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The present paper provides a brief overview of the rationale behind magnetic resonance imaging (MRI) techniques, a description of the most common sequences used, and a general approach to performing liver MRI. [ABSTRACT FROM AUTHOR]

Aims: The presence of ground glass hepatocytes in a liver biopsy may be related to different conditions, including fibrinogen storage disease. Three types of fibrinogen storage disease have been described, namely types I, II and III. Type I is an hereditary hypofibrinogenaemia genetically characterized by a mutant variant of the fibrinogen molecule designated as fibrinogen Brescia, consistent with a γ284 Gly→Arg mutation. Only rare cases of types II and III fibrinogen storage disease have been described. The purpose of the present paper is to describe two cases of fibrinogen storage disease without associated hypofibrinogenaemia, which appeared during acute infectious diseases. Methods and results: Both patients were female, aged 77 and 73 years, who developed high transaminases during an infectious disease. In each case blood coagulation tests were within the normal range, and despite clinical and laboratory investigations no possible cause for liver disease could be found. Liver biopsies were performed; in both cases weakly eosinophilic cytoplasmic inclusions were observed. Using immunohistochemistry the inclusions were found to be due to fibrinogen accumulation. At ultrastructural level features corresponding to type II inclusions were observed. Molecular studies, performed in case 2, excluded the mutation typical of type I fibrinogen storage disease. Both patients also presented features of chronic hepatitis. In case 1, giant cell granulomas were additionally present. No close relatives of the patients presented any clinical or laboratory features of liver disease. In both patients altered liver function test values gradually, spontaneously, returned to within normal ranges after infectious disease was resolved. Conclusions: These cases suggest that, on rare occasions, hepatocytes may accumulate fibrinogen during an infectious disease. [ABSTRACT FROM AUTHOR]

Global egg production is mainly based on cage systems, which have been associated with negative effects on the welfare of birds. Stress factors in restrictive production systems can lead to changes in gene transcription and protein synthesis, ultimately impacting the quality of poultry products. The liver serves various metabolic functions, such as glycogen storage, and plays a crucial role in animals' adaptation to environmental changes. Consequently, both internal and external conditions can influence liver functions. The aim of this study was to evaluate the gene expression of AGP, CRP, NOX4, SOD1, CAT, GPX1, SREBF1, and FXR in the liver of laying hens under two different production systems. Liver tissues from Hy-Line Brown hens housed in conventional cage and cage-free egg production systems at 60 and 80 weeks of production were used. mRNA transcript levels were determined by qPCR using the relative quantification method and ACTB as the reference gene. AGP, SOD1, and SREBF1 gene expressions were significantly higher in the conventional cage group at the 60 weeks of production. Furthermore, the mRNA levels of transcripts related to oxidative stress and lipid metabolism were higher in the group of laying hens housed in conventional cages compared to those in cage-free systems. These results suggest differential gene expression of genes related to oxidative stress in liver tissues from hens housed in conventional cages compared to cage-free systems. The conditions of the egg production system can impact the gene expression of oxidative stress and lipid synthesis genes, potentially leading to changes in the metabolism and performance of hens, including egg quality. [ABSTRACT FROM AUTHOR]

Background: End‐stage liver disease (ESLD) and end‐stage renal disease (ESRD) are prevalent diseases for which the definitive treatment is transplantation. With limited organ supply, strategies to maximize organ availability has led to increasing rates of split liver transplantations for ESLD patients. Therefore, simultaneous split liver and kidney transplantations (SSLK) for patients with ESLD and ESRD could represent a treatment option for comorbid patients. However, current practice and outcomes after SSLK are unknown. Methods: We aim to report national trends and our experience with patients undergoing SSLK. We performed a retrospective review of the United Network for Organ Sharing (UNOS) Standard Transplant Analysis and Research file from January 2011–April 2022. Descriptive analysis of preoperative characteristics, postoperative outcomes and actuarial graft and patient survivals are reported. Results: National review of the UNOS transplant registry from 2011–2021 of adult patients undergoing initial transplantation via SSLK demonstrates that this procedure remains uncommon, with only 76 such cases captured in that time. Nevertheless, survival rates at 1, 3, and 5 years remains robust, at 94%, 92%, and 90% for patients overall, 90%, 88%, 88%, for the liver graft, and 93%, 91%, 88% for the kidney graft, respectively. Review of a single center experience with three such patients from 2019–2021 has shown a safe, enduring transplant option with no graft complications seen. Conclusions: SSLK is both safe and a feasible option to optimize organ supply while allowing recipients to receive quality liver and kidney grafts and should be considered more often by transplant centers going forward. [ABSTRACT FROM AUTHOR]

Background: Donors with hyperbilirubinemia are often not utilized for liver transplantation (LT) due to concerns about potential liver dysfunction and graft survival. The potential to mitigate organ shortages using such donors remains unclear. Methods: This study analyzed adult deceased donor data from the United Network for Organ Sharing database (2002–2022). Hyperbilirubinemia was categorized as high total bilirubin (3.0–5.0 mg/dL) and very high bilirubin (≥5.0 mg/dL) in brain‐dead donors. We assessed the impact of donor hyperbilirubinemia on 3‐month and 3‐year graft survival, comparing these outcomes to donors after circulatory death (DCD). Results: Of 138 622 donors, 3452 (2.5%) had high bilirubin and 1999 (1.4%) had very high bilirubin levels. Utilization rates for normal, high, and very high bilirubin groups were 73.5%, 56.4%, and 29.2%, respectively. No significant differences were found in 3‐month and 3‐year graft survival between groups. Donors with high bilirubin had superior 3‐year graft survival compared to DCD (hazard ratio.83, p =.02). Factors associated with inferior short‐term graft survival included recipient medical condition in intensive care unit (ICU) and longer cold ischemic time; factors associated with inferior long‐term graft survival included older donor age, recipient medical condition in ICU, older recipient age, and longer cold ischemic time. Donors with ≥10% macrosteatosis in the very high bilirubin group were also associated with worse 3‐year graft survival (p =.04). Discussion: The study suggests that despite many grafts with hyperbilirubinemia being non‐utilized, acceptable post‐LT outcomes can be achieved using donors with hyperbilirubinemia. Careful selection may increase utilization and expand the donor pool without negatively affecting graft outcome. [ABSTRACT FROM AUTHOR]

Chronic tobacco use can lead to liver damage and inflammation due to the accumulation of various toxins in the body. This study aimed to investigate the correlation between the molecular mechanisms of nicotine‐induced liver injury, the caspase cascade, and the Akt/NF‐κB signaling pathway, as well as the protective effects of dexpanthenol (DEX). Male rats were subjected to intraperitoneal injections of nicotine at a concentration of 0.5 mg/kg/day and/or DEX at a concentration of 500 mg/kg/day for 8 weeks. After the treatment period, liver function tests were conducted on serum samples, and tissue samples were analyzed for protein levels of Akt, NF‐κB, Bax, Bcl‐xL, Caspase‐3, and Caspase‐9, along with histopathological changes. Additionally, assessments of oxidative stress markers and proinflammatory cytokines were carried out. Nicotine administration led to elevated levels of IL‐6, IL‐1β, MDA, TOS, and oxidative stress index, accompanied by decreased TAS levels. Moreover, nicotine exposure reduced the p‐Akt/Akt ratio, increased NF‐κB, Bax, Caspase‐3, and Caspase‐9 protein levels, and decreased the antiapoptotic protein Bcl‐xL levels. DEX treatment significantly mitigated these effects, restoring the parameters to levels comparable to those of the control group. Nicotine‐induced liver injury resulted in oxidative stress, inflammation, and apoptosis, mediated by Bax/Bcl‐xL, Caspase‐3, Caspase‐9, and Akt/NF‐κB pathways. Conversely, DEX effectively attenuated nicotine‐induced liver injury by modulating apoptosis through NF‐κB, Caspase‐3, Caspase‐9, Bax inhibition, and Bcl‐xL activation. [ABSTRACT FROM AUTHOR]

