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Le Kremlin-Bicêtre, France

Hamzaoui O.,Hopitaux universitaires Paris Sud | Teboul J.-L.,Hopitaux universitaires Paris Sud | Teboul J.-L.,University Paris - Sud | Teboul J.-L.,Center Hospitalier University Of Bicetre
Minerva Anestesiologica | Year: 2015

β-blockers are widely used to treat cardiovascular diseases and in the peri-operative period in selected patients. The main benefit in terms of morbidity and/or mortality of their use is believed to be linked to specific effects on myocardial oxygen supply/demand balance, to anti-arrhythmic effects and anti-inflammatory effects. Use of β-blockers in severe sepsis is still under debate and if any, their appropriate indications remain unclear. In this article, we analyze the recent literature addressing the metabolic, immuno-modulatory and hemodynamic effects of non cardio-selective and of cardio-selective β-blockers in experimental and human sepsis in order to help clarifying the potential place of these drugs in patients with severe sepsis. From this analysis, it appears that β-adrenoceptor blocking agents may represent a therapeutic approach in patients with severe sepsis, in whom catecholaminergic hyperactivity including excessive tachycardia is supposed to play an aggravating role. However, many questions about effectiveness, safety and cardio-selectivity of the drugs and about the appropriate target population remain partially unanswered. Recently, esmolol, a short-time acting β1-adrenoceptor blocker titrated to decrease heart rate below 95 beats/min was shown to exert beneficial effects in a monocentric randomized clinical trial including selected septic patients. Further large multicenter randomized trials are required to confirm the potential benefit of such a therapy in patients with severe sepsis. COPYRIGHT © 2015 EDIZIONI MINERVA MEDICA. Source

Tazarourte K.,Center Hospitalier Melun | Riou B.,University Pierre and Marie Curie | Tremey B.,Center Medico Chirurgical Ambroise Pare | Samama C.-M.,University of Paris Descartes | And 2 more authors.
Critical Care | Year: 2014

Introduction: In vitamin K antagonist (VKA)-treated patients with severe hemorrhage, guidelines recommend prompt VKA reversal with prothrombin complex concentrate (PCC) and vitamin K. The aim of this observational cohort study was to evaluate the impact of guideline concordant administration of PCC and vitamin K on seven-day mortality.Methods: Data from consecutive patients treated with PCC were prospectively collected in 44 emergency departments. Type of hemorrhage, coagulation parameters, type of treatment and seven-day mortality mortality were recorded. Guideline-concordant administration of PCC and vitamin K (GC-PCC-K) were defined by at least 20 IU/kg factor IX equivalent PCC and at least 5 mg of vitamin K performed within a predefined time frame of eight hours after admission. Multivariate analysis was used to assess the effect of appropriate reversal on seven-day mortality in all patients and in those with intracranial hemorrhage (ICH).Results: Data from 822 VKA-treated patients with severe hemorrhage were collected over 14 months. Bleeding was gastrointestinal (32%), intracranial (32%), muscular (13%), and " other" (23%). In the whole cohort, seven-day mortality was 13% and 33% in patients with ICH. GC-PCC-K was performed in 38% of all patients and 44% of ICH patients. Multivariate analysis showed a two-fold decrease in seven-day mortality in patients with GC-PCC-K (odds ratio (OR) = 2.15 (1.20 to 3.88); P = 0.011); this mortality reduction was also observed when only ICH was considered (OR = 3.23 (1.53 to 6.79); P = 0.002).Conclusions: Guideline-concordant VKA reversal with PCC and vitamin K within eight hours after admission was associated with a significant decrease in seven-day mortality. © 2014 Tazarourte et al.; licensee BioMed Central Ltd. Source

Davit-Spraul A.,University Paris - Sud | Gonzales E.,Pediatric Hepatology and National Reference Center for Biliary Atresia | Gonzales E.,University Paris - Sud | Baussan C.,University Paris - Sud | And 3 more authors.
Seminars in Liver Disease | Year: 2010

