Unexpected combination of inherited chorea-acanthocytosis with MDR3 (ABCB4) defect mimicking Wilson's disease.

International audienc

Dynamics of detachment of Escherichia coli from plasma-mediated coatings under shear flow

A series of plasma-mediated coatings, containing silver nanoparticles embedded in an organosilicon or silica-like matrix, were deposited onto stainless steel and chemically characterized. Their anti-adhesive properties were evaluated in vitro towards Escherichia coli by performing shear-flow induced detachment experiments. Increasing the wall shear stress facilitated E. coli cell detachment, irrespective of the coating characteristics. When nanosilver was incorporated, cell detachment was lower, probably due to the affinity of the embedded silver for biological components of the cell wall. The presence of methyl groups in the matrix network could also promote enhanced hydrophobic interactions. Within the population fraction remaining attached to the coating under increasing shear flow, different association phenotypes were observed, viz. progressively lying flat, moving laterally, remaining tethered, or rotating by a single anchoring point, until alignment with the flow direction. This re-orientation phenotype and its relation with detachment were dependent of the coating. The effects of such heterogeneities should be more deeply explored

Impact of early remote organ dysfunction on long-term survival after liver transplantation

International audienceBackground: Attention is focused on graft function although extrahepatic organ dysfunction often occurs. Renal failure, cardiovascular events and sepsis have individually shown a significant impact on short- and long-term outcomes. The aim of the study was to identify how extrahepatic organ dysfunction (EROD) and allograft dysfunction (EAD) may be associated and their relative impact on long-term survival.Methods: A retrospective study was conducted in a unicentric cohort of 294 patients transplanted between 2009 and 2014. The composite endpoint EROD was defined as requirement during the hospitalization of de novo renal replacement therapy, reintubation/ventilation > 7 days or cardiovascular event. Donor and recipient characteristics were evaluated as predictive of EROD in uni- and multivariate analysis. Main endpoint was overall survival evaluated by Kaplan-Meier method.Results: EROD occurred in 91 patients (31%) among whom 42 also experienced EAD (46%). Predicting factors associated with EROD were IL6 level (P = 0.002) and lab-MELD (P < 0.001). Only patients experiencing both EAD and EROD had a worse survival (P = 0.001). In patients without EAD, time to normalization of bilirubin and INR were longer in patients with EROD compared to those without EROD (P = 0.002 and P = 0.008 respectively).Conclusions: The composite endpoint described as early remote organ dysfunction could be used as a predictive factor after transplantation and should be included in future studies together with early allograft dysfunction. Identifying patients in whom EROD and EAD occur together or one after the other could help to better predict long-term outcomes

Early Evolution of Hepatitis C Virus (HCV) Quasispecies after Liver Transplant for HCV‐Related Disease

International audienceEnd-stage liver disease as a result of chronic hepatitis C virus (HCV) infection is the main indication for liver transplant (LT), but allografts are systematically infected with HCV soon after transplant. Viral quasispecies are poorly described during the early posttransplant period

Immunosuppression in patients with grade 3 acute‐on‐chronic liver failure at transplantation: A practice analysis study

Transplantation for patients with acute-on-chronic liver failure grade 3 (ACLF3) has encouraging results with 1-year-survival of 80-90%. These patients with multiple organ failure meet the conditions for serious alterations of drug metabolism and increased toxicity. The goal of this study was to identify immunosuppression-dependent factors that affect survival. This retrospective monocentric study was conducted in patients with ACLF3 consecutively transplanted between 2007 and 2019. The primary endpoint was 1-year survival. Secondary endpoints were overall survival, treated rejection, and surgical complications. Immunosuppression was evaluated as to type of immunosuppression, post-transplant introduction timing, trough levels, and trough level intra-patient variability (IPV). One hundred patients were included. Tacrolimus IPV < 40% (P = .019), absence of early tacrolimus overdose (P = .033), use of anti-IL2-receptor antibodies (P = .034), and early mycophenolic acid introduction (P = .038) predicted 1-year survival. Treated rejection was an independent predictor of survival (P = .001; HR 4.2 (CI 95%: 1.13-15.6)). Early everolimus introduction was neither associated with higher rejection rates nor with more surgical complications. Management of immunosuppression in ACLF3 critically ill patients undergoing liver transplantation is challenging. Occurrence and treatment of rejection impacts on survival. Early introduction of mTOR inhibitor seems safe and efficient in this situation. Keywords: basilliximab; critically ill patients; everolimus; mycophenolic acid; rejection

