[Nosocomial infections with regard to medical liability]. / Les infections nosocomiales au regard de la responsabilité médicale.

Nosocomial infections in the light of medical liability. The law of March 4, 2002 unified in France the various liability regimes for nosocomial infections without, however, terminating the previous regimes which still apply in special circumstances. Currently, if the doctor is only liable in case of fault, healthcare establishments are still subjected to a strict system of full liability, from which they can only be exempted by providing the difficult proof of an external cause. A public body, Oniam, has to take care of the most serious infections, without prejudice to any recourse against the professional or the health establishment in case of misconduct.

Les infections nosocomiales au regard de la responsabilité médicale. La loi du 4 mars 2002 a unifié en France les différents régimes de responsabilité en matière d'infections nosocomiales sans mettre fin, pour autant, aux régimes antérieurs qui s'appliquent encore dans des circonstances particulières. Actuellement, si le médecin n'est responsable qu'en cas de faute, les établissements de santé restent soumis à un strict régime de responsabilité de plein droit, dont ils ne peuvent s'exonérer qu'en rapportant la preuve difficile d'une cause étrangère. Un organisme public, l'Oniam, étant tenu de prendre en charge les infections les plus graves, sans préjudice d'un éventuel recours contre le professionnel ou l'établissement de santé en cas de faute.

Glycation abolishes the cardioprotective effects of albumin during ex vivo ischemia-reperfusion.

Hyperglycemia-induced oxidative stress plays a key role in the onset/progression of cardiovascular diseases. For example, it can trigger formation of advanced glycation end (AGE) products with ischemia-reperfusion performed under hyperglycemic conditions. For this study, we hypothesized that albumin modified by glycation loses its unique cardioprotective properties in the setting of ischemia-reperfusion under high glucose conditions. Here, ex vivo rat heart perfusions were performed under simulated normo- and hyperglycemic conditions, that is Krebs-Henseleit buffer containing 11 mmol/L and 33 mmol/L glucose, respectively, ± normal or glycated albumin preparations. The perfusion protocol consisted of a 60 min stabilization step that was followed by 20 min of global ischemia and 60 min reperfusion. Additional experiments were completed to determine infarct sizes in response to 20 min regional ischemia and 120 min reperfusion. At the end of perfusions, heart tissues were isolated and evaluated for activation of the AGE pathway, oxidative stress, and apoptosis. Our data reveal that native bovine serum albumin treatment elicited cardioprotection (improved functional recovery, decreased infarct sizes) under high glucose conditions together with enhanced myocardial antioxidant capacity. However, such protective features are lost with glycation where hearts displayed increased infarct sizes and poor functional recovery versus native albumin treatments. Myocardial antioxidant capacity was also lowered together with activation of the intracellular AGE pathway. These data therefore show that although albumin acts as a cardioprotective agent during ischemia-reperfusion, it loses its cardioprotective and antioxidant properties when modified by glycation.

Diabetes-induced hepatic oxidative stress: a new pathogenic role for glycated albumin.

Increased oxidative stress and advanced glycation end-product (AGE) formation are major contributors to the development of type 2 diabetes. Here plasma proteins e.g. albumin can undergo glycoxidation and play a key role in diabetes onset and related pathologies. However, despite recent progress linking albumin-AGE to increased oxidative stress and downstream effects, its action in metabolic organs such as the liver remains to be elucidated. The current study therefore investigated links between oxidative perturbations and biochemical/structural modifications of plasma albumin, and subsequent downstream effects in transgenic db/db mouse livers and HepG2 cells, respectively. Our data reveal increased oxidative stress biomarkers and lipid accumulation in plasma and livers of diabetic mice, together with albumin glycoxidation. Purified mouse albumin modifications resembled those typically found in diabetic patients, i.e. degree of glycation, carbonylation, AGE levels and in terms of chemical composition. Receptor for AGE expression and reactive oxygen species production were upregulated in db/db mouse livers, together with impaired proteolytic, antioxidant and mitochondrial respiratory activities. In parallel, acute exposure of HepG2 cells to glycated albumin also elicited intracellular free radical formation. Together this study demonstrates that AGE-modified albumin can trigger damaging effects on the liver, i.e. by increasing oxidative stress, attenuating antioxidant capacity, and by impairment of hepatic proteolytic and respiratory chain enzyme activities.