Class III multidrug resistance P-glycoproteins, Mdr2 in mice and MDR3 in human, are canalicular phospholipid translocators involved in biliary phospholipid (phosphatidylcholine) excretion. The role of an ABCB4 gene defect in liver disease has been initially proven in a subtype of progressive familial intrahepatic cholestasis called PFIC3, a severe pediatric liver disease that may require liver transplantation. Several ABCB4 mutations have been identified in children with PFIC3 and are associated with low level of phospholipids in bile leading to a high biliary cholesterol saturation index. ABCB4 mutations are associated with loss of canalicular MDR3 protein and /or loss of protein function. There is evidence that a biallelic or monoallelic ABCB4 defect causes or predisposes to several human liver diseases (PFIC3, low phospholipid associated cholelithiasis syndrome, intrahepatic cholestasis of pregnancy, drug-induced liver injury, transient neonatal cholestasis, adult biliary fibrosis, or cirrhosis). Most patients with MDR3 deficiency have a favorable outcome with ursodeoxycholic acid (UDCA) therapy, but some PFIC3 patients who do not respond to UDCA treatment still require liver transplantation. The latter should be good candidates for a targeted pharmacologic approach and/or to cell therapy in the future. © 2010 by Thieme Medical Publishers, Inc. Source

Sarfati J.,University Paris - Sud | Sarfati J.,French Institute of Health and Medical Research | Dode C.,French Institute of Health and Medical Research | Young J.,University Paris - Sud | Young J.,Center Hospitalier University Of Bicetre
Frontiers of Hormone Research | Year: 2010

Mutations in the prokineticin 2 peptide (PROK2) and its seven-transmembrane domain type 2 receptor PROKR2 are newly identified molecular culprits in autosomal Kallmann syndrome (KS). Prok2 and prokr2 gene knockout mice both have agenesis or hypoplasia of the olfactory bulbs, associated with hypogonadotropic hypogonadism linked to abnormal GnRH neuron migration. Prok2-/-and prokr2-/-mice are the first murine models of this human disease. KS patients of both sexes have a variety of point mutations, missense mutations, frameshifts and nonsense mutations in the PROK2 and PROKR2 genes that lead to a loss of peptide or receptor function. When only one allele is affected, penetrance of the two main clinical features of KS may be incomplete: subjects with only one mutant allele may have (1) no symptoms, with normal olfaction and complete pubertal development, (2) congenital isolated (idiopathic) hypogonadotropic hypogonadism (IHH) but normal olfaction, (3) anosmia/hyposmia but normal pubertal development and gonadal function or (4) the two cardinal clinical KS signs, anosmia and IHH. These phenotypic dissociations can be seen in family members with the same PROK2/PROKR2 mutations. By contrast, patients with two mutant alleles almost always have the cardinal signs of KS. Even when monoallelic PROK2/PROKR2 mutations are associated with full-blown KS, the reproductive phenotype in males is less severe than in KS associated with biallelic mutations, evidenced by significantly lower frequency of cryptorchidism and micropenis, greater testicular volume, and higher serum levels of LH, FSH and testosterone. Moreover, at least some of these monoallelic cases are in fact digenic, in that they also carry mutations of other KS/IHH genes. Overall, these observations point towards a combination of mendelian autosomal recessive transmission, with more complex oligogenic transmission. Patients with this genetic form of KS have been reported to have a possible increased prevalence of obesity and sleep disorders, which may be related to the role of PROK2 and PROKR2 in food intake and circadian rhythms. However, diurnal variation of serum cortisol levels appears to be physiologically maintained. Copyright © 2010 S. Karger AG, Basel. Source

Bouligand J.,University Paris - Sud | Ghervan C.,University of Medicine and Pharmacy, Cluj-Napoca | Guiochon-Mantel A.,University Paris - Sud | Young J.,University Paris - Sud | Young J.,Center Hospitalier University Of Bicetre
Frontiers of Hormone Research | Year: 2010

The neuropeptide gonadotropin-releasing hormone (GnRH) plays a key regulatory role in mammalian reproduction. It is synthesized by hypothalamic neurons and released from nerve endings into the portal circulation. After binding to membrane GnRH type 1 receptors on gonadotropic cells of the anterior pituitary, it stimulates the synthesis and release of luteinizing hormone and follicle-stimulating hormone. These two peptides travel through the general circulation to the gonads, where they stimulate the synthesis and secretion of sex steroid hormones and trigger gametogenesis. The discovery in 1977 of a hypogonadal mouse lacking GnRH (hpg mice) and, in 1986, that the gnrh1 gene was deleted in this mouse, suggested that GNRH1 mutations might also cause human congenital idiopathic (or isolated) hypogonadotropic hypogonadism. This was finally demonstrated in 2009. Copyright © 2010 S. Karger AG, Basel. Source

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