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Chenu C.,Toulouse University Hospital Center
Arteriosclerosis, Thrombosis, and Vascular Biology | Year: 2017

OBJECTIVE—: Chronic nonhealing wounds are a substantial medical concern and are associated with morbidity and mortality; thus, new treatment strategies are required. The first step toward personalized/precision medicine in this field is probably in taking sex differences into account. Impaired wound healing is augmented by ischemia, and we previously demonstrated that 17β-estradiol exerts a major preventive effect against ischemia-induced skin flap necrosis in female mice. However, the equivalent effects of testosterone in male mice have not yet been reported. We then investigated the role of steroid hormones in male mice using a skin flap ischemia model. APPROACH AND RESULTS—: Castrated male mice developed skin necrosis after ischemia, whereas intact or castrated males treated with testosterone were equally protected. Testosterone can (1) activate the estrogen receptor after its aromatization into 17β-estradiol or (2) be reduced into dihydrotestosterone, a nonaromatizable androgen that activates the androgen receptor. We found that dihydrotestosterone protected castrated WT mice by promoting skin revascularization, probably through a direct action on resistance arteries, as evidenced using a complementary model of flow-mediated outward remodeling. 17β-estradiol treatment of castrated male mice also strongly protected them from ischemic necrosis through the activation of estrogen receptor-α by increasing skin revascularization and skin survival. Remarkably, 17β-estradiol improved skin survival with a greater efficiency than dihydrotestosterone. CONCLUSIONS—: Testosterone provides males with a strong protection against cutaneous necrosis and acts through both its estrogenic and androgenic derivatives, which have complementary effects on skin survival and revascularization. © 2017 American Heart Association, Inc.

Kamar N.,Toulouse University Hospital Center | Kamar N.,University Paul Sabatier
Transplantation | Year: 2012

Background: Hepatitis E virus (HEV) infection is an emerging disease in industrialized countries. Few data regarding genotype 3 HEV extrahepatic manifestations exist. Methods: We assessed kidney function and histology in solid-organ transplant patients during HEV infection. In all, 51 cases of genotype 3 HEV infections were diagnosed (34 kidney, 14 liver, and 3 kidney-pancreas transplant patients). Of these, 43.2% were cleared of the virus spontaneously within 6 months of infection, whereas 56.8% evolved to chronic hepatitis. Twelve of these patients completed a 3-month antiviral therapy and were followed up for 6 months posttreatment. Kidney function (estimated glomerular filtration rate [eGFR] obtained by the Modification of Diet in Renal Disease equation) and proteinuria were assessed before infection, during HEV infection and during follow-up. Kidney biopsies were obtained from patients with high proteinuria and decreased eGFR levels. Results: During HEV infection, there was a significant decrease in eGFR in both kidney-and liver-transplant patients. Glomerular diseases were observed in kidney biopsies obtained during the acute and chronic phases. This included membranoproliferative glomerulonephritis and relapses in IgA nephropathy. The majority of patients had cryoglobulinemia that became negative after HEV clearance. Kidney function improved and proteinuria decreased after HEV clearance. Conclusion: HEV-associated glomerulonephritis seems to be an HEV-related extrahepatic manifestation. Further studies are required to confirm these observations. Copyright © 2012 by Lippincott Williams & Wilkins.

Minville V.,Toulouse University Hospital Center
British journal of anaesthesia | Year: 2011

The aim of this study was to assess any interaction between ondansetron and paracetamol on a model of post-fracture pain in mice. In protocol A, after fracture of the tibia, mice were assigned to four groups: paracetamol 30 mg kg 1, paracetamol 50 mg kg 1, paracetamol 100 mg kg 1, or a saline vehicle i.p. In protocol B, after fracture of the tibia, mice were randomized to receive either paracetamol (100 mg kg 1) plus saline (vehicle), paracetamol (100 mg kg 1) plus ondansetron (1 mg kg 1), paracetamol (100 mg kg 1) plus ondansetron (2 mg kg 1), saline plus ondansetron (2 mg kg 1), or saline plus saline i.p. Three tests were used to assess pain behaviour: von Frey filament application, hot-plate test, and a subjective pain scale. Rescue analgesia with morphine was administered as necessary. In protocol A, paracetamol (100 mg kg 1)-treated animals had less mechanical nociception, thermal nociception, and a lower subjective pain scale rating, when compared with those receiving paracetamol at 30 or 50 mg kg 1 or saline [ED paracetamol=46.3 (6.34) mg kg 1]. No difference was found between paracetamol (30 mg kg 1) and saline-treated animals. In protocol B, the mechanical withdrawal threshold, the thermal withdrawal latency, and the subjective pain scale were lower after injection of paracetamol (100 mg kg 1)+saline, paracetamol (100 mg kg 1)+ondansetron (1 mg kg 1), and paracetamol (100 mg kg 1)+ondansetron (2 mg kg 1), whereas in mice receiving saline+ondansetron (2 mg kg 1) or saline+saline, there was no difference. We found that paracetamol 100 mg kg 1 blocked the development of hyperalgesia and allodynia after fracture pain and ondansetron did not modify the antinociceptive effect of paracetamol in this model.