Background and Purpose: The low efficacy of mesenchymal stem cells (MSCs) has restricted their application in the treatment of liver disease. Emerging evidence suggested that ferroptosis may provoke hepatocyte dysfunction and exacerbate damage to the liver microenvironment. Here, we have investigated the contribution of liver ferroptosis to the elimination and effectiveness of human MSC (hMSC). Furthermore, potential links between liver ferroptosis and aryl hydrocarbon receptors (AhR) were explored. Experimental Approach: Two mouse models, iron supplement‐induced hepatic ferroptosis and hepatic ischaemia/reperfusion (I/R) injury, were used to identify effects of ferroptosis on hMSC pharmacokinetics (PK)/pharmacodynamics (PD). Key Results: AhR inhibition attenuated hepatic ferroptosis and improved survival of hMSCs. hMSC viability was decreased by iron supplementation or serum from I/R mice. The AhR antagonist CH223191 reversed iron overload and oxidative stress induced by ferroptosis and increased hMSC concentration and efficacy in mouse models. Effects of CH223191 were greater than those of deferoxamine, a conventional ferroptosis inhibitor. Transcriptomic results suggested that the AhR–signal transducer and activator of transcription 3 (STAT3)–haem oxygenase 1/COX‐2 signalling pathway is critical to this process. These results were confirmed in a mouse model of hepatic I/R injury. In mice pre‐treated with CH223191, hMSC exhibited more potent protective effects, linked to decreased hepatic ferroptosis. Conclusion and Implications: Our findings showed that ferroptosis was a critical factor in determining the fate of hMSCs. Inhibition of AhR decreased hepatic ferroptosis, thereby increasing survival and therapeutic effects of hMSCs in mouse models of liver disease. [ABSTRACT FROM AUTHOR]

In the North Sea and North Atlantic coastal areas, fish experience relatively high background levels of persistent organic pollutants. This study aimed to compare the mode of action of environmentally relevant concentrations of mixtures of halogenated compounds in Atlantic cod. Juvenile male cod with mean weight of 840 g were exposed by gavage to dietary mixtures of chlorinated (PCBs, DDT analogs, chlordane, lindane, and toxaphene), brominated (PBDEs), and fluorinated (PFOS) compounds for 4 weeks. One group received a combined mixture of all three compound groups. The results showed that the accumulated levels of chemicals in cod liver after 4 weeks of exposure reflected concentrations found in wild fish in this region. Pathway analysis revealed that the treatment effects by each of the three groups of chemicals (chlorinated, brominated, and fluorinated) converged on activation of the unfolded protein response (UPR). Upstream regulator analysis predicted that almost all the key transcription factors (XBP1, ERN1, ATF4, EIF2AK3, and NFE2L2) regulating the UPR were significantly activated. No additive effect was observed in cod co‐treated with all three compound groups. In conclusion, the genome‐wide transcriptomic study suggests that the UPR pathway is a sensitive common target of halogenated organic environmental pollutants in fish. Juvenile Atlantic cod (mean weight of 840 g) were exposed by gavage to environmentally realistic dietary concentrations of chlorinated, brominated, and fluorinated chemical mixtures. After 1 month of dietary exposure, the accumulated levels of the studied chemicals in cod liver reflected concentrations reported in wild fish from the North Atlantic. Transcriptomic analysis showed that all three types of chemicals most strongly affected the unfolded protein response (UPR). The study suggests that the UPR pathway is a sensitive target of halogenated compounds in fish liver. [ABSTRACT FROM AUTHOR]

Aims: Polymyxin B (PMB) is widely used to treat infections caused by multidrug‐resistant Gram‐negative pathogens. Currently, the pharmacokinetic data of PMB in patients with liver dysfunction are limited. This study aimed to develop a population pharmacokinetic (PopPK) model of PMB in patients with liver dysfunction and identify the factors affecting PMB pharmacokinetics. Methods: We conducted a retrospective pharmacokinetic study involving 136 adults with different levels of liver function. Nonlinear mixed effects modelling was used to develop a PopPK model of PMB. Monte Carlo simulation was used to design PMB dosage schedules across various liver and renal functions. Results: PMB pharmacokinetic analyses included 401 steady‐state concentrations in 136 adult patients. A one‐compartment pharmacokinetic model with first‐order absorption and elimination was used to describe the data. The typical population value of PMB clearance was 2.43 L/h and the volume of distribution was 23.11 L. This study revealed that creatinine clearance (CrCL) and Child–Pugh class were significantly associated with PMB pharmacokinetic parameters; however, clinically relevant variations of dose‐normalized drug exposure were not significant. For patients with a minimum inhibitory concentration of ≤0.5 mg/L, the appropriate dose was 40–75 mg/12‐h. When the dose exceeded 100 mg/12‐h, the risk of nephrotoxicity increased significantly. Conclusions: This study provided PMB pharmacokinetic information for patients with liver dysfunction. Patients with renal and liver dysfunctions may not require an initial dose adjustment. Rather than PopPK‐guided dose adjustment, therapeutic drug monitoring of PMB plays a more direct role in optimizing dosing regimens based on its therapeutic window. [ABSTRACT FROM AUTHOR]

Background: Despite advancements in liver transplantation (LT) over the past two decades, liver re‐transplantation (re‐LT) presents challenges. This study aimed to assess improvements in re‐LT outcomes and contributing factors. Methods: Data from the United Network for Organ Sharing database (2002–2021) were analyzed, with recipients categorized into four‐year intervals. Trends in re‐LT characteristics and postoperative outcomes were evaluated. Results: Of 128,462 LT patients, 7254 received re‐LT. Graft survival (GS) for re‐LT improved (91.3%, 82.1%, and 70.8% at 30 days, 1 year, and 3 years post‐LT from 2018 to 2021). However, hazard ratios (HRs) for GS remained elevated compared to marginal donors including donors after circulatory death (DCD), although the difference in HRs decreased in long‐term GS. Changes in re‐LT causes included a reduction in hepatitis C recurrence and an increase in graft failure post‐primary LT involving DCD. Trends identified included recent decreased cold ischemic time (CIT) and increased distance from donor hospital in re‐LT group. Meanwhile, DCD cohort exhibited less significant increase in distance and more marked decrease in CIT. The shortest CIT was recorded in urgent re‐LT group. The highest Model for End‐Stage Liver Disease score was observed in urgent re‐LT group, while the lowest was recorded in DCD group. Analysis revealed shorter time interval between previous LT and re‐listing, leading to worse outcomes, and varying primary graft failure causes influencing overall survival post‐re‐LT. Discussion: While short‐term re‐LT outcomes improved, challenges persist compared to DCD. Further enhancements are required, with ongoing research focusing on optimizing risk stratification models and allocation systems for better LT outcomes. [ABSTRACT FROM AUTHOR]

Introduction: Given the global aging population, the average age of liver donors is increasing. This study aimed to evaluate the surgical outcomes of grafts from pure laparoscopic donor right hepatectomy (PLDRH) in liver donors aged > 50 years. Methods: The medical records of liver donors were retrospectively reviewed. The donors underwent conventional donor right hepatectomy (CDRH) from January 2011 to May 2019 or PLDRH from March 2016 to May 2019. We divided the donors into three groups: PLDRH donors aged ≥50 (n = 26; Group 1) and aged < 50 (n = 257; Group 2), and CDRH donors aged ≥50 years (n = 66; Group 3). Results: Operation time (p <.01) and hospital stay (p <.01) were significantly lower in Group 1 than in Group 3. Other postoperative outcomes of donors including graft anatomical variation, graft weight, graft‐to‐recipient weight ratio, and hepatic steatosis were similar among the three groups. Although no postoperative complications occurred in Groups 1 and 3, they were detected in 17 cases (6.6%) in Group 2. No postoperative complications were detected among the recipients. Conclusions: PLDRH was feasible and safe in donors aged over 50 years, with outcomes similar to those for donors aged <50 years. PLDRH should not be avoided solely based on the donor's age ≥50 years. [ABSTRACT FROM AUTHOR]

