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

Five distinct biological processes and 14 differentially expressed genes characterize TEL/AML1-positive leukemia

<p>Abstract</p> <p>Background</p> <p>The t(12;21)(p13;q22) translocation is found in 20 to 25% of cases of childhood B-lineage acute lymphoblastic leukemia (B-ALL). This rearrangement results in the fusion of <it>ETV6 </it>(<it>TEL</it>) and <it>RUNX1 </it>(<it>AML1</it>) genes and defines a relatively uniform category, although only some patients suffer very late relapse. <it>TEL/AML1</it>-positive patients are thus an interesting subgroup to study, and such studies should elucidate the biological processes underlying TEL/AML1 pathogenesis. We report an analysis of gene expression in 60 children with B-lineage ALL using Agilent whole genome oligo-chips (44K-G4112A) and/or real time RT-PCR.</p> <p>Results</p> <p>We compared the leukemia cell gene expression profiles of 16 <it>TEL/AML1</it>-positive ALL patients to those of 44 <it>TEL/AML1</it>-negative patients, whose blast cells did not contain any additional recurrent translocation. Microarray analyses of 26 samples allowed the identification of genes differentially expressed between the TEL/AML1-positive and negative ALL groups. Gene enrichment analysis defined five enriched GO categories: cell differentiation, cell proliferation, apoptosis, cell motility and response to wounding, associated with 14 genes -<it>RUNX1, TCFL5, TNFRSF7, CBFA2T3</it>, <it>CD9</it>, <it>SCARB1, TP53INP1, ACVR1C, PIK3C3, EGFL7</it>, <it>SEMA6A, CTGF, LSP1, TFPI </it>– highlighting the biology of the <it>TEL/AML1 </it>sub-group. These results were first confirmed by the analysis of an additional microarray data-set (7 patient samples) and second by real-time RT-PCR quantification and clustering using an independent set (27 patient samples). Over-expression of <it>RUNX1 (AML1) </it>was further investigated and in one third of the patients correlated with cytogenetic findings.</p> <p>Conclusion</p> <p>Gene expression analyses of leukemia cells from 60 children with <it>TEL/AML1</it>-positive and -negative B-lineage ALL led to the identification of five biological processes, associated with 14 validated genes characterizing and highlighting the biology of the <it>TEL/AML1</it>-positive ALL sub-group.</p

[Antivitamins K].

International audienc

[Indications for anticoagulants].

International audienceAnticoagulant therapy includes heparin, either unfractionned or of low molecular weight, danaparoid, vitamin K antagonists and direct thrombin inhibitors. Low molecular weight heparins are now the cornerstone of venous thromboembolism prevention in surgery, and once daily regimen is available for the treatment of acute deep vein thrombosis. Vitamin K antagonists are mostly used for secondary prevention of venous thromboembolism and for primary prevention of arterial embolism in patients with permanent atrial fibrillation or with cardiac prosthetic valve. Thrombotic complications of heparin-induced thrombocytopenia are prevented and treated by direct thrombin inhibitors or danaparoid

[Deep venous thrombosis and pulmonary embolism].

International audienc

[Current status of anticoagulants].

International audienceINDICATIONS: Direct inhibitors of thrombin, such as hirudin, are directed against the active site and the recognition site of thrombin. Because of their low-molecular-weight, they can inactivate thrombin bound to fibrin. Prevention of thromboembolic complications in patients undergoing primary total hip or knee replacement is now an authorized indication of desirudin in France. The recommended treatment for heparin-induced thrombocytopenia is lepirudin when there is a clinically evident thrombosis and danaparoid sodium, a mixture of anticoagulant glycosaminoglycans in an antithrombotic prophylaxis setting. LMWH: Low-molecular weight heparins are not yet authorized in France for the treatment of pulmonary embolism. However, deep venous thrombosis can be securely treated with one daily fixed dose of nadroparin or tinzaparin. ORAL ANTICOAGULATION: The duration of anticoagulation therapy in patients with venous thromboembolism remains controversial. Three to six months of therapy is recommended after a first episode of venous thromboembolism; the shorter regimen may be chosen when there is an identifiable and transient risk factor, and the longer when the thrombosis is idiopathic. In the context of primary prevention of ischaemic heart disease low intensity oral anticoagulation could be recommended in men at high risk

Fausses couches et morts fœtales inexpliquées (des mécanismes aux traitements)

