bluuebunny/crossref_metadata_2025 huggingface dataset:
Decreased immunogenicity of recombinant hepatitis B vaccine in chronic hepatitis C
Authors: Wiedmann Marcus , Liebert Uwe G. , Oesen Ute , Porst Heiner , Wiese Manfred , Schroeder Sabine , Halm Ulrich , Mössner Joachim , Berr Frieder
Published: July 2004

The immunogenicity of hepatitis B vaccine is unknown for patients with chronic hepatitis C, although hepatitis B vaccination is highly recommended in these patients. We therefore studied in a prospective open trial of 59 patients with chronic hepatitis C (mean age 42 years, hepatitis C for >10 years, Child-Pugh score ≤5) and 58 healthy hospital staff persons the rate of nonresponse (anti-HBs <10 mIU/mL at 9 months) to recombinant hepatitis B vaccine (Gen H-B-VaxR,10μg intradeltoidal at month 0, 1, and 6). Nonresponse was observed in 18/59 (31%) patients with chronic hepatitis C and 5/58 (9%) healthy staff persons (P< .005) (vs. 7% in historical controls; P< .005), low response (anti-HBs 10-99 mIU/mL) in 19% of patients with chronic hepatitis C and 17% of staff persons. High-dose booster vaccination led to seroconversion in 12/15 (80%) of primary nonresponders. Primary nonresponse to HB vaccine was related neither to presence of early-stage liver cirrhosis nor magnitude of serum hepatitis C virus (HCV) RNA concentration, nor explained by the presence of human leukocyte antigen (HLA) types (B8 DR3, B44, DR7, DQ2) predisposing to low antibody response to hepatitis B surface antigen. The rate of primary nonresponse to the standard regimen of recombinant hepatitis B vaccine is surprisingly high in patients with longstanding chronic hepatitis C. Therefore, the antibody to HBV surface antigen (anti-HBs) titer response should be determined in these patients. Depending on the response titer, higher booster doses may be required to achieve and maintain seroprotection in these patients.
Derivation of hepatocytes from bone marrow cells in mice after radiation-induced myeloablation
Authors: Theise Neil D. , Badve Sunil , Saxena Romil , Henegariu Octavian , Sell Stewart , Crawford James M. , Krause Diane S.
Published: July 2004

Following a report of skeletal muscle regeneration from bone marrow cells, we investigated whether hepatocytes could also derive in vivofrom bone marrow cells. A cohort of lethally irradiated B6D2F1 female mice received whole bone marrow transplants from age-matched male donors and were sacrificed at days 1, 3, 5, and 7 and months 2, 4, and 6 posttransplantation (n = 3 for each time point). Additionally, 2 archival female mice of the same strain who had previously been recipients of 200 male fluorescence-activated cell sorter (FACS)-sorted CD34+lin− cells were sacrificed 8 months posttransplantation under the same protocol. Fluorescence in situ hybridization (FISH) for the Y-chromosome was performed on liver tissue. Y-positive hepatocytes, up to 2.2% of total hepatocytes, were identified in 1 animal at 7 days posttransplantation and in all animals sacrificed 2 months or longer posttransplantation. Simultaneous FISH for the Y-chromosome and albumin messenger RNA (mRNA) confirmed male-derived cells were mature hepatocytes. These animals had received lethal doses of irradiation at the time of bone marrow transplantation, but this induced no overt, histologically demonstrable, acute hepatic injury, including inflammation, necrosis, oval cell proliferation, or scarring. We conclude that hepatocytes can derive from bone marrow cells after irradiation in the absence of severe acute injury. Also, the small subpopulation of CD34+lin− bone marrow cells is capable of such hepatic engraftment.
Microstructural evolution of lipid aggregates in nucleating model and human biles visualized by cryogenic transmission electron microscopy
Authors: Konikoff Fred M. , Danino Dganit , Weihs Daphna , Rubin Moshe , Talmon Yeshayahu
Published: July 2004

Obtaining reliable information on the physical state and ultrastructure of bile is difficult because of its mixed aqueous-lipid composition and thermodynamic metastability. We have used time-lapse cryogenic transmission electron microscopy (cryo-TEM) combined with video-enhanced light microscopy (VELM) to study microstructural evolution in nucleating bile. A well-characterized model bile and gallbladder biles from cholesterol and pigment gallstone patients were studied sequentially during cholesterol nucleation and precipitation. In model bile, cholesterol crystallization was preceded by the appearance of the following distinct microstructures: spheroidal micelles (3-5 nm), discoidal membrane patches (50-150 nm) often in multiple layers (2-10), discs (50-100 nm), and unilamellar (50-200 nm) and larger multilamellar vesicles (MLVs). The membrane patches and discs appeared to be short-lived intermediates in a micelle-to-vesicle transition. Vesicular structures formed by growth and closure of patches as well as by budding off from vesicles with fewer bilayers. MLVs became more abundant, uniform, and concentric as a function of time. In native bile, all the above microstructures, except discoidal membrane patches, were observed. However, native MLVs were more uniform and concentric from the beginning. When cholesterol crystals appeared by light microscopy, MLVs were always detected by cryo-TEM. Edges of early cholesterol crystals were lined up with micelles and MLVs in a way suggesting an active role in feeding crystal growth from these microstructures. These findings, for the first time documented by cryo-TEM in human bile, provide a microstructural framework that can serve as a basis for investigation of specific factors that influence biliary cholesterol nucleation and crystal formation.
The isolated artery: An intrahepatic arterial pathway that can bypass the lobular parenchyma in mammalian livers
Authors: Ekataksin Wichai
Published: July 2004

