A cellular model to study drug-induced liver injury in nonalcoholic fatty liver disease: application to acetaminophen

International audienceObesity and nonalcoholic fatty liver disease (NAFLD) can increase susceptibility to hepatotoxicity induced by some xenobiotics including drugs, but the involved mechanisms are poorly understood. For acetaminophen (APAP), a role of hepatic cytochrome P450 2E1 (CYP2E1) is suspected since the activity of this enzyme is consistently enhanced during NAFLD. The first aim of our study was to set up a cellular model of NAFLD characterized not only by triglyceride accumulation but also by higher CYP2E1 activity. To this end, human HepaRG cells were incubated for one week with stearic acid or oleic acid, in the presence of different concentrations of insulin. Although cellular triglycerides and the expression of lipid-responsive genes were similar with both fatty acids, CYP2E1 activity was significantly increased only by stearic acid. CYP2E1 activity was reduced by insulin and this effect was reproduced in cultured primary human hepatocytes. Next, APAP cytotoxicity was assessed in HepaRG cells with or without lipid accretion and CYP2E1 induction. Experiments with a large range of APAP concentrations showed that the loss of ATP and glutathione was almost always greater in the presence of stearic acid. In cells pretreated with the CYP2E1 inhibitor chlormethiazole, recovery of ATP was significantly higher in the presence of stearate with low (2.5 mM) or high (20 mM) concentrations of APAP. Levels of APAP-glucuronide were significantly enhanced by insulin. Hence, HepaRG cells can be used as a valuable model of NAFLD to unveil important metabolic and hormonal factors which can increase susceptibility to drug-induced hepatotoxicit

De 20 000 à 18 000 BP en Quercy : apports de la séquence du Cuzoul de Vers à la compréhension de l'évolution des comportements socio-économiques entre Solutréen récent et Badegoulien

Essai de synthèse des travaux menés autour du gisement du Cuzoul de Vers (Lot)

La stratégie du cocooning chez l'enfant prématuré (vaccination coqueluche et grippe)

Nous avons étudié la couverture vaccinale des parents d'enfants nés prématurés. vis-à-vis de la coqueluche, de la grippe (saisonnière et A(H1N1)) au regard des recommandations nationales. Cette étude observationnelle a porté sur 108 familles dont les enfants ( n=125) ont été hospitalisés à la naissance dans le service de pédiatrie néonatale du CHU de Rouen du 01 octobre 2009 au 31 mars 2010. La couverture vaccinale contre la coqueluche de l'entourage des enfants de moins de 33 SA progresse. Près de 75 % des enfants avaient leur deux parents correctement vaccinés lors de l'enquête téléphonique. Pour 17 % des parents, les vaccinations étaient effectuées avant la naissance de leur enfant et pour plus des 2/3 d'entre eux au cours du séjour de leur enfant à l'hôpital. Concernant la grippe, les résultats sont beaucoup plus contrastés, avec un taux de couverture vaccinale autour de 20% . L'adhésion aux recommandations est meilleure pour les parents d'enfants nés avant 33 SA ou porteur d'une cardiopathie congénitale. On note l'importance de l'information donnée aux parents sur le ni\eau de couverture vaccinale. L'initiation de la vaccination des enfants nés Prématurément est effectuée avec peu de retard en movenne à 66 jours (min [46 - 111]max). Les parents qui ne se sont pas vaccinés ont tendance à faire vacciner leur enfant plus tard. L'initiation de la vaccination est effectuée pour 45% des enfants de moins de 33 SA avant leur retour à domicile (91% pour les enfants hospitalisés plus de 8 semaines et 100% des enfants de moins de 29 SA). Pour 16 % des enfants de moins de 33 SA sortis à domicile avant l'âge de 60jours. la 1er dose vaccinale a été administrée entre 6 et 8 semaines de vie. Près d'un parent sur deux considère la coqueluche comme redoutable mais un tiers des parents déclare ne pas connaître la coqueluche ni sa gravité. En revanche, les parents semblent mieux percevoir la gravité de la grippe chez le nourrisson sans que cela se traduise par une bonne adhésion aux recommandations vaccinales. Ces résultats incitent à poursuivre les efforts de sensibilisation et d'information pour convaincre. rassurer et inciter l'entourage des grands prématurés et des nourrissons à risque à mettre à jour leur vaccination avant le retour de leurs enfants à domicile. Il s'agit d'une démarche globale qui doit intégrer à cette stratégie du cocooning un renforcement des vaccinations de tout l'entourage des jeunes nourrissons pour l'ensemble des maladies à prévention vaccinale dans les service de néonatalogie mais aussi en amont de toute naissance.ROUEN-BU Médecine-Pharmacie (765402102) / SudocSudocFranceF

