bluuebunny/crossref_metadata_2025 huggingface dataset:
Surgery for Ductal Adenocarcinoma of the Pancreatic Head: Staging, Complications, and Survival after Regional versus Extended Lymphadenectomy
Authors: Henne‐Bruns Doris , Vogel Ilka , Lüttges Jutta , Klöppel Günter , Kremer Bernd
Published: August 2002

The purpose of this study was to evaluate the influence of regional versus extended lymphadenectomy on survival after partial pancreaticoduodenectomy for pancreatic cancer. From October 1988 to December 1991 (Department of Surgery, University of Hamburg) and from January 1992 to March 1998 (Department of Surgery, University of Kiel) 72 patients with histologically proven ductal adenocarcinoma of the pancreatic head were treated. Partial pancreaticoduodenectomy with regional lymphadenectomy was performed in 26 patients. In 46 patients lymphadenectomy was expanded to include extended retroperitoneal lymphatic and connective tissue clearance. Comparing these two groups and including only patients with R0 resections (n= 58) no significant differences in long‐term survival could be shown. The following parameters were shown to have a significant or nearly significant influence on long‐term survival: (1) stage of the disease: The 5‐year survival of patients with stage I/II pancreatic head cancer was 63%, compared to 15% in patients with stage III/IV a + b of the disease (p= 0.0087). (2) Grading: The 1‐year survival of patients with well or moderately differentiated tumors was 55%, compared to 0% for patients with poorly differentiated ductal adenocarcinoma (p= 0.0022). (3) N stage: The 5‐year survival of patients in N0 stage was 46.9%, compared with 15% for N1 stage patients. The difference was not quite significant (p= 0.081). (4) Portal vein involvement: The 1‐year survival was 0% in patients with R0 resections and histologically proven tumor infiltration of the portal vein, compared to 63% for patients with curative resections without portal vein involvement (p= 0.0063). In conclusion our data indicate that extensive retroperitoneal tissue clearance during pancreaticoduodenectomy for ductal pancreatic cancer does not improve survival compared to regional lymphadenectomy restricted to the right side of the mesenteric artery.
Metabolic Management of Patients with Severe Burns
Authors: Demling Robert H. , Seigne Patrick
Published: August 2002

Burn injury results in profound metabolic abnormalities perpetuated by an exaggerated stress response to injury. Hypermetabolism and marked catabolism, with rapid erosion of lean body mass, becomes evident shortly after injury. Much of the morbidity and mortality of a major burn can be attributed to this process, which increases infection risks, decreases the healing rate, and alters cell function. Rapid removal of devitalized burn tissue combined with early aggressive nutritional support significantly attenuates this autodestructive process. The addition of anabolic agents decreases the degree of lean mass loss and increases the rate of restoration. Immediate attention to the metabolic response to a severe burn significantly decreases complications and improves outcome.
Metabolic Response to Severe Surgical Illness: Overview
Authors: Wilmore Douglas W.
Published: August 2002

Severe surgical illness results in metabolic responses that mobilize substrate (amino acids and fatty acids) from body stores to support vital organs, enhance resistance to infection, and ensure wound healing. Central to this process is the redistribution of body protein, which moves from skeletal muscle to support the central viscera. If unsupported, this protein‐wasting state could result in prolonged convalescence, diminished immunity, and poor wound healing. Present evidence suggests that the central nervous system plays a major role in regulating this protein catabolic response. Infusing exceedingly small quantities of the proinflammatory cytokines into the brain can mimic injury responses, and central cytokine blockade may be one therapeutic approach to attenuating these responses safely in the future. Additional evidence also demonstrates that the function of the hypothalamus and anterior pituitary is dampened during the later stages of severe surgical illness, and the possibility of hormonal replacement therapy needs to be explored.
A host shift from wild blue cohosh to cultivated potato by the phytophagous ladybird beetle, Epilachna yasutomii (Coleoptera, Coccinellidae)
Authors: Shirai Y. , Morimoto Naotake
Published: August 2002

Life history traits of the phytophagous ladybird beetle Epilachna yasutomii were compared between a nonpest population feeding on wild blue cohosh and a pest population feeding on cultivated solanaceous crops, mainly potato. Newly emerged adults of the nonpest population entered diapause early in midsummer when blue cohosh withered, while adults of the pest population were found in tomato and eggplant fields until late autumn. The pest population had larger females, a higher population growth rate, a shorter larval developmental period, and reduced longevity of overwintered females, compared with the nonpest population. ANOVA indicated that all these life history traits were influenced by the food plant, and that the number of eggs laid per female and the longevity of overwintered females were also affected by the population type. These findings suggest that the life history pattern of E. yasutomii changed to high fecundity with a short life span from low fecundity with a long life span as a result of the host shift from wild blue cohosh to cultivated solanaceous crops.
Preconditioning Protects Against Systemic Disorders Associated With Hepatic Ischemia–Reperfusion Through Blockade of Tumor Necrosis Factor-Induced P–Selectin Up–Regulation in the Rat
Authors: Peralta Carmen , Fernández Leticia , Panés Julià , Prats Neus , Sans Miquel , Piqué Josep Maria , Gelpí Emilio , Roselló-Catafau Joan
Published: August 2002

