Inhibition of myocardial reperfusion injury by ischemic postconditioning requires sirtuin 3-mediated deacetylation of cyclophilin D.

RATIONALE: How ischemic postconditioning can inhibit opening of the mitochondrial permeability transition pore (PTP) and subsequent cardiac myocytes death at reperfusion remains unknown. Recent studies have suggested that de-acetylation of cyclophilin D (CyPD) by sirtuin 3 (SIRT3) can modulate its binding to the PTP. OBJECTIVE: The aim of the present study was to examine whether ischemic postconditioning (PostC) might activate SIRT3 and consequently prevent lethal myocardial reperfusion injury through a deacetylation of CyPD. METHODS AND RESULTS: Using hypoxia-reoxygenation (H/R) in H9C2 cells, we showed that SIRT3 overexpression prevented CyPD acetylation, limited PTP opening and reduced cell death by 24%. In vitro modification of the CyPD acetylation status in MEFs by site-directed mutagenesis altered capacity of PTP opening by calcium. Calcium Retention Capacity (CRC) was significantly decreased with CyPD-KQ that mimics acetylated protein compared with CyPD WT (871 ± 266 vs 1193 ± 263 nmoles Ca(2+)/mg protein respectively). Cells expressing non-acetylable CyPD mutant (CyPD-KR) displayed 20% decrease in cell death compared to cells expressing CyPD WT after H/R. Correspondingly, in mice we showed that cardiac ischemic postconditioning could not reduce infarct size and CyPD acetylation in SIRT3 KO mice, and was unable to restore CRC in mitochondria as it is observed in WT mice. CONCLUSIONS: Our study suggests that the increased acetylation of CyPD following myocardial ischemia-reperfusion facilitates PTP opening and subsequent cell death. Therefore ischemic postconditioning might prevent lethal reperfusion injury through an increased SIRT3 activity and subsequent attenuation of CyPD acetylation at reperfusion.

Thiazolidinediones partially reverse the metabolic disturbances observed in Bscl2/seipin-deficient mice.

AIMS/HYPOTHESIS: Mutations in BSCL2/seipin cause Berardinelli-Seip congenital lipodystrophy (BSCL), a rare recessive disorder characterised by near absence of adipose tissue and severe insulin resistance. We aimed to determine how seipin deficiency alters glucose and lipid homeostasis and whether thiazolidinediones can rescue the phenotype. METHODS: Bscl2 (-/-) mice were generated and phenotyped. Mouse embryonic fibroblasts (MEFs) were used as a model of adipocyte differentiation. RESULTS: As observed in humans, Bscl2 (-/-) mice displayed an early depletion of adipose tissue, with insulin resistance and severe hepatic steatosis. However, Bscl2 (-/-) mice exhibited an unexpected hypotriglyceridaemia due to increased clearance of triacylglycerol-rich lipoproteins (TRL) and uptake of fatty acids by the liver, with reduced basal energy expenditure. In vitro experiments with MEFs demonstrated that seipin deficiency led to impaired late adipocyte differentiation and increased basal lipolysis. Thiazolidinediones were able to rescue the adipogenesis impairment but not the alteration in lipolysis in Bscl2 (-/-) MEFs. In vivo treatment of Bscl2 (-/-) mice with pioglitazone for 9 weeks increased residual inguinal and mesenteric fat pads as well as plasma leptin and adiponectin concentrations. Pioglitazone treatment increased energy expenditure and improved insulin resistance, hypotriglyceridaemia and liver steatosis in these mice. CONCLUSIONS/INTERPRETATION: Seipin plays a key role in the differentiation and storage capacity of adipocytes, and affects glucose and lipid homeostasis. The hypotriglyceridaemia observed in Bscl2 (-/-) mice is linked to increased uptake of TRL by the liver, offering a new model of liver steatosis. The demonstration that the metabolic complications associated with BSCL can be partially rescued with pioglitazone treatment opens an interesting therapeutic perspective for BSCL patients.

[4 years using clozapine in community psychiatry]. / Quatre ans d'utilisation de la clozapine en psychiatrie de secteur.

This study report clinical experience of Clozapine treatment in 48 chronic schizophrenic patients. At the study time, 35 patients are still under this treatment while 13 patients have stopped it. These two populations and their differences are presented. Clozapine experience is positive as testifies quality of life and social situation improvement in numerous cases.

[Evaluation of the socioeconomic costs of cutaneous leishmaniasis in French Guiana]. / Evaluation du coût socio-économique de la leishmaniose cutanée en Guyane française.

The socio-economic cost of leishmaniasis in French Guiana was estimated using a retrospective survey spreading over a period of one year: 1979-80. The financial cost elements taken into account were the following: dermatological consultations, biological tests, treatments and hospitalisation days. Other elements were not evaluated, such as days of military hospital stays, work days suspended and unavailability of service. The cost of leishmaniasis represented 0.13% of the general budget of French Guiana and 0.43% of the global budget of the French Guiana Social Security.

[Prolonged delta antigen in the blood without occurrence of anti-delta antibodies in 2 immunosuppressed patients]. / Antigénémie delta prolongée sans apparition d'anticorps anti-delta chez deux patients immunodéprimés.

Delta coinfection or superinfection in a patient with chronic hepatitis B is characterized by a very transient delta antigenemia and an early seroconversion of IgM to IgG anti-delta. The persistent expression of delta antigen in the liver can be associated with acute, severe, or chronic hepatitis. In our two patients, delta antigenemia persisted respectively 10 weeks and 14 months with aggravation of liver histopathologic lesions without seroconversion. Such a serologic profile during delta infection does not seem to have been reported previously. These two cases concerned two patients with an important immunosuppression, one by a major immunosuppressive therapy and HIV superinfection, the other by an acquired immunodeficiency syndrome. The cytotoxic effect of delta virus in such circumstances is discussed.