Colonization-induced host-gut microbial metabolic interaction

The gut microbiota enhances the host's metabolic capacity for processing nutrients and drugs and modulate the activities of multiple pathways in a variety of organ systems. We have probed the systemic metabolic adaptation to gut colonization for 20 days following exposure of axenic mice (n = 35) to a typical environmental microbial background using high-resolution (1)H nuclear magnetic resonance (NMR) spectroscopy to analyze urine, plasma, liver, kidney, and colon (5 time points) metabolic profiles. Acquisition of the gut microbiota was associated with rapid increase in body weight (4%) over the first 5 days of colonization with parallel changes in multiple pathways in all compartments analyzed. The colonization process stimulated glycogenesis in the liver prior to triggering increases in hepatic triglyceride synthesis. These changes were associated with modifications of hepatic Cyp8b1 expression and the subsequent alteration of bile acid metabolites, including taurocholate and tauromuricholate, which are essential regulators of lipid absorption. Expression and activity of major drug-metabolizing enzymes (Cyp3a11 and Cyp2c29) were also significantly stimulated. Remarkably, statistical modeling of the interactions between hepatic metabolic profiles and microbial composition analyzed by 16S rRNA gene pyrosequencing revealed strong associations of the Coriobacteriaceae family with both the hepatic triglyceride, glucose, and glycogen levels and the metabolism of xenobiotics. These data demonstrate the importance of microbial activity in metabolic phenotype development, indicating that microbiota manipulation is a useful tool for beneficially modulating xenobiotic metabolism and pharmacokinetics in personalized health care. IMPORTANCE: Gut bacteria have been associated with various essential biological functions in humans such as energy harvest and regulation of blood pressure. Furthermore, gut microbial colonization occurs after birth in parallel with other critical processes such as immune and cognitive development. Thus, it is essential to understand the bidirectional interaction between the host metabolism and its symbionts. Here, we describe the first evidence of an in vivo association between a family of bacteria and hepatic lipid metabolism. These results provide new insights into the fundamental mechanisms that regulate host-gut microbiota interactions and are thus of wide interest to microbiological, nutrition, metabolic, systems biology, and pharmaceutical research communities. This work will also contribute to developing novel strategies in the alteration of host-gut microbiota relationships which can in turn beneficially modulate the host metabolism

Pharmacological activation of constitutive androstane receptor induces female-specific modulation of hepatic metabolism

Background &amp; Aims: The constitutive androstane receptor (CAR) is a nuclear receptor that binds diverse xenobiotics and whose activation leads to the modulation of the expression of target genes involved in xenobiotic detoxification and energy metabolism. Although CAR hepatic activity is considered to be higher in women than in men, its sex-dependent response to an acute pharmacological activation has seldom been investigated. Methods: The hepatic transcriptome, plasma markers, and hepatic metabolome, were analysed in Car+/+ and Car-/- male and female mice treated either with the CAR-specific agonist 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP) or with vehicle. Results: Although 90% of TCPOBOP-sensitive genes were modulated in a sex-independent manner, the remaining 10% showed almost exclusive female liver specificity. These female-specific CAR-sensitive genes were mainly involved in xenobiotic metabolism, inflammation, and extracellular matrix organisation. CAR activation also induced higher hepatic oxidative stress and hepatocyte cytolysis in females than in males. Hepatic expression of flavin monooxygenase 3 (Fmo3) was almost abolished and was associated with a decrease in hepatic trimethylamine-N-oxide (TMAO) concentration in TCPOBOP-treated females. In line with a potential role in the control of TMAO homeostasis, CAR activation decreased platelet hyper-responsiveness in female mice supplemented with dietary choline. Conclusions: More than 10% of CAR-sensitive genes are sex-specific and influence hepatic and systemic responses such as platelet aggregation. CAR activation may be an important mechanism of sexually-dimorphic drug-induced liver injury. Impact and implications: CAR is activated by many drugs and pollutants. Its pharmacological activation had a stronger impact on hepatic gene expression and metabolism in females than in males, and had a specific impact on liver toxicity and trimethylamine metabolism. Sexual dimorphism should be considered when testing and/or prescribing xenobiotics known to activate CAR