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Hepatic
Terms modified by Hepatic Selected AbstractsThe role of endothelin-1 and the endothelin B receptor in the pathogenesis of hepatopulmonary syndrome in the ratHEPATOLOGY, Issue 6 2004Yiqun Ling Endothelin-1 (ET-1) stimulation of endothelial nitric oxide synthase (eNOS) via pulmonary endothelial endothelin B (ETB) receptors and pulmonary intravascular macrophage accumulation with expression of inducible nitric oxide synthase (iNOS) and heme oxygenase-1 (HO-1) are implicated in experimental hepatopulmonary syndrome (HPS) after common bile duct ligation (CBDL). Our aim was to evaluate the role of ET-1 in the development of experimental HPS. The time course of molecular and physiological changes of HPS and the effects of selective endothelin receptor antagonists in vivo were assessed after CBDL. Effects of ET-1 on intralobar pulmonary vascular segment reactivity and on eNOS expression and activity in rat pulmonary microvascular endothelial cells (RPMVECs) were also evaluated. Hepatic and plasma ET-1 levels increased 1 week after CBDL in association with a subsequent increase in pulmonary microvascular eNOS and ETB receptor levels and the onset of HPS. Selective ETB receptor inhibition in vivo significantly decreased pulmonary eNOS and ETB receptor levels and ameliorated HPS. CBDL pulmonary artery segments had markedly increased ETB receptor mediated, nitric oxide dependent vasodilatory responses to ET-1 compared with controls and ET-1 triggered an ETB receptor dependent stimulation of eNOS in RPMVECs. Pulmonary intravascular macrophages also accumulated after CBDL and expressed HO-1 and iNOS at 3 weeks. Selective ETB receptor blockade also decreased macrophage accumulation and iNOS production. In conclusion, ET-1 plays a central role in modulating pulmonary micovascular tone in experimental HPS. (HEPATOLOGY 2004;39:1593,1602.) [source] p53 may positively regulate hepatocyte proliferation in ratsHEPATOLOGY, Issue 2 2002Yukiko Inoue p53, known as a tumor suppressor gene, is a transcription factor that regulates various cellular functions. Recently, several growth factor gene promoters, including that of transforming growth factor , (TGF-,), were shown to be direct targets of p53-mediated transcription. Hepatic p53 mRNA is up-regulated during liver regeneration in rats. The aim of this study is to examine the role of p53 in hepatocyte proliferation. p53 protein levels were examined in rat hepatocytes cultured in the medium containing hepatocyte growth factor (HGF). p53 levels began to increase after 6 hours of incubation, reached a maximum at 18 hours, and decreased thereafter. DNA synthesis increased at 12 hours and peaked at 30 hours. When hepatocytes were incubated with p53 antisense oligonucleotide in addition to HGF, increases of p53 and TGF-, levels were suppressed, and DNA synthesis was reduced. The increases of TGF-, levels and DNA synthesis were also suppressed by a chemical inhibitor of p53, pifithrin-,. In rats after two-thirds partial hepatectomy, hepatic p53 increased and reached maximal levels around 16 hours when hepatic HGF levels have been shown to reach a maximum followed by an increase in hepatic TGF-, levels or hepatocyte proliferation. In contrast, sham-operated rats showed minor elevations of hepatic p53 levels. In conclusion, p53 production is stimulated by HGF and may contribute to the proliferation of rat hepatocytes. Considering previous findings indicating the importance of endogenous TGF-, for the proliferation of hepatocytes stimulated by HGF, TGF-, might play a role in HGF-p53 mediated hepatocyte proliferation. [source] Macrophage aggregates in gilthead sea bream fed copper, iron and zinc enriched dietsJOURNAL OF FISH BIOLOGY, Issue 2 2000M. Manera Gilthead sea bream Sparus aurata from consecutive year classes (0+ and 1+) and from the same parent stock were fed four diets, three of which were fortified with copper, iron and zinc. Concentrations of these elements were little affected by the diet. Hepatic, renal and splenic tissues sections were examined to detect the influence of the diet on the number and morphology of macrophage aggregates (MAs); in particular their structure was examined in the spleen. Three different types of MAs were detected: (1) unstructured, (2) partially structured and scarcely defined and (3) fully structured and well defined. Melanin was the most abundant pigment in the pigmented macrophages which form MAs and the amount of this pigment was influenced by season. Ferritin, in contrast with previous data obtained in other fish species, was more abundant in renal than in splenic MAs. Significant differences in splenic MA numbers among fish fed different diets and among different periods of the year were detected. The results suggest that a polyfactorial regulation could act on the splenic MA number in gilthead sea bream. [source] Tezosentan normalizes hepatomesenteric perfusion in a porcine model of cardiac tamponadeACTA ANAESTHESIOLOGICA SCANDINAVICA, Issue 2 2009A. ÅNEMAN Background: To investigate endothelin-1 (ET-1)-dependent hepatic and mesenteric vasoconstriction, and oxygen and lactate fluxes in an acute, fixed low cardiac output (CO) state. Methods: Sixteen anesthetized, mechanically ventilated pigs were studied. Cardiac tamponade was established to reduce portal venous blood flow (QPV) to 2/3 of the baseline value. CO, hepatic artery blood flow (QHA), QPV, hepatic laser-Doppler flow (LDF), hepatic venous and portal pressure, and hepatic and mesenteric oxygen and lactate fluxes were measured. Hepatic arterial (RHA), portal (RHP) and mesenteric (Rmes) vascular resistances were calculated. The combined ETA,ETB receptor antagonist tezosentan (RO 61-0612) or normal saline vehicle was infused in the low CO state. Measurements were made at baseline, after 30, 60, 90 min of tamponade, and 30, 60, 90 min following the infusion of tesozentan at 1 mg/kg/h. Results: Tamponade decreased CO, QPV, QHA, LDF, hepatic and mesenteric oxygen delivery, while hepatic and mesenteric oxygen extraction and lactate release increased. RHA, RHP and Rmes all increased. Ninety minutes after tesozentan, QPV, LDF and hepatic and mesenteric oxygen delivery and extraction increased approaching baseline values, but no effect was seen on CO or QHA. Hepatic and mesenteric handling of lactate converted to extraction. RHA, RHP and Rmes returned to baseline values. No changes were observed in these variables among control animals not receiving tesozentan. Conclusion: In a porcine model of acute splanchnic hypoperfusion, unselective ET-1 blockade restored hepatomesenteric perfusion and reversed lactate metabolism. These observations might be relevant when considering liver