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Heart failure—either with reduced or preserved ejection fraction (HFrEF/HFpEF)—is a clinical syndrome of multifactorial and gender-dependent aetiology, indicating the insufficiency of the heart to pump blood adequately to maintain blood flow to meet the body's needs. Typical symptoms commonly include shortness of breath, excessive fatigue with impaired exercise capacity, and peripheral oedema, thereby alluding to the fact that heart failure is a syndrome that affects multiple organ systems. Patients suffering from progressed heart failure have a very limited life expectancy, lower than that of numerous cancer types. In this position paper, we provide an overview regarding interactions between the heart and other organ systems, the clinical evidence, underlying mechanisms, potential available or yet-to-establish animal models to study such interactions and finally discuss potential new drug interventions to be developed in the future. Our working group suggests that more experimental research is required to understand the individual molecular mechanisms underlying heart failure and reinforces the urgency for tailored therapeutic interventions that target not only the heart but also other related affected organ systems to effectively treat heart failure as a clinical syndrome that affects and involves multiple organs. [ABSTRACT FROM AUTHOR]

Carcinoid heart disease (CaHD) is an important complication among patients with metastatic neuroendocrine tumors and carcinoid syndrome (CS). CS patients (25%-65%) eventually develop CaHD; these patients face a significantly increased risk of morbidity and mortality. Guidance papers (eg, clinical practice guidelines, consensus guidelines, and expert statements) have been established by major organizations across the disciplines of cardiology and oncology; however, these recommendations are not routinely implemented. The aim of this article is to encourage the integration of current recommendations from national societies into clinical practice. Early screening upon recognition of CS and prior to the development of CaHD symptoms is paramount, as no existing therapies are approved to reverse the fibrotic damage to the heart once it occurs. Valvular replacement is the only definitive treatment for CaHD once it has developed. When patients are noted to have urinary 5-hydroxyindoleacetic acid (5-HIAA) levels ≥300 µmol/24 h and/or serum N-terminal pro B-type natriuretic peptide (NT-proBNP) levels >260 pg/mL, echocardiography is recommended. Systemic approaches to control tumor growth and hormonal secretion include somatostatin analogs (SSAs), followed by options including peptide receptor radiotherapy (PRRT), everolimus and liver embolization. Telotristat is the primary choice for control of diarrhea refractory to SSA. Diuretics are the mainstay of heart failure symptom management for patients who develop CaHD. Considerations for future research are discussed, including the ongoing TELEHEART (TELotristat Ethyl in a HEART biomarker study) trial involving telotristat and not yet activated CHARRT (Carcinoid Heart disease And peptide Receptor Radiotargetted Therapy) study involving PRRT with lutetium 177 (177Lu) dotatate. [ABSTRACT FROM AUTHOR]

This article is a meta-analysis that examines the risk of tumor seeding in patients with liver lesions undergoing biopsy with or without concurrent ablation. The study found that the overall risk of needle tract seeding during liver biopsies was as low as 1%. The analysis included 23 studies representing 8,857 patients, and the majority of the studies were retrospective. The results suggest that the risk of seeding associated with liver biopsies may be lower than previously thought, which could inform clinicians and patients when considering the procedure. However, the study acknowledges limitations, such as the small sample size of patients undergoing biopsy with concurrent ablation and the lack of a standardized definition for needle tract seeding. [Extracted from the article]

In this paper, we describe the case of a 40-year-old patient with an expanding and symptomatic complex liver cyst. Despite comprehensive diagnostics, including labs, imaging and biopsy, a clear etiology could not be determined. As a result, a partial liver resection was performed. The histopathological examination revealed evidence of schistosomas. We postulate that the displacement of the portal fields created a pseudocyst and that the resultant ischemia was the root cause of the patient's discomfort. Postoperatively, the patient received an antihelmintic therapy with praziquantel with which she was able to fully recover. [ABSTRACT FROM AUTHOR]

In recent years, there has been growing interest in the possible use of nutraceuticals to improve and optimize dyslipidemia control and therapy. Based on the data from available studies, nutraceuticals might help patients obtain theraputic lipid goals and reduce cardiovascular residual risk. Some nutraceuticals have essential lipidlowering properties confirmed in studies; some might also have possible positive effects on nonlipid cardiovascular risk factors and have been shown to improve early markers of vascular health such as endothelial function and pulse wave velocity. However, the clinical evidence supporting the use of a single lipid-lowering nutraceutical or a combination of them is largely variable and, for many of the nutraceuticals, the evidence is very limited and, therefore, often debatable. The purpose of this position paper is to provide consensus-based recommendations for the optimal use of lipid-lowering nutraceuticals to manage dyslipidemia in patients who are still not on statin therapy, patients who are on statin or combination therapy but have not achieved lipid goals, and patients with statin intolerance. This statement is intended for physicians and other healthcare professionals engaged in the diagnosis and management of patients with lipid disorders, especially in the primary care setting. [ABSTRACT FROM AUTHOR]

Turner syndrome is one of the most frequently reported sex chromosomal abnormalities, affecting approximately 40 in every 100 000 live female births. The underlying chromosomal alteration is the complete or partial loss of X chromosome or mosaicism. Because of primary ovarian insufficiency, the synthesis of estrogen hormones is compromised, and patients require hormone substitution. Apart from the phenotypical presentation (short stature, primary amenorrhea), the effects of ovarian insufficiency can affect diverse organ systems (such as cardiovascular, endocrine, and lymphatic systems). Hepatobiliary pathology can present on a broad spectrum: from mild asymptomatic hypertransaminasemia to marked architectural changes. Estrogen hormone replacement therapy in these patients can improve the perturbations of laboratory values and can attenuate the progression of hepatic structural changes. Moreover, providing sufficient estrogen replacement has numerous benefits for other conditions of the patients as well. Both the all-cause mortality and deaths from cardiovascular complications are greatly increased in Turner syndrome, and hormone replacement might contribute to the decreased incidence of these events. The diagnostics of Turner syndrome are outside the scope of our paper, and we briefly discuss the cardiovascular complications because many the liver involvement partially involves alterations of vascular origin. Though we sought to highlight the importance of proper hormone replacement therapy, we did not attempt to write a comprehensive recommendation for exact treatment protocols. We provided an overview of preferred therapeutic approaches, as the treatment should be tailored according to the individual patient's needs. [ABSTRACT FROM AUTHOR]

Background Textbook outcome is a valuable tool for assessing surgical outcomes. The aim of this study was to analyse textbook-outcome rates in the prospective Spanish National Registry of the Liver-First Approach (RENACI Project) and the factors influencing textbook-outcome achievement. Additionally, a model for assessing a procedure-specific textbook outcome for the liver-first approach was proposed. Methods A retrospective analysis of a prospective and multicentre database that included consecutive patients with colorectal cancers and synchronous liver metastases who underwent a liver-first approach between June 2019 and August 2020 was performed. Two types of textbook outcome were measured: classic textbook outcome and liver-first-approach-specific textbook outcome (which included negative margins, no perioperative transfusion, no postoperative major surgical complications, no prolonged length of hospital stay, no readmissions, no mortality, and full treatment completion). The primary endpoint was textbook-outcome rate for a liver-first approach at 90 days. Results A total of 149 patients were included in the analysis. Classic and liver-first-approach-specific textbook-outcome rates were 71.8 per cent (107 patients) and 46 per cent (69 patients) respectively. Factors significantly associated with liver-first-approach-specific textbook-outcome achievement in the multivariable analysis were the number of metastases (OR 0.82 (95 per cent c.i. 0.73 to 0.92); P = 0.001) and intraoperative blood loss (OR 0.99 (95 per cent c.i. 0.99 to 1.00); P = 0.007). Prolonged length of hospital stay (33 patients, 41 per cent), positive margins (31 patients, 39 per cent), perioperative transfusion (27 patients, 34 per cent), and no full treatment completion (18 patients, 23 per cent) were the items that most frequently prevented liver-first-approach-specific textbook-outcome achievement. Conclusion Liver-first-approach-specific textbook outcome is a promising tool for measuring the quality of care when using the liver-first approach for synchronous colorectal liver metastases. [ABSTRACT FROM AUTHOR]