Background: Textbook outcome (TO) is an objective, composite measure of clinical outcomes in surgery. TO in liver surgery has been used in previous international studies to define and compare performance across centres. This study aimed to review TO rates following liver resection at a single institution. The secondary aim was to use a CuSum analysis to evaluate monitoring of performance quality over time for colorectal cancer liver metastases (CRCLM). Methods: All patients undergoing liver resection for benign and malignant causes from Christchurch Hospital hepatobiliary unit between 2005 and 2022 were included. Textbook outcomes measures were the absence of; intraoperative incidents, Clavien‐Dindo >3 complication, 90 day re‐admission, 90 day mortality, R1 resection, and post‐operative bile leak/liver failure. Sequential CuSum analysis was performed to review achievement of TO in liver resections for colorectal cancer liver metastases (CRCLM). Results: Four hundred and seventy‐eight patients were included in this study, 54 had resection for benign pathology, 290 for CRCLM and 134 for other malignancies. TO was achieved in 74% of cases overall, with rates for benign, CRCLM and other malignancy being 82%, 73% and 74% respectively (P = 0.405). CuSum analysis documented a deterioration in performance after patient 60, with return to baseline by end of study period. Conclusions: TO for liver resection in a medium sized centre in New Zealand are comparable to published rates. It is possible to use process control techniques like CuSum with the binary result of TO to monitor performance, providing opportunity for continuous improvement in surgical units. [ABSTRACT FROM AUTHOR]

Background: Domino liver transplant (DLT) represents another type of liver donor to expand the donor pool. Recent reports of successful DLT in children with maple syrup urine disease (MSUD) show promising long‐term outcomes. Methods: It was a retrospective study. All children with MSUD were paired with either recipients with end‐stage liver disease (ESLD) or non‐MSUD metabolic disease. Each pair underwent simultaneous liver transplant (LT), where the MSUD recipient received the graft from a living‐related donor and the liver explanted from the MSUD donor was transplanted to the respective paired domino recipient. We report our experience regarding the techniques and outcomes of DLT at our center. Results: Eleven children with MSUD and 12 respective DLT recipients were enrolled, one of which was domino split‐liver transplantation. DLT recipients included seven ESLD, two propionic acidemia (PA), one glycogen storage disease(GSD) type‐1, one GSD type‐3, and one Citrullinemia. Post‐LT ICU and hospital stays were comparable (p >.05). Patient and graft survival was 100% and 66.6% in the MSUD group and DLT recipients at a mean follow‐up of 13.5 and 15 months. There was no death in the MSUD group as compared to four in the DLT group. The amino acid levels rapidly normalized after the LT in the children with MSUD and they tolerated the normal unrestricted diet. No vascular, biliary, or graft‐related complications were seen in the post‐transplant period. No occurrence of MSUD was noted in DLT recipients. Conclusion: DLTs have excellent post‐surgical outcomes. DLT should be strongly considered and adopted by transplant programs worldwide to circumvent organ shortage. [ABSTRACT FROM AUTHOR]

Background and Aims: Several studies reported an association between liver stiffness measurement (LSM) obtained through vibration‐controlled transient elastography (VCTE) and all‐cause mortality in patients with nonalcoholic fatty liver disease (NAFLD). The objective of this systematic review and meta‐analysis was to summarize available evidence on the nature and magnitude of this association. Methods: We systematically searched PubMed‐MEDLINE and Scopus up to April 2023 for observational cohort studies in which LSM was measured with VCTE in patients with NAFLD or in general population settings, with a follow‐up ≥1 year and with available data on all‐cause mortality. Measures of association from individual studies were meta‐analysed using random effects models. Of the 517 titles initially scrutinized, we included seven studies with data on 18 771 participants (47.1% male) and a mean follow‐up of 3.6 years. We included effect estimates obtained in the models with the highest degree of adjustment for potential confounders available in each study. Results: When analysed as a categorical variable based on specific LSM cut‐offs, liver fibrosis was associated with an increased risk of all‐cause death (HR 2.10, 95% CI 1.56–2.83; test for overall effect z = 4.919, p < 0.001). Results were consistent when LSM was considered as a continuous variable (HR for 1 kPa increase: 1.03, 95% CI 1.01–1.05; test for overall effect z = 3.341, p = 0.001). There was borderline significant heterogeneity among the studies (I2 = 50.2% and I2 = 66.7% in the two analyses, respectively). No significant publication bias was detected by funnel plot analysis and Egger's and Begg's tests. Conclusion: The present meta‐analysis indicates that LSM, as a proxy of liver fibrosis, is independently and directly associated with a higher mortality risk in patients with NAFLD. [ABSTRACT FROM AUTHOR]

Background: Understanding the changes occurring in biological tissue during thermal ablation is at the heart of many current challenges in both therapy and medical imaging research. Purpose: The objective of this work is to quantitatively interpret the scattering response of human liver samples, before and after thermal ablation. We report acoustic measurements performed involving n = 21 human liver samples. Thermal ablation is achieved at temperatures between 45 and 80°C and quantification of the irreversible changes in acoustic attenuation and Backscattering Coefficient (BSC) is reported, with a particular attention to the latter. Methods: Both attenuation coefficient and BSCs were measured in the frequency range from 10 to 52 MHz. Scans were performed before heating and after cooling down. Attenuation coefficients were calculated using spectral difference method and BSC estimated using the reference phantom method. Results: Strong increases of attenuation coefficients and BSCs with heating temperature were observed. Quantitative ultrasonic parameters obtained with the polydisperse structure factor model (poly‐SFM)are compared to histological observations and seen to be close to hepatocyte mean diameter (HMD). Conclusions: The results presented in this study provide a description of the impact of thermal ablation in human liver tissue on acoustic attenuation and the BSC. For the first time, quantitative agreement between the Effective Scatterer Diameter (ESD) estimated from BSC and HMD was shown, highlighting the important role of cellular network in the scattering response of the medium. This core result is an important step toward the determination of the nature of scattering sources in biological tissues. [ABSTRACT FROM AUTHOR]

Summary: Background: No prospective diagnostic studies have directly compared widespread non‐invasive liver tests in patients with type 2 diabetes (T2D) using the intention‐to‐diagnose method for each of the three main histological features of metabolic dysfunction associated steatotic liver disease ‐ namely fibrosis, metabolic dysfunction‐associated steatohepatitis (MASH), and steatosis. Aims: To compare the performance of nine tests using the intention‐to‐diagnose rather than the standard method, which would exclude non‐evaluable participants Methods: Biopsy was used as the reference with predetermined cut‐offs, advanced fibrosis being the main endpoint. The Nash‐FibroTest panel including FibroTest‐T2D, SteatoTest‐T2D and MashTest‐T2D was optimised for type 2 diabetes. FibroTest‐T2D was compared to vibration‐controlled transient elastography stiffness (VCTE), two‐dimensional shear‐wave elastography stiffness (TD‐SWE), and Fibrosis‐4 blood test. NashTest‐T2D was compared to aspartate aminotransferase. SteatoTest‐T2D was compared to the controlled attenuation parameter and the hepatorenal gradient. Results: Among 402 cases, non‐evaluable tests were 6.7% for VCTE, 4.0% for hepatorenal gradient, 3.2% for controlled attenuation parameter, 1.5% for TD‐SWE, 1.2% for NashTest‐T2D, and 0.02% for Fibrosis‐4, aspartate aminotransferase and SteatoTest‐T2D. The VCTE AUROC for advanced fibrosis was over‐estimated by 6% (0.83 [95% CI: 0.78–0.87]) by standard analysis compared to intention‐to‐diagnose (0.77 [0.72–0.81] p = 0.008). The AUROCs for advanced fibrosis did not differ significantly in intention‐to‐diagnose between FibroTest‐T2D (0.77; 95% CI: 0.73–0.82), VCTE (0.77; 95% CI: 0.72–0.81) and TD‐SWE(0.78; 0.74–0.83) but were all higher than the Fibrosis‐4 score (0.70; 95% CI all differences ≥7%; p ≤ 0.03). For MASH, MashTest‐T2D had a higher AUROC (0.76; 95% CI: 0.70–0.80) than aspartate aminotransferase (0.72; 95% CI: 0.66–0.77; p = 0.035). For steatosis, AUROCs did not differ significantly between SteatoTest‐T2D, controlled attenuation parameter and hepatorenal gradient. Conclusions: In intention‐to‐diagnose analysis, FibroTest‐T2D, TD‐SWE and VCTE performed similarly for staging fibrosis, and out‐performed Fibrosis‐4 in outpatients with type 2 diabetes. The standard analysis over‐estimated VCTE performance. ClinicalTrial.gov: NCT03634098. [ABSTRACT FROM AUTHOR]