protection in low CO states. [source] Review article: nonalcoholic fatty liver disease and hepatitis C virus , partners in crimeALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 10 2008J. J. BLONSKY Summary Background, Both nonalcoholic fatty liver disease (NAFLD) and chronic hepatitis C (CHC) are frequent causes of chronic liver disease. In recent years, there have been significant revelations as regards the relationship between NAFLD and CHC. Aim, To conduct a systematic, evidence-based review of the epidemiology, pathophysiology and potential treatments of coexistent NAFLD and CHC. Methods, The terms such as hepatitis C, fatty liver, NAFLD, nonalcoholic steatohepatitis and steatosis were searched on PubMed up to January 2008. References from selected articles and pertinent abstracts were also included. Results, Hepatic steatosis affects up to 80% of patients with CHC and is dependent on both viral and host factors. While insulin resistance (IR) is associated with hepatic steatosis and hepatitis C virus, genotype-specific pathogenic mechanisms have been identified and are currently the focus of intense investigation in the literature. Clinical implications of concurrent NAFLD, CHC and IR include increased disease progression, elevated risk of hepatocellular carcinoma, and decreased response to antiviral therapy. Conclusions, NAFLD and IR are common in patients with CHC virus infection. IR is a driving force in the development of hepatic steatosis. Because of the clinical implications of hepatic steatosis and IR in the setting of CHC, further studies evaluating treatments, which may increase response to antiviral therapy, are needed. [source] Impact of amino acid substitutions in the hepatitis C virus genotype 1b core region on liver steatosis and hepatic oxidative stress in patients with chronic hepatitis CLIVER INTERNATIONAL, Issue 4 2010Yoshihiko Tachi Abstract Background: Liver steatosis and hepatic oxidative stress are the histopathological features of chronic hepatitis C. Hepatitis C virus (HCV) genotype 1 core protein induces hepatic steatosis and reactive oxygen species production in transgenic mice. The amino acid substitutions in the HCV core region appear to be related to hepatocarcinogenesis. Aims: The aim of this study was to clarify the impact of mutations in the HCV core region on oxidative stress and lipid metabolism in patients with chronic hepatitis C. Methods: Sixty-seven patients (35 men, 32 women; mean age, 58.4 ± 10.2 years) with chronic hepatitis C with high titres (>5 log IU/ml) were enrolled. Substitutions in amino acids 70, 75 and 91 of the HCV genotype 1b core region, the percentage of hepatic steatosis, and hepatic 8-hydroxy-2,-deoxyguanosine (8-OHdG) levels were investigated in all patients. Urinary 8-OHdG levels were measured in 35 patients. Results: Body mass index, alanine aminotransferase, ,-glutamyl transferase, and triglyceride levels and substitutions of amino acid 70/Q (glutamine) were significantly associated with the presence of steatosis on univariate analysis. Multivariate analysis showed that substitution of amino acid 70 of glutamine and triglyceride levels were the independent factors related to liver steatosis. Hepatic and urinary 8-OHdG levels were significantly higher in patients with methionine at amino acid 91 of the HCV core region than in those with leucine. Conclusion: Substitutions in the amino acids of the HCV genotype1b core region are associated with hepatic steatosis and oxidative stress in patients with chronic hepatitis C. [source] Live donor/split liver grafts for adult recipients: When should we use them?LIVER TRANSPLANTATION, Issue S2 2005Peter Neuhaus Key Points 1Split liver transplantation for a child and an adult recipient is standard today. Living donor liver transplantation for small children should only be necessary in exceptional situations in a country with a well-organized organ donation program. 2True split liver transplantation for two adults is still not very common. In the United States between April 2000 and May 2001, 89 surgical teams transplanted only 15 left lobes and 13 right lobes. Especially left lobes from deceased donors have a poor outcome; in Europe the ELTR shows a 1-year graft survival of 47%. 3While in Asia left lobes, right lateral segments, and dual left lateral segments are more frequently used, living donor liver transplantation for adults in Europe and the United States is predominantly performed with right lobes.7, 8 This carries a significant morbidity and mortality risk for the donor. Outcome compared to deceased donor liver transplantation (DDLTx) is similar with a trend towards more short-term and long-term biliary complications. 4Living donor and split liver transplantation should be used mainly in an elective situation. Candidates are tumor patients, patients with cholestatic liver disease, and elective patients with bile disease. 5Urgent liver transplantation is not a good option for living donor and split liver transplantation. Hepatic assist devices may change the picture in the future. 6Living donor liver transplantation for metabolic disorders like Alpha-1-Antitrypsin deficiency, Hyperoxaluria, and others cannot be recommended at present since the genetically related donor and the patient may carry an unknown risk. (Liver Transpl 2005;11:S6,S9.) [source] Flow in Lymphatic Networks: Interaction between Hepatic and Intestinal Lymph VesselsMICROCIRCULATION, Issue 4 2001RANDOLPH H. STEWART ABSTRACT Objective: Lymph from both the liver and intestine flows into the cisterna chyli. We hypothesized that increasing liver lymph flow would increase cisterna chyli pressure and, thereby, decrease intestinal lymph flow, potentiating intestinal edema formation. Methods: Anesthetized dogs were instrumented to measure and manipulate portal vein pressure and cisterna chyli pressure. The effects of directly increasing portal pressure with and without directly increasing cisterna chyli pressure on intestinal wet-to-dry ratio and intestinal ascites formation rate were determined. Target values for portal and cisterna chyli pressures were determined following elevation of inferior vena caval pressure to levels seen in patients with obstructive caval disease. Results: Direct elevation of portal pressure (Pport) alone to 17.5 mm Hg caused a significant increase in intestinal wet-to-dry ratio (3.98 ± 0.24 vs. 3.40 ± 0.43) and the rate of ascites formation (0.36 ± 0.12 vs. 0.05 ± 0.03 mL/g dry wt/h). Simultaneous direct elevation of cisterna chyli pressure to 6.0 mm Hg and Pport to 17.5 mm Hg caused further increases in intestinal wet-to-dry ratio (5.52 ± 1.20) and ascites formation (0.57 ± 0.11 mL/g dry wt./h). Conclusions: Inferior vena caval hypertension increases