Aging increases the risk of liver diseases and systemic susceptibility to aging-related diseases. However, cell type-specific changes and the underlying mechanism of liver aging in higher vertebrates remain incompletely characterized. Here, we constructed the first single-nucleus transcriptomic landscape of primate liver aging, in which we resolved cell type-specific gene expression fluctuation in hepatocytes across three liver zonations and detected aberrant cell–cell interactions between hepatocytes and niche cells. Upon in-depth dissection of this rich dataset, we identified impaired lipid metabolism and upregulation of chronic inflammation-related genes prominently associated with declined liver functions during aging. In particular, hyperactivated sterol regulatory element-binding protein (SREBP) signaling was a hallmark of the aged liver, and consequently, forced activation of SREBP2 in human primary hepatocytes recapitulated in vivo aging phenotypes, manifesting as impaired detoxification and accelerated cellular senescence. This study expands our knowledge of primate liver aging and informs the development of diagnostics and therapeutic interventions for liver aging and associated diseases. [ABSTRACT FROM AUTHOR]

Aims Mitochondria are plastic organelles that continuously undergo biogenesis, fusion, fission, and mitophagy to control cellular energy metabolism, calcium homeostasis, hormones, sterols, and bile acids (BAs) synthesis. Here, we evaluated how the impairment of mitochondrial fusion in hepatocytes affects diet-induced liver steatosis and obesity. Methods and results Male mice selectively lacking the key protein involved in inner mitochondrial fusion, optic atrophy 1 (OPA1) (OPA1ΔHep) were fed a high fat diet (HFD) for 20 weeks. OPA1ΔHep mice were protected from the development of hepatic steatosis and obesity because of reduced lipid absorption; a profile which was accompanied by increased respiratory exchange ratio in vivo, suggesting a preference for carbohydrates in OPA1ΔHep compared to controls. At the molecular level, this phenotype emerged as a consequence of poor mitochondria-peroxisome- endoplasmic reticulum (ER) tethering in OPA1 deficient hepatocytes, which impaired BAs conjugation and release in the bile, thus impacting lipid absorption from the diet. Concordantly, the liver of subjects with non-alcoholic fatty liver disease (NAFLD) presented an increased expression of OPA1 and of the network of proteins involved in mitochondrial function when compared with controls. Conclusion Patients with NAFLD present increased expression of proteins involved in mitochondrial fusion in the liver. The selective deficency of OPA1 in hepatocytes protects mice from HFD-induced metabolic dysfunction by reducing BAs secretion and dietary lipids absorption as a consequence of reduced liver mitochondria-peroxisome-ER tethering. [ABSTRACT FROM AUTHOR]

Objective To retrospectively compare and evaluate ablation zone volume and its reduction from baseline to 1 month follow-up post-percutaneous microwave ablation (MWA) between healthy and cirrhotic liver parenchyma. Methods Institutional database research identified 84 patients (118 hepatic tumors) who underwent percutaneous MWA with the same system. Caudal-right lobe ratio was applied to distinguish cirrhotic (n = 51) and healthy (n = 67) group; ITK-SNAP software was used to quantify ablation zone volume. Long (LAD) and short 1 (SAD-1) and 2 (SAD-2) axis, tumor size diameter (mm) and volume (cm³) of the ablation zones were evaluated for each treated lesion in both groups at baseline (immediately post-ablation) and at 1 month follow-up. Results There was no significant difference comparing ablation zone volumes at baseline (healthy group: mean ablation volume 14.84 cm³ vs cirrhotic group: mean ablation volume 17.85 cm³, p = 0.31) and 1 month postablation (healthy group: mean ablation volume 9.15 cm³ vs cirrhotic group: mean ablation volume 11.58 cm³, p = 0.24). When both “healthy” and “cirrhotic” liver group were evaluated independently, there was a significant difference of ablation volumes reduction (p-value < 0.001) from baseline to 1 month follow-up. When both groups were compared based on reduction (35.12– 38.34%) there was no significant difference in ablation zone volumes (p-value = 0.77). Conclusion Percutaneous MWA results in ablation zones of a comparable volume in both healthy and cirrhotic liver parenchyma. Both cirrhotic and healthy liver parenchyma experience a similar significant reduction of ablation zone volume at 1 month post-therapy. Advances in knowledge statement This study evaluates and compares the volume of the ablation zone after MWA between healthy and cirrhotic liver parenchyma from baseline to 1 month follow-up and attempts to identify potential differences. It is the first study to demonstrate significant shrinkage of ablation volumes in healthy livers as compared to cirrhotic livers after 4 weeks of follow-up. The results of this study can help us understand the effect of MWA when applied in different backgrounds of liver parenchyma, which could lead to different treatment planning. [ABSTRACT FROM AUTHOR]

Background: Doxorubicin has become the first-line antitumor drug clinically, but severely limited by multiple side effects, especially cardiotoxicity. Liposomal doxorubicin therefore replaced traditional doxorubicin for low toxicity and high efficiency. Previous studies have suggested liver and kidney may be the main organs affected by liposomal doxorubicin. Due to insufficient clinical evidence, we set out to analyze the effect of liposomal doxorubicin on liver and renal function in breast cancer patients. Materials and Methods: Our retrospective analysis included breast cancer patients aged 30–70 years old who were assigned to two groups based on liposomal doxorubicin intake. We evaluated changes in liver and renal function. Multivariate logistic regression model was used to assess the risk factors of liver function damage. Results: Ultimately, 631 patients for liver function analysis cohort and 611 cases for renal function analysis cohort. Patients receiving liposomal doxorubicin had significantly higher liver function damage rate compared to control group (52.20% vs 9.82%, p < 0.001), but there was no difference in the incidence of renal damage events between the two groups. Multivariate analysis shows total doses divided by body surface area is a significant, independent risk factor for liver function damage (odds ratio 1.005 [1.002–1.018], p < 0.001). Conclusion: Liposomal doxorubicin treatment is associated with higher liver function damage in breast cancer patients, but has no effect on renal function. Together with risk factor analysis, our study underlines the importance to pay attention for patient's age before taking liposomal doxorubicin, alongside liver function after the first and long-term treatments. [ABSTRACT FROM AUTHOR]

The unique properties of nickel oxide nanoparticles distinguish it from classical nickel compounds, increasing its use in agriculture, industry, and many industrial areas. The aim of this study is to investigate the possible toxicity of nickel oxide and nickel oxide nanoparticles in the liver. For this purpose, Wistar rats were given nickel oxide and nickel oxide nanoparticles orally, intraperitoneally, and intravenously for 21 days. Liver organ weight, biochemical and hematological parameters, oxidative stress (malondialdehyde, catalase, superoxide dismutase, glutathione peroxidase, and glutathione S transferase), acetylcholinesterase activities, inflammation levels, apoptotic markers, and histopathological changes were evaluated comparatively. When the data obtained were examined in general, it was observed that nickel oxide nanoparticles caused more hepatotoxicity in liver tissue than nickel oxide in terms of oxidative stress parameters, apoptotic markers, inflammation indicators, and other parameters examined. The results suggest that toxicity induced by both nickel oxide and nickel oxide nanoparticles plays an important role in hepatocyte apoptosis. [ABSTRACT FROM AUTHOR]

Objectives: Scutellaria baicalensis leaf (SLE), the above-ground part of the traditional Chinese medicine Scutellaria baicalensis Georgi, is rich in resources and contains a large number of flavonoids with anti-inflammatory, antioxidant and neuroprotective functions. The present study evaluated the ameliorative effects and related mechanisms of SLE on d-gal-induced ageing rats, providing a theoretical basis for the exploitation of SLE. Methods: This experiment investigated the mechanism of SLE for anti-ageing by non-targeted metabonomics technology combined with targeted quantitative analysis and molecular biology technology. Key findings: Non-targeted metabonomics analysis showed that 39 different metabolites were screened out. Among them, 38 metabolites were regulated by SLE (0.4 g/kg), and 33 metabolites were regulated by SLE (0.8 g/kg). Through enrichment analysis, glutamine–glutamate metabolic pathway was identified as the key metabolic pathway. Subsequently, the results of targeted quantitative and biochemical analysis displayed that the contents of key metabolites and the activities of enzymes in glutamine-glutamate metabolic pathway and glutathione synthesis could be regulated by SLE. Furthermore, the results of Western blotting indicated that SLE significantly modulated the expression of Nrf2, GCLC, GCLM, HO-1, and NQO1 proteins. Conclusion: To sum up, the anti-ageing mechanism of SLE was related to glutamine-glutamate metabolism pathway and Nrf2 signalling pathway. Graphical Abstract [ABSTRACT FROM AUTHOR]