Controversy persists concerning the distribution of intrahepatic arterial termination. Apart from nourishing structures in the portal tract, several authors have suggested arterial supply to some isolated vascular beds that bypass the parenchyma, but this was not verified morphologically. In the present study, the existence of an isolated hepatic artery unaccompanied by a portal vein or a bile duct was shown in livers of pigs and other mammals including the dog, seal, ox, horse, and man. After colored media injection, liver blocks were sampled near the hepatic capsule and hepatic vein and subject to histologic assessment. The hepatic artery dissociated from superficial portal tract, ramified, and anastomosed extensively, forming a capsular plexus that drained at places into peripheral sinusoids in which resistive structural elaborations were observed. The artery also dissociated and fed an intramural plexus (vasa vasorum) of hepatic veins. This was collected into a vessel that penetrated the intima into the vein’s lumen. In smaller sublobular veins, the plexus emptied into adjacent sinusoids; in central veins, the plexus was poorly developed. In canine and phocine livers, which have a special throttling musculature in sublobular veins, the isolated arterioles were numerous; in bovine and equine livers, which have a thick fibrous investment, the capsular plexus was well-developed. Occurrence of the isolated artery also was confirmed in the human but not in the rodent liver. In conclusion, the isolated artery is responsible for isolated vascular beds, in which the transintimal pathway can bypass the lobular sinusoids.
Photodynamic therapy for advanced bile duct cancer: Evidence for improved palliation and extended survival
Authors: Berr Frieder , Wiedmann Marcus , Tannapfel Andrea , Halm Ulrich , Kohlhaw Kay R. , Schmidt Frank , Wittekind Christian , Hauss Johann , Mössner Joachim
Published: July 2004

Median survival time of nonresectable hilar bile duct cancer is only 4 to 6 months owing to tumor spread in the biliary tree, refractory cholestasis, and sepsis or liver failure. We explored whether local photodynamic therapy of nonresectable bile duct cancer could improve survival. A sample size of 23 patients is required to detect an increase in 6-month survival rate from less than 50% to greater than 70% in a single-arm phase-II trial with a statistical power of 80% (Fleming’s single step procedure; α = 0.05). Twenty-three consecutive patients (8 women, 15 men; 67 ± 14 years) with nonresectable bile duct cancer (Bismuth type III n = 2, type IV n = 21) were treated with photodynamic therapy and biliary endoprosthesis. Photofrin (QLT Pharmaceuticals, Vancouver, Canada) (2 mg/kg body weight intravenously) was photoactivated after 1 to 4 days with laser light (630 nm; 242 J/cm2) via endoscopic retrograde access. The 6-month survival rate was 91% after diagnosis and 74% after start of photodynamic therapy (30-day mortality rate was 4%) at a median follow-up time of 10.3 months after diagnosis. Causes of death were tumor progression (n = 9) and bacterial infections (n = 4). The median rate of local tumor response was 74%, 54%, 29%, and 67% after the first, second, third, fourth, and fifth photodynamic therapy. Time to progression ranged from 3 to 8 months. All patients, except 1 with diffuse liver metastases, improved in cholestasis, performance, and quality of life. Photodynamic therapy can prevent tumor occlusion of hilar bile ducts. The apparent benefit in survival time should be confirmed in a controlled trial versus palliation by endoprosthesis only.
Association of diabetes, serum insulin, and c-peptide with gallbladder disease
Authors: Ruhl Constance E. , Everhart James E.
Published: July 2004

An inconsistent association has been found between gallbladder disease and diabetes mellitus. We hypothesized that insulin resistance rather than diabetes status may be a primary factor involved in gallstone formation. A total of 5,653 adult participants in the third United States National Health and Nutrition Examination Survey without known diabetes underwent gallbladder ultrasonography and phlebotomy after an overnight fast for measurement of serum insulin, C-peptide, and glucose. Gallbladder disease was defined as ultrasound-documented gallstones or evidence of cholecystectomy. Subjects were characterized as having normal fasting glucose (<110 mg/dL), impaired fasting glucose (110 to <126 mg/dL), or undiagnosed diabetes (≥126 mg/dL). After controlling for other known gallbladder disease risk factors, among women, undiagnosed diabetes was associated with increased risk of gallbladder disease (prevalence ratio [PR] = 1.91, 95% confidence interval [CI] = 1.29-2.83); whereas impaired fasting glucose was unassociated. Gallbladder disease risk in women increased with levels of fasting insulin (PR = 1.63, 95% CI = 1.11-2.40) and C-peptide (PR = 2.07, 95% CI = 1.32-3.25) comparing highest to lowest quintiles. However, the association of gallbladder disease with undiagnosed diabetes was not diminished when the model included fasting insulin (PR = 1.85, 95% CI = 1.24-2.77). In men, there was a statistically nonsignificant association with undiagnosed diabetes (PR = 2.11, 95% CI = 0.76-5.85), but no association of gallbladder disease with insulin or C-peptide. Among women higher fasting serum insulin levels increased the risk of gallbladder disease, but did not account for the increased risk in persons with diabetes.
Long-term results of a clinical trial of nadolol with or without isosorbide mononitrate for primary prophylaxis of variceal bleeding in cirrhosis
Authors: Merkel Carlo , Marin Renato , Sacerdoti David , Donada Carlo , Cavallarin Giorgio , Torboli Pierluigi , Amodio Piero , Sebastianelli Giuliana , Bolognesi Massimo , Felder Martina , Mazzaro Cesare , Gatta Angelo
Published: July 2004