liver lymph flow that elevates cisterna chyli pressure, which inhibits intestinal lymph flow and augments intestinal edema formation. [source] Increased Hepatic and Decreased Urinary Metallothionein in Rats after Cessation of Oral Cadmium ExposureBASIC AND CLINICAL PHARMACOLOGY & TOXICOLOGY, Issue 4 2010Yihuai Liang Wistar rats of both genders were given CdCl2 in drinking water at daily doses of 0, 2.5, 5.0 or 10.0 mg Cd/kg body-weight for 12 weeks. Half of the animals were then killed; the others were given Cd-free water for the following 16 weeks, i.e. until 28 weeks after start of the experiment (28-week rats). We observed dose-dependent increases in the levels of MT in the tissues of rats 12 weeks after beginning the experiment (12-week rats). After the exposure ceased, levels of MT in the 28-week rats changed in three ways: an increase in the liver, persistence in the kidney cortex and a decrease in the medulla, relative to those levels in their 12-week counterparts. Biomarkers of kidney dysfunction were determined to be urinary MT (UMT) and urinary N -acetyl-,- d -glucosaminidase (UNAG). After 12 weeks, we observed dose-related statistically significant increases in UMT and UNAG in all of the Cd-exposed groups. A statistically significant decrease for UNAG between the 12- and 28-week rats occurred among males at the lowest Cd dose and for UMT in all of the Cd-exposed groups. The unchanged tissue levels of MT in the kidney cortex suggest that decreased UMT is a sign either of (i) decreased transport of Cd-MT from the liver via blood plasma to the renal tubules or (ii) increased tubular reabsorption and recovery of renal tubular function. [source] Amelioration of Cyclosporine A-Induced Renal, Hepatic and Cardiac Damages by Ellagic Acid in Rats,BASIC AND CLINICAL PHARMACOLOGY & TOXICOLOGY, Issue 2 2008Abdurrauf Yüce Cyclosporine A also causes a dose-related decrease in body functions in experimental animals and human beings. The generation of reactive oxygen species has been implicated in cyclosporine A-induced dysfunctions. The aim of this study was to determine the effects of ellagic acid on cyclosporine A-induced alterations in the kidney, liver and heart oxidant/antioxidant system. The control group was treated with placebo and subcutaneous injection of 0.5 ml isotonic saline + 0.5 ml slightly alkaline solution for 21 days. The cyclosporine A group received a subcutaneous injection of cyclosporine A (15 mg/kg) + 0.5 ml slightly alkaline solution for 21 days. The ellagic acid group was treated with a subcutaneous injection of 0.5 ml isotonic saline + ellagic acid (10 mg/kg) for 21 days. The cyclosporine A plus ellagic acid group received a subcutaneous injection of cyclosporine A + ellagic acid for 21 days. Ellagic acid and slightly alkaline solution were administered by gavage. The rats were killed at the end of the treatment period. Malondialdehyde (MDA) and reduced glutathione (GSH) levels, glutathione peroxidase (GSH-Px) and catalase (CAT) activities were determined in kidney, liver and heart tissues. While administration of cyclosporine A increased the MDA levels in kidney, liver and heart tissues, it decreased the GSH, GSH-Px and CAT in these samples when compared to the control group. However, the simultaneously administration of ellagic acid markedly normalized the cyclosporine A-induced liver and heart MDA levels, liver CAT activities and GSH-Px activities of all samples. Cyclosporine A caused marked damages in the histopathological status of kidney, liver and heart tissues, which were partially ameliorated by ellagic acid administration. In conclusion, ellagic acid may be used in combination with cyclosporine A in transplantation treatment to improve the cyclosporine A-induced oxidative stress parameters and other adverse effects. [source] Hepatic and cardiac iron overload among patients with end-stage liver disease referred for liver transplantationCLINICAL TRANSPLANTATION, Issue 5 2010Avital Y. O'Glasser O'Glasser AY, Scott DL, Corless CL, Zaman A, Sasaki A, Gopal DV, Rayhill SC, Orloff SL, Ham JM, Rabkin JM, Flora K, Davies CH, Broberg CS, Schwartz JM. Hepatic and cardiac iron overload among patients with end-stage liver disease referred for liver transplantation. Clin Transplant 2009 DOI: 10.1111/j.1399-0012.2009.01136.x. © 2009 John Wiley & Sons A/S. Abstract:,Background:, Iron overload is associated with fatal cardiovascular events following liver transplantation. Myocardial iron deposits were observed post-mortem in patients who died of cardiac events after transplantation at our institution. This observation prompted testing to exclude cardiac iron in subsequent transplant candidates. Aims:, To assess the results of testing for iron overload in liver transplant candidates at our institution. Methods:, Ferritin, TIBC, and serum iron were measured in cirrhotics referred for transplantation. Patients with transferrin saturation ,50% and ferritin ,250 ng/mL underwent liver biopsy graded for iron. Patients with 3,4+ hepatic iron deposits underwent HFE mutation analysis and endomyocardial biopsy with iron staining. Results:, Eight hundred and fifty-six patients were evaluated for liver transplantation between January 1997 and March 2005. Two hundred and eighty-seven patients (34%) had transferrin saturation ,50% and ferritin ,250 ng/mL. Patients with markers of iron overload had more advanced liver disease than those with normal iron indices. One hundred and fifty-three patients underwent liver biopsy. Twenty-six patients (17%) had 3,4+ hepatic iron staining. One patient was a C282Y heterozygote. Endomyocardial biopsy was performed in 14 patients of whom nine had cardiac iron deposition. Conclusions:, Non-HFE-related cardiac iron overload can occur in advanced liver disease We therefore recommend screening for cardiac iron prior to liver transplantation. [source] Forearm and leg amino acid metabolism in the basal state and during combined insulin and amino acid stimulation after a 3-day fastACTA PHYSIOLOGICA, Issue 3 2009J. Gjedsted Abstract Aim:, Fasting is characterized by a progressive loss of protein, but data on protein kinetics are unclear and few have studied the effects of re-feeding. The present study was designed to test the hypothesis that a combined infusion of insulin and amino acids after fasting would induce compensatory increases in protein synthesis and reductions in protein breakdown at the whole body level and in muscle. Methods:, We included 10 healthy male volunteers and studied them twice: (1) in the post-absorptive state and (2) after 72 h of fasting. Amino acid kinetics was measured using labelled phenylalanine and tyrosine, whole body energy expenditure was assessed and urea nitrogen synthesis rates were