Background and Aims: Porto‐sinusoidal vascular disease (PSVD) has been described as the prominent pathology in liver explants of patients with cystic fibrosis (CF), but data outside the transplant setting are lacking. We aimed to investigate the prevalence of portal hypertension (PH) in CF‐associated liver disease (CFLD) and develop an algorithm to classify liver involvement in CF patients. Methods: This is a cross‐sectional study of consecutive paediatric and adult patients in a tertiary centre between 2018 and 2019, who underwent ultrasound, liver (LSM) and spleen stiffness (SSM) measurement. CFLD was defined according to physical examination, liver tests and ultrasound findings. PSVD was likely if there were PH signs in the absence of advanced chronic liver disease (CF‐ACLD, LSM <10 kPa). A historical cohort was used to validate the prognostic significance of the new definitions. Results: Fifty (27.5%) patients met CFLD criteria. At least one sign of PH was found in 47 (26%) patients, but most (81%) had LSM <10 kPa and were likely to have PSVD; only 9 (5%) had CF‐ACLD. PSVD and CFLD (LSM <10 kPa) co‐existed in most (23/36) cases. In the historical cohort (n = 599 patients), likely PSVD and CFLD+PH were independently associated with a 2‐fold and 3.5‐fold increase in mortality compared to patients without PH, respectively. In 34 patients with SSM, values <21 and >50 kPa accurately diagnosed specific signs of PH. Conclusions: PSVD is the prevailing cause of PH in CF patients. We developed a new diagnostic algorithm based on clinical and elastosonography criteria to classify liver involvement in patients with CF. [ABSTRACT FROM AUTHOR]

Purpose: Liver cirrhosis disrupts liver function and tissue perfusion, detectable by magnetic resonance imaging (MRI). Assessing liver function at the voxel level with 13‐b value intravoxel incoherent motion diffusion‐weighted imaging (IVIM‐DWI) could aid in radiation therapy liver‐sparing treatment for patients with early impairment. This study aimed to evaluate the feasibility of IVIM‐DWI for liver function assessment and correlate it with other multiparametric (mp) MRI methods at the voxel level. Method: This study investigates the variability of apparent diffusion coefficient (ADC) derived from 13‐b value IVIM‐DWI and B1‐corrected dual flip angle (DFA) T1 mapping. Experiments were conducted in‐vitro with QIBA and NIST phantoms and in 10 healthy volunteers for IVIM‐DWI. Additionally, 12 patients underwent an mp‐MRI examination. The imaging protocol included a 13‐b value IVIM‐DWI sequence for generating IVIM parametric maps. B1‐corrected DFA T1 pulse sequence was used for generating T1 maps, and Gadoxatate low temporal resolution dynamic contrast‐enhanced (LTR‐DCE) MRI was used for generating the Hepatic extraction fraction (HEF) map. The Mann‐Whitney U test was employed to compare IVIM‐DWI parameters (Pure Diffusion, Dslow; Pseudo diffusion, Dfast; and Perfusion Fraction, Fp) between the healthy volunteer and patient groups. Furthermore, in the patient group, statistical correlations were assessed at a voxel level between LTR‐DCE MRI‐derived HEF, T1 post‐Gadoxetate administration, ΔT1%, and various IVIM parameters using Pearson correlation. Results: For‐vitro measurements, the maximum coefficient of variation of the ADC and T1 parameters was 12.4% and 16.1%, respectively. The results also showed that Fp and Dfast were able to distinguish between healthy liver function and mild liver function impairment at the global level, with p = 0.002 for Fp and p < 0.001 for Dfast. Within the patient group, these parameters also exhibited a moderate correlation with HEF at the voxel level. Conclusion: Overall, the study highlighted the potential of Dfast and Fp for detecting liver function impairment at both global and pixel levels. [ABSTRACT FROM AUTHOR]

Peroxisomal proliferators induce in rodents hepatic hyperplasia and hypertrophy; the significant increase in the peroxisomal population is accompanied by specific and reversible induction of some peroxisomal enzymes. In suckling rats born from clofibrate-treated mothers, a massive removal of proliferated organelles occurs within 3 days of recovery. In the present paper we examined the early stages of the recovery period in liver of male rats treated with clofibrate for 5 days. The lysosomal involvement in the removal of drug-induced peroxisomes was investigated under physiological conditions, i.e. in the absence of inhibitors of the autophagic process. Biochemical results indicate that peroxisomal beta-oxidation, but not catalase activity, returns to the control values within the examined period. Total acid phosphatase activity is not affected by clofibrate treatment, but following fractionation on a linear density gradient the lysosomal marker enzyme activity is shifted towards lower density values, particularly at day 1 and 2 of recovery. This class of organelles possibly represents lysosomes involved in active autophagic processes. Acid phosphatase cytochemistry shows an increase of lysosome number at day 1 of recovery. Combination of acid phosphatase cytochemistry either with catalase cytochemistry or with catalase immunogold labelling allows to reveal organelles containing both marker enzymes. These results strongly support the involvement of autophagic processes in the removal of proliferated peroxisomes.

In this paper, we report on the development of a technique for the kinetic characterization of the metabolic reactions of liver cells in adhesion culture. The technique is based on the use of a continuous-flow bioreactor which is designed and operated in such a way as to ensure a uniform distribution of metabolite at the cell site: hence, the metabolite concentration at the surface of cells cultured in adhesion at the bottom of the bioreactor equals that in the stream leaving the bioreactor. Under steady conditions, the rate of a given cell reaction is directly estimated from the metabolite concentration difference in the streams entering and leaving the bioreactor and can be correctly related to the actual concentration at the cell surface. Such a technique was used for a preliminary investigation of the kinetics of ammonia elimination, urea synthesis, and phenolsulfonphthalein (PSP) elimination by primary rat hepatocytes cultured in adhesion on collagen, with respect to ammonia and PSP concentration, respectively. The rate at which the hepatocytes eliminated ammonia increased with increasing ammonia concentrations according to a Michaelis-Menten kinetics. The hepatocytes synthesized urea also in the absence of ammonia in the medium: as ammonia concentration increased, the cells synthesized urea at a rate that increased according to a saturation kinetics. In the concentration range investigated, the hepatocytes eliminated PSP at a rate that increased linearly with the actual PSP concentration in the medium. Such kinetic information can be coupled to the mechanism of metabolite transport in a hybrid liver support device to yield an effective device design for the treatment of acute liver failure.

In The Netherlands, the public funding of a number of health care services is controversial. What can we learn from this about the moral concerns that underlie these judgements? And, if there is anything to learn, can we use this improved understanding to scrutinise the adequacy of particular decisions concerning the public funding of health care services? In the present paper, I will analyse three cases: corrective surgery, In Vitro Fertilisation and liver transplantation. I will summarise the arguments that have been used to support or to challenge the public funding of these services. I will then assess the merits of Daniels' fair equality of opportunity account of justice in health care. Can this account improve our understanding of the moral concerns underlying our judgements about the public funding of these services? Can it serve to scrutinise the adequacy of particular decisions that are made concerning the public funding of health care services? My answer to both questions will be a qualified yes. Daniels' account can provide guidance, but not because we can deductively infer from it what is right and what is wrong. Instead, I will argue for a more casuistic use of the concept of fair equality of opportunity.

Occupational medicine programs use medical surveillance tests to measure physiologic parameters that may be affected by workplace exposures. Surveillance tests can detect early detrimental changes before workers manifest recognizable symptoms. Hepatic function testing is one type of surveillance test used to monitor workers exposed to hepatotoxins. However, a significant proportion of these test reports return showing abnormal hepatic function without a readily apparent etiology. Follow-up investigation of abnormal liver enzyme tests is a commonly encountered problem in occupational medicine clinics. The algorithm proposed in this paper will outline a systematic approach for investigating abnormal hepatic function tests from asymptomatic workers.