It is clearly established that β-blockers decrease the risk of a first variceal bleeding in cirrhosis. We have recently shown that the addition of isosorbide mononitrate to nadolol decreases the rate of variceal bleeding in patients with cirrhosis and varices, compared with nadolol alone, after a median follow-up of 30 months. It is not established if the long-term treatment with the combination continues to be beneficial. Therefore, we assessed the long-term effect of this combination on first variceal bleeding, complications, and death. One hundred forty-six cirrhotic patients with esophageal varices included in a previously published multicenter, randomized study comparing nadolol (40-160 mg/d) with the combination nadolol plus isosorbide mononitrate (10-20 mg 3 times per day) were followed up for up to 7 years (median follow-up, 55 months). The primary end-point was variceal bleeding of any severity. Twenty-four patients (16 in the nadolol group, and 8 in the combination group) experienced variceal bleeding (log rank test,P= .02). Cumulative risk of bleeding was 29% and 12%, respectively (95% CI for the difference, 1%-23%). Two and 4 patients, respectively, had bleeding from portal hypertensive gastropathy (log rank test,P= .20). Thirty and 25 patients, respectively, died during follow-up (log rank test,P= .13). Twelve and 10 patients, respectively, hadde novooccurrence of ascites during follow-up (log rank test,P= .29). In conclusion, nadolol plus isosorbide mononitrate is significantly more effective than nadolol alone in the long-term use. Side effects are few, and no deleterious effects on ascites occurrence or on survival occur after long-term use of this combination.
Early detection of hepatocellular carcinoma increases the chance of treatment: Hong Kong experience
Authors: Yuen Man-Fung , Cheng Chi-Chung , Lauder I. J. , Lam Shui-Kam , Ooi Clara Gaik , Lai Ching-Lung
Published: July 2004

The prognosis for patients with hepatocellular carcinoma (HCC) is poor because of the low chance of curative treatment. To increase the chance of intervention and to improve survival, early detection of subclinical HCC (SCHCC) by α-fetoprotein (AFP) and/or ultrasonography (USG) screening is implemented in many countries. Three hundred six Chinese patients with HCC diagnosed between January 1995 and December 1997 were recruited. They were categorized into two groups: 142 patients (group 1) had SCHCC diagnosed by screening (AFP and/or USG), and 164 patients (group 2) presented with symptomatic HCC. The tumor size was significantly smaller in group 1 compared with that of group 2 (3.5 cm vs. 8.1 cm;P< .0001). A significantly higher proportion of patients had bilobar involvement, multifocal HCC, diffuse-type HCC, portal vein infiltration, and distant metastasis in group 2 when compared with group 1. Operability and feasibility of treatment by transcatheter intra-arterial chemoembolization (TACE) in group 1 patients (26.8% and 45.1%, respectively) were significantly better than in group 2 patients (7.9% and 32.3%,P< .0001 andP= .03, respectively). The cumulative survival rate was significantly higher in group 1 than in group 2 (P< .0001). For those who had surgical resection and those who had TACE, group 1 patients had a higher cumulative survival rate compared with that of group 2 patients (P= .04 andP= .0003, respectively). Screening for HCC by AFP and/or USG can identify tumors at an early stage, resulting in a higher chance of receiving treatment. Whether it can improve survival requires a further prospective, randomized study.
Effects of the histamine H1 receptor blocker, pyrilamine, on spontaneous locomotor activity of rats with long-term portacaval anastomosis
Authors: Lozeva Violina , Valjakka Antti , Lecklin Anne , Olkkonen Hannu , Hippeläinen Mikko , Itkonen Matti , Plumed Carme , Tuomisto Leena
Published: July 2004

To find out whether the changes in the brain histaminergic system are involved in the pathophysiology of portal-systemic encephalopathy, we examined the effects of histamine H1receptor blockade on spontaneous locomotor activity, feeding, and circadian rhythmicity in rats with portacaval anastomosis (PCA). Pyrilamine, an H1receptor blocker (15 mg/kg/day), was delivered with osmotic minipumps. Spontaneous locomotor activity was recorded for 72 hours in the open-field with an electromagnetic detector. Food intake was monitored twice daily at the end of the light (7 pm) and the dark (7 am) phases for 3 days. Histamine H1receptor density in the suprachiasmatic nucleus (SCN) was examined with receptor autoradiography, employing [3H]pyrilamine. PCA surgery led to decreased movement time and velocity and flattened amplitude of the circadian rhythms of locomotion and feeding. In sham-operated rats, pyrilamine significantly decreased the movement time and velocity, as well as the total food consumption and completely abolished the circadian rhythmicity of locomotion. In contrast, pyrilamine increased the movement time and velocity in PCA-operated rats, particularly in the dark phase, and improved the precision of the circadian rhythms of locomotion and feeding. Histamine H1receptor density was not altered by PCA surgery, whereas pyrilamine treatment led to the complete blockade of H1receptors in both sham- and PCA-operated rats. We suggest that histaminergic imbalance has contributed to the generation and maintenance of the decreased spontaneous locomotor activity and altered circadian rhythmicity following PCA surgery in the rat, probably via an H1receptor-mediated mechanism.
Inherited coagulation disorders in cirrhotic patients with portal vein thrombosis
Authors: Amitrano Lucio , Brancaccio Vincenzo , Guardascione Maria Anna , Margaglione Maurizio , Iannaccone Luigi , D’Andrea Giovanna , Marmo Riccardo , Ames Paul R. , Balzano Antonio
Published: July 2004