calculated. Results:, After fasting we observed an increase in arterial blood concentration of branched chain amino acids and a decrease in gluconeogenic amino acids (P < 0.05). Isotopically determined whole body, forearm and leg phenylalanine fluxes were unaltered apart from a 30% decrease in phenylalanine-to-tyrosine conversion (2.0 vs. 1.4 ,mol kg,1 h,1, P < 0.01). During infusion of insulin and amino acids, amino acid concentrations increased. Conclusion:, Our data indicate that after a 72-h fast basal and insulin/amino acid-stimulated regional phenylalanine fluxes in leg and forearm muscle are unaltered. During fasting concentrations of gluconeogenic amino acids decrease and hepatic and/or renal phenylalanine-to-tyrosine conversion decreases. Thus, as opposed to glucose and lipid metabolism, fasting does not induce insulin resistance as regards amino acid metabolism. [source] Transcriptional dynamics of endodermal organ formationDEVELOPMENTAL DYNAMICS, Issue 1 2009Richard I. Sherwood Abstract Although endodermal organs including the liver, pancreas, and intestine are of significant therapeutic interest, the mechanism by which the endoderm is divided into organ domains during embryogenesis is not well understood. To better understand this process, global gene expression profiling was performed on early endodermal organ domains. This global analysis was followed up by dynamic immunofluorescence analysis of key transcription factors, uncovering novel expression patterns as well as cell surface proteins that allow prospective isolation of specific endodermal organ domains. Additionally, a repressive interaction between Cdx2 and Sox2 was found to occur at the prospective stomach,intestine border, with the hepatic and pancreatic domains forming at this boundary, and Hlxb9 was revealed to have graded expression along the dorsal,ventral axis. These results contribute to understanding the mechanism of endodermal organogenesis and should assist efforts to replicate this process using pluripotent stem cells. Developmental Dynamics 238:29,42, 2009. © 2008 Wiley-Liss, Inc. [source] Plasma anhydro- d -glucitol (1,5-AG) as an indicator of hyperglycaemic excursions in pregnant women with diabetesDIABETIC MEDICINE, Issue 2 2006M. Dworacka Abstract Aims To evaluate the use of the plasma 1,5-anhydro- d -glucitol (1,5-AG) level as a possible marker for glucose excursions in pregnant women with diabetes. Methods The study group consisted of 55 pregnant women with diabetes (gestational diabetes mellitus,GDM, n = 28 or pre-gestational diabetes mellitus ,PGDM, n = 27), without hepatic or renal insufficiency, gestational age range 5,38 weeks. In each patient, 24-h glucose profile, glycated haemoglobin and 1,5-AG plasma levels were measured. Mean blood glucose (MBG) and M-value (by Schlichtkrull) were calculated. MBG, M-value and maximal daily glycaemia (MxG) were used as indexes of daily glycaemic excursions. Results A significant correlation was found between the 1,5-AG plasma level and MxG [r = (,0.3)] and between the 1,5-AG level and M-value [r = (,0.36)]. There was no association between the 1,5-AG level and gestational age. Multivariate regression analysis, with 24-h glucose profile, gestational age and MxG as independent variables, showed that MxG was the main parameter determining the 1,5-AG plasma level [, = (,0.68)]. The M-value, the coefficient of glucose fluctuations, also determined the 1,5-AG level but with lower statistical power [, = (0.41)]. No statistical differences were found in the group with HbA1c < 6% or > 6% for 1,5-AG and M-value, while MBG was higher in poorly controlled patients (HbA1c > 6%). Conclusions The plasma 1,5-AG level may be a useful marker of daily glucose excursion in pregnant women with diabetes, as an adjunct to HbA1c monitoring. [source] Effects of dietary N -acetylcysteine on the oxidative stress induced in tilapia (Oreochromis Niloticus) exposed to a microcystin-producing cyanobacterial water bloom,ENVIRONMENTAL TOXICOLOGY & CHEMISTRY, Issue 8 2009María Puerto Abstract Fish can be exposed to toxic cyanobacterial cells in natural waters and fish farms and suffer from oxidative damage. The present study investigates the effects of N-acetylcysteine (NAC), a glutathione (GSH) precursor, on the oxidative stress induced by Microcystis cyanobacterial cells containing microcystins (MCs) in tilapia fish (Oreochromis niloticus). Variation in lipid peroxidation (LPO) levels, carbonyl group content, reduced glutathione to oxidized glutathione ratio (GSH: GSSG), and catalase (Enzyme Commission [EC] 1.11.1.6), superoxide dismutase (SOD; EC 1.15.1.1), glutathione reductase (GR; EC 1.8.1.7), glutathione peroxidase (GPx; EC 1.11.1.9), and glutathione S-transferase (EC 2.5.1.18) activities in liver and kidney of tilapia exposed to a single oral dose of 120 ,g MC-LR (with leucine [L] and arginine [R])/fish and killed in 24 h were investigated in the absence and presence of 20.0, 44.0, and 96.8 mg NAC/fish/d. Results showed a protective role of NAC, depending on the dose and the biomarker considered. The increase in LPO (1.9-and 1.4-fold in liver and kidney, respectively) and the decreased protein content and GSH:GSSG in the liver induced by MCs were recovered mainly by the lower doses of NAC employed. Antioxidant enzyme activities increased (range, 1.4-to 1.7-fold) by MCs also were ameliorated by NAC, although the highest level used induced significant alteration of some enzymatic activities, such as SOD, GPx, and GR. Thus, NAC can be considered to be a useful chemoprotectant that reduces hepatic and renal oxidative stress in the prophylaxis and treatment of MC-related intoxications in fish when careful attention is given to its application dose because of its own pro-oxidant activity, as shown in the present study at 96.8 mg NAC/ fish/d. [source] Equine recurrent uveitis: A clinical manifestation of leptospirosisEQUINE VETERINARY EDUCATION, Issue 10 2009L. Frellstedt Summary Leptospirosis is a zoonosis of worldwide distribution affecting domestic animals, wildlife and man. The bacterial disease is caused by pathogenic Leptospira spp., which are transmitted from reservoir hosts to accidental hosts. Horses are accidental hosts and can become susceptible to leptospiral infections. Widespread exposure to leptospires exists and is significantly more common than clinical disease. Leptospirosis can have different clinical manifestations including abortion, still birth, systemic disease with hepatic or renal dysfunction, and equine recurrent uveitis (ERU). ERU is the most frequently encountered clinical manifestation and this article will focus on the review of leptospira-associated ERU. Equine recurrent uveitis is the most common cause of vision impairment