Context The use of non-nutritive sweeteners (NNSs) is dramatically increasing in food commodities, and their effects on biochemical parameters have been the subject of great controversy. Liver enzymes as markers of liver injury may be helpful measures of non-alcoholic fatty liver disease (NAFLD), but the outcomes of randomized controlled trials (RCTs) suggest their associations with NNSs are contentious. Objective The current study was designed to provide a GRADE-assessed systematic review and meta-analysis of RCTs studying the consequences of NNS consumption on ALT, AST, and GGT concentrations (ie, the 3 main liver enzymes in adults). Data Sources Scopus, PubMed, and EMBASE were searched for relevant studies up to April 2021, with no time and language limitations. Data Extraction Two independent researchers extracted information from qualified studies, and a third researcher rechecked it. Data Analysis Of 3212 studies, 10 studies that enrolled a total of 854 volunteers were included. A random-effects or fixed-effects model was utilized to calculate weighted mean differences (WMDs) and 95% confidence intervals (CIs). Heterogeneity between studies was evaluated using Cochran's Q test and quantified using the I2 statistic. The pooled results demonstrated that, compared with control groups, NNS intake led to nonsignificant reductions in ALT (WMD: −.78, 95% CI: –2.14,.57, P = .25) and GGT (WMD: –.21, 95% CI: –1.46, 1.04, P = .74). Also, a small nonsignificant increasing effect on AST level was found (WMD:.02, 95% CI: –1.26, 1.30, P = .97). NNS significantly reduced AST levels in type 2 diabetes patients when subgroup analyses were performed. Also, in trials with ≥24-week intervention or studies that utilized stevioside for intervention, a significant reducing effect on ALT level was observed. Conclusion The results of this study showed that NNS intake has no significant effect on liver enzyme levels in adults. Systematic Review Registration PROSPERO registration no. CRD42021250067. [ABSTRACT FROM AUTHOR]

There is uncertainty regarding carotenoid intake recommendations, because positive and negative health effects have been found or are correlated with carotenoid intake and tissue levels (including blood, adipose tissue, and the macula), depending on the type of study (epidemiological vs intervention), the dose (physiological vs supraphysiological) and the matrix (foods vs supplements, isolated or used in combination). All these factors, combined with interindividual response variations (eg, depending on age, sex, disease state, genetic makeup), make the relationship between carotenoid intake and their blood/tissue concentrations often unclear and highly variable. Although blood total carotenoid concentrations <1000 nmol/L have been related to increased chronic disease risk, no dietary reference intakes (DRIs) exist. Although high total plasma/serum carotenoid concentrations of up to 7500 nmol/L are achievable after supplementation, a plateauing effect for higher doses and prolonged intake is apparent. In this review and position paper, the current knowledge on carotenoids in serum/plasma and tissues and their relationship to dietary intake and health status is summarized with the aim of proposing suggestions for a "normal," safe, and desirable range of concentrations that presumably are beneficial for health. Existing recommendations are likewise evaluated and practical dietary suggestions are included. [ABSTRACT FROM AUTHOR]

Wild fish attracted to salmon farms feed on waste feed that presently contain high levels of fatty acids of terrestrial origin. This study examines whether mature Atlantic cod (Gadus morhua) caught at spawning grounds has eaten salmon waste feed. Cod were caught at four spawning grounds around Smøla (Norway), an area with multiple salmon farms, during the spawning season in 2018 (n = 327) and 2019 (n = 488). The fatty acid (FA) profile of their livers, gonads (ovary and testis), and muscles (2019) were determined. Multivariate k-mean cluster analysis of liver FA profiles revealed three main clusters, which could be allocated to trophic niches using known fatty acid trophic markers (FATMs). Of the sampled cod in 2018 and 2019, 13 % and 20 % respectively had high liver concentrations of terrestrial FATMs (18:1n-9, 18:2n-6, and 18:3n-3), indicating waste feed feeding. The remaining cod could be assigned to either the pelagic or benthic food chain. The cod identified as feeding on waste feed had large, fatty livers. The terrestrial FAs were also transferred to the muscle and gonad lipids. It is postulated that the latter may result in gametes with sub-optimal lipid composition, potentially impacting fitness, which warrants further investigation. [ABSTRACT FROM AUTHOR]

Background: Abnormal liver function is a common manifestation of human disease and may also occur in approved and investigational medications as drug-induced liver injury (DILI). Capillary blood collection devices may allow for more frequent and convenient measurement outside of the clinic. Validation of such approaches is lacking. Methods: This prospective, biospecimens collection study evaluated the Tasso+ in patients with abnormal liver tests (NCT05259618). The primary objective was to define the concordance of alanine aminotransferase (ALT) obtained via Tasso+ compared to standard venipuncture. Secondary objectives included measurement of 14 other analytes and patient surveys. At the time of venipuncture, 2 Tasso+ samples were collected: one was centrifuged and shipped, and the other was refrigerated and shipped as whole blood. Results: Thirty-six patients with elevated ALT values were enrolled. In total, 100 venipuncture, 50 Tasso+ centrifuged, and 48 Tasso+ whole blood samples were obtained. Tasso+ centrifuged samples demonstrated concordance correlation coefficients (CCC) of >0.99 for ALT, alkaline phosphatase (ALP), aspartate aminotransferase (AST), and total bilirubin and CCC >0.95 for albumin, chloride, enzymatic creatinine, serum glucose, magnesium, and phosphorus. Tasso+ whole blood showed CCC of >0.99 for AST, bilirubin total, and enzymatic creatinine and CCC >0.95 for ALT, ALP, albumin, magnesium, and phosphorus. Hemolysis was comparable across the 3 sample types, but its impact was reflected in the Tasso+ potassium data. Patient feedback indicated a very favorable patient experience. Conclusions: The capillary blood collection device, Tasso+, showed substantial to almost perfect concordance to standard venipuncture for measurement of abnormal liver function. Studies are ongoing to validate longitudinal sampling outside of the clinic. Clinicaltrials.gov Registration Number: NCT05259618 [ABSTRACT FROM AUTHOR]

Chronic hepatitis B is one of the most common infectious diseases worldwide. In patients with an impaired immune system the prevalence of HBsAg is even higher and the course of hepatitis B infection is often aggravated. In HIV/HBV co-infected patients, liver related morbidity and mortality can be reduced by implementing highly active antiretroviral treatment (HAART) that contains substances active against HBV. Reactivation of HBV during chemotherapy may occur in HBsAg positive patients but can even occur in serologically recovered anti-HBc positive, HBsAg negative patients resulting in high mortality from liver disease. HBsAg positive patients irrespective of HBV DNA levels should receive preemptive treatment with HBV polymerase inhibitors which should be continued for 12 months after cessation of chemo- and or immunosuppressive therapy. The combination prophylaxis of passive immunisations with hepatitis B immunoglobulins (HBIG) and nucleos(t)ide analogues (NUC) is able to reduce HBV recurrence rates after transplantation to 0–10%. This review will summarise the current knowledge on pathogenesis, frequency and treatment options of HBV reactivations in patients with impaired immunity. [ABSTRACT FROM PUBLISHER]

HFPO-DA (ammonium, 2,3,3,3-tetrafluoro-2-(heptafluoropropoxy)propanoate) is a short-chain polyfluorinated alkyl substance (PFAS) used in the manufacture of some types of fluorinated polymers. Like many PFAS, toxicity studies with HFPO-DA indicate the liver is the primary target of toxicity in rodents following oral exposure. Due to the structural diversity of PFAS, the mode of action (MOA) can differ between PFAS for the same target tissue. There is significant evidence for involvement of peroxisome proliferator-activated receptor alpha (PPARα) activation based on molecular and histopathological responses in the liver following HFPO-DA exposure, but other MOAs have also been hypothesized based on limited evidence. The MOA underlying the liver effects in mice exposed to HFPO-DA was assessed in the context of the Key Events (KEs) outlined in the MOA framework for PPARα activator-induced rodent hepatocarcinogenesis. The first 3 KEs (ie, PPARα activation, alteration of cell growth pathways, and perturbation of cell growth/survival) are supported by several lines of evidence from both in vitro and in vivo data available for HFPO-DA. In contrast, alternate MOAs, including cytotoxicity, PPARγ and mitochondrial dysfunction are generally not supported by the scientific literature. HFPO-DA-mediated liver effects in mice are not expected in humans as only KE 1, PPARα activation, is shared across species. PPARα-mediated gene expression in humans produces only a subset (ie, lipid modulating effects) of the responses observed in rodents. As such, the adverse effects observed in rodent livers should not be used as the basis of toxicity values for HFPO-DA for purposes of human health risk assessment. [ABSTRACT FROM AUTHOR]

