Low NO bioavailability in CCl(4 )cirrhotic rat livers might result from low NO synthesis combined with decreased superoxide dismutase activity allowing superoxide-mediated NO breakdown: A comparison of two portal hypertensive rat models with healthy controls

BACKGROUND: In cirrhotic livers, the balance of vasoactive substances is in favour of vasoconstrictors with relatively insufficient nitric oxide. Endothelial dysfunction has been documented in cirrhotic rat livers leading to a lower activity of endothelial nitric oxide synthase but this might not be sufficient to explain the low nitric oxide presence. We compared the amount of all nitric oxide synthase isoforms and other factors that influence nitric oxide bioavailability in livers of two portal hypertensive rat models: prehepatic portal hypertension and carbon tetrachloride induced cirrhosis, in comparison with healthy controls. RESULTS: Endothelial nitric oxide synthase was the solely detected isoform by Western blotting in all livers. In cirrhotic livers, the amount of endothelial nitric oxide synthase protein was lower than in healthy controls, although an overlap existed. Levels of caveolin-1 messenger RNA were within the normal range but endothelin-1 messenger RNA levels were significantly higher in cirrhotic livers (p < 0.05). A markedly lower superoxide dismutase activity was observed in cirrhotic livers as compared to healthy controls (p < 0.05). CONCLUSIONS: In contrast to prehepatic portal hypertension, cirrhotic livers had decreased endothelial nitric oxide synthase protein and enhanced endothelin-1 messenger RNA amount. We hypothesise that a vasodilator/vasoconstrictor imbalance may be further aggravated by the reduced activity of superoxide dismutase. Decreased activity allows enhanced superoxide action, which may lead to breakdown of nitric oxide in liver sinusoids

Treatment of severe alcoholic hepatitis: A systematic review

Severe alcoholic hepatitis is the most severe form of alcohol-related liver disease. Corticosteroids remain the first choice of treatment. However, they are only effective in a subset of patients and are associated with an increased infection risk. Furthermore, nonresponders to corticosteroids have a poor prognosis with a mortality of 70% over 6 months. As such, there is a high need for a more personalized use of corticosteroids and the development and identification of alternative therapeutic strategies. In this review, we summarize the recent and ongoing randomized controlled trials concerning the treatment of severe alcoholic hepatitis

Effectiveness and tolerability of pegylated interferon alfa-2b in combination with ribavirin for treatment of chronic hepatitis C: the PegIntrust Study

Background and study aims : Large international clinical trials conducted in the past 5 years rapidly improved the treatment of chronic hepatitis C; however, it is unclear whether the advances seen in clinical trials are being paralleled by similar improvements in routine clinical practice. PegIntrust is a Belgian community-based trial evaluating the sustained virological response. Patients and Methods : Observational study of 219 patients receiving pegylated interferon alfa-2b (1.5 mu g/kg/wk) and weight. based ribavirin (800-1200 mg/day) for 48 weeks. Primary study end point was sustained virological response (SVR), defined as undetectable HCV RNA 6 months after the completion of treatment. Results : In total, 108 patients (49.3 %) had undetectable HCV RNA at the end of therapy, 91(41.6%) attaining SVR. Of the 111 patients without an end-of-treatment response, 28 were non-responders, and 21 had virological breakthrough. In total, 134 patients attained early virological response (EVR); 88 (65.7%) of those patients attained SVR. In contrast, 82 (96.5 %) of the 85 patients who did not attain EVR also did not attain SVR. Age, fibrosis score and baseline viral load were identified as important predictors of treatment outcome. The most frequently reported serious adverse events resulting in treatment discontinuation were anemia (n = 10), fatigue/asthenia/malaise (n = 6) and fever (n = 3). Conclusion : Our data indicate that treatment of chronic hepatitis C with PEG-IFN alfa-2b plus weight-based ribavirin results in favourable treatment outcomes in a Belgian cohort of patients treated in community-based clinical practice. (Ada gastroenterol. belg., 2010, 73, 5-11)

Setanaxib, a first-in-class selective NADPH oxidase 1/4 inhibitor for primary biliary cholangitis: A randomized, placebo-controlled, phase 2 trial