We have reviewed studies reporting biochemical abnormalities consequent upon anorexia nervosa (AN). Hitherto, these reports have lacked any coherent synthesis in the account of how such abnormalities arise. The paper firstly addresses electrolyte imbalances, changes in underlying physiology, and the clinical consequences if such abnormalities are not recognized. Mechanisms contributing to changes in renal function are discussed. The use of alternative energy sources for the Krebs' cycle is considered in the context of catabolic processes occurring in the AN subject. Liver function, and protein and fat metabolism are considered in this context. Comparisons with the catabolism of starvation and the processes found in dietary-deficient forms of malnutrition are made. The AN subject has many features in common with the state of marasmus. The implications of chronic dietary abnormalities in activating rarely exploited metabolic pathways are considered and well recognized findings, for example hypercarotinemia, are explained through such processes. Evidence for specific trace element and vitamin deficiencies are also reviewed. [ABSTRACT FROM AUTHOR]

The colon and lung amiloride-binding proteins were cloned from rat tissues. Two sizes of transcripts were identified. The 2.7-kb transcript codes for an 85-kDa protein, whereas the 1.2-kb transcript codes for a 25-kDa polypeptide. The 2.7-kb transcript was detected in the proximal and distal colon and in duodenum, liver, placenta and thymus. The 1.2-kb transcript was the only form present in lung and spleen, and it was also detected in placenta and colon. The short form corresponds to the 3′ terminus of the longer one. It is formed by alternative transcription under the control of an internal promoter. Cells stably transfected with cDNAs encoding these two proteins were used for binding studies using [3H]phenamil, a potent blocker of the epithelial Na+ channel, derived from amiloride. Both the long and short forms of the protein bind amiloride and some of its derivatives, but they have distinct pharmacologies. The order of potency of the different amiloride derivatives to inhibit [3H]phenamil binding was phenamil (K0.5 =10 nM) > benzamil (K0.5 = 43 nM) > amiloride (K0.5 = 1.4 μM) ≈ ethylisopropylamiloride (K0.5 = 1.6 μM) for the long form, whereas it was phenamil (K0.5 = 68 nM) > amiloride (K0.5 = 3.2 μM) ≈ ethylisopropylamiloride (K0.5 = 4 μM) ≈ benzamil (K0.5 = 6.3 μM) for the short form. Although the binding proteins described here are distinct from the pore-forming protein of the epithelial Na+ channel, the pharmacological profile of the long form of the ABP is identical to that described previously in pig and human kidney, and similar to that expected for an epithelial Na+ channel. The pharmacological profile of the short form resembles that previously described for an amiloride-binding protein in pneumocytes. Results presented in this paper suggest that previously purified preparations showing Na+ channel activity contain different forms of the amiloride-binding protein, possibly associated with other proteins. The similarity between amiloride-binding proteins and a protein identified in seminal vesicles suggests that amiloride-binding proteins are the best members of a new family of epithelial-specific proteins. [ABSTRACT FROM AUTHOR]

Nucleoli, isolated from rat liver, synthesize in vitro high-molecular-weight RNA, the base composition and sedimentation pattern of which resembles that of ribosomal precursor RNA. In addition, RNA molecules larger than 45 S have been found. In this paper experiments are described which indicate that these large RNA molecules represent genuine transcription products and are not aggregates arising under the experimental conditions employed. This was established by comparing different extraction methods, by sedimentation analysis of the RNA after denaturation with formamide and by pulse-chase experiments. Hybridisation-competition studies showed that 45-S RNA competes with those rapidly sedimenting molecules to about 80-90%, thus providing evidence for the presence of ribosomal precursor RNA sequences in those long transcription products. Intact nuclei are able to synthesize in the presence of Mg2+ and α-amanitin RNA molecules larger than 45 S too, provided that the RNAase activity is suppressed effectively by the addition of cytoplasmic RNAase inhibitor. The significance of these results is discussed with respect to the initial transcript of the rDNA genes in rat liver nucleoli. [ABSTRACT FROM AUTHOR]

Aflatoxin B1 strongly inhibits protein synthesis in rat liver cells. We previously demonstrated that tiffs inhibition could be divided into two steps: up to 5 h aflatoxin blocks protein synthesis directly and specifically at the polysome level; beyond 7 h protein synthesis inhibition appears chiefly as a consequence of transcription impairment due to drug action. This paper confirms the foregoing results and represents an attempt to localize the translational step inhibited in vivo by Aflatoxin B1. We used the simulation study developed by Li, Kisilevsky, Wasan and Hammond, 1972(Biochim. Biophys. Acta, 272, 451-462) to determine precisely the site inhibited in vivo after drug intoxication. This analysis is based on two parameters: the kinetics of polysome labeling to follow the nascent peptide synthesis, and the kinetics of supernatant labeling to follow the completed protein synthesis. Up to 5 h after dosing, aflatoxin specifically inhibits the elongation and/or termination steps during protein synthesis; after longer periods of time inhibition occurs essentially at the initiation step. When the intracellular concentration of aflatoxin is too high, particularly 2 h after dosing, each step of protein synthesis is blocked. Polypeptide synthesis by the postmitochondrial supernatants isolated from aflatoxin-treated animals is impaired in the same proportion as protein synthesis in vivo. The damage caused by aflatoxin is mostly observed on microsomes. However, purified polysomes isolated from aflatoxin-treated rats synthesize proteins in vitro the same extent as those from controls. These results suggest that aflatoxin metabolite(s) are bound to polysomes with noncovalent bonds. These active metabolites are probably lost during polysome isolation procedures. Finally, relationships between protein metabolism and aflatoxin carcinogenesis are discussed. [ABSTRACT FROM AUTHOR]

Debate continues over the physical characteristics and even the existence of arginase isoenzymes. This paper gives additional support for such multiplicity and reports differences in physical characteristics among the various forms. After 2500-5000-fold purification of rat liver arginase, three molecular forms were separated on carboxymethyl-cellulose columns and were purified 2500-5000-fold, 800-1000-fold and 600-1000-fold, respectively. The molecular forms have also been identified by chromatography in the supernatant of tissue extracts. The isolation of these molecular forms by affinity chromatography, using Sepharose-lysine as a competitive inhibitor of arginase, shows only one main form, however. Kinetic studies were done for two of the molecular forms isolated, specifically the activation energy (Ea, the energy of denaturatization (Ed), Km, pH and the effect of divalent cations were determined. Significant differences were found for the Ea between the two molecular forms. The isolated isoenzymes are cationic at pH 5.5 and pH 8.8. However, they show different mobilities in electrophoresis. The molecular weight determination by gel filtration yields a value of 110000 to 115000 for both forms. The use of thin-layer immunochromatography plates, a combination of molecular weight and immunodiffusion technique, gave only one peak with the same molecular weight as that determined by gel filtration. The immunological studies showed that the isoenzymes have similar antigenic determinants. [ABSTRACT FROM AUTHOR]

In this paper we describe the first in vitro response to the liver alloantigen F. The anti-F response serves as a valuable model for autoimmune phenomena since priming appropriate strains of mice (responders) with allogeneic but not syngeneic type F leads to autoantibody production. The in vitro system is based on the proliferation of T cells, from mice primed in vivo with F, when coincubated with splenic adherent cells (SAC) prepulsed with F in vivo. The system displays two important correlates of the in vivo antibody response to F:1.T cells from mice primed with syngeneic F do not proliferate when incubated with SAC prepulsed with syngeneic F and 2. Mice that do not make antibody responses to allo F in vivo (DBA/2) do not show in vitro proliferative responses. These findings indicate that the proliferative assay is a good in vitro model for the F response. [ABSTRACT FROM AUTHOR]