Laparoscopy is being applied more frequently and in broader applications. Complications of this technique are infrequent, and rare among them are gas emboli due to insufflation. This paper describes a 65-year-old obese female presenting for elective laparoscopic cholecystectomy who suffered a cerebral vascular accident after Veress needle insertion into undiagnosed severe fatty liver led to a massive gas embolus. Our patient experienced immediate cardiac compromise and acute monoparesis. Intra-operative transesophageal echocardiogram revealed copious air in the right atria and ventricle. A needle track within the liver was visible on a post-operative computerized tomography scan. The patient made a full recovery, but this acts as a reminder to be vigilant for potential complications of laparoscopy and highlights challenges of laparoscopic entry in the severely obese. [ABSTRACT FROM AUTHOR]

2,3,7,8-Tetrachlorodibenzo- p -dioxin (TCDD) dose-dependently induces the development of hepatic fat accumulation and inflammation with fibrosis in mice initially in the portal region. Conversely, differential gene and protein expression is first detected in the central region. To further investigate cell-specific and spatially resolved dose-dependent changes in gene expression elicited by TCDD, single-nuclei RNA sequencing and spatial transcriptomics were used for livers of male mice gavaged with TCDD every 4 days for 28 days. The proportion of 11 cell (sub)types across 131 613 nuclei dose-dependently changed with 68% of all portal and central hepatocyte nuclei in control mice being overtaken by macrophages following TCDD treatment. We identified 368 (portal fibroblasts) to 1339 (macrophages) differentially expressed genes. Spatial analyses revealed initial loss of portal identity that eventually spanned the entire liver lobule with increasing dose. Induction of R-spondin 3 (Rspo3) and pericentral Apc , suggested dysregulation of the Wnt/β-catenin signaling cascade in zonally resolved steatosis. Collectively, the integrated results suggest disruption of zonation contributes to the pattern of TCDD-elicited NAFLD pathologies. [ABSTRACT FROM AUTHOR]

Study Question: Does maternal smoking in early pregnancy affect metallothionein 1 and 2 (MT1 and MT2) mRNA and protein expression in first trimester placenta or embryonic/fetal liver?Summary Answer: In the first trimester, MT protein expression is seen only in liver, where smoking is associated with a significantly reduced expression.What Is Known Already: Zinc homeostasis is altered by smoking. Smoking induces MT in the blood of smokers properly as a result of the cadmium binding capacities of MT. In term placenta MT is present and smoking induces gene and protein expression (MT2 in particular), but the MT presence and response to smoking have never been examined in first trimester placenta or embryonic/fetal tissues.Study Design, Size, Duration: Cross sectional study where the presence of MT mRNA and protein was examined at the time of the abortion. The material was collected with informed consent after surgical intervention and frozen immediately. For protein expression analysis, liver tissue originating from smoking exposed n = 10 and unexposed n = 12 pregnancies was used. For mRNA expression analyses, placental tissue originating from smokers n = 19 and non-smokers n = 23 and fetal liver tissue from smoking exposed n = 16 and smoking unexposed pregnancies n = 13, respectively, were used.Participants/materials, Setting, Methods: Tissues were obtained from women who voluntarily and legally chose to terminate their pregnancy between gestational week 6 and 12. Western blot was used to determine the protein expression of MT, and real-time PCR was used to quantify the mRNA expression of MT2A and eight MT1 genes alongside the expression of key placental zinc transporters: zinc transporter protein-1 (ZNT1), Zrt-, Irt-related protein-8 and -14 (ZIP8 and ZIP14).Main Results and the Role Of Chance: A significant reduction in the protein expression of MT1/2 in liver tissue (P = 0.023) was found by western blot using antibodies detecting both MT forms. Overall, a similar tendency was observed on the mRNA level although not statistically significant. Protein expression was not present in placenta, but the mRNA regulation suggested a down regulation of MT as well. A suggested mechanism based on the known role of MT in zinc homeostasis could be that the findings reflect reduced levels of easily accessible zinc in the blood of pregnant smokers and hence a reduced MT response in smoking exposed fetal/embryonic tissues.Limitations and Reasons For Caution: Smoking was based on self-reports; however, our previous studies have shown high consistency regarding cotinine residues and smoking status. Passive smoking could interfere but was found mainly among smokers. The number of fetuses was limited, and other factors such as medication and alcohol might affect the findings. Information on alcohol was not consistently obtained, and we cannot exclude that it was more readily obtained from non-users. In the study, alcohol consumption was reported by a limited number (less than 1 out of 5) of women but with more smokers consuming alcohol. However, the alcohol consumption reported was typically limited to one or few times low doses. The interaction between alcohol and smoking is discussed in the paper. Notably we would have liked to measure zinc status to test our hypothesis, but maternal blood samples were not available.Wider Implications Of the Findings: Zinc deficiency-in particular severe zinc deficiency-can affect pregnancy outcome and growth. Our findings indicate that zinc homeostasis is also affected in early pregnancy of smokers, and we know from pilot studies that even among women who want to keep their babies, the zinc status is low. Our findings support that zinc supplements should be considered in particular to women who smoke.Study Funding/competing Interest(s): We thank the Department of Biomedicine for providing laboratory facilities and laboratory technicians and the Lundbeck Foundation and Læge Sofus Carl Emil Friis og Hustru Olga Doris Friis Legat for financial support. The authors have no competing interests to declare.Trial Registration Number: N/A. [ABSTRACT FROM AUTHOR]

Effect of cobalt manganese ferrite nanoparticles (M-NPs) (Co0.5Mn0.5Fe2O4) on vanadium hazards was assessment in the present study. Four groups of adult male albino rats [control group and three variably treated groups with ammonium metavanadate accompanied with or without cobalt M-NPs] were studied. The oral administration of ammonium metavanadate (Am.V) (20 mg/kg b. wt.) demonstrated the facility of vanadium to distribute and accumulate in the distinctive body organs and ordered as kidney > liver > lung > brain > spleen. Also, Am.V administration induce a significant disturbance in many physiological parameters (RBS, cholesterol, triglyceride, aspartate transaminase, alanine transaminase, Alb., bilirubin, Alk. Ph., urea, creat., Hb%, red blood cell count and packed cell volume) which might be expected to the liberation of free radicals according to the vanadium intoxication or its ability to disturb many body metabolisms. On the other hand, the intraperitoneal administration of 5% M-NPs in parallel with Am.V orally administration showed the ability of M-NPs to reduce Am.V dangerous impacts, which might be resulted from the essentiality of M-NPs metals to the body metabolism and to its free radicals scavenging properties. So, M-NPs could reduce Am.V hazardous effects. [ABSTRACT FROM AUTHOR]

Effect of cobalt manganese ferrite nanoparticles (M-NPs) (Co0.5Mn0.5Fe2O4) on vanadium hazards was assessment in the present study. Four groups of adult male albino rats [control group and three variably treated groups with ammonium metavanadate accompanied with or without cobalt M-NPs] were studied. The oral administration of ammonium metavanadate (Am.V) (20 mg/kg b.wt.) demonstrated the facility of vanadium to distribute and accumulate in the distinctive body organs and ordered as kidney > liver > lung > brain > spleen. Also, Am.V administration induce a significant disturbance in many physiological parameters (RBS, cholesterol, triglyceride, aspartate transaminase, alanine transaminase, Alb., bilirubin, Alk.Ph., urea, creat., Hb%, red blood cell count and packed cell volume) which might be expected to the liberation of free radicals according to the vanadium intoxication or its ability to disturb many body metabolisms. On the other hand, the intraperitoneal administration of 5% M-NPs in parallel with Am.V orally administration showed the ability of M-NPs to reduce Am.V dangerous impacts, which might be resulted from the essentiality of M-NPs metals to the body metabolism and to its free radicals scavenging properties. So, M-NPs could reduce Am.V hazardous effects. [ABSTRACT FROM AUTHOR]