The prevalence and pathogenesis of portal vein thrombosis (PVT) in patients with cirrhosis without hepatocellular carcinoma are not clearly defined. The role of thrombophilic genetic factors is well established in other venous thrombotic diseases, as well as in noncirrhotic portal thrombosis. Recently, new, inherited thrombophilic disorders (factor V Leiden [FVL], mutation G20210A of prothrombin [PTHR A20210], and mutation TT677 of methylenetetrahydrofolate reductase [MTHFR C677→T]) have been identified and associated with increased risk of venous thrombosis. The aim of our study was to investigate the role of these thrombophilic disorders in the pathogenesis of PVT in cirrhotic patients. Twenty-three cirrhotic patients with PVT and 40 cirrhotics without PVT were included. A group of 184 patients with deep vein thrombosis (DVT) and 431 healthy persons served as controls. The FVL, PTHR A20210, and MTHFR C677→T genotypes were identified by a polymerase chain reaction and restriction analysis. The frequencies of FVL, PTHR A20210mutation, and homozygous MTHFR C677→T were 13%, 34.8%, and 43.5% in cirrhotic patients with PVT and 7.5%, 2.5%, and 5% in cirrhotic patients without PVT, respectively. Five patients in the former group had associated defects. A thrombophilic genotype was detected in 69.5% of the patients with PVT. Identification of this high-risk group may have implications in patients who are candidates for major surgery or liver transplantation, and may influence the duration of oral anticoagulation.
Diurnal changes of fibrinolysis in patients with liver cirrhosis and esophageal varices
Authors: Piscaglia Fabio , Siringo Sebastiano , Hermida Ramon C. , Legnani Cristina , Valgimigli Marco , Donati Gabriele , Palareti Gualtiero , Gramantieri Laura , Gaiani Stefano , Burroughs Andrew K. , Bolondi Luigi
Published: July 2004

Variceal bleeding, whose triggering mechanisms are largely unknown, occurs with a circadian rhythmicity, with 2 peaks, one greater, in the evening, and one smaller, in the early morning. We assessed some clotting and hemodynamic parameters, possibly involved in variceal hemorrhage, over a 24-hour period, at 4-hour intervals, in 16 patients with cirrhosis and esophageal varices and in 9 controls. At each time interval, tissue plasminogen activator (tPA) and tPA inhibitor-1 (PAI-1) antigens and activities and total euglobulin fibrinolytic activity were determined and portal-vein flow velocity, volume, and congestion index were measured by duplex-Doppler. Significant circadian rhythms were searched for by least-squares and cosinor methods. tPA activity showed a circadian rhythm in cirrhosis, with a peak of 2.85 times the trough value, calculated at 18:42, and remained over 2.5-fold until shortly after 22:00. Total fibrinolytic activity showed a similar pattern, which was statistically significant also in controls. tPA and PAI antigens also showed significant circadian rhythm both in controls and cirrhotics, with higher values in the morning. Among the portal hemodynamic parameters only the congestion index showed significant rhythmic changes and only in cirrhosis, with the highest values in the late evening, but with limited diurnal excursion (± 5.5%). In conclusion, we showed the existence of a circadian rhythm of fibrinolysis in cirrhosis, whose temporal distribution might suggest a role of fibrinolysis in variceal hemorrhage on the basis of the comparison to the known chronorisk of variceal bleeding.
Cost-effectiveness analysis of transjugular intrahepatic portosystemic shunt (TIPS) versus endoscopic therapy for the prevention of recurrent esophageal variceal bleeding
Authors: Russo Mark W. , Zacks Steven L. , Sandler Robert S. , Brown Robert S.
Published: July 2004

For the prevention of recurrent esophageal variceal bleeding, studies show that patients treated with transjugular intrahepatic portosystemic shunt (TIPS) have lower rebleeding rates compared with endoscopic therapy. However, TIPS is associated with higher rates of portosystemic encephalopathy and possibly higher costs. The aim of this study was to conduct a cost-effectiveness analysis comparing TIPS with endoscopic sclerotherapy and endoscopic ligation for the prevention of recurrent esophageal variceal bleeding. Data for rates of rebleeding, death, complications, and crossover from endoscopy to TIPS were obtained from the literature. Costs for procedures and hospitalizations were obtained from two medical centers. Sensitivity analyses were performed varying probabilities of key variables. The patient population consisted of a hypothetical cohort of cirrhotic patients successfully treated for esophageal variceal bleeding with endoscopic sclerotherapy who received prophylactic sclerotherapy, ligation, or TIPS over 1 year. Endoscopic patients would receive propranolol. Mortality was similar for the three groups. The number of bleeds per patient for sclerotherapy, ligation, and TIPS would be 0.39, 0.32, and 0.07, respectively. The total annual costs per patient for sclerotherapy, ligation, and TIPS were $23,459, $23,111, and $26,275, respectively. The incremental cost per bleed prevented for TIPS compared with sclerotherapy and ligation was $8,803 and $12,660, respectively. The incremental cost per bleed prevented for TIPS compared with sclerotherapy or ligation was sensitive to the cost of TIPS and the TIPS stenosis rate. Ligation had lower costs and lower recurrent bleeding rates than sclerotherapy. Compared with endoscopic therapy, TIPS leads to lower recurrent variceal bleeding rates and it is more cost effective in the short term for the prevention of recurrent esophageal variceal bleeding.
Repeated concanavalin a challenge in mice induces an interleukin 10-producing phenotype and liver fibrosis
Authors: Louis Hubert , Le Moine Alain , Quertinmont Eric , Peny Marie-Odile , Geerts Albert , Goldman Michel , Le Moine Olivier , Devière Jacques
Published: July 2004