Les pertes foetales inexpliquées constituent un sujet de préoccupation pour médecins et couples, tant au plan des investigations que des traitements. Par analogie avec le syndrome des antiphospholipides, l étude des déterminants thrombophiliques génétiques connaît un vif succès depuis une dizaine d années. Néanmoins, leur implication est controversée. Ont été initiés 3 projets de recherche complémentaires: 1/ Une étude cas témoins incidente pour étayer l hypothèse d un état prothrombotique et explorer d autres pistes étiologiques, dont le rôle d un dysfonctionnement endothélial. Les cas (311 femmes/284 couples) ont eu au moins une mort in utero après la 21ème semaine d aménorrhée ou au moins deux pertes consécutives plus précoces, sans cause identifiée. Les témoins (600 femmes!297 couples) avec enfant, sans perte foetale ont été recrutés à partir des listes électorales. Aucune association n est retrouvée entre perte foetale et -facteur V Leiden ou mutation G20210A de la prothrombine chez l un des membres du couple, -I inactivation préférentielle d un X chez la femme. Génération de thrombine, microparticules endothéliales, lipoprotéine(a), forme soluble de l adhésine endothéliale CD146et de la chémokine fractalkine sont significativement augmentées chez les femmes cas alors que les microparticules plaquettaires sont diminuées. 2/ Une enquête de cohorte des femmes incluses dans l étude 1/. Des antécédents familiaux d hypertension artérielle et des taux élevés de microparticules leucocytaires sont des facteurs prédictifs de récidive. 3/ Un essai thérapeutique multicentrique randomisé eu double insu, énoxaparine versus placebo dans les fausses couches spontanées inexpliquées est en cours depuis mars 2007.There are no clear guidelines for investigations and therapeutic interventions in unexplained pregnancy loss. A parallel has been drawn with the antiphospholipid syndrome. Thus, since the 1990s, inherited thrombophilias have been explored with great enthusiasm. However, since an initial impressive impact, a critical] appraisal of this issue is steadily growing. We successively initiated 3 studies: 1/ an incident case-control study designed to support the implication of a prothrombic state and to explore other mechanisms such as an endothelial dysfunction. 311 women (284 couples) have been referred for unexplained pregnancy losses (2 or more consecutive losses at or before 21 weeks of gestation, or at least one later loss): 600 control women (297 couples) with no pregnancy loss and at least one living child have been recruited using electoral lists. We did not find any association between unexplained pregnancy loss and - maternal or paternal factor V Leiden and Prothrombin G20210A mutations, - highly skewed X chromosome maternal inactivation. The thrombin generation, the endothelial microparticules, the plasma level of lipoprotein(a), CD 146 soluble form (endothelial adhesin) and fractalkine (CX3 chemokine) are ah significantly increased in female cases whereas platelet microparticles are lower than in controls. 2/ a prospective cohort study of the women included in 1/. Familial hypertension and high levels of leukocyte microparticles are risk factors for miscarriage recurrence. 3/ a double-blind placebo-control trial, studying enoxaparin in unexplained recurrent miscarriages (since March 2007).BREST-BU Médecine-Odontologie (290192102) / SudocSudocFranceF

[Value and role of clinical findings in the diagnosis of pulmonary embolism].

International audienceThe value and role of clinical findings in the diagnosis of pulmonary embolism were analysed in the three steps of clinical reasoning: firstly, they lead the physician to suspect the diagnosis; however, no sign or association of clinical signs allow confirmation or infirmation of the diagnosis; they are simply a guide to diagnosis; secondly, they contribute to the exclusion of a number of differential diagnoses, with the help of simple complementary investigations such as blood gases, electrocardiograms and chest X-ray; finally, when grouped together and expressed in terms of probability, clinical data are essential for the interpretation of pulmonary scintigraphy and for assessing the indications of further investigations

Incidence of venous thromboembolism: a community-based study in Western France. EPI-GETBP Study Group. Groupe d'Etude de la Thrombose de Bretagne Occidentale.

International audienceThe incidence of venous thromboembolism has been studied during one year in a defined population of 342,000 inhabitants. The overall incidence (95% confidence interval) of venous thromboembolism was found to be 1.83 per thousand per year (1.69 to 1.98). The incidences of deep venous thrombosis and pulmonary embolism were 1.24 per thousand per year (1.12 to 1.36) and 0.60 per thousand per year (0.52 to 0.69), respectively. The incidence of venous thromboembolism rose markedly with increasing age for both sexes; over the age of 75, the annual incidence reached 1 per 100. Sixty three percent of the patients were at home when venous thromboembolism occurred. Of these, sixteen percent had been previously hospitalised within three months. These results raise concerns on identification of medical patients at high risk and effective prophylaxis