Calcitonin gene-related peptide (CGRP) signaling inhibitors have shown efficacy in both the acute and preventive treatment of migraine. Telcagepant, a first-generation CGRP receptor antagonist, was effective but failed in clinical trials due to hepatotoxicity. Subsequently, although 4 next-generation CGRP receptor antagonists (rimegepant, zavegepant, atogepant, and ubrogepant) were being advanced into late-stage clinical trials, due to telcagepant's failure, more confidence in the liver safety of these compounds was needed. DILIsym v6A, a quantitative systems toxicology (QST) model of drug-induced liver injury (DILI), was used to model all 5 compounds and thus to compare the 4 next-generation CGRP receptor antagonists to telcagepant. In vitro experiments were performed to measure the potential for each compound to inhibit bile acid transporters, produce oxidative stress, and cause mitochondrial dysfunction. Physiologically based pharmacokinetic models were produced for each compound in order to appropriately estimate liver exposure. DILIsym predicted clinical elevations of liver enzymes and bilirubin for telcagepant, correctly predicting the observed DILI liability of the first-generation compound. By contrast, DILIsym predicted that each of the 4 next-generation compounds would be significantly less likely to cause DILI than telcagepant. Subsequent clinical trials have validated these predictions for each of the 4 compounds, and all 3 of the compounds submitted to FDA to date (rimegepant, ubrogepant, and atogepant) have since been approved by the FDA with no warning for hepatotoxicity. This work demonstrates the potential for QST modeling to prospectively differentiate between hepatotoxic and nonhepatotoxic molecules within the same class. [ABSTRACT FROM AUTHOR]

Major liver resection is an effective treatment option for patients with liver malignancy. The future liver remnant (FLR) volume and complications after portal vein embolization (PVE) were compared between the ipsilateral right portal vein (PTPE) and transileocolic (TIPE) approaches. A total of 42 patients (TIPE, n = 22; PTPE, n = 20) underwent right lobectomy after PVE. CT and hepatobiliary scintigraphy were repeated before and after PVE. The blood examination findings and the FLR values (FLRCT: calculated from CT, %FLRCT: FLRCT ratio, %FLRSPECT: FLR ratio using single photon emission CT, FLRCT/BS: FLRCT to body surface ratio) were compared between two approach sites. The complications and mortality were also analyzed after PVE and major right hepatectomy. There were no significant differences in the patient characteristics, blood examination findings or FLR values between two groups. Adequate liver regeneration was observed without significant differences between PTPE and TIPE (increased ratio of FLRCT: 8.7% vs 19.2%, p = 0.15 [25–75 percentile: 17.1–60.4], %FLRCT: 11.2% vs 8.3%, p = 0.25 [6.3–13.3], %FLRSPECT: 15.4% vs 19.2%, p = 0.09 [16.0–22.4], FLRCT/BS: 33.6% vs 47.1%, p = 0.19 [17.2–60.4], respectively), but TIPE required a significantly longer procedure time than PTPE [181.4 min vs 108.7 min, p < 0.01 (103.3–193.5)]. However, one patient was converted to TIPE due to bleeding during PTPE. After right lobectomy, portal vein stenosis or thrombosis was noted in three patients [two with TIPE (9.1%) and one with PTPE (5%)] and three TIPE patients died within 90 days (13.6%) after right hepatectomy. FLR volume significantly increased after PVE, regardless of the approach sites; however, PTPE is a useful technique with a shorter procedure time. [ABSTRACT FROM AUTHOR]

Background Hydrogen sulfide (H2S), as the third gasotransmitter participates in both cellular physiological and pathological processes, including chemical-induced injuries. We recently reported acute acrylonitrile (AN) treatment inhibited endogenous H2S biosynthesis pathway in rat and astrocyte models. However, there is still no evidence to address the correlation between endogenous H2S and sub-chronic AN exposure. Objectives This study aims to explore the modulatory effects of prolonged AN exposure on endogenous H2S levels and its biosynthetic enzymes in rat blood, brain and liver. Methods A total of 50 male Sprague-Dawley rats were randomly divided into 5 groups, including the control group and AN-treated groups at dosages of 6.25, 12.5, 25 or 50 mg/kg. Rats received one exposure/day, 5 days/week, for 4 consecutive weeks. The rat bodyweight and brain/liver organ coefficient were detected, along with liver cytochrome P450 2E1(CYP2E1) expression. In addition, the H2S contents in rat serum and plasma, and in cerebral cortex and liver tissues were measured by methylene blue method. The expression of H2S-generating enzymes, including cystathionine β-synthase (CBS), cystathionine γ-lyase (CSE) and 3-mercaptopyruvate sulfurtransferase (3-MPST) was also measured with Western blot both in rat cerebral cortex and liver. Results Subchronic exposure to AN significantly inhibited bodyweight-gain and increased the liver CYP2E1 expression compared with the control. In addition, AN significantly increased H2S levels in rat plasma and serum, but not in liver. The endogenous H2S level in rat cerebral cortex was also significantly increased upon AN treatment, when expression of the major H2S-generating enzymes, CBS and 3-MPST were significantly enhanced. However, hepatic protein levels of CBS and CSE were significantly increased, whereas hepatic levels of 3-MPST were significantly decreased. Conclusion This study showed that sub-chronic AN exposure increased endogenous H2S contents in rat blood and brain tissues, but not liver, which may be resulted from the distinct expression profile of H2S-producing enzymes in response to AN. The blood H2S contents may be applied as a potential novel biomarker for surveillance of chronically AN-exposed populations. Highlights Subchronic intraperitoneal exposure to acrylonitrile increased H2S content in rat blood and cerebral cortex, but not in liver. Distinct tissue expression profiles of H2S-producing enzymes contribute to the acrylonitrile-induced differential effects on the H2S level. Blood H2S level may be a biomarker for subchronic exposure to acrylonitrile. [ABSTRACT FROM AUTHOR]

Acrylamide is a well-known neurotoxicant and carcinogen. Apart from industrial exposure, acrylamide is also found in different food products. The present study deals with in vivo experiment to test the protective effect of rutin against acrylamide induced toxicity in rats. The study was carried out on female rats with exposure of acrylamide at the dose of 38.27 mg/kg body weight, orally for 10 days followed by the therapy of rutin (05, 10, 20 and 40 mg/kg orally), for three consecutive days. All animals were sacrificed after 24 h of last treatment and various biochemical parameters in blood and tissue were investigated. Histopathology of liver, kidney and brain was also done. On administration of acrylamide for 10 days, neurotoxicity was observed in terms of decreased acetylcholinesterase activity and oxidative stress was observed in terms of increased lipid peroxidation, declined level of reduced glutathione, antioxidant enzymes (superoxide dismutase and catalase) in liver, kidney and brain. Acrylamide exposure increased the activities of serum transaminases, lipid profile, bilirubin, urea, uric acid and creatinine in serum indicating damage. Our experimental results conclude that rutin showed remarkable protection against oxidative DNA damage induced by acrylamide, which may be due to its antioxidant potential. Graphical Abstract [ABSTRACT FROM AUTHOR]

An extensive literature base combined with advances in sequencing technologies demonstrate microRNA levels correlate with various metabolic diseases. Mechanistic studies also establish microRNAs regulate central metabolic pathways and thus play vital roles in maintaining organismal energy balance and metabolic homeostasis. This review highlights research progress on the roles and regulation of microRNAs in the peripheral tissues that confer insulin sensitivity. We discuss sequencing technologies used to comprehensively define the target spectrum of microRNAs in metabolic disease that complement studies reporting physiologic roles for microRNAs in the regulation of glucose and lipid metabolism in animal models. We also discuss the emerging roles of exosomal microRNAs as endocrine signals to regulate lipid and carbohydrate metabolism. [ABSTRACT FROM AUTHOR]