Exposure of perfused rat livers to zymosan, arachidonic acid and phenylephrine, but not to latex particles, induces pronounced oxygen uptake, glycogenolysis and Ca2+ mobilization. The oxygen uptake induced by arachidonic acid and by zymosan remains elevated even after the agents have been removed. NaN3 was found to be much more effective in inhibiting the oxygen uptake induced by phenylephrine than that induced by zymosan or arachidonic acid. Glucose release induced by zymosan and by arachidonic acid reaches a maximum after about 2 min and then declines very rapidly even while the agents are still being infused. In contrast, glucose release induced by phenylephrine remains elevated for the duration of the infusion. Ca2+ fluxes induced by arachidonic acid are similar to those induced by phenylephrine in that efflux occurs when the agent is administered and influx occurs only when the agent is removed. This contrasts to the Ca2+ flux changes induced by zymosan where both Ca2+ effiux and Ca2+ influx occur even while zymosan is still being infused. Glucose release induced by zymosan is inhibited by bromophenacylbromide and nordihydroguaiaretic acid, but not by indomethacin. Indomethacin, however inhibits the arachidonic-acid-induced glucose release which is also inhibited by nordihydroguaiaretic acid but not by bromophenacylbromide. Indomethacin inhibits also the arachidonic-acid-induced Ca2+ flux changes whereas the zymosan- and the phenylephrine-induced Ca2+ flux changes are not inhibited by the cyclooxygenase inhibitor. The data presented in tbs paper suggest that in the perfused rat liver the zymosan-induced glycogenolysis, as well as the Ca2+ flux changes and glycogenolysis induced by arachidonic acid, are mediated by eicosanoids. [ABSTRACT FROM AUTHOR]

Nuclear RNP complexes, cytoplasmic mRNP particles and free and membrane-bound polysomes were prepared from rat liver and their tow-molecular-muss RNA components were analyzed on polyacrylamide/formamide gels. The separated small RNAs transferred to diazophenylthioether paper were hybridized to the nick-translated recombinant plasmid pA6 containing cDNA sequences for the low-Mr RNA called 7S(L) RNA. Nuclear RNP particles and free and membrane-bound polysomes were found to contain 7S(L) RNA. In the cytoplasm 7S(L) RNA could be identified as the major small RNA in 20-S cmRNP particles. [ABSTRACT FROM AUTHOR]

Apolipoprotein A-I, the major protein in mammalian high-density lipoprotein, acts as a cofactor for lecithin—cholesterol acyltransferase during the formation of cholesterol ester and as such, is thought to promote cholesterol efflux from peripheral cells to the liver. In this paper, we report the partial purification of rat liver apolipoprotein A-I mRNA by a polysome immunoadsorption technique, and its cDNA cloning. Isolation of two overlapping cDNA clones enabled us to derive the whole rate apolipoprotein A-I cDNA coding sequence. Comparison of the deduced protein sequence with its human counterpart reveals a striking homology between the prepropeptide precursors. Both mature protein amino-terminal regions are very homologous, suggesting that this particular domain could be involved in lipid/protein binding or lecithin—cholesterol acyltransferase activation. [ABSTRACT FROM AUTHOR]

As previously reported [Favilla, R. & Cavatorta, P. (1975) FEBS Lett. 50, 324–329], the enzyme horse liver alcohol dehydrogenase catalyzes a reaction between NAD+ and H2O2. The final isolated product was then called NADX because of its unknown structure. In this paper the results of spectroscopic investigations on this compound are described. They indicate that only the nicotinamide moiety of the original NAD+ molecule was modified by the action of hydrogen peroxide. From the ¹H and 13C nuclear magnetic resonance spectra of NADX the following structure was deduced: adenosine(5′)diphospho(5)-β-D-ribose-NH-CH=C(CHO)-CONH2. This structure is consistent with both ultraviolet and reactivity measurements performed on NADX. A tentative mechanism for the whole peroxidatic reaction pathway leading to NADX is finally proposed. [ABSTRACT FROM AUTHOR]

Liver and muscle aldolase display similar reaction mechanisms. Both the enzymes, by reacting with dihydroxyacetone phosphate, form an acid-labile intermediate which is in rapid equilibrium with an eneamine intermediate. Differences are found in the equilibrium concentration of the acid-labile intermediate, which represents approximately 25% of the total intermediates in the liver (this paper) and 60% in the muscle enzyme [E. Grazi and G. Trombetta, Biochem. J. 175, 361 (1978)] and in the rate of formation of the eneamine intermediate which is much slower in the liver enzyme. Furthermore, with liver aldolase, the rate by which the C-3H bond of dihydroxyacetone phosphate is cleaved is increased by 60 times in the presence of glyceraldehyde 3-phosphate. This, mechanistically, indicates that glyceraldehyde 3-phosphate is bound to the enzyme before the formation of the eneamine from dihydroxyacetone phosphate, and, physiologically, that in liver aldolase the gluconeogenetic activity is favoured over the glycolytic activity. [ABSTRACT FROM AUTHOR]

The mechanism of action of 3-hydroxy-3-methylglutaryl-CoA reductase solubilized from rat liver microsomes has been investigated. In the reduction of 3-hydroxy-3-methylglutaryl-CoA to mevalonate, an overall initial velocity study gave a linear intersecting pattern when both 3-hydroxy-3- methylglutaryi-CoA and NADPH were variable substrates. Adenosine 2′-monophospho-5′-diphos- phoribose, which was found to be a reversible inhibitor of reductase, inhibited the enzyme competitively with respect to NADPH, and uncompetitively with respect to 3-hydroxy-3-methylglutaryl-CoA. On the other hand, the inhibition of reductase by ML-236B (sodium salt), a specific reversible inhibitor of the enzyme isolated from the culture of a Penicillium (whose structure is given in the paper) is competitive with respect to 3-hydroxy-3-methylglutaryl-CoA and noncompetitive with respect to NADPH [Endo et al. (1976) FEBS Lett. 72, 323-326]. The reduction of 3-hydroxy-3-methylglutaryl-CoA to mevalonate was subject to the substrate inhibition by NADPH attributed to the formation of a productive enzyme-NADPH complex. These results indicate that the two substrates bind to the enzyme effectively in an ordered manner; reductase first interacts with 3-hydroxy-3-methylglutaryl-CoA to make a binary complex, which, in turn, forms a ternary complex with one molecule of NADPH. Considered together with the results of product inhibition study, and assuming a hemithioacetal of mevaldate and CoA is an intermediate of the reductase reaction, a bi-uni-uni-ter-ping- pong mechanism is proposed as a model of the overall reaction. [ABSTRACT FROM AUTHOR]

A product of mitochondrial protein synthesis in rat liver mitochondria, characterized by a low molecular weight (Mr < 10000) and an unusually high hydrophobicity, has been identified as the dicyclohexylcarbodiimide-binding protein and as a peptide of the hydrophobic sector of the mitochondrial ATPase complex. The purified protein still possesses the ability to bind dicyclohexylcarbodiimide. [ABSTRACT FROM AUTHOR]

The object of this paper is to analyse the effects of the coenzymes NAD(P)+ and NAD(P)H, and the effectors ADP and GTP, on the polyhexameric structure of pig-liver dehydrogenase. The linear polymerisation model proposed by Eisenberg for the native quaternary structure of this protein is valid with any effector; the observed variations of the degree of polymerization are explained by the modification of the apparent association constant of the hexamers. The appendices I and II define the free and associated areas and give, the theoretical foundations of the variation of the association constant of hexamers in terms of the binding of the ligands to the protemers. The increase in the degree of polymerization of the glutamate dehydrogenase with the binding of NAD(P)H is explained by a higher affinity of the coenzymes for the protomers which have an associated area compared to the protomers which have a free area. No variation is observed with NAD(P)+, ADP, or GTP alone. The formation of the protein · GTP · NAD(P)H ternary complex leads to a complete depolymerization when the two ligands are in saturating concentrations. The systematic study of the variations of polymerization in terms of increasing concentration of NAD(P)H at constant concentration of GTP, or in terms of increasing concentration of GTP at constant concentration of NAD(P)H shows that the interaction between the two opposite protomers of two consecutive hexamers is responsible for the sigmoidal shape of the depolymerization curves. The reversibility of this effect by ADP is assigned to a competition between the binding of ADP and the binding of GTP. [ABSTRACT FROM AUTHOR]