A Pleiotropic Role of the Hepatitis B Virus Core Protein in Hepatocarcinogenesis

International audienceChronic hepatitis B virus (HBV) infection is one of the most common factors associated with hepatocellular carcinoma (HCC), which is the sixth most prevalent cancer among all cancers worldwide. However, the pathogenesis of HBV-mediated hepatocarcinogenesis is unclear. Evidence currently available suggests that the HBV core protein (HBc) plays a potential role in the development of HCC, such as the HBV X protein. The core protein, which is the structural component of the viral nucleocapsid, contributes to almost every stage of the HBV life cycle and occupies diverse roles in HBV replication and pathogenesis. Recent studies have shown that HBc was able to disrupt various pathways involved in liver carcinogenesis: the signaling pathways implicated in migration and proliferation of hepatoma cells, apoptosis pathways, and cell metabolic pathways inducing the development of HCC; and the immune system, through the expression and production of proinflammatory cytokines. In addition, HBc can modulate normal functions of hepatocytes through disrupting human host gene expression by binding to promoter regions. This HBV protein also promotes HCC metastasis through epigenetic alterations, such as micro-RNA. This review focuses on the molecular pathogenesis of the HBc protein in HBV-induced HCC

The Role of STING in Liver Injury Is Both Stimulus- and Time-Dependent

STING, Tmem173, is involved in liver injury caused by both infectious and sterile inflammatory models. Its role in toxic liver injury and non-alcoholic fatty liver disease (NAFLD), however, is less clear. While a few groups have investigated its role in NAFLD pathogenesis, results have been conflicting. The objective of this study was to clarify the exact role of STING in toxic liver injury and NAFLD models. Goldenticket mice (Tmem173gt), which lack STING protein, were subjected to either a toxic liver injury with tunicamycin (TM) or one of two dietary models of non-alcoholic fatty liver disease: high fructose feeding or Fructose-Palmitate-Cholesterol (FPC) feeding. Three days after TM injection, Tmem173gt mice demonstrated less liver injury (average ALT of 54 ± 5 IU/L) than control mice (average ALT 108 ± 24 IU/L). In contrast, no significant differences in liver injury were seen between WT and Tmem173gt mice fed either high fructose or FPC. Tmem173gt mice only distinguished themselves from WT mice in their increased insulin resistance. In conclusion, while STING appears to play a role in toxic liver injury mediated by TM, it plays little to no role in two dietary models of NAFLD. The exact role of STING appears to be stimulus-dependent

Practical approach to method verification in plasma and validation in cerebrospinal fluid under accreditation using a flexible scope in molecular virology: setting up the HIV, HBV and HCV Aptima™ Quant Dx assays