Aspartame is a synthetic dipeptide artificial sweetener, frequently used in foods, medications, and beverages, notably carbonated and powdered soft drinks. Since 1981, when aspartame was first approved by the US Food and Drug Administration, researchers have debated both its recommended safe dosage (40mg/kg/d) and its general safety to organ systems. This review examines papers published between 2000 and 2016 on both the safe dosage and higher-thanrecommended dosages and presents a concise synthesis of current trends. Data on the safe aspartame dosage are controversial, and the literature suggests there are potential side effects associated with aspartame consumption. Since aspartame consumption is on the rise, the safety of this sweetener should be revisited. Most of the literature available on the safety of aspartame is included in this review. Safety studies are based primarily on animal models, as data from human studies are limited. The existing animal studies and the limited human studies suggest that aspartame and its metabolites, whether consumed in quantities significantly higher than the recommended safe dosage or within recommended safe levels, may disrupt the oxidant/antioxidant balance, induce oxidative stress, and damage cell membrane integrity, potentially affecting a variety of cells and tissues and causing a deregulation of cellular function, ultimately leading to systemic inflammation. [ABSTRACT FROM AUTHOR]

Innate immunity plays a critical role in the development of alcohol-induced liver inflammation. Understanding the inter-relationship of signals from within and outside of the liver that trigger liver inflammation is pivotal for development of novel therapeutic targets of alcoholic liver disease (ALD).~Background~Unassigned~The aim of this paper is to review recent advances in the field of alcohol-induced liver inflammation.~Aim~Unassigned~A detailed literature review was performed using the PubMed database published between January 1980 and December 2016.~Methods~Unassigned~We provide an update on the role of intestinal microbiome, metabolome and the gut-liver axis in ALD, discuss the growing body of evidence on the diversity of liver macrophages and their differential contribution to alcohol-induced liver inflammation, and highlight the crucial role of inflammasomes in integration of inflammatory signals in ALD. Studies to date have identified a multitude of new therapeutic targets, some of which are currently being tested in patients with severe alcoholic hepatitis. These treatments aim to strengthen the intestinal barrier, ameliorate liver inflammation and augment hepatocyte regeneration.~Results~Unassigned~Given the complexity of inflammation in ALD, multiple pathobiological mechanisms may need to be targeted at the same time as it seems unlikely that there is a single dominant pathogenic pathway in ALD that would be easily targeted using a single target drug approach.~Conclusion~Unassigned~Here, we focus on recent advances in immunopathogenesis of alcoholic liver disease (ALD), including gut-liver axis, hepatic macrophage activation, sterile inflammation and synergy between bacterial and sterile signals. We propose a multiple parallel hit model of inflammation in ALD and discuss its implications for clinical trials in alcoholic hepatitis.~Short summary~Unassigned [ABSTRACT FROM AUTHOR]

Background Innate immunity plays a critical role in the development of alcohol-induced liver inflammation. Understanding the inter-relationship of signals from within and outside of the liver that trigger liver inflammation is pivotal for development of novel therapeutic targets of alcoholic liver disease (ALD). Aim The aim of this paper is to review recent advances in the field of alcohol-induced liver inflammation. Methods A detailed literature review was performed using the PubMed database published between January 1980 and December 2016. Results We provide an update on the role of intestinal microbiome, metabolome and the gut–liver axis in ALD, discuss the growing body of evidence on the diversity of liver macrophages and their differential contribution to alcohol-induced liver inflammation, and highlight the crucial role of inflammasomes in integration of inflammatory signals in ALD. Studies to date have identified a multitude of new therapeutic targets, some of which are currently being tested in patients with severe alcoholic hepatitis. These treatments aim to strengthen the intestinal barrier, ameliorate liver inflammation and augment hepatocyte regeneration. Conclusion Given the complexity of inflammation in ALD, multiple pathobiological mechanisms may need to be targeted at the same time as it seems unlikely that there is a single dominant pathogenic pathway in ALD that would be easily targeted using a single target drug approach. Short summary Here, we focus on recent advances in immunopathogenesis of alcoholic liver disease (ALD), including gut–liver axis, hepatic macrophage activation, sterile inflammation and synergy between bacterial and sterile signals. We propose a multiple parallel hit model of inflammation in ALD and discuss its implications for clinical trials in alcoholic hepatitis. [ABSTRACT FROM AUTHOR]

Background: Fatty liver disease is a common metabolic abnormality in adolescents with obesity but remains understudied in early childhood.Objectives: To describe hepatic fat deposition in prepubertal children and examine cross-sectional associations with metabolic markers and body composition.Methods: Data were from 286 children ages 4 to 8 years old in the Healthy Start Study, a longitudinal prebirth cohort in Colorado (USA). Assessments included magnetic resonance imaging to quantify hepatic and abdominal fats, fasting blood draws to measure metabolic markers, and air displacement plethysmography to measure body composition (fat mass and fat-free mass).Results: The median (interquartile range) for hepatic fat was 1.65% (1.24%, 2.11%). Log-transformed hepatic fat was higher in Hispanic [mean (95% CI): 0.63 (0.52, 0.74)] vs non-Hispanic white children [0.46 (0.38, 0.53), P = 0.01] and children with overweight/obesity [0.64 (0.49, 0.79)] vs normal-weight [0.47 (0.40, 0.53), P = 0.02]. Higher log-hepatic fat was associated with higher insulin [β (95% CI): 1.47 (0.61, 2.33) uIU/mL, P = 0.001] and estimated insulin resistance (homeostatic model assessment) [0.40 (0.20, 0.60), P < 0.001] in the full sample and glucose [5.53 (2.84, 8.21) mg/dL, P < 0.001] and triglycerides [10.92 (2.92,18.91) mg/dL, P = 0.008] in boys, in linear regression models adjusted for sociodemographics, maternal/perinatal confounders, and percentage body fat. Log-hepatic fat was also associated with abdominal subcutaneous adipose tissue [SAT; 7.37 (1.12,13.60) mm2, P = 0.02] in unadjusted models, but this was attenuated and insignificant after adjusting for confounders.Conclusions: While hepatic fat was low in children 4 to 8 years old, it was independently associated with estimated insulin resistance and exhibited sex-specific associations with glucose and triglycerides, suggesting hepatic fat may be an early indicator of metabolic dysfunction in youth. [ABSTRACT FROM AUTHOR]

Context: Studies in rodents and humans suggest that high-fructose corn syrup (HFCS)-sweetened diets promote greater metabolic dysfunction than sucrose-sweetened diets.Objective: To compare the effects of consuming sucrose-sweetened beverage (SB), HFCS-SB, or a control beverage sweetened with aspartame on metabolic outcomes in humans.Methods: A parallel, double-blinded, NIH-funded study. Experimental procedures were conducted during 3.5 days of inpatient residence with controlled feeding at a research clinic before (baseline) and after a 12-day outpatient intervention period. Seventy-five adults (18-40 years) were assigned to beverage groups matched for sex, body mass index (18-35 kg/m2), and fasting triglyceride, lipoprotein and insulin concentrations. The intervention was 3 servings/day of sucrose- or HFCS-SB providing 25% of energy requirement or aspartame-SB, consumed for 16 days. Main outcome measures were %hepatic lipid, Matsuda insulin sensitivity index (ISI), and Predicted M ISI.Results: Sucrose-SB increased %hepatic lipid (absolute change: 0.6 ± 0.2%) compared with aspartame-SB (-0.2 ± 0.2%, P < 0.05) and compared with baseline (P < 0.001). HFCS-SB increased %hepatic lipid compared with baseline (0.4 ± 0.2%, P < 0.05). Compared with aspartame-SB, Matsuda ISI decreased after consumption of HFCS- (P < 0.01) and sucrose-SB (P < 0.01), and Predicted M ISI decreased after consumption of HFCS-SB (P < 0.05). Sucrose- and HFCS-SB increased plasma concentrations of lipids, lipoproteins, and uric acid compared with aspartame-SB. No outcomes were differentially affected by sucrose- compared with HFCS-SB. Beverage group effects remained significant when analyses were adjusted for changes in body weight.Conclusion: Consumption of both sucrose- and HFCS-SB induced detrimental changes in hepatic lipid, insulin sensitivity, and circulating lipids, lipoproteins and uric acid in 2 weeks. [ABSTRACT FROM AUTHOR]