Weekly injections of Concanavalin A (Con A) were performed in BALB/c mice to evaluate the pattern of cytokine production and liver injury. High serum levels of tumor necrosis factor α (TNF-α), interleukin 2 (IL-2), IL-4, and interferon gamma (IFN-γ) were found in the serum after the first 2 injections of Con A but rapidly decreased from the third injection. Conversely, IL-10 serum levels after repeated Con A challenge increased by 7 times from week 1 to 20.In vivodepletion studies indicated that CD4+T cells are essential in IL-10 production. Hepatocyte necrosis was only observed after the first injections of Con A whereas centrilobular inflammatory infiltrates persisted up to 20 weeks. Perisinusoidal liver fibrosis was also increasingly detected in BALB/c mice, whereas no fibrous change was observed in nude mice after 6 weeks of Con A challenge. The number of stellate cells, detected by immunostaining, increased after 20 weeks of Con A injections. Liver cytokine messenger RNA (mRNA) expression after 20 weeks showed expression of transforming growth factor β1 (TGF-β1), IL-10, and IL-4 whereas IL-2 was no more expressed. The present study shows that mice repeatedly injected with Con A develop liver fibrosis. The cytokine-release pattern observed after 1 injection of Con A is rapidly shifted towards an immunomodulatory phenotype characterized by the systemic production of large amounts of IL-10.
The glutathione precursor l-2-oxothiazolidine-4-carboxylic acid protects against liver injury due to chronic enteral ethanol exposure in the rat
Authors: Iimuro Yuji , Bradford Blair U. , Yamashina Shunhei , Rusyn Ivan , Nakagami Mikio , Enomoto Nobuyuki , Kono Hiroshi , Frey William , Forman Donald , Brenner David , Thurman Ronald G.
Published: July 2004

l -2-oxothiazolidine-4-carboxylic acid (OTC) is a cysteine prodrug that maintains glutathione in tissues. Here, its effect on alcohol-induced liver injury in an enteral alcohol feeding model was investigated. Male Wistar rats were given control high-fat or ethanol containing diets enterally for 4 weeks. Treated rats received 500 mg/kg/d of dietary OTC. Ethanol delivery, weight gain, and the cyclic pattern of ethanol in the urine were not different between the OTC-ethanol and ethanol groups. After 4 weeks, serum aspartate transaminase (AST), necrosis and inflammation were elevated significantly by ethanol compared with appropriate high-fat controls, effects blocked by OTC. Moreover, ethanol elevated hepatic tumor necrosis factor α (TNF-α) messenger RNA (mRNA) and the nuclear transcription factor nuclear factor κB (NFκB) 2-3 fold. NFκB in isolated Kupffer cells was also increased by ethanol. These effects were all blocked by OTC treatment. Additionally, superoxide production was higher in Kupffer cells isolated from ethanol-treated rats, an effect blunted by OTC. OTC also increased circulating glutathione (GSH) levels about 2-fold; however, GSH levels were not affected by ethanol or OTC in livers from the groups studied. Surprisingly, GSH was elevated by ethanol and OTC treatment in isolated Kupffer cells about 2-fold. Moreover, GSH (Ki-10 μmol/L) and cysteinyl-glycine, but not oxidized glutathione (GSSG) or OTC, blunted the LPS-induced increase in calcium in isolated Kupffer cells, possibly by activating a glycine-gated chloride channel due to their structural similarity with glycine. Collectively, it is concluded that GSH is protective, in part, by increasing circulating GSH, which blunts activation of Kupffer cells via the glycine-gated chloride channel.
Galectin-1 exerts immunomodulatory and protective effects on concanavalin a-induced hepatitis in mice
Authors: Santucci Luca , Fiorucci Stefano , Cammilleri Francesco , Servillo Giuseppe , Federici Barbara , Morelli Antonio
Published: July 2004

Galectin-1, an endogenous lectin with immunomodulatory activities, induces selective, Fas-independent apoptosis of activated T cells. The aim of the present study was to evaluate the effect galectin-1 exerts on concanavalin A (Con A)-induced hepatitis, a T-cell-dependent model of liver injury. Con A administration resulted in liver injury, as shown by the increased transaminase plasma levels and liver DNA fragmentation, and caused spleen T-cell activation, which was associated with a strong increment in liver infiltrating T helper cells. Moreover, Con A injection leads to a marked increase in plasma tumor necrosis factor α (TNF-α) and interferon gamma (IFN-γ) levels. Galectin-1 pretreatment dose-dependently prevented both liver injury and T-helper cell liver infiltration induced by Con A. In vivo and in vitro experiments indicated that the protective effects of galectin-1 depend on the selective elimination of Con A-activated T cells. In addition, galectin-1 almost completely prevented the Con A-induced increase in plasma TNF-α and IFN-γ, an effect that was, at least in part, independent on the elimination of activated T helper cells, because galectin-1 prevented lipopolysaccharide (LPS)-induced release of TNF-α and IFN-γ also from macrophages in vitro, without affecting their viability. The present study suggests that galectin-1 is potentially useful in the treatment of T-cell-mediated human liver disorders.
Impact of hyperthermic preconditioning on postischemic hepatic microcirculatory disturbances in an isolated perfusion model of the rat liver
Authors: Terajima Hiroaki , Enders Georg , Thiaener Axel , Hammer Claus , Kondo Tadashi , Thiery Joachim , Yamamoto Yuzo , Yamaoka Yoshio , Messmer Konrad
Published: July 2004

Sublethal hyperthermia and the following recovery from this heat exposure, referred to as hyperthermic preconditioning, elicits a transient state of tolerance to oxidative insults through an intracellular protective response: stress response. The impact of hyperthermic preconditioning on hepatic microcirculatory disturbance, which is one of the determinants of ischemia/reperfusion-induced injury of the liver, was investigated by using intravital fluorescence microscopy. Thirty minutes of ischemia and a subsequent 120 minutes of reperfusion was induced in an in situ isolated perfusion model of Sprague-Dawley rats. Heat stress was given by whole-body hyperthermia, and a subsequent recovery was allowed for 18 or 48 hours, respectively. Postischemic decrease in sinusoidal perfusion rate and sinusoidal diameter, leukocyte stagnation in sinusoids, and leukocyte adhesion in postsinusoidal venules were significantly attenuated in both hyperthermia-pretreated groups. A recovery of bile production, a reduction of liver enzyme release, and an attenuation of tissue edema and histological damage were also observed. A marked expression of heat shock protein (HSP) 70 and heme oxygenase (HO-1)/HSP32 was correlatively observed in the liver tissue coincident with the induction of these protective effects. Hyperthermic preconditioning provides a continuous long-term and constant inhibitory effect (up to 48 hours after heat exposure) on postischemic injury of the liver through the attenuation of microcirculatory disturbances. These beneficial effects might be associated with a concomitant increase in HSP70 and HO-1/HSP32 expression.
Doxorubicin preconditioning: A protection against rat hepatic ischemia-reperfusion injury
Authors: Ito Koji , Ozasa Hisashi , Sanada Katsuhiro , Horikawa Saburo
Published: July 2004