Enhanced oxidative stress in adipose tissue from diabetic mice, possible contribution of glycated albumin.

Although enhanced oxidative stress and proteotoxicity constitute major contributors to the pathogenesis of multiple diseases, there is limited understanding of its role in adipose tissue. Here, we aimed at evaluating oxidative stress biomarkers in adipocytes from diabetic/obese db/db mice. The current study revealed that reactive oxygen species production was upregulated in adipocytes, together with lipid peroxidation 4-hydroxynonenal accumulation, and altered proteolytic and antioxidant activities. In parallel, acute exposure of 3T3L1 adipocyte cell lines to glycated albumin (known to be enhanced with diabetes) also elicited intracellular free radical formation. Our data provide novel insights into redox and proteolytic homeostasis in adipocytes.

Oxidative stress and adipocyte biology: focus on the role of AGEs.

Diabetes is a major health problem that is usually associated with obesity, together with hyperglycemia and increased advanced glycation endproducts (AGEs) formation. Elevated AGEs elicit severe downstream consequences via their binding to receptors of AGEs (RAGE). This includes oxidative stress and oxidative modifications of biological compounds together with heightened inflammation. For example, albumin (major circulating protein) undergoes increased glycoxidation with diabetes and may represent an important biomarker for monitoring diabetic pathophysiology. Despite the central role of adipose tissue in many physiologic/pathologic processes, recognition of the effects of greater AGEs formation in this tissue is quite recent within the obesity/diabetes context. This review provides a brief background of AGEs formation and adipose tissue biology and thereafter discusses the impact of AGEs-adipocyte interactions in pathology progression. Novel data are included showing how AGEs (especially glycated albumin) may be involved in hyperglycemia-induced oxidative damage in adipocytes and its potential links to diabetes progression.

Cardio-metabolic effectsof HIV protease inhibitors (lopinavir/ritonavir).

Although antiretroviral treatment decreases HIV-AIDS morbidity/mortality, long-term side effects may include the onset of insulin resistance and cardiovascular diseases. However, the underlying molecular mechanisms responsible for highly active antiretroviral therapy (HAART)-induced cardio-metabolic effects are poorly understood. In light of this, we hypothesized that HIV protease inhibitor (PI) treatment (Lopinavir/Ritonavir) elevates myocardial oxidative stress and concomitantly inhibits the ubiquitin proteasome system (UPS), thereby attenuating cardiac function. Lopinavir/Ritonavir was dissolved in 1% ethanol (vehicle) and injected into mini-osmotic pumps that were surgically implanted into Wistar rats for 8 weeks vs. vehicle and sham controls. We subsequently evaluated metabolic parameters, gene/protein markers and heart function (ex vivo Langendorff perfusions). PI-treated rats exhibited increased serum LDL-cholesterol, higher tissue triglycerides (heart, liver), but no evidence of insulin resistance. In parallel, there was upregulation of hepatic gene expression, i.e. acetyl-CoA carboxylase b and 3-hydroxy-3-methylglutaryl-CoA-reductase, key regulators of fatty acid oxidation and cholesterol synthesis, respectively. PI-treated hearts displayed impaired cardiac contractile function together with attenuated UPS activity. However, there was no significant remodeling of hearts exposed to PIs, i.e. lack of ultrastructural changes, fibrosis, cardiac hypertrophic response, and oxidative stress. Western blot analysis of PI-treated hearts revealed that perturbed calcium handling may contribute to the PI-mediated contractile dysfunction. Here chronic PI administration led to elevated myocardial calcineurin, nuclear factor of activated T-cells 3 (NFAT3), connexin 43, and phosphorylated phospholamban, together with decreased calmodulin expression levels. This study demonstrates that early changes triggered by PI treatment include increased serum LDL-cholesterol levels together with attenuated cardiac function. Furthermore, PI exposure inhibits the myocardial UPS and leads to elevated calcineurin and connexin 43 expression that may be associated with the future onset of cardiac contractile dysfunction.