\ua9 2023 The Authors. Liver International published by John Wiley &amp; Sons Ltd. Background: Primary biliary cholangitis (PBC) is a rare liver disease with significant unmet need for second-line/add-on treatments. Setanaxib, a NOX1/4 inhibitor, has shown anti-fibrotic effects in in vitro and animal studies. This phase 2, randomized, multicentre study investigated the efficacy and safety of setanaxib in patients with PBC. Methods: Patients with ≥6 months of ursodeoxycholic acid (UDCA) treatment were randomized 1:1:1 to oral setanaxib 400 mg once daily (OD), twice daily (BID), or placebo, in addition to UDCA for 24 weeks. Other inclusion criteria included alkaline phosphatase (ALP) ≥1.5 7 ULN and gamma-glutamyl transferase (GGT) ≥1.5 7 ULN. The primary endpoint was percentage change from baseline in GGT at Week 24; secondary endpoints included change from baseline in ALP, liver stiffness (LS; via transient elastography), fatigue at Week 24, and safety outcomes. p values compare setanaxib 400 mg BID and placebo groups. Results: Of patients randomized (setanaxib 400 mg OD and BID: 38, and 36; placebo: 37), 104/111 completed Week 24. Mean (standard deviation [SD]) change in GGT to Week 24 was −4.9% (59.6%) for setanaxib 400 mg OD, −19.0% (28.9%) for setanaxib 400 mg BID, and −8.4% (21.5%) for placebo; p =.31. Patients treated with setanaxib 400 mg OD and BID showed decreased serum ALP levels from baseline to Week 24 (p =.002: setanaxib BID versus placebo). Patients treated with setanaxib 400 mg OD and BID showed mean (SD) percentage increases in LS to Week 24 of 3.3% (35.0%) and 7.9% (43.7%), versus 10.1% (33.1%) for placebo (p =.65). Changes in mean (SD) PBC-40 fatigue domain scores to Week 24 were +0.3% (24.9%) for setanaxib 400 mg OD, −9.9% (19.8%) for setanaxib 400 mg BID and +2.4% (23.1%) for placebo, p =.027. Two patients (one placebo, one setanaxib 400 mg BID) experienced serious treatment-emergent adverse events, deemed unrelated to study drug. Conclusions: The primary endpoint was not met. However, the secondary endpoints provide preliminary evidence for potential anti-cholestatic and anti-fibrotic effects in PBC, supporting the further evaluation of setanaxib in a future phase 2b/3 trial

Acute-on-chronic liver failure in cirrhosis

The definition of acute-on-chronic liver failure (ACLF) remains contested. In Europe and North America, the term is generally applied according to the European Association for the Study of the Liver-Chronic Liver Failure (EASL-CLIF) Consortium guidelines, which defines this condition as a syndrome that develops in patients with cirrhosis and is characterized by acute decompensation, organ failure and high short-term mortality. One-third of patients who are hospitalized for acute decompensation present with ACLF at admission or develop the syndrome during hospitalization. ACLF frequently occurs in a closed temporal relationship to a precipitating event, such as bacterial infection or acute alcoholic, drug-induced or viral hepatitis. However, no precipitating event can be identified in approximately 40% of patients. The mechanisms of ACLF involve systemic inflammation due to infections, acute liver damage and, in cases without precipitating events, probably intestinal translocation of bacteria or bacterial products. ACLF is graded into three stages (ACLF grades 1–3) on the basis of the number of organ failures, with higher grades associated with increased mortality. Liver and renal failures are the most common organ failures, followed by coagulation, brain, circulatory and respiratory failure. The 28-day mortality rate associated with ACLF is 30%. Depending on the grade, ACLF can be reversed using standard therapy in only 16–51% of patients, leaving a considerable proportion of patients with ACLF that remains steady or progresses. Liver transplantation in selected patients with ACLF grade 2 and ACLF grade 3 increases the 6-month survival from 10% to 80%

Acute-on-Chronic Liver Failure: Definition, Diagnosis, and Clinical Characteristics

Acute-on-chronic liver failure (ACLF) is a recently recognized syndrome in cirrhosis characterized by acute decompensation (AD), organ failure(s), and high short-term mortality. Organ failure(s) is defined by the Chronic Liver Failure-Sequential Organ Failure (CLIF-SOFA) score or by its simplified version Chronic Liver Failure-Organ Failure Assessment (CLIF-OF) score. They include six types of organ failure: liver, renal, coagulation, cerebral, respiratory, and circulatory. One third of patients hospitalized with AD present with ACLF at admission or develop ACLF during hospitalization. Acute-on-chronic liver failure frequently occurs in a closed relationship to a precipitating event. According to the number of organ failures, ACLF is graded into three stages: ACLF-1 = single renal failure or single nonrenal organ failure if associated with renal dysfunction and/or cerebral dysfunction; ACLF-2 = two organ failures; and ACLF-3 = three to six organ failures, with increasing 28-day mortality rate (from 23%–74%). Acute-on-chronic liver failure may develop at any phase during the clinical course of the disease. Patients without prior AD develop a severe form of ACLF