Doxorubicin produces clinically useful responses in a variety of human cancers. However, the toxicity of doxorubicin has limited its usefulness. This side effect is mainly due to the doxorubicin-mediated free radical formation. Administration of doxorubicin (10 mg/kg body weight) to rats intravenously induces heme oxygenase-1 (HO-1) in the liver. The levels of HO-1 protein were first detected at 6 hours and peaked at about 18 to 24 hours after the injection. It is known that HO-1 plays a protective role against the oxidative injury. Therefore, we have examined the protective effect of doxorubicin preconditioning against the hepatic ischemia-reperfusion injury. Partial hepatic ischemia was produced in the left and medium lobes for 45 minutes followed by 120 minutes reperfusion. When low doses of doxorubicin (1 mg/kg body weight) was intravenously administered to rats 2 days before the ischemia, the serum alanine transaminase (ALT) levels in the preconditioning rat were clearly improved compared with those in the rat without preconditioning. Under this situation, zinc-protoporphyrin IX, a specific inhibitor of HO-1, was injected subcutaneously to rats at 3 and 16 hours before the ischemia, the ALT levels were not improved by doxorubicin preconditioning. Histopathologic examination also supported these results. Although the HO-1 protein level was fairly low 2 days after the doxorubicin administration, significant amounts of HO-1 protein were detected. Our results indicated that the induction of HO-1 played a protective role against hepatic ischemia-reperfusion injury and that doxorubicin preconditioning is more clinically useful than other preconditioning methods.
The role of protein kinase B and mitogen-activated protein kinase in epidermal growth factor and tumor necrosis factor α-mediated rat hepatocyte survival and apoptosis
Authors: Roberts Ruth A. , James Neil H. , Cosulich Sabina C.
Published: July 2004

Perturbation of hepatocyte growth regulation is associated with a number of liver diseases such as fibrosis and cancer. These diseases are mediated by a network of growth factors and cytokines that regulate the induction of hepatocyte proliferation and apoptosis. In this study, we have investigated the role of signaling pathways activated by tumor necrosis factor α (TNF-α) and epidermal growth factor (EGF) in the regulation of apoptosis induced by transforming growth factor β1 (TGF-β1), because this physiological factor is believed to regulate spontaneous apoptosis in the liver. We show that pretreatment with (10 ng/mL) EGF or (25 ng/mL) TNF-α can suppress TGF-β1-induced apoptosis by 73% and 50%, respectively, in isolated rat hepatocytes. However, suppression of TGF-β1-induced apoptosis by EGF and TNF-α occurs via different protein kinase signaling pathways. Using specific inhibitors, we show that suppression of apoptosis by EGF is dependent on activation of phosphoinositide 3-kinase (PI 3-kinase) and the extracellular signal regulated kinase (ERK) mitogen-activated protein (MAP) kinase pathways, but not p38 MAP kinase. In contrast, suppression of TGF-β1-induced apoptosis by TNF-α does not require PI 3-kinase and protein kinase B (PKB or Akt)-mediated pathways, but is dependent on ERK and p38 MAP kinase activity. These data contribute to our understanding of the intracellular survival signals that play a role in normal liver homeostasis and in diverse pathological conditions.
Endotoxin induces structure-function alterations of rat liver peroxisomes: Kupffer cells released factors as possible modulators
Authors: Contreras Miguel A. , Khan Mushfiquddin , Smith Brian T. , Cimini Anna M. , Gilg Anne G. , Orak John , Singh Inderjit , Singh Avtar K.
Published: July 2004

We report that endotoxin treatment results in decreased amounts of peroxisomes as well as changes in structure and function of peroxisomal membranes. Peroxisomes isolated from the liver of control and treated animals showed a marked decrease in total protein, but no significant alteration in the sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) protein profile. However, the Western blot study of the peroxisomal β-oxidation enzymes and catalase showed an increase in those enzymes in the peroxisomal peak of normal density in endotoxin-treated rats. Disintegration of peroxisomal membranes by carbonate treatment from endotoxin-treated liver and change in the fluidity of peroxisomal membranes suggests alterations in peroxisomal membrane structure. No such alterations were found in mitochondrial or microsomal membranes of endotoxin-treated livers. The lipid analysis of these organelles showed that the only organelle affected was the peroxisome, with a significant decrease in the phospholipid and cholesterol concentrations. To understand the mechanism of endotoxin-mediated alterations in peroxisomes, we studied the possible role of Kupffer cell secreted soluble factors (tumor necrosis factor α [TNF-α]) on the peroxisomal structure/function. Inactivation/elimination of Kupffer cells by gadolinium chloride before endotoxin treatment did not normalize the overall peroxisomal protein amount and the lipid composition of isolated peroxisomes. However, the levels of individual protein amount in remaining peroxisomes were normalized. Endotoxin also decreased peroxisomal β-oxidation, and this was partially restored with gadolinium treatment. These results clearly show that peroxisomes are severely affected by endotoxin treatment and suggest that the damage to this organelle may contribute, at least in part, to endotoxin-induced hepatic cytotoxicity.
Iron overload in cirrhosis— HFE genotypes and outcome after liver transplantation
Authors: Brandhagen David J. , Alvarez William , Therneau Terry M. , Kruckeberg Kent E. , Thibodeau Stephen N. , Ludwig Jurgen , Porayko Michael K.
Published: July 2004