International audienceAbstract Background Our laboratory obtained the ISO 15189 accreditation for the plasmatic HIV-1, HBV and HCV viral load (VL) using the m2000 RealTi m e™ system, which was recently changed for the platform Panther ® . Here, we discuss a strategy for performing method validation/verification very quickly. Methods We performed the mandatory (repeatability, internal quality assessment [IQA], measurement uncertainty [MU]) and optional technical verifications for CE/IVD assays using the flexible scope range A. We also performed the mandatory assays for the validation of HIV-1 VL in the cerebrospinal fluid (CSF) using the flexible scope range B. The change was checked by following up on the turnaround time (TAT). Results The coefficient of variation (CV%) for repeatability and IQA complied with the limit of 0.25 log. The MU results ranged from 0.04 to 0.25 log copies or IU/mL. The comparisons of methods showed excellent correlations (R 2 = 0.96 for the three parameters) but a delayed centrifugation on HCV VL showed variations of up to 2 log IU/mL. An excellent linearity for HIV-1 in the CSF was obtained from 1.5 to 5 log copies/mL with R 2 = 0.99. The TAT increased (84%–98%) in routine usage. Conclusions The three Aptima assays are well suited for routine laboratory use and can be integrated within less than 2 weeks in accordance with flexible scope range A. Our data allows us to confidently perform HIV-1 VL in CSF following flexible scope range B. Finally, we provide an organizational guide for flexible scope management in molecular virology within a short time frame

What is the true place of the SARS‐CoV‐2 rapid point‐of‐care antigen test in the hospital setting? Lessons learned from real life

International audienc

Making sense of the French public hospital system: a network-based approach to hospital clustering using unsupervised learning methods

International audienceBackground: Hospitals in the public and private sectors tend to join larger organizations to form hospital groups. This increasingly frequent mode of functioning raises the question of how countries should organize their health system, according to the interactions already present between their hospitals. The objective of this study was to identify distinctive profiles of French hospitals according to their characteristics and their role in the French hospital network. Methods: Data were extracted from the national hospital database for year 2016. The database was restricted to public hospitals that practiced medicine, surgery or obstetrics. Hospitals profiles were determined using the k-means method. The variables entered in the clustering algorithm were: the number of stays, the effective diversity of hospital activity, and a network-based mobility indicator (proportion of stays followed by another stay in a different hospital of the same Regional Hospital Group within 90 days). Results: Three hospital groups were identified by the clustering algorithm. The first group was constituted of 34 large hospitals (median 82,100 annual stays, interquartile range 69,004-117,774) with a very diverse activity. The second group contained medium-sized hospitals (with a median of 258 beds, interquartile range 164-377). The third group featured less diversity regarding the type of stay (with a mean of 8 effective activity domains, standard deviation 2.73), a smaller size and a higher proportion of patients that subsequently visited other hospitals (11%). The most frequent type of patient mobility occurred from the hospitals in group 2 to the hospitals in group 1 (29%). The reverse direction was less frequent (19%). Conclusions: The French hospital network is organized around three categories of public hospitals, with an unbalanced and disassortative patient flow. This type of organization has implications for hospital planning and infectious diseases control

Evaluation of the Aptima™ HBV Quant Dx assay for semi-quantitative HBV viral load from dried blood spots

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Efficiency of Continuous Subcutaneous Insulin Infusion for Premature Neonate: A Case Report

Neonatal hyperglycaemia is common in extremely low birth weight (ELBW, <1,000 g) infants, associated with a number of adverse clinical outcomes, and usually treated with continuous intravenous insulin infusion (CIVII). We report a case of continuous subcutaneous insulin infusion (CSII) in an ELBW neonate (730 g, 25 weeks GA) requiring insulin infusion for transient idiopathic hyperglycaemia. After presenting hyperglycaemia on day 4, the patient was treated with CIVII. From day 12 to 34, CSII was used to replace central venous catheter. Insulin requirements were lower and glycaemia more stable under CSII. No side effect was noticed. CSII was also beneficial for developmental care, allowing parents to be more easily involved in their baby’s care. Thus, CSII appeared to be a safe and reliable alternative for insulin administration in ELBW infants. However, indication and management requires training of the NICU team by paediatric diabetes specialists