The PDGFRα-laminin B1-keratin 19 cascade drives tumor progression at the invasive front of human hepatocellular carcinoma

Human hepatocellular carcinomas (HCCs) expressing the biliary/hepatic progenitor cell marker keratin 19 (K19) have been linked with a poor prognosis and exhibit an increase in platelet-derived growth factor receptor a (PDGFR alpha) and laminin beta 1 (LAMB1) expression. PDGFR alpha has been reported to induce de novo synthesis of LAMB1 protein in a Sjogren syndrome antigen B (La/SSB)-dependent manner in a murine metastasis model. However, the role of this cascade in human HCC remains unclear. This study focused on the functional role of the PDGFR alpha-La/SSB-LAMB1 pathway and its molecular link to K19 expression in human HCC. In surgical HCC specimens from a cohort of 136 patients, PDGFR alpha expression correlated with K19 expression, microvascular invasion and metastatic spread. In addition, PDGFR alpha expression in pre-operative needle biopsy specimens predicted poor overall survival during a 5-year follow-up period. Consecutive histological staining demonstrated that the signaling components of the PDGFR alpha-La/SSB-LAMB1 pathway were strongly expressed at the invasive front. K19-positive HCC cells displayed high levels of alpha 2 beta 1 integrin (ITG) receptor, both in vitro and in vivo. In vitro activation of PDGFR alpha signaling triggered the translocation of nuclear La/SSB into the cytoplasm, enhanced the protein synthesis of LAMB1 by activating its internal ribosome entry site, which in turn led to increased secretion of laminin-111. This effect was abrogated by the PDGFR alpha-specific inhibitor crenolanib. Importantly LAMB1 stimulated ITG-dependent focal adhesion kinase/Src proto-oncogene non-receptor tyrosine kinase signaling. It also promoted the ITG-specific downstream target Rho-associated coiled-coil containing protein kinase 2, induced K19 expression in an autocrine manner, invadopodia formation and cell invasion. Finally, we showed that the knockdown of LAMB1 or K19 in subcutaneous xenograft mouse models resulted in significant loss of cells invading the surrounding stromal tissue and reduced HepG2 colonization into lung and liver after tail vein injection. The PDGFR alpha-LAMB1 pathway supports tumor progression at the invasive front of human HCC through K19 expression

Reinforced reasoning in medicine

Some philosophers have argued that evidence of underlying mechanisms does not provide evidence for the effectiveness of a medical intervention. One such argument appeals to the unreliability of mechanistic reasoning. However, mechanistic reasoning is not the only way that evidence of mechanisms might provide evidence of effectiveness. A more reliable type of reasoning may be distinguished by appealing to recent work on evidential pluralism in the epistemology of medicine. A case study from virology provides an example of this so‐called reinforced reasoning in medicine. It is argued that in this case study, the available evidence of underlying mechanisms did in fact play a role in providing evidence in favour of a medical intervention. This paper therefore adds a novel and recent case study to the literature in support of evidential pluralism in medicine

Investigation of Performance and Cavitation Treatment in a Kaplan Hydro Turbine

Cavitation is a phenomenon that occurs in various turbomachinery applications causing drawbacks on the. Some of these downsides are damaging the components of the system, generating noise and vibration, and loss of the turbine efficiency over time. Thus, it is imperative to address issue of cavitation to increase the life span of the equipment in addition to improve the system performance. This thesis introduces a method used to mitigate the cavitation phenomenon in a 3-inch Kaplan hydro turbine via injecting air at the leading edge of the rotor blades. The study is based on modeling the turbine using Computational Fluid Dynamics (CFD) software as well as carrying out experimental tests. The simulations were conducted at different air injection pressures over a spectrum of rotational speeds using Large Eddy Simulation (LES) for turbulence and volume of fluid for multiphase interactions: water, vapor water and air. The cavitation behavior was observed first without aeration, then followed by air injection simulations to investigate the effect of aeration. Each case was simulated for 12 cycles at rotational speeds of 1000, 2000, 3000, 4000, and 5000 rpm. The Vapor Volume Fraction (VVF) and the output mechanical power were monitored throughout the simulations. The data acquired from the simulations were compared to the experimental results for verifications. It was observed that the cavitation was mitigated in both the computer simulations and the experiment testing reaching up to 49.7% as an average reduction, while the output power was reduced by 6.6%