Previously, we found appreciable hepatic iron deposition in one third of our patients undergoing liver transplantation (LTx) with approximately 10% of cases having quantifiable iron in the range of that seen in hereditary hemochromatosis (HHC). The aim of this study was to compare clinical outcome in liver transplant patients with and without iron overload. We also sought to determine the prevalence of HFE mutations in liver transplant patients with iron overload. Of 456 consecutive liver transplants, 41 explants had an hepatic iron index (HII) greater than 1.9, and these cases were compared to 41 matched liver transplant recipients without increased hepatic iron. Posttransplantation complications, along with patient and graft survival were monitored. HFE gene testing was performed using DNA-based techniques. Kaplan-Meier 5-year patient survival after LTx was significantly lower in cases with hepatic iron overload compared to matched controls without iron excess (48% vs. 77%; P= .045). Fatal infections (especially fungal) were more common in patients with iron overload (24% vs. 7%; P = .03). Of the 41 patients with a liver explant HII greater than 1.9, only 4 were C282Y homozygotes. Patients with severe hepatic explant iron overload undergoing LTx have a reduced survival compared to liver transplant recipients without explant iron excess. The reduced survival was attributable mainly to fatal bacterial and fungal infections. Despite the iron overload, HFE gene mutations were uncommon in patients with hepatic explant hemosiderosis.
Hepatitis B immunoglobulin discontinuation followed by hepatitis B virus vaccination: A new strategy in the prophylaxis of hepatitis B virus recurrence after liver transplantation
Authors: Sánchez-Fueyo Alberto , Rimola Antoni , Grande Luis , Costa Josep , Mas Antoni , Navasa Miguel , Cirera Isabel , Sánchez-Tapias Jose Maria , Rodés Juan
Published: July 2004

It is widely agreed that hepatitis B virus immunoglobulin (HBIG) should be administered for at least 12 months to patients transplanted for hepatitis B virus (HBV)-related diseases to prevent HBV recurrence. No data are available, however, on how long this treatment should be used, and most centers currently administer HBIG on a life-long basis. Herein, we report the results of a new prophylactic strategy aiming at the discontinuation of HBIG treatment and consisting of the administration of double dose recombinant HBV vaccine (0, 1-, and 6-month schedule) to liver transplant recipients fulfilling the following criteria: (1) liver transplantation for conditions related to nonreplicative HBV infection (hepatitis B surface antigen [HBsAg] positive, hepatitis B e antigen [HBeAg] negative, and HBV DNA negative); (2) at least 18 months of HBIG administration; and (3) no HBV infection recurrence, normal or slightly altered liver graft function, and low-grade immunosuppression at the time of vaccination. Seventeen patients received HBV vaccination and 14 of them (82%) developed protective serum titers of anti-HBs (>10 IU/L). Six patients seroconverted after a first course of vaccination, whereas 8 patients required a second course (3 additional doses of vaccine). Responding patients were followed for a median of 14 months (range, 3-50) after seroconversion. During this period no HBV recurrence occurred and in only 2 patients a decrease of anti-HBs titers below 10 UI/L was observed. Our data suggest that in selected liver transplant recipients, posttransplantation HBV vaccination may be a useful and cost-effective strategy in the prophylaxis of HBV recurrence, allowing the discontinuation of life-long HBIG treatment.
Quantification of intrahepatic hepatitis B virus (HBV) DNA in patients with chronic HBV infection
Authors: Cacciola Irene , Pollicino Teresa , Squadrito Giovanni , Cerenzia Giovanni , Villari Daniela , de Franchis Roberto , Santantonio Teresa , Brancatelli Santa , Colucci Giuseppe , Raimondo Giovanni
Published: July 2004

No data are available about the amount of hepatitis B virus (HBV) genomes in liver of patients with chronic HBV infection. The aim of this study was to quantify the intrahepatic HBV DNA in hepatitis B surface antigen (HBsAg)-positive patients with either active or suppressed viral replication and in HBsAg-negative subjects with occult HBV infection. We optimized the Roche “Amplicor HBV Monitor” kit for quantifying liver HBV DNA and analyzed hepatic DNA extracts and serum samples from 19 HBs-Ag-positive and 43 HBsAg-negative individuals. Eight of the HBsAg carriers had active HBV replication, and for 3 of them we analyzed samples obtained before and at the end of 1 year of lamivudine treatment. Five hepatitis Delta virus (HDV) coinfected patients and 6 healthy HBsAg carriers had inhibited HBV activity. Among the HBsAg-negative subjects 21 had occult HBV infection and 22 had no evidence of HBV infection. The median of HBV genomes per microgram of liver DNA milliliter of serum was 34,500 to 2,620,000 in patients with active viral replication, 20,000 to 3,900,000 before and 10,000 to 2,800 at the end of therapy in lamivudine-treated individuals, 9,800 to 600 in HDV-infected individuals, and 7,450 to 17,400 in healthy HBsAg carriers. These data indicate that cases with suppressed HBV activity, despite the very low levels of viremia, maintain a relatively high amount of intrahepatic viral genomes. This virus reservoir is likely involved in HBV reactivation, which is usually observed after stopping lamivudine treatment. Finally, the analysis of cases with occult HBV infection showed that the assay we used was able to specifically detect and quantify as few as 100 copies of viral genomes per microgram of liver DNA.
Which patients with hepatitis C develop liver complications?
Authors: Khan Mahbub H. , Farrell Geoffrey C. , Byth Karen , Lin Rita , Weltman Martin , George Jacob , Samarasinghe Dev , Kench James , Kaba Songal , Crewe Evelyn , Liddle Chris
Published: July 2004