and blindness in horses. The pathogenesis of leptospira-associated ERU involves direct bacterial effects and immune-mediated responses. Clinical signs vary between the acute and chronic phases of the disease and progress over time. The diagnosis of leptospira-associated ERU can be difficult and usually requires a combination of diagnostic tests. Medical and surgical treatments have been described with varying outcomes. The prognosis for sight is usually poor, although core vitrectomy may improve the outcome. Avoidance of leptospiral exposure of horses is the only reliable prevention of leptospira-associated disease. [source] Increased insulin resistance and risk of incident cerebrovascular events in patients with pre-existing atherothrombotic diseaseEUROPEAN JOURNAL OF NEUROLOGY, Issue 11 2009D. Tanne Background and purpose:, Diabetes and the metabolic syndrome are known risk factors for ischaemic stroke. Our aim was to examine whether amongst patients with pre-existing atherothrombotic disease, increased insulin resistance is associated with incident cerebrovascular events. Methods:, Patients with stable coronary heart disease included in a secondary prevention trial were followed up for a mean of 6.2 years. Coronary heart disease was documented by a history of myocardial infarction ,6 months and <5 years before enrollment and/or stable angina pectoris with evidence of ischaemia confirmed by ancillary diagnostic testing. Main exclusion criteria were insulin treated diabetes, hepatic or renal failure, and disabling stroke. Baseline insulin levels were measured in 2938 patients from stored frozen plasma samples and increased insulin resistance assessed using the homeostatic model assessment of insulin resistance (HOMA-IR), categorized into tertiles or quartiles. Results:, Crude rates of incident cerebrovascular events rose from 5.0% for HOMA-IR at the bottom tertile to 5.7% at the middle tertile, and 7.0% at the top tertile (P = 0.07). HOMA-IR at the top versus bottom tertile was associated with an unadjusted hazard ratio (HR) of 1.37 (95%CI, 0.94,1.98) and a 1-unit increase in the ln HOMA-IR was associated with a HR of 1.14 (95%CI, 0.97,1.35). In further analyses adjusting for potential confounders, or categorizing baseline HOMA-IR into quartiles, or excluding diabetic patients, we did not identify an increased risk for incident cerebrovascular events conferred by the top category. Conclusions:, Increased insulin resistance did not predict incident cerebrovascular events amongst patients with pre-existing atherothrombotic disease. [source] A clinical and genetic study of 56 Saudi Wilson disease patients: identification of Saudi-specific mutationsEUROPEAN JOURNAL OF NEUROLOGY, Issue 2 2004M. Al Jumah Wilson disease (WD) is a hereditary disorder, with recessive transmission and genetic heterogeneity. Several mutations of ATP7B, the gene underlying WD, were reported in many ethnic groups. In this study, mutation screening in ATP7B of 56 Saudi Arabian WD patients was undertaken. The clinical data of all patients were recorded. The entire ATP7B coding sequence, including intron,exon boundaries were screened for mutation by the polymerase chain reaction (PCR)-based mutation detection technique and DNA sequencing. Thirty-nine patients were symptomatic at presentation and 17 subjects were pre-symptomatic siblings of affected patients. Fourteen patients had neurological, 11 patients had mixed (hepatic and neurological), and 14 patients had hepatic presentations. Family history suggestive of WD was present in 72% of cases and 68% had consanguineous parents. Genetic analysis showed disease-causing mutations in three exons (exons 8, 19 and 21) of the ATP7B gene in 28 patients (50%). Mutations in exons 21 (18 cases) and 19 (one case) were unique for Saudis. This large series of Saudi patients with WD has shown wide variability in the genomic substrate of WD. There is no correlation between genotype and clinical presentation. [source] Influence of Genetically Predisposed Diabetes on Ethanol-Induced Depression of Cardiac Contraction in Adult Rat Ventricular MyocytesEXPERIMENTAL PHYSIOLOGY, Issue 3 2002Jun Ren Diabetes mellitus and alcohol (ethanol) intake are two positively correlated major risk factors for cardiovascular abnormalities. However, the interaction of the two on cardiac function is largely unknown. The purpose of the present study was to examine the impact of genetically predisposed diabetes on acute ethanol exposure-induced cardiac contractile depression at the myocyte level. Ventricular myocytes from spontaneously biobreeding diabetes-prone (BBDP) rats and their diabetes-resistant littermates (BBDR) were stimulated to contract at 0.5 Hz. Contractile properties analysed include: peak shortening amplitude (PS), time-to-PS (TPS), time-to-90% relengthening (TR90) and maximal velocities of shortening/relengthening (± dL/dt). BBDP rats displayed hyperglycaemia, reduced body weight gain and increased cardiac, hepatic and renal size. Myocytes isolated from BBDP rat hearts exhibited prolonged TPS and TR90 associated with normal PS and ± dL/dt, compared with myocytes from the BBDR group. Acute ethanol exposure (80-640 mg dl,1) caused a concentration-dependent inhibition of PS in both BBDR and BBDP myocytes. However, the degree of inhibition of PS was significantly reduced in BBDP myocytes compared to that of BBDR myocytes. The maximal inhibition was 52.9% and 28.4% in BBDR and BBDP groups, respectively. Ethanol significantly depressed ± dL/dt in both BBDR and BBDP myocytes. In addition, ethanol did not affect TPS or TR90 in either the BBDR or BBDP group. Collectively, these results suggest that the ethanol-induced depression in cardiac myocyte contraction may be ,shadowed' by genetically predisposed diabetes. [source] Biotransformation in vitro of the 22R and 22S epimers of budesonide by human liver, bronchus, colonic mucosa and skinFUNDAMENTAL & CLINICAL PHARMACOLOGY, Issue 1 2001Julio Cortijo The pharmacological effects of glucocorticoids are greatly influenced by their pharmacokinetic properties. In the present report, the in vitro biotransformation of the 22R and 22S epimers of the topical steroid budesonide was studied in the S-9 fraction of human liver, bronchus, skin and colonic mucosa. The disappearance of unchanged epimers of budesonide was measured during 90 min of incubation by high performance liquid chromatography. The rate of disappearance was high in human liver while little biotransformation occurred in bronchial tissue and colonic mucosa, and none was detected in the skin. A marked decay of the initial concentration of unchanged budesonide epimers was noticed after 2 h incubation in cultured human hepatocytes, while only a small decrease