Invasive Ductular Reaction Operates Hepatobiliary Junctions upon Hepatocellular Injury in Rodents and Humans.

Ductular reaction (DR) is observed in virtually all liver diseases in both humans and rodents. Depending on the injury, DR is confined within the periportal area or invades the parenchyma. On severe hepatocellular injury, invasive DR has been proposed to arise for supplying the liver with new hepatocytes. However, experimental data evidenced that DR contribution to hepatocyte repopulation is at the most modest, unless replicative capacity of hepatocytes is abrogated. Herein, we proposed that invasive DR could contribute to operating hepatobiliary junctions on hepatocellular injury. The choline-deficient ethionine-supplemented mouse model of hepatocellular injury and human liver samples were used to evaluate the hepatobiliary junctional role of the invasive form of DR. Choline-deficient ethionine-supplemented-induced DR expanded as biliary epithelium into the lobule and established new junctions with the canaliculi. By contrast, no new ductular-canalicular junctions were observed in mouse models of biliary obstructive injury exhibiting noninvasive DR. Similarly, in humans, an increased number of hepatobiliary junctions were observed in hepatocellular diseases (viral, drug induced, or metabolic) in which DR invaded the lobule but not in biliary diseases (obstruction or cholangitis) in which DR was contained within the portal mesenchyme. In conclusion, our data in rodents and humans support that invasive DR plays a hepatobiliary junctional role to maintain structural continuity between hepatocytes and ducts in disorders affecting hepatocytes

Tumoral response and tumoral phenotypic changes in a rat model of diethylnitrosamine-induced hepatocellular carcinoma after salirasib and sorafenib administration.

Several intracellular signaling pathways that are deregulated during hepatocarcinogenesis might constitute potential targets for hepatocellular carcinoma (HCC) therapy. The aim of this study was to test the potential synergic antitumor effect of salirasib and sorafenib in a diethylnitrosamine (DEN)-induced HCC model in rat. The hypothesis of tumor phenotype changes during treatment was also analyzed. DEN was administered to Wistar rats during 9 weeks to induce cirrhosis and liver cancer. After tumor development, rats were treated with intraperitoneal injections of dimethyl sulfoxide (DMSO), or salirasib, and/or with oral sorafenib 5 days/week, during 4 weeks. At sacrifice, number and size of liver tumors as well as tumor burden were recorded, and all liver tumors were processed for histological and immunohistological analyses. Mortality rate was significantly higher in rats treated with salirasib and/or sorafenib than in the control group ( <i>P</i> =0.001). Tumor burden was smaller in the treated group compared with the DMSO control group ( <i>P</i> =0.044), but a synergistic effect of the two chemotherapies could not be observed. In 62.5% of rats (10/16) treated with salirasib and/or sorafenib, a cytokeratin-7 and -19-positive hepatocholangiocellular carcinoma (HCC/CHC) was found vs 20% (5/25) developing such phenotype in the DMSO control group ( <i>P</i> =0.018). Ki67 immunostaining showed significantly reduced tumor cell proliferation in treated rats ( <i>P</i> =0.001), whereas apoptosis as assessed by caspase-3 activity in cell lysate was similar in all groups. The addition of sorafenib to salirasib did not seem to provide any synergistic therapeutic effect in this study. Both chemotherapeutic agents, administered alone or in combination, induced tumoral phenotypic changes in the majority of rats, a finding not associated with an increased tumor cell proliferation or decreased apoptosis. The rat model described in this work constitutes the first experimental tool generating putatively more aggressive combined HCC/CHC tumors following chemotherapy. Further work is required to better characterize this clinically relevant phenomenon

Autoantibodies against type I IFNs in patients with life-threatening COVID-19

Interindividual clinical variability in the course of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is vast. We report that at least 101 of 987 patients with life-threatening coronavirus disease 2019 (COVID-19) pneumonia had neutralizing immunoglobulin G (IgG) autoantibodies (auto-Abs) against interferon-w (IFN-w) (13 patients), against the 13 types of IFN-a (36), or against both (52) at the onset of critical disease; a few also had auto-Abs against the other three type I IFNs. The auto-Abs neutralize the ability of the corresponding type I IFNs to block SARS-CoV-2 infection in vitro. These auto-Abs were not found in 663 individuals with asymptomatic or mild SARS-CoV-2 infection and were present in only 4 of 1227 healthy individuals. Patients with auto-Abs were aged 25 to 87 years and 95 of the 101 were men. A B cell autoimmune phenocopy of inborn errors of type I IFN immunity accounts for life-threatening COVID-19 pneumonia in at least 2.6% of women and 12.5% of men

2019 ESC/EAS guidelines for the management of dyslipidaemias: Lipid modification to reduce cardiovascular risk

Cardiolog

30-day morbidity and mortality of sleeve gastrectomy, Roux-en-Y gastric bypass and one anastomosis gastric bypass: a propensity score-matched analysis of the GENEVA data

Background: There is a paucity of data comparing 30-day morbidity and mortality of sleeve gastrectomy (SG), Roux-en-Y gastric bypass (RYGB), and one anastomosis gastric bypass (OAGB). This study aimed to compare the 30-day safety of SG, RYGB, and OAGB in propensity score-matched cohorts. Materials and methods: This analysis utilised data collected from the GENEVA study which was a multicentre observational cohort study of bariatric and metabolic surgery (BMS) in 185 centres across 42 countries between 01/05/2022 and 31/10/2020 during the Coronavirus Disease-2019 (COVID-19) pandemic. 30-day complications were categorised according to the Clavien–Dindo classification. Patients receiving SG, RYGB, or OAGB were propensity-matched according to baseline characteristics and 30-day complications were compared between groups. Results: In total, 6770 patients (SG 3983; OAGB 702; RYGB 2085) were included in this analysis. Prior to matching, RYGB was associated with highest 30-day complication rate (SG 5.8%; OAGB 7.5%; RYGB 8.0% (p = 0.006)). On multivariate regression modelling, Insulin-dependent type 2 diabetes mellitus and hypercholesterolaemia were associated with increased 30-day complications. Being a non-smoker was associated with reduced complication rates. When compared to SG as a reference category, RYGB, but not OAGB, was associated with an increased rate of 30-day complications. A total of 702 pairs of SG and OAGB were propensity score-matched. The complication rate in the SG group was 7.3% (n = 51) as compared to 7.5% (n = 53) in the OAGB group (p = 0.68). Similarly, 2085 pairs of SG and RYGB were propensity score-matched. The complication rate in the SG group was 6.1% (n = 127) as compared to 7.9% (n = 166) in the RYGB group (p = 0.09). And, 702 pairs of OAGB and RYGB were matched. The complication rate in both groups was the same at 7.5 % (n = 53; p = 0.07). Conclusions: This global study found no significant difference in the 30-day morbidity and mortality of SG, RYGB, and OAGB in propensity score-matched cohorts. © 2021, The Author(s)