolism in postmenopausal women. Absolute excess risk is low but higher than for contraceptive pills. Biological data and observational studies suggest that transdermal estrogens are associated with a lower risk for venous thromboembolism than oral estrogens but safety has yet to be proved. Whether addition of progestin plays a significant role is undetermined so far

Primary prevention of venous thromboembolism in elderly medical patients

Karine Lacut, Grégoire Le Gal, Dominique MottierGETBO EA 3878, CHU de Brest, Department of Internal Medicine and Chest Diseases, Hôpital Cavale Blanche, Brest, FranceAbstract: Primary prophylaxis with the use of an effective and safe intervention appears the best approach of venous thromboembolism (VTE) management in medical elderly patients, the most affected by VTE. With increasing life expectancy, prevention of VTE, particularly in elderly patients, will arise as a major public health problem. Few well designed clinical trials evaluating thromboprophylaxis in medical settings were conducted in the specific population of geriatric patients. However, among the several pharmacological treatments evaluated, low molecular weight heparins enoxaparin 40 mg daily or dalteparin 5000 IU daily appeared effective and safe in the prevention of VTE in elderly patients. Despite available data, and recommendations for VTE prevention in medical patients, thromboprophylaxis is underused or misused in practice. Heterogeneity of clinical studies, selected populations, concern about bleeding, and lack of a clear clinical benefit are some of the reasons that could explain the gap between theory and practice. In this review, after a brief report of epidemiologic data and specificities of VTE in elderly patients, the authors discuss the available results of VTE primary prevention trials for elderly medical patients, the limitations of these data, and the challenges to improve the practice and to reduce the incidence of this frequent but preventable disease.Keywords: venous thromboembolism, prophylaxis, elderly patients, medical settings, revie

[Aspirin for secondary prevention of venous thromboembolism. WARFASA: Far from being conclusive.]

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[Do observational studies have a role in assessing treatment?].

International audienceCase-control and cohort studies are the two principal types of observational studies. Case-control studies compare a group of patients with a given disease and a group of subjects without it (controls). An association between the risk factor tested (which may be a drug) and the disease is assessed by comparing the frequency of exposure to this risk factor in each group. In a cohort study, a large group of subjects initially free from the disease is followed over time. Exposure is assessed at the beginning of the study. The risk factor is associated with the disease if the incidence of the disease during follow-up is higher among exposed than non-exposed subjects. Associations observed in observational studies cannot be considered causal, in contrast to those in randomized controlled trials. Observational studies generate hypotheses that must be formally tested in randomized trials, even when all the elements supporting causality (dose-effect relation, biological plausibility, strength and independence of the association) are present. In trials, randomization, blinding and intention-to-treat analysis allow assessment of initial and secondary comparability between the two groups, so that any difference between the two groups can be attributed to the intervention or agent tested

[Deep venous thrombosis: epidemiology, acquired risk factors].

International audienceDeep vein thrombosis is a frequent disease with an annual incidence reaching 5 per thousand among subjects over 75 years. Major acquired risk factors for venous thrombosis include surgery, neoplasm, reduced mobility or paresis, and a previous episode of deep vein thrombosis. Among women, hormonal status (pregnancy, oral contraceptive, hormone replacement therapy) is responsible for the majority of all venous thrombotic events. The impact of other factors is controversial: obesity, tobacco use and varicose veins. Venous thrombosis is a multifactorial disease and analysis of the interactions between acquired and inherited risk factors is an extremely interesting field of investigation