was observed after 24 h incubation in cultured human airway smooth muscle cells and BEAS-2B cells. The 22R epimer of budesonide suffered greater in vitro biotransformation than the 22S epimer in human hepatic, bronchial and colonic tissues. These findings extend those of other studies, and confirm that the high therapeutic ratio of budesonide is due to negligible local biotransformation combined with high level of liver metabolism for locally absorbed budesonide. [source] A common variant in the patatin-like phospholipase 3 gene (PNPLA3) is associated with fatty liver disease in obese children and adolescents,,HEPATOLOGY, Issue 4 2010Nicola Santoro The genetic factors associated with susceptibility to nonalcoholic fatty liver disease (NAFLD) in pediatric obesity remain largely unknown. Recently, a nonsynonymous single-nucleotide polymorphism (rs738409), in the patatin-like phospholipase 3 gene (PNPLA3) has been associated with hepatic steatosis in adults. In a multiethnic group of 85 obese youths, we genotyped the PNLPA3 single-nucleotide polymorphism, measured hepatic fat content by magnetic resonance imaging and insulin sensitivity by the insulin clamp. Because PNPLA3 might affect adipogenesis/lipogenesis, we explored the putative association with the distribution of adipose cell size and the expression of some adipogenic/lipogenic genes in a subset of subjects who underwent a subcutaneous fat biopsy. Steatosis was present in 41% of Caucasians, 23% of African Americans, and 66% of Hispanics. The frequency of PNPLA3(rs738409) G allele was 0.324 in Caucasians, 0.183 in African Americans, and 0.483 in Hispanics. The prevalence of the G allele was higher in subjects showing hepatic steatosis. Surprisingly, subjects carrying the G allele showed comparable hepatic glucose production rates, peripheral glucose disposal rate, and glycerol turnover as the CC homozygotes. Carriers of the G allele showed smaller adipocytes than those with CC genotype (P = 0.005). Although the expression of PNPLA3, PNPLA2, PPAR,2(peroxisome proliferator-activated receptor gamma 2), SREBP1c(sterol regulatory element binding protein 1c), and ACACA(acetyl coenzyme A carboxylase) was not different between genotypes, carriers of the G allele showed lower leptin (LEP)(P = 0.03) and sirtuin 1 (SIRT1) expression (P = 0.04). Conclusion: A common variant of the PNPLA3 gene confers susceptibility to hepatic steatosis in obese youths without increasing the level of hepatic and peripheral insulin resistance. The rs738409 PNPLA3 G allele is associated with morphological changes in adipocyte cell size. (HEPATOLOGY 2010.) [source] Hepatitis B virus X protein blunts senescence-like growth arrest of human hepatocellular carcinoma by reducing Notch1 cleavage,HEPATOLOGY, Issue 1 2010Jiejie Xu One of the serious sequelae of chronic hepatitis B virus (HBV) infection is hepatocellular carcinoma (HCC). Among all the proteins encoded by the HBV genome, hepatitis B virus X protein (HBx) is highly associated with the development of HCC. Although Notch1 signaling has been found to exert a tumor-suppressive function during HCC development, the mechanism of interaction between HBx expression and Notch1 signaling needs to be explored. In this study, we report that HBx expression in hepatic and hepatoma cells resulted in decreased endogenous protein levels of Notch1 intracellular domain (ICN1) and messenger RNA levels of its downstream target genes. These effects were due to a reduction of Notch1 cleavage by HBx through the suppression of presenilin1 (Psen1) transcription rather than inhibition of Notch1 transcription or its ligands' expression. Through transient HBx expression, decreased ICN1 resulted in enhanced cell proliferation, induced G1-S cell cycle progression, and blunted cellular senescence in vitro. Furthermore, the effect of blunted senescence-like growth arrest by stable HBx expression through suppression of ICN1 was shown in a nude mouse xenograft transplantation model. The correlation of inhibited Psen1-dependent Notch1 signaling and blunted senescence-like growth arrest was also observed in HBV-associated HCC patient tumor samples. Conclusion: Our results reveal a novel function of HBx in blunting senescence-like growth arrest by decreasing Notch1 signaling, which could be a putative molecular mechanism mediating HBV-associated hepatocarcinogenesis. (HEPATOLOGY 2010;) [source] Interplay of hepatic and myeloid signal transducer and activator of transcription 3 in facilitating liver regeneration via tempering innate immunity,HEPATOLOGY, Issue 4 2010Hua Wang Liver regeneration triggered by two-thirds partial hepatectomy is accompanied by elevated hepatic levels of endotoxin, which contributes to the regenerative process, but liver inflammation and apoptosis remain paradoxically limited. Here, we show that signal transducer and activator of transcription 3 (STAT3), an important anti-inflammatory signal, is activated in myeloid cells after partial hepatectomy and its conditional deletion results in an enhanced inflammatory response. Surprisingly, this is accompanied by an improved rather than impaired regenerative response with increased hepatic STAT3 activation, which may contribute to the enhanced liver regeneration. Indeed, conditional deletion of STAT3 in both hepatocytes and myeloid cells results in elevated activation of STAT1 and apoptosis of hepatocytes, and a dramatic reduction in survival after partial hepatectomy, whereas additional global deletion of STAT1 protects against these effects. Conclusion: An interplay of myeloid and hepatic STAT3 signaling is essential to prevent liver failure during liver regeneration through tempering a strong innate inflammatory response mediated by STAT1 signaling. (HEPATOLOGY 2010.) [source] Long-term exclusive zinc monotherapy in symptomatic Wilson disease: Experience in 17 patients,HEPATOLOGY, Issue 5 2009Francisca H. H. Linn Exclusive monotherapy with zinc in symptomatic Wilson disease is controversial. Seventeen symptomatic patients with Wilson disease were treated with zinc only. The mean age at diagnosis and start of treatment was 18 years (range 13,26) with approximately half presenting as adolescents. Presentation was exclusively hepatic, exclusively neurologic, and combined in seven, five, and five patients, respectively. The median follow-up was 14 years (range 2,30). At baseline, two of the 12 patients with hepatic disease exhibited decompensated cirrhosis, five exhibited compensated cirrhosis, and five had less severe disease. Both patients with decompensated cirrhosis improved to a compensated state after initiation of therapy. Two of the five patients with initial compensated cirrhosis progressed to decompensated state, and three remain