To identify variables that are independent predictors of adverse outcomes in chronic hepatitis C, we analyzed a cohort of 455 patients followed for a median of 4.7 years. Associations were sought between demographic and behavioral factors, hepatitis C virus (HCV) genotype, liver histology and liver tests at entry, and development of liver complications, hepatocellular carcinoma (HCC), hepatic transplantation and liver-related death. Independent predictors were identified by multivariate analysis. The following were associated with a significantly higher rate of liver complications: age; birth in Asia, Europe, Mediterranean region, or Egypt; transmission by blood transfusion or sporadic cases; HCV genotypes 1b and 4 (compared with 1/1a); fibrosis stage 3 or 4 (cirrhosis); serum albumin; bilirubin; prothrombin time; and α-fetoprotein. However, the only independent predictors of liver-related complications were sporadic transmission (P < .001), advanced fibrosis (P = .004), and low albumin (P < .001). The corresponding independent risk factors for HCC were male gender (P= .07), sporadic transmission (P < .001), and albumin (P < .001); bilirubin (P= .02) was an additional predictor of transplantation or liver-related death. It is concluded that only patients with advanced hepatic fibrosis or cirrhosis, are at risk of developing hepatic complications of chronic hepatitis C during 5-year follow-up. Among such patients, abnormalities in serum albumin, bilirubin, or prothrombin time indicate a high probability of complications. Patients without definite risk factors for HCV (sporadic cases) are at higher risk of complications, possibly because of interaction between older age, duration of infection, country of birth, and HCV genotypes 1b and 4.
Cellular and humoral immune responses induced by intradermal or intramuscular vaccination with the major hepatitis B surface antigen
Authors: Rahman Fareed , Dahmen Anja , Herzog-Hauff Sabine , Böcher Wulf O. , Galle Peter R. , Löhr Hanns F.
Published: July 2004

The vaccination route may influence the success of immunization against pathogens. The conventional intramuscular (i.m.) application of a vaccine containing the hepatitis B virus (HBV) surface antigen (HBsAg) led to protective anti-HBs antibody levels in the majority of vaccine recipients. In this study, we vaccinated healthy volunteers and a group of i.m. vaccine nonresponders via the intradermal (i.d.) route and analyzed the HBV-specific B-cell response as well as class-II- and class-I-restricted T-cell responses by 3H-thymidine uptake, enzyme-linked immunosorbent assay (ELISA) and enzyme-linked immunospot assay (ELISPOT). The results were then compared with i.m. vaccinated controls. I.d. vaccinations were well tolerated and induced neutralizing anti-HBs antibodies in all naive vaccine recipients and, importantly, all but one former i.m. nonresponder developed protective anti-HBs serum antibody levels after 2 or 3 i.d. immunizations. On the cellular level, i.d. vaccine recipients showed significantly higher anti-HBs producing B-cell frequencies and more vigorous class-II-restricted T-helper (Th) cell responses than i.m. controls. However, although the HBsAg-specific T cells were characterized by their cytokine release as Th1-like cells in both groups, human leukocyte antigen (HLA)-A2+ individuals who received the soluble HBsAg via the i.d. route developed higher peptide-specific cytotoxic CD8+ T cell precursor (CTLp) frequencies. In conclusion, i.d. HBsAg vaccination is more effective even in former i.m. vaccine nonresponders with respect to antibody induction and specific B- and T-cell responses. The induction of virus-specific CTLp may provide the rationale to study the i.d. HBsAg vaccine in the treatment of chronic hepatitis B.
Local arterial vasoconstriction induced by octreotide in patients with cirrhosis
Authors: Chatila Rajaa , Ferayorni Lisa , Gupta Tarun , Groszmann Roberto J.
Published: July 2004

Peripheral vasodilation initiates the hyperdynamic circulation in cirrhosis. Somatostatin and its analogues, such as octreotide, have a vasoconstrictive effect in cirrhotic patients and experimental animals with portal hypertension. The exact mechanism of octreotide-induced vasoconstriction remains unknown. To investigate whether octreotide produces vasoconstriction through suppression of vasodilatory peptides, such as glucagon, or through a local effect, we evaluated the effect of an intra-arterial dose on forearm blood flow (FBF), while measuring systemic glucagon levels. FBF was measured in 10 cirrhotic patients by venous occlusion plethysmography. The brachial artery of the nondominant arm was catheterized, and vasoactive drugs were administered: methacholine 4 μg/min; octreotide 20 μg/h, and octreotide 20 μg/h + methacholine 4 μg/min. Each infusion, lasting 5 minutes, was followed by saline for washout. FBF was measured in both arms during the last minute of each infusion and at the end of washout, with the uninfused arm acting as the control. Nitrates and nitrites, octreotide, and glucagon blood levels were determined at baseline and after each infusion. Percent change in flow (%△) was obtained by comparing the flow during drug administration to that during the preceding saline infusion. Saline infusion did not alter FBF, but octreotide infusion resulted in a 34% ± 7.7 (P < .005) reduction in FBF in the infused arm. FBF in the control arm was unchanged despite a significant decrease in systemic glucagon levels. Methacholine infusion increased FBF around 300%, which was not altered by the concomitant infusion of octreotide. Octreotide has a local vasoconstrictive effect that seems nitric oxide (NO)-independent. Octreotide probably has a facilitating effect over vasoconstrictors increased in chronic liver diseases.