An enzyme, exhibiting NAIDPH-dependent oxidoreductase activity towards alicyclic ketones has been extracted from pig liver and purified 122-fold with respect to the protein contained in the crude extract after centrifugation at 54000×g. General properties, ultraviolet spectrum, stability, kinetic constants (V and Km) for NADPH and for typical substrates are reported. The molecular weight of the enzyme was estimated at 500000 by gel-filtration. The enzyme is HS(HB)-specific with respect to coenzyme. Alicyclic ketones can be conveniently used to measure the activity at all stages of purification. The topography of the active site responsible for oxidoredutase activity has been investigated by use of rigid alicyclic ketones such as trans-decal-1-ones as probes. In the accompanying paper it is shown (1) that the biological function of the whole enzyme complex is that of a fatty acid synthetase and (2) that the oxidoreductase activity can be ascribed to its 3-oxoacyl-acyl-carrier protein reductase component. [ABSTRACT FROM AUTHOR]

This paper deals with investigations in isolated perfused rat livers on tryptophan-oxygenase a under various experimental conditions. Enzyme-activity Showed a linear rise with amounts of tryptophan (0; 125 and 250 mg of tryptophan/kg) in the perfusate. Adrenalectomized and sham-operated animals have been compared and activity in the adrenalectomized rats were significantly lower in all cases. A significant decrease in the substrate induced increase of tryptophan-oxygenase-activity occured 12 h after adrenaleetomy. Substrate-concentration was 250 mg/kg in these experiments. The influence of substrate and cortisol on tryptophan-oxygenase-activity has been investigated 7 days after operation, Combined application of both substrate and steroid resulted in no difference to sham-operated animals when compared to substrate only in the same concentration. On the other hand, in livers from adrenlectomized rats values were significantly higher with combined application than in livers of adrenalectomized animals which received substrate only. The substrate-dependent rise in trsyptophan-oxygenase-activity could not be influenced by actinomycin D in contrast to to he cortisol effect which was significantly inhibited under these conditions. Both "inducers" were inhibited by cycloheximid. These inhibition-experiments suggest and confirm two different mechanisms of the substrate-activation and steroid-induction of tryptophan-oxygenase. [ABSTRACT FROM AUTHOR]

This paper reports the partial purification and characterization of a new type of arginase from chicken liver. The enzyme can be demonstrated only in less than 10% of a fasting chicken population, and has never been found in fed animals. The new arginase differs with respect to several properties (chromatographic behaviour, sedimentation coefficient, Km for arginne) from the arginase normally found in chicken liver and is more like the ureotelic arginase isolated from rat liver. [ABSTRACT FROM AUTHOR]

LINKED CONTENT This article is linked to Shen et al and Dong and Cai papers. To view these articles, visit https://doi.org/10.1111/apt.15298 and https://doi.org/10.1111/apt.15410. [ABSTRACT FROM AUTHOR]

Linked Content This article is linked to Shen et al and Shen and Fan papers. To view these articles, visit https://doi.org/10.1111/apt.15298 and https://doi.org/10.1111/apt.15387. [ABSTRACT FROM AUTHOR]

Advances in the development of noninvasive imaging techniques have spurred investigations into ectopic lipid deposition in the liver and muscle and its implications in the development of metabolic diseases such as type 2 diabetes. Computed tomography and ultrasound have been applied in the past, though magnetic resonance‐based methods are currently considered the gold standard as they allow more accurate quantitative detection of ectopic lipid stores. This review focuses on methodological considerations of magnetic resonance‐based methods to image hepatic and muscle fat fractions, and it emphasizes anatomical and morphological aspects and how these may influence data acquisition, analysis, and interpretation. [ABSTRACT FROM AUTHOR]

The aim of this study is to investigate the protective effects of Elaeagnus angustifolia fruit extract (EAFE) on hematology, biochemical parameters, liver enzymes and damage of different tissues of male mice exposed to graphene oxide nanoparticles (GO NPs). In this research, 48 mice were divided into six groups. Hematology parameters including red blood cells (RBC), white blood cells (WBC), hematocrit (Ht), and hemoglobin (Hb), biochemical parameters such as cholesterol, triglyceride, glucose, protein, albumin, creatinine and bilirubin, liver enzymes including aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP) and lactate dehydrogenase (LDH) and histological damage of liver, kidney, lung and testis of mice were investigated. The results show that GO NPs in both concentrations (30 and 60 mg/kg/bw) decrease the number of RBC compared to the control group (p < 0.05). EAFE has no effect on RBC count while EAFE in combination with both concentrations of 30 and 60 mg/kg/bw GO NPs significantly (p < 0.05) improves the RBC count of mice. Also, the results show that EAFE improves the number of WBC, Ht, Hb, and biochemical parameters of mice exposed to different concentrations of GO NPs. A series of morphological changes were observed in the RBC of rats exposed to 60 mg/kg/bw GO NPs, including Dacrocyte, Poikilocyte and Schistocyte, which EAFE can improve the morphological changes caused in RBC. A series of histological damages such as degeneration and dilatation in the central vein in liver tissue, thickening and inflammatory cell infiltration in the renal capsule, peribronchiolar inflammatory cell infiltration and congestion in peribronchiolar blood vessels in lung tissue and decrease in the height of the germinal epithelium and a decrease in the population of spermatozoid cells in spermatogenic cells were observed in the testis of mice exposed to 60 mg/kg/bw GO NPs. The results show that EAFE can improve the damage caused by GO NPs in the liver, kidney and lung tissues, while it has no effect on the damage in the mice testis tissue. Therefore, GO NPs cause damage in the blood and different tissues of mice, and the use of EAFE can be effective in improving these damages. [ABSTRACT FROM AUTHOR]

Puerarin (Pue) is a kind of isoflavone compound extracted from Pueraria lobata, which has significant antioxidant activity. Excessive use of acetaminophen (APAP) can cause oxidative stress in the liver and eventually lead to acute liver injury. The purpose of this study was to investigate the protective effect and the mechanism of puerarin on APAP‐induced liver oxidative damage. In in vitro experiments, puerarin significantly increased the cell activity of HepG2 cells, reduced the ROS accumulation, alleviated the oxidative damage and mitochondrial dysfunction. In in vivo studies, our results showed that puerarin enhanced antioxidant activity and alleviated histopathological damage. Further studies showed that puerarin decreased the expression of Keap1, promoted the nuclear migration of Nrf2, and up‐regulated the expression of GCLC, GCLM, HO‐1 and NQO1. This study demonstrated that puerarin can protect APAP‐induced liver injury via alleviating oxidative stress and mitochondrial dysfunction by affecting the nuclear migration of Nrf2 via inhibiting Keap1. [ABSTRACT FROM AUTHOR]

Objectives: The primary aim was to estimate the influence of various depths on ultrasound attenuation coefficient (AC) of multiple vendors in the liver. The secondary aim was to evaluate the impact of region of interest (ROI) size on AC measurements in a subset of participants. Methods: This Institutional Review Board (IRB)‐approved Health Insurance Portability and Accountability Act (HIPAA)‐compliant retrospective study was carried out in two centers using AC‐Canon and AC‐Philips algorithms and extracting AC‐Siemens values from ultrasound‐derived fat fraction algorithm. Measurements were performed positioning ROI upper edge (3 cm size) at 2, 3, 4, 5 cm from the liver capsule with AC‐Canon and AC‐Philips and at 1.5, 2, 3 cm with Siemens algorithm. In a subset of participants, measurements were obtained with 1 and 3 cm ROI size. Univariate and multivariate linear regression models and Lin's concordance correlation coefficient (CCC) were used for statistical analysis as appropriate. Results: Three different cohorts were studied. Sixty‐three participants (34 females; mean age: 51 ± 14 years) were studied with AC‐Canon, 60 (46 females; mean age: 57 ± 11 years) with AC‐Philips, and 50 (25 females; 61 ± 13 years) with AC‐Siemens. There was a decrease in AC values per 1 cm increase in depth in all. In multivariable analysis, the coefficient was −0.049 (−0.060; −0.038 P <.001) with AC‐Canon, −0.058 (−0.066; −0.049 P <.001) with AC‐Philips and −0.081 (−0.112; −0.050 P <.001) with AC‐Siemens. AC values with 1 cm ROI were significantly higher than those obtained with 3 cm ROI at all depths (P <.001) but the agreement between AC values obtained with different ROI size was excellent (CCC 0.82 [0.77–0.88]). Conclusions: There is depth dependence in AC measurement that affects results. A standardized protocol with fixed ROI's depth and size is needed. [ABSTRACT FROM AUTHOR]