stable. Three of the five patients with moderate or mild liver disease remain stable and two improved. Apart from decreasing bilirubin levels, no significant changes occurred in the liver biochemistry or function during long-term follow-up. Nine of 10 neurologic patients improved markedly and one deteriorated. Two patients with exclusively neurologic presentation developed liver disease during zinc treatment. Two patients with exclusively hepatic presentation developed mild neurologic symptoms. According to 24-hour urinary copper excretions (213 ± 38 versus 91 ± 23 ,g: P = 0.01) and serum non,ceruloplasmin-bound copper concentrations (11 ± 2 versus 7 ± 1 ,g/dL: P = 0.1) at the end of follow-up, the efficacy of decoppering was less in the exclusively hepatic than in the neurologic group. The prescribed zinc dose and 24-hour urinary zinc excretions tended to be less in the exclusively hepatic group. Conclusion: The outcome of exclusive zinc therapy is generally good in cases of neurologic disease. A less satisfactory outcome in hepatic disease may relate to less efficient decoppering. (HEPATOLOGY 2009.) [source] New school in liver development: Lessons from zebrafish,HEPATOLOGY, Issue 5 2009Jaime Chu There is significant overlap in the genes and pathways that control liver development and those that regulate liver regeneration, hepatic progenitor cell expansion, response to injury, and cancer. Additionally, defects in liver development may underlie some congenital and perinatal liver diseases. Thus, studying hepatogenesis is important for understanding not only how the liver forms, but also how it functions. Elegant work in mice has uncovered a host of transcription factors and signaling molecules that govern the early steps of hepatic specification; however, the inherent difficulty of studying embryogenesis in utero has driven developmental biologists to seek new systems. The rapidly developing vertebrate zebrafish is a favorite model for embryology. The power of forward genetic screens combined with live real-time imaging of development in transparent zebrafish embryos has highlighted conserved processes essential for hepatogenesis and has uncovered some exciting new players. This review presents the advantages of zebrafish for studying liver development, underscoring how studies in zebrafish and mice complement each other. In addition to their value for studying development, zebrafish models of hepatic and biliary diseases are expanding, and using these small, inexpensive embryos for drug screening has become de rigueur. Zebrafish provide a shared platform for developmental biology and translational research, offering innovative methods for studying liver development and disease. The story of hepatogenesis has something for everyone. It involves transcriptional regulation, cell-cell interaction, signaling pathways, control of cell proliferation and apoptosis, plus morphogenic processes that sculpt vasculature, parenchymal cells, and mesenchyme to form the multifaceted liver. Decades of research on liver development in mice and other vertebrates offer valuable lessons in how the multipotent endoderm is programmed to form a functional liver. Of equal importance are insights that have illuminated the mechanisms by which hepatic progenitors are activated in a damaged liver, how the adult liver regenerates, and, possibly, the basis for engineering liver cells in vitro for cell transplantation to sustain patients with liver failure. Moreover, processes that are key to liver development are often co-opted during pathogenesis. Therefore, reviewing hepatogenesis is informative for both basic and translational researchers. In this review, we bring to light the many advantages offered by the tropical freshwater vertebrate zebrafish (Danio rerio) in studying hepatogenesis. By comparing zebrafish and mice, we highlight how work in each system complements the other and emphasize novel paradigms that have been uncovered using zebrafish. Finally, we highlight exciting efforts using zebrafish to model hepatobiliary diseases. (HEPATOLOGY 2009.) [source] Aerobic exercise training reduces hepatic and visceral lipids in obese individuals without weight loss,HEPATOLOGY, Issue 4 2009Nathan A. Johnson Weight loss remains the most common therapy advocated for reducing hepatic lipid in obesity and nonalcoholic fatty liver disease. Yet, reduction of body weight by lifestyle intervention is often modest, and thus, therapies which effectively modulate the burden of fatty liver but are not contingent upon weight loss are of the highest practical significance. However, the effect of aerobic exercise on liver fat independent of weight loss has not been clarified. We assessed the effect of aerobic exercise training on hepatic, blood, abdominal and muscle lipids in 19 sedentary obese men and women using magnetic resonance imaging and proton magnetic resonance spectroscopy (1H-MRS). Four weeks of aerobic cycling exercise, in accordance with current physical activity guidelines, significantly reduced visceral adipose tissue volume by 12% (P < 0.01) and hepatic triglyceride concentration by 21% (P < 0.05). This was associated with a significant (14%) reduction in plasma free fatty acids (P < 0.05). Exercise training did not alter body weight, vastus lateralis intramyocellular triglyceride concentration, abdominal subcutaneous adipose tissue volume, 1H-MRS,measured hepatic lipid saturation, or HOMA-IR (homeostasis model assessment of insulin resistance; P > 0.05). Conclusion: These data provide the first direct experimental evidence demonstrating that regular aerobic exercise reduces hepatic lipids in obesity even in the absence of body weight reduction. Physical activity should be strongly promoted for the management of fatty liver, the benefits of which are not exclusively contingent upon weight loss. (HEPATOLOGY 2009.) [source] Mutual changes of thioredoxin and nitrosothiols during biliary cirrhosis: Results from humans and cholestatic rats,HEPATOLOGY, Issue 2 2007Ignazio Grattagliano Cholestasis is associated with changes in NO metabolism and thiol oxidation. Thioredoxin contributes to regulate vascular tone and intracellular redox status by cleaving nitrosothiols and maintaining ,SH groups. This study investigated the changes in circulating thioredoxin and nitrosothiols and the relationship with protein sulfhydryls (PSH), hepatic concentrations, hyaluronate, and histology in patients with primary biliary cirrhosis (PBC) and in rats with bile duct ligation (BDL). PSH in erythrocytes were significantly decreased in stage III and IV PBC and at day 10 after BDL. Compared with controls, erythrocyte thioredoxin levels were higher in stage I through III PBC and lower in stage IV patients. Serum