Hanaire H.,Toulouse University Hospital Center
Diabetes and Metabolism | Year: 2011

The aim of diabetes treatment is to achieve tight glucose control to avoid the development of chronic diabetes complications while reducing the frequency of hypoglycaemic episodes. The main clinical indications of pump therapy in type 1 diabetes are persistently elevated HbA 1c in spite of the best attempts of intensified insulin therapy with multiple daily injections (MDI) and/or frequent, disabling or severe hypoglycaemia. Several trials have demonstrated the superiority of continuous subcutaneous insulin infusion (CSII) over MDI, and highlighted the benefits of using short-acting insulin analogues. However, new MDI regimens with long-acting insulin analogues challenge insulin pump therapy in some indications, thus indicating the need for precise selection of those patients who will benefit the most from CSII. In type 2 diabetes, pump therapy may be an invaluable tool in selected patients characterized by chronic elevation of HbA 1c, obesity and high insulin requirements. In addition, in any case, specific education, training and ongoing evaluation of the benefit/risk ratio of the treatment are mandatory. Furthermore, there is continuing progress in the development of pump and catheter features, and insulin kinetics can still be improved. These technical advances are part of the work in progress towards developing closed-loop systems. © 2011 Elsevier Masson SAS.

BACKGROUND: The accumulation of beta amyloid (Aβ) peptides, a hallmark of Alzheimer's disease (AD) is related to mechanisms leading to neurodegeneration. Among its pleiotropic cellular effects, Aβ accumulation has been associated with a deregulation of sphingolipid metabolism. Sphingosine 1-phosphate (S1P) derived from sphingosine is emerging as a critical lipid mediator regulating various biological activities including cell proliferation, survival, migration, inflammation, or angiogenesis. S1P tissue level is low and kept under control through equilibrium between its synthesis mostly governed by sphingosine kinase-1 (SphK1) and its degradation by sphingosine 1-phosphate lyase (SPL). We have previously reported that Aβ peptides were able to decrease the activity of SphK1 in cell culture models, an effect that could be blocked by the prosurvival IGF-1/IGF-1R signaling.RESULTS: Herein, we report for the first time the expression of both SphK1 and SPL by immunohistochemistry in frontal and entorhinal cortices from 56 human AD brains. Immunohistochemical analysis revealed a decreased expression of SphK1 and an increased expression of SPL both correlated to amyloid deposits in the entorhinal cortex. Otherwise, analysis of brain tissue extracts showed a decrease of SphK1 expression in AD brains whereas SPL expression was increased. The content of IGF-1R, an activator of SphK1, was found decreased in AD brains as well as S1P1, the major receptor for S1P.CONCLUSIONS: Collectively, these results highlight the importance of S1P in AD suggesting the existence of a global deregulation of S1P signaling in this disease from its synthesis by SphK1 and degradation by SPL to its signaling by the S1P1 receptor.

Chollet F.,Toulouse University Hospital Center
Dialogues in Clinical Neuroscience | Year: 2013

Brain plasticity is an intrinsic characteristic of the nervous system that allows continuous remodeling of brain functions in pathophysiological conditions. Although normal aging is associated with morphological modifications and decline of cerebral functions, brain plasticityis at least partially preserved in elderly individuals. A growing body of evidence supports the notion that cognitive enrichment and aerobic training induce a dynamic reorganization of higher cerebral functions, thereby helping to maintain operational skills in the elderly and reducing the incidence of dementia. The stroke model clearly shows that spontaneous brain plasticity exists after a lesion, even in old patients, and that it can be modulated through external factors like rehabilitation and drugs. Whether drugs can be used with the aim of modulating the effects of physical training or cognitive stimulation in healthy aged people has not been addressed until now. The risk:benefit ratio will be the key question with regard to the ethical aspect of this challenge. We review in this article the main aspects of human brain plasticityas shown in patients with stroke, the drug modulation of brain plasticity and its consequenceson recovery, and finally we address the question of the influence of aging on brain plasticity. © 2013 LLS SAS.

French Institute of Health, Medical Research, Aix - Marseille University and Toulouse University Hospital Center | Date: 2014-08-29

The present invention relates to a compound which is an agonist of the oxytocin receptor o for use in the treatment of a feeding disorder with early-onset. In a particular embodiment, the agonist of the oxytocin receptor is the oxytocin or an active fragment thereof.

Toulouse University Hospital Center, French Institute of Health and Medical Research | Date: 2012-04-02

The present invention relates to a method, in particular an in vitro method, for predicting a risk of onset of abdominal obesity in a subject, which method comprises the steps of: a1) measuring the concentration of bacterial 16S rDNA in a biological sample of said subject; and b) based on the result of the measurement in step a1), determining a risk of onset of abdominal obesity in the subject.

Toulouse University Hospital Center, French Institute of Health and Medical Research | Date: 2012-04-02

The present invention relates to the use of the bacterial flora for vaccine development, identification of therapeutic targets and prediction and/or diagnosis of metabolic diseases, such as diabetes, overweight and obesity, and their cardiovascular complications. In particular, the present invention provides immunogenic or vaccinal composition for preventing metabolic diseases and cardiovascular complications using attenuated or inactivated bacterial flora, or antigens derived thereof. The present invention also provides methods for identifying prognostic markers for metabolic diseases onset and cardiovascular complications and methods for in vitro prognosis of metabolic diseases and cardiovascular complications using bacterial flora.

Toulouse University Hospital Center, French Institute of Health and Medical Research | Date: 2012-04-02

The present invention relates to an in vitro method, for predicting a risk of onset of type 2 diabetes in a subject, which method comprises the steps of: a) measuring the concentration of bacterial 16S rDNA in a biological sample of said subject; and b) comparing said measured concentration of bacterial 16S rDNA to a threshold level; wherein a measured concentration of bacterial 16S rDNA higher than the threshold level is indicative of an increased risk of onset of type 2 diabetes in the subject, and a measured concentration of bacterial 16S rDNA lower than the threshold level is indicative of a decreased risk of onset of type 2 diabetes in the subject.

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