To evaluate time-dependent changes in hepatic extracellular volume (ECV) fraction using contrast-enhanced CT (CECT) and serological liver fibrosis markers, the fibrosis-4 (FIB-4) index and aspartate aminotransferase to platelet ratio index (APRI), before and after direct-acting antiviral therapy (DAA) for hepatitis C virus (HCV) infection. 41 HCV-infected patients who achieved sustained virological response (SVR) after DAA (SVR group) and 10 control patients (untreated or unresponsive to treatment) who underwent CECT and serum biochemical tests before or after the first examination/DAA (T1) and at intervals thereafter (T2:<6 months after T1, T3: at 6–12 months, T4: at 12–24 months, and T5:>24 months) were evaluated. In the control group, ECV fractions remained relatively unchanged through the study, and significant differences in FIB-4 index comparisons and APRI comparisons were only seen between the T2 and T4 values (p = 0.046 and p = 0.028, respectively). In the SVR group, ECV fractions were significantly different between T1 and T4 and T1 and T5 (p = 0.046 and 0.022, respectively), and both FIB-4 index and APRI were significantly different between T1 and all other time points (p = 0.017 to p < 0.001 and p = 0.001 to p < 0.001, respectively). After DAA, ECV fraction decreased slowly, suggesting an improvement in hepatic fibrosis, while serological liver fibrosis markers decreased immediately, probably due to improvement in hepatic inflammation. ECV fraction has the potential to be a non-invasive biomarker for the assessment of liver fibrosis after direct-acting antiviral therapy. [ABSTRACT FROM AUTHOR]

The extent of liver fibrosis predicts prognosis and is important for determining treatment strategies for chronic hepatitis. During the fibrosis progression, serum levels of Mac2 binding protein (M2BP) increase and the N -glycan structure changes to enable binding to Wisteria floribunda agglutinin (WFA) lectin. As a novel diagnostic marker, glycosylation isomer of M2BP (M2BPGi) has been developed. However, its glycan structures recognized by WFA are unclear. In this study, we analyzed site-specific N -glycan structures of serum M2BP using Glyco-RIDGE (Glycan heterogeneity-based Relational IDentification of Glycopeptide signals on Elution profile) method. We evaluated five sample types: (1) M2BP immunoprecipitated from normal healthy sera (NHS-IP(+)), (2) M2BP immunoprecipitated from sera of patients with liver cirrhosis (stage 4; F4-IP(+)), (3) M2BP captured with WFA from serum of patients with liver cirrhosis (stage 4; F4-WFA(+)), (4) recombinant M2BP produced by HEK293 cells (rM2BP) and (5) WFA-captured rM2BP (rM2BP-WFA(+)). In NHS-IP(+) M2BP, bi-antennary N -glycan was the main structure, and LacNAc extended to its branches. In F4-IP(+) M2BP, many branched structures, including tri-antennary and tetra-antennary N -glycans, were found. F4-WFA(+) showed a remarkable increase in branched structures relative to the quantity before enrichment. In recombinant M2BP, both no sialylated-LacdiNAc and -branched LacNAc structures were emerged. The LacdiNAc structure was not found in serum M2BP. Glycosidase-assisted HISCL assays suggest that reactivity with WFA of both serum and recombinant M2BP depends on unsialylated and branched LacNAc and in part of recombinant depends on LacdiNAc. On M2BPGi, the highly branched LacNAc, probably dense cluster of LacNAc, would be recognized by WFA. [ABSTRACT FROM AUTHOR]

Objective: To report the final long-term safety and efficacy analyses of pati ents with acromegaly treated with pegvisomant from the ACROSTUDY. Design: Global (15 countries), multicentre, non-interventional study (2004-2017). Methods: The complete ACROSTUDY cohort comprised patients with acromegal y, who were being treated with pegvisomant (PEGV) prior to the study or at enrolment. The main endpoints were long-term safety (comorbidities, adverse events (AEs), pituitary tumour volumes, liver tests) an d efficacy (IGF1 changes). Results: Patients (n = 2221) were treated with PEGV for a median of 9.3 years (range, 0-20.8 years) and followed up for a median of 7.4 years (range, 0-13.9 years). Before PEGV, 96.3% had received other acromegaly treatments (surgery/radiotherapy/medications). Before PEGV treatment, 87.2% of patients reported comorbidities. During ACROSTUDY, 5567 AEs were reported in 56.5% of patients and of these 613 were considered treatment-related (in 16.5% of patients) and led to drug withdrawal in 1.3%. Pituitary imaging showed a tumour size increase in 7.1% of patients; the majority (71.1%) reported no changes. Abnormal AST or ALT liver tests oc curred in 3.2% of patients. IGF1 normalization rate improved over time, increasing from 11.4% at PEGV start to 53.7 % at year 1, and reaching 75.4% at year 10 with the use of =30 mg PEGV/day in an increasing proportion of patients. Conclusion: This comprehensive review of the complete cohort in ACROSTUDY confirmed the overall favourable benefit-to-risk profile and high efficacy of PEGV as mono- and comb ination therapy in patients with an aggressive course/uncontrolled/active acromegaly requiring long-term medical therapy for control. [ABSTRACT FROM AUTHOR]

Phosmet is a non-systemic organophosphorus insecticide exerting its toxicity by inhibiting acetylcholinesterase upon entering the body via contact, ingestion and inhalation. Data regarding its sublethal effects on fish are limited, and therefore, with this study it was aimed to investigate the effects of phosmet on liver and brain tissues of juvenile Oncorhynchus mykiss following 24, 48, 72 and 96 h of exposure to 5, 25 and 50 μg/l concentrations. Pesticide treatment caused notable decrease in the levels of serum glucose, protein and cholesterol, whereas there was prominent elevation in the activities of alanine aminotransferase, aspartate aminotransferase and alkaline phosphatase. Anticholinesterase activity of phosmet was observed in brain tissue reaching maximum of 46%. In both tissues, increase in the activities of superoxide dismutase, catalase and glutathione peroxidase and level of glutathione was accompanied by elevated thiobarbituric acid reactive substances level. Our results clearly indicate the modulatory effect of phosmet on acetylcholinesterase activity and its potency to provoke oxidative stress condition. The determined alteration in alanine aminotransferase, aspartate aminotransferase and alkaline phosphatase activities indicates hepatotoxic potential of pesticide; meanwhile, obtained hypoglycaemia and hypoproteinaemia are evaluated as adaptive responses to handle the stress to survive. [ABSTRACT FROM AUTHOR]

The endoplasmic reticulum (ER) is a contiguous and complicated membrane network in eukaryotic cells, and membrane contact sites (MCSs) between the ER and other organelles perform vital cellular functions, including lipid homeostasis, metabolite exchange, calcium level regulation, and organelle division. Here, we establish a whole pipeline to reconstruct all ER, mitochondria, lipid droplets, lysosomes, peroxisomes, and nuclei by automated tape-collecting ultramicrotome scanning electron microscopy and deep learning techniques, which generates an unprecedented 3D model for mapping liver samples. Furthermore, the morphology of various organelles and the MCSs between the ER and other organelles are systematically analyzed. We found that the ER presents with predominantly flat cisternae and is knitted tightly all throughout the intracellular space and around other organelles. In addition, the ER has a smaller volume-to-membrane surface area ratio than other organelles, which suggests that the ER could be more suited for functions that require a large membrane surface area. Our data also indicate that ER‒mitochondria contacts are particularly abundant, especially for branched mitochondria. Our study provides 3D reconstructions of various organelles in liver samples together with important fundamental information for biochemical and functional studies in the liver. [ABSTRACT FROM AUTHOR]

Background: Given the susceptibility of organs to ischaemic injury, alternative preservation methods to static cold storage (SCS), such as normothermic machine perfusion (NMP) are emerging. The aim of this study was to perform a comparison between NMP and SCS in liver transplantation with particular attention to bile duct lesions. Methods: The outcomes of 59 consecutive NMP-preserved donor livers were compared in a 1 : 1 propensity score-matched fashion to SCS control livers. Postoperative complications, patient survival, graft survival and bile duct lesions were analysed. Results: While patients were matched for cold ischaemia time, the total preservation time was significantly longer in the NMP group (21h versus 7h, P<0.001). Patient and graft survival rates at 1 year were 81 versus 82 per cent (P=0.347) and 81 versus 79 per cent (P=0.784) in the NMP and SCS groups, respectively. The postoperative complication rate was comparable (P=0.086); 37 per cent NMP versus 34 per cent SCS patients had a Clavien-Dindo grade IIIb or above complication. There was no difference in early (30days or less) (NMP 22 versus SCS 19 per cent, P=0.647) and late (more than 30days) (NMP 27 versus SCS 36 per cent, P=0.321) biliary complications. However, NMP-preserved livers developed significantly fewer ischaemic-type bile duct lesions (NMP 3 versus SCS 14 per cent, P=0.047). Conclusion: The use of NMP allowed for a significantly prolonged organ preservation with a lower rate of observed ischaemic-type bile duct lesions. [ABSTRACT FROM AUTHOR]