thioredoxin levels were significantly higher in PBC stages I and II and lower in stages III and IV. Serum nitrosothiols were higher in all PBC patients and inversely related to thioredoxin and hyaluronate. In rats, serum, hepatic, and mitochondrial thioredoxin had initially increased after BDL (day 1-3) and then decreased. After day 7 BDL, nitrosothiols were 10-fold increased in serum and liver, and even higher in mitochondria. In the liver, thioredoxin was inversely related to both nitrosothiols and PSH. In rats, the difference in time average changes from baseline among serum, hepatic, and erythrocyte thioredoxin suggests that most of circulating thioredoxin originates from the liver. Conclusion: Our findings indicate that cholestasis is associated with significant mutual and interrelated changes between circulating and hepatic thioredoxin and nitrosothiols. The increase of hepatic, mitochondrial, and circulating nitrosothiols with ongoing cholestasis suggests an active participation of NO in both liver injury and extrahepatic changes. (HEPATOLOGY 2007;45:331,339.) [source] Influence of beta-2 adrenergic receptor gene polymorphism on the hemodynamic response to propranolol in patients with cirrhosis,HEPATOLOGY, Issue 1 2006Juan Turnes The beta-2-adrenergic receptor (,2- -AR) has several single-nucleotide polymorphisms. These influence the functional response to adrenergic stimulation; genotypes homozygous for Gly16-Glu27 or Gly16-Gln27 alleles (Gly16-Glu/Gln27 haplotypes) are associated with enhanced response, whereas genotypes homozygous for Arg16-Gln27 alleles (Arg16-Gln27) show a decreased response. We hypothesized that gene polymorphisms at the ,2 -AR may influence the hemodynamic response to propranolol in patients with cirrhosis. The ,2 -AR gene polymorphisms were determined by direct sequencing of the polymerase chain reaction (PCR) products in 48 patients with cirrhosis. All patients also had hepatic and systemic hemodynamic studies before and after propranolol administration. Prevalence of Gly16-Glu/Gln27 haplotypes was 29.1%, Arg16-Gln27 haplotype was 16.7%, and 54.2% were compound heterozygotes. Patients with cirrhosis with Gly16-Glu/Gln27 haplotypes had a greater decrease in heart rate, cardiac index, and hepatic blood flow after propranolol administration than those with Arg16-Gln27 haplotype. However, the HVPG response to propranolol was similar in both groups, whereas estimated hepatic sinusoidal resistance increased significantly in Gly16-Glu/Gln27 haplotypes but not in Arg16-Gln27 (+27.1 ± 17.8% vs -17.9 ± 13.9%, P = .042), suggesting that unopposed vasoconstrictive activity at the intrahepatic circulation hinders the fall in HVPG despite enhanced hemodynamic response to propranolol in Gly16-Glu/Gln27 haplotypes. In conclusion, ,2 -AR gene polymorphisms influence the response to beta-blockade. However, HVPG reduction cannot be predicted from polymorphism analysis. Patients with the Gly16-Glu/Gln27 haplotypes may benefit from the association of hepatic vasodilators to propranolol therapy. (HEPATOLOGY 2005;43:34,41.) [source] Quantitative isolation of ,1AT mutant Z protein polymers from human and mouse livers and the effect of heat,HEPATOLOGY, Issue 1 2005Jae-Koo An Alpha-1-antitrypsin (,1AT) deficiency in its most common form is caused by homozygosity for the ,1AT mutant Z gene. This gene encodes a mutant Z secretory protein, primarily synthesized in the liver, that assumes an abnormal conformation and accumulates within hepatocytes causing liver cell injury. Studies have shown that mutant ,1ATZ protein molecules form unique protein polymers. These Z protein polymers have been hypothesized to play a critical role in the pathophysiology of liver injury in this disease, although a lack of quantitative methods to isolate the polymers from whole liver has hampered further analysis. In this study, we demonstrate a quantitative ,1ATZ polymer isolation technique from whole liver and show that the hepatocellular periodic acid-Schiff,positive globular inclusions that are the histopathological hallmark of this disease are composed almost entirely of the polymerized ,1ATZ protein. Furthermore, we examine the previously proposed but untested hypothesis that induction of ,1ATZ polymerization by the heat of physiological fever is part of the mechanism of hepatic ,1ATZ protein accumulation. The results, however, show that fever-range temperature elevations have no detectable effect on steady-state levels of intrahepatic Z protein polymer in a model in vivo system. In conclusion, methods to separate insoluble protein aggregates from liver can be used for quantitative isolation of ,1ATZ protein polymers, and the effect of heat from physiological fever may be different in vivo compared with in vitro systems. (HEPATOLOGY 2005;41:160,167.) [source] Inhibition of microsomal triglyceride transfer protein: Another mechanism for drug-induced steatosis in miceHEPATOLOGY, Issue 1 2003Philippe Lettéron Although many steatogenic drugs inhibit mitochondrial fatty acid ,-oxidation, limited information is available on possible effects on hepatic lipoprotein secretion. In the endoplasmic reticulum (ER) lumen, microsomal triglyceride transfer protein (MTP) lipidates apolipoprotein B (Apo B), to form triglyceride (TG)-rich very low density lipoprotein (VLDL) particles, which follow vesicular flow to the plasma membrane to be secreted, whereas incompletely lipidated Apo B particles are partly degraded. We studied hepatic MTP activity, the lipoproteins present in the ER lumen, and hepatic lipoprotein secretion 4 hours after administration of a single dose of amineptine (1 mmol/kg), amiodarone (1 mmol/kg), doxycycline (0.25 mmol/kg), tetracycline (0.25 mmol/kg), tianeptine (0.5 mmol/kg), or pirprofen (2 mmol/kg) in mice. These various doses have been shown previously to markedly inhibit fatty acid oxidation after a single dose, and to trigger steatosis either after repeated doses (doxycycline) or a single dose (other compounds) in mice. In the present study, amineptine, amiodarone, pirprofen, tetracycline, and tianeptine, but not doxycycline, inhibited MTP activity in vitro, decreased ex vivo MTP activity in the hepatic homogenate of treated mice, decreased TG in the luminal VLDL fraction of hepatic microsomes of treated mice, and decreased in vivo hepatic lipoprotein secretion (TG and Apo B). In conclusion, several steatogenic drugs inhibit not only mitochondrial ,-oxidation, as previously shown, but also MTP activity, Apo B lipidation into TG-rich VLDL particles, and hepatic lipoprotein secretion. Drugs with these dual effects may be more steatogenic than drugs acting only on ,-oxidation or only MTP. [source] | |||||||||||||||||||||||||||||||||||||||||||||||||