Background: Since November 2020, Italy was the first country to carry out a protocol and use liver from COVID‐19 donors. We aimed to evaluate the medium‐term outcome of patients who underwent liver transplant (LT) with those grafts. Methods: We consecutively enrolled 283 patients who underwent first LT from November 2020 to December 2022 in our Center (follow‐up 468 days). Twenty‐five of 283 (8.8%, study population) received a graft from donors with previous (4%) or active (96%) SARS‐CoV‐2 infection, and 258/283 (91.2%, control group) received a graft from COVID‐19‐negative donors. SARS‐CoV‐2‐RNA was tested on graft tissue of COVID‐19 donors and their recipients underwent weekly evaluation of SARS‐CoV‐2‐RNA in nasal swabs for the first month after LT. Results: One‐year and 2‐year patient survival was 88.5% and 88.5% in study group versus 94.5% and 93.5% in control group, respectively (p =.531). In study population there was no evidence of donor‐recipient virus transmission, but three (12%) patients (vs. 7 [2.7%] of control group, p =.048) developed hepatic artery thrombosis (HAT): they were SARS‐CoV‐2‐RNA negative at LT and 1/3 grafts tested SARS‐CoV‐2‐RNA positive on liver tissue. COVID‐19 donor was independently associated with HAT (odds ratio (OR) = 4.85, 95% confidence interval (CI) 1.10–19.15; p =.037). By comparing study population with control group, acute rejection and biliary complication rates were not significantly different (16% vs. 8.1%, p =.26; 16% vs. 16.3% p =.99, respectively). Conclusions: Our 1‐year results of transplant strategy including liver grafts from COVID‐19 donors were favorable. HAT was the only complication with significantly higher rate in patients transplanted with COVID‐19 donors compared with control group. [ABSTRACT FROM AUTHOR]

The study of azo dyes degradation products and their harmfulness is an important topic because their diffusion in the environment is still a serious problem. We investigated the reduction by pig liver microsomal fraction of four bis‐azo dyes, Acid Red 73, Acid Red 150, Direct Red 24, and Direct Red 28, in anaerobic condition. These complex molecules, different for position/nature of substituent groups and for the group interposed between the two azo bonds, allowed to investigate the correlation between substrate molecular structure and action of a subcellular fraction representative of the xenobiotic degradation by a living organism and the consequent possible appearance of harmful reaction products. Dyes were first carefully purified to eliminate interferences in the enzymatic assays. The reduction products were identified by gas chromatography/mass spectrometry. Acid Red 73 and Acid Red 150 were markedly reduced with production of harmful aromatic amines, while Direct Red 24 and Direct Red 28 were neither reduced to their synthesis amines nor to other amines. These results suggest that azo dyes with a benzidine derivative group are not degraded by microsomal fraction and therefore molecules with a similar structure could be classified with a lower risk index not producing any harmful catabolic product. [ABSTRACT FROM AUTHOR]

Xenotransplantation using pigs' liver offers a potentially alternative method to overcome worldwide donor shortage, or more importantly as a bridge to allotransplantation. However, it has been challenged by profound thrombocytopenia and fatal coagulopathy in non‐human primate models. Here we suggest that a left auxiliary technique can be a useful method to achieve extended survival of the xenograft. Fifteen consecutive liver xenotransplants were carried out in a pig‐to‐cynomolgus model. Right auxiliary technique was implemented in two cases, orthotopic in eight cases, and left auxiliary in five cases. None of the right auxiliary recipients survived after surgery due to hemorrhage during complex dissection between the primate's right lobe and inferior vena cava. Orthotopic recipients survived less than 7 days secondary to profound thrombocytopenia and coagulopathy. Two out of five left auxiliary xenotransplants survived more than 3 weeks without uncontrolled thrombocytopenia or anemia, with one of them surviving 34 days, the longest graft survival reported to date. Left auxiliary xenotransplant is a feasible approach in non‐human primate experiments, and the feared risk of thrombocytopenia and coagulopathy can be minimized. This may allow for longer evaluation of the xenograft and help better understand histopathological and immunological changes that occur following liver xenotransplantation. [ABSTRACT FROM AUTHOR]

Background & Aims: PIEZO1 and TRPV4 are mechanically and osmotically regulated calcium‐permeable channels. The aim of this study was to determine the relevance and relationship of these channels in the contractile tone of the hepatic portal vein, which experiences mechanical and osmotic variations as it delivers blood to the liver from the intestines, gallbladder, pancreas and spleen. Methods: Wall tension was measured in freshly dissected portal veins from adult male mice, which were genetically unmodified or modified for either a non‐disruptive tag in native PIEZO1 or endothelial‐specific PIEZO1 deletion. Pharmacological agents were used to activate or inhibit PIEZO1, TRPV4 and associated pathways, including Yoda1 and Yoda2 for PIEZO1 and GSK1016790A for TRPV4 agonism, respectively. Results: PIEZO1 activation leads to nitric oxide synthase‐ and endothelium‐dependent relaxation of the portal vein. TRPV4 activation causes contraction, which is also endothelium‐dependent but independent of nitric oxide synthase. The TRPV4‐mediated contraction is suppressed by inhibitors of phospholipase A2 and cyclooxygenases and mimicked by prostaglandin E2, suggesting mediation by arachidonic acid metabolism. TRPV4 antagonism inhibits the effect of agonising TRPV4 but not PIEZO1. Increased wall stretch and hypo‐osmolality inhibit TRPV4 responses while lacking effects on or amplifying PIEZO1 responses. Conclusions: The portal vein contains independently functioning PIEZO1 channels and TRPV4 channels in the endothelium, the pharmacological activation of which leads to opposing effects of vessel relaxation (PIEZO1) and contraction (TRPV4). In mechanical and osmotic strain, the PIEZO1 mechanism dominates. Modulators of these channels could present important new opportunities for manipulating liver perfusion and regeneration in disease and surgical procedures. [ABSTRACT FROM AUTHOR]

Background: Intestinal barrier dysfunctions have been associated with liver steatosis and metabolic diseases. Besides nutritional factors, like a Western‐style diet (WSD), serotonin has been linked with leaky gut. Therefore, we aimed to evaluate the role of serotonin in the pathogenesis of intestinal barrier dysfunctions and liver steatosis in mice fed high‐fat and high‐sugar diets. Methods: 6–8 weeks old male serotonin reuptake transporter knockout mice (SERT−/−) and wild‐type controls (SERT+/+) were fed either a WSD or a control diet (CD) ad libitum with or without fructose 30% (F) added to the drinking water for 12 weeks. Markers of liver steatosis and intestinal barrier function were assessed. Key Results: SERT−/− mice showed increased weight gain compared with SERT+/+ mice when fed a WSD ± F for 12 weeks (p < 0.05), whereby SERT−/− mice exhibited reduced energy (−21%) intake. Furthermore, SERT knockout resulted in a more pronounced liver steatosis (p < 0.05), enhanced levels of endotoxin in portal vein plasma (p < 0.05), and increased liver expression of Tnf and Myd88 (p < 0.05), when mice were fed a WSD ± F. Finally, SERT−/− mice, when compared with SERT+/+ mice, had a decreased mRNA expression of Muc2 (p < 0.01), Ocln (p < 0.05), Cldn5 (p = 0.054) and 7 (p < 0.01), Defa5 (p < 0.05) and other antimicrobial peptides in the ileum. On the protein level, ZO‐1 (p < 0.01) and DEFA5 protein (p < 0.0001) were decreased. Conclusion and Inferences: Our data demonstrate that SERT knockout causes weight gain, liver steatosis, and leaky gut, especially in mice fed a WSD. Therefore, SERT induction could be a novel therapeutic approach to improve metabolic diseases associated with intestinal barrier dysfunction. [ABSTRACT FROM AUTHOR]