Owing to the promising applications of C-dots in biomedical engineering, concerns about their safety have drawn increasing attention recently. In this study, mice were intraperitoneally injected at different C-dot concentrations (0, 6.0, 12.0 and 24.0 mg kg−1) once every 2 days for 30 days. A 1H NMR-based metabolic approach supplemented with biochemical analysis and histopathology was used for the first time to explore the toxicity of C-dots in vivo. Histopathological inspection revealed that C-dots did not induce any obvious impairment in tissues. Biochemical assays showed no significant alterations of most measured biochemical parameters in tissues and serum, except for a slight reduction of the albumin level in serum as well as AChE activity in the liver and kidneys. Orthogonal signal correction-partial least squares-discriminant analysis (OSC-PLS-DA) of NMR profiles supplemented with correlation network analysis and SUS-plots disclosed that C-dots not only triggered the immune system but also disturbed the function of cell membranes as well as the normal liver clearance, indicating that the 1H NMR based metabolomics approach provided deep insights into the toxicity of C-dots in vivo and gained an advantage over traditional toxicological means, and should be helpful for the understanding of its toxic mechanism. [ABSTRACT FROM AUTHOR]

Objectives This study was aimed to investigate the effects of garlic oil (GO), an important natural constituent used in alleviating diabetes and its complications, on the expression levels of irisin and related genes. Methods Thirty-two rats were divided into four groups: Control, Diabetes-Control, Diabetes+GO 100 mg/kg/day and Control+GO 100 mg/kg/day for 45 days. The measurements included: changes in liver Peroxisome proliferator-activated receptor-gamma-coactivator (PGC)-1a, Fibronectin Type-III-Domain-Containing5 (FNDC5), irisin expression, mRNA expression of p38 and TNF-a (Tumour necrosis factor-a), total-antioxidant-status (L-TAS; S-TAS), total-oxidant-status (L-TOS; S-TOS) in liver and serum, respectively. Key findings There was a significant reduction in serum levels of irisin and S-TAS and expression of PGC-1a and FNDC5 in liver in Diabetes-control compared to Control-group, while a significant increase in serum levels of fasting blood glucose (FBG) and TOS, also p38 and TNF-a expressions in liver. In Diabetes+GO group, there was a significant increase in serum irisin and S-TAS, also expression of PGC-1a and FNDC5 in liver, while serum FBG, S-TOS levels, and mRNA expression of p38 and TNF-a in liver were decreased compared to Diabetes-control group (P < 0.05). Conclusions GO alleviated the diabetic liver injury by decreasing Oxidative-Stress parameters and regulation PGC-la, FNDC5, irisin and P38, keeping the balance of TAS/TOS and TNF-a. [ABSTRACT FROM AUTHOR]

Low intake of diverse complementary foods causes critical nutrient gaps in the diets of young children. Inadequate nutrient intake in the first 2 years of life can lead to poor health, educational, and economic outcomes. In this study, the extent to which food affordability is a barrier to consumption of several nutrients critical for child growth and development was examined in Ethiopia, Mozambique, South Africa, Tanzania, Uganda, and Zambia. Drawing upon data from nutrient gap assessments, household surveys, and food composition tables, current consumption levels were assessed, the cost of purchasing key nutritious foods that could fill likely nutrient gaps was calculated, and these costs were compared with current household food expenditure. Vitamin A is affordable for most households (via dark leafy greens, orange-fleshed vegetables, and liver) but only a few foods (fish, legumes, dairy, dark leafy greens, liver) are affordable sources of iron, animal-source protein, or calcium, and only in some countries. Zinc is ubiquitously unaffordable. For unaffordable nutrients, approaches to reduce prices, enhance household production, or increase household resources for nutritious foods are needed. [ABSTRACT FROM AUTHOR]

Taraxacum syriacum (TS) with natural antioxidant and pharmacological activities may be considered for treatment of oxidative stress induced by acetaminophen (APAP). The aim of this study was to evaluate the ameliorative effects of the ethanol extract of TS root against hepatorenal toxicity induced by APAP in comparison to N-acetylcysteine (NAC) as a standard drug. Thirty male Wistar rats were randomly divided into five groups. Control group; APAP (1 g/kg) group; APAP–NAC (160 mg/kg) group and APAP-TS100 and APAP-TS200 groups: APAP plus 100 and 200 mg/kg of TS extract, respectively. After 7 days treatment, serum and liver and kidney tissues were prepared and evaluated. TS extract ameliorated the increased lipid peroxidation level and decreased antioxidant enzymes activities and glutathione level in liver and kidney of APAP-treated rats. Moreover, treatment with the TS extract caused significant reduction in the histopathological damages and high levels of serum biochemical markers of hepatic and renal functions after APAP treatment. This study suggests that the extract of TS roots has dose-dependent ameliorative effect against APAP-induced oxidative damage in liver and kidney due to its free radical scavenging and antioxidant properties. The overall efficacy of the extract at 200 mg/kg dose is comparable with NAC. [ABSTRACT FROM AUTHOR]

The concepts of postmortem redistribution (PMR, F) factor, and "theoretical" PMR (Ft) - based upon a drug's characteristic L/P ratio-have been defined to express the direct relationship between postmortem peripheral blood and the corresponding antemortem whole-blood concentration. This paper applies recent data describing liver/peripheral blood (L/P) ratios for many commonly detected drugs to assess these models, and provide a ranking of drugs'propensity for (and degree of) PMR. [ABSTRACT FROM AUTHOR]

Exposure to the herbicides Paraquat and Roundup® may cause cell lesions due to an increase in oxidative stress levels in different biological systems, even in the liver. The aim of this study was to analyze the effect of melatonin on liver of rats exposed to herbicides. A total of 35 rats were randomly divided into seven equal-sized groups: control, Paraquat, Roundup®, Paraquat + Roundup®, Paraquat + melatonin, Roundup® + melatonin, and Paraquat + Roundup® + melatonin. Samples of blood and hepatic tissue were collected at the end of the seventh day of exposure and treatment with melatonin. Body weight, hematological parameters, and histopathological, biochemical analyses and determination of oxidative stress levels in liver were evaluated. Body weight was compromised (P < 0.01). Alterations of hematologic parameters were significant when compared to control (P < 0.001). Biochemically, serum levels of albumin decreased (P < 0.001), but serum levels of alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase increased (P < 0.001). Histopathology revealed necrotic hepatocytes, portal and central-lobular inflammatory infiltrate, congestion of capillaries. Serum levels of thiobarbituric acid reactive substances were found to be significantly elevated (P < 0.05; P < 0.001), and serum level of reduced glutathione was significantly lower (P < 0.05; P < 0.001). The groups treated concomitantly with melatonin revealed results similar to those of the control. However, melatonin acted as a protective agent for the liver against experimentally induced hepatic toxicity, promoting prevention of body weight, oxidative stress, and normalization of hematological and biochemical parameters. Graphical Abstract Body weight gain during exposure to herbicides Paraquat (PQ) and its association with Roundup® caused decrease in weight P < 0.01, P < 0.001 and treatment with melatonin (MLT) P < 0.01. All rates are given as means ± SE of seven experimental groups (n = 5). [ABSTRACT FROM AUTHOR]

Insulinoma is the most frequent functional neuroendocrine tumor of the pancreas, which causes organic hyperinsulinism with severe hypoglycemia. There are no cases of primary insulinoma of the liver described. A 63-year-old female was admitted to our center presenting symptoms of severe hypoglycemia due to confirmed endogenic hyperinsulinism. None of the performed diagnostic procedures could reveal a pancreatic tumor. However, a pathologic mass in the sixth segment of the liver was detected. We performed arterial calcium stimulation that showed increased levels of insulin and c-peptide in almost all stimulated arteries. The highest and most prolonged peaks were detected at the points of the common hepatic artery and the right hepatic artery. After the surgical removal of the liver tumor, the blood glucose level was stabilized within the normal range. Post-operative pathomorphological investigation confirmed the diagnosis of a neuroendocrine tumor. The long-term survival results show correct treatment tactics without any signs of disease recurrence. [ABSTRACT FROM AUTHOR]