Previous studies indicate that ischemic preconditioning protects against lung injury resulting from hepatic ischemia–reperfusion (I/R) through inhibition of tumor necrosis factor (TNF) release from Kupffer cells. The present study investigated whether this effect is limited to the lung or is a generalized systemic response and explores the molecular mechanisms involved. Hepatic I/R led to an increase in neutrophil accumulation in liver, lung, and splanchnic organs. Although preconditioning did not modify neutrophil infiltration in liver during reperfusion, it conferred protection against hepatic injury associated with I/R. In remote organs, preconditioning abrogated the increase in P–selectin up–regulation, preventing neutrophil infiltration and thus reducing the oxidative stress and microvascular disorders following hepatic I/R in these organs. Administration of Abs against P–selectin or TNF previous to ischemia had the same effects as preconditioning. The effects of preconditioning on the blockade of P–selectin up–regulation probably results from inhibition of systemic TNF release from Kupffer cells. Supplementation of TNF abolished the benefits of preconditioning, whereas the injurious effects of TNF were prevented by previous blockade of P–selectin. The results of the present study suggest that ischemic preconditioning protects the liver against I/R injury by a mechanism independent of adhesion molecule expression and neutrophil accumulation. In remote organs, however, hepatic preconditioning prevents inflammatory damage by reducing the systemic TNF release from the liver and thus preventing P–selectin up–regulation.
Risk Factors for Primary Biliary Cirrhosis in A Cohort of Patients From the United States
Authors: Parikh-Patel Arti , Gold Ellen B. , Worman Howard , Krivy Kathryn E. , Gershwin Eric M.
Published: August 2002

Although the etiology of primary biliary cirrhosis (PBC) remains unknown, environmental factors may act to trigger the disease in genetically susceptible hosts. To assess specific risk factors, we conducted a survey using standardized NHANES questions to 241 PBC patients in the United States, 261 of their siblings, and 141 friends without PBC. The overall response rate was 199 of 241 (83%) among PBC cases, 171 of 261 (67%) among siblings, and 141 of 225 (62.7%) among friend controls. The female–to–male ratio among cases in this sample was approximately 10:1; the mean age was 53 years, and 97% were Caucasian. Other autoimmune diseases reported most frequently by PBC cases included Sjogren's syndrome (17.4%) and Raynaud's syndrome (12.5%). Approximately 6% of cases reported at least one family member with PBC. Adjusted odds ratios (OR) were elevated for cases compared with friends for other autoimmune diseases (OR = 4.92, 95% confidence interval [CI] = 2.38, 10.18), smoking (OR = 2.04, 95% CI = 1.10, 3.78), tonsillectomy (OR = 1.86, 95% CI = 1.02, 3.39), and vaginal or urinary tract infection (UTI) in females only (OR = 2.12, 95% CI = 1.10, 4.07). Similarly elevated ORs were observed for these risk factors when cases were compared with their siblings. The higher rate of UTI among cases is particularly interesting in light of previous data, and raises the possibility of an infectious etiology for PBC and of molecular mimicry as an etiologic mechanism. The significance of smoking in the multivariate models supports the findings of previous studies and raises the issue of the influence of smoking on a Th1 response.
Living Donor Liver Transplantation for Early Hepatocellular Carcinoma: A Life–Expectancy and Cost–Effectiveness Perspective
Authors: Sarasin François P. , Majno Pietro E. , Llovet Josep M. , Bruix Jordi , Mentha Gilles , Hadengue Antoine
Published: August 2002

Cadaveric liver transplantation (CLT) is an excellent treatment for early hepatocellular carcinoma (HCC). Its use, however, is limited by the shortage of grafts, with up to 30% of patients developing contraindications to the procedure while waiting for a donor. Living donor liver transplantation (LDLT) has emerged as an alternative to overcome this limitation. We compared the consequences of LDLT versus CLT using a Markov model balancing the gains and losses in life expectancy among donors and recipients. For a 60–year–old recipient with a 70% 5–year survival after transplantation, a 4% monthly drop–out rate, and a donor with 1% mortality, LDLT became more effective than CLT after 3.5 months on the waiting list. These results varied with the probability of developing contraindications to transplantation, the survival after transplantation, and the donor's mortality. For a 12–month delay saved on the waiting list, the gain in survival provided by LDLT compared with CLT ranged between 0 and 2.8 life years depending on survival after transplantation, time spent on the waiting list, and drop–out rate. LDLT was cost–effective (less than $50,000 per quality–adjusted life year saved) in all scenarios of waiting lists exceeding 7 months, and this figure ranged from 2 to 16 months when varying the drop–out rate. LDLT for early HCC offered substantial gains in life expectancy with acceptable cost–effectiveness ratios when the waiting list exceeds 7 months. The gain in life expectancy and the cost–effectiveness of LDLT were more dependent on the drop–out rate and the outcome after transplantation than on donor's mortality.
Altered Peripheral Vascular Responses to Exogenous and Endogenous Endothelin–1 in Patients With Well–Compensated Cirrhosis
Authors: Helmy Ahmed , Jalan Rajiv , Newby David Ernest , Johnston Neil Russell , Hayes Peter Clive , Webb David John
Published: August 2002

Plasma endothelin concentrations are elevated in cirrhosis and correlate with disease severity. This study assessed forearm vascular responses to exogenous endothelin–1 (ET–1), and evaluated the contribution of endogenous ET–1 to the maintenance of basal peripheral vascular tone in patients with well–compensated cirrhosis (n = 11) and matched healthy controls (n = 8). Bilateral forearm blood flow (FBF) was measured at baseline and following unilateral, subsystemic, intrabrachial artery infusions of ET–1 (2 and 6 pmol/min); BQ–123, a selective ETA receptor antagonist (3 and 10 nmol/min); and BQ–788, a selective ETB receptor antagonist (0.3 and 1 nmol/min) using venous occlusion plethysmography. Baseline systemic hemodynamics and plasma ET–1 and big ET–1 concentrations were measured using electrical bioimpedance and radioimmunoassay, respectively. Patients and controls had similar baseline FBF, systemic hemodynamics, and plasma ET–1 and big ET–1 concentrations. In both groups, ET–1 and BQ–788 caused significant vasoconstriction (P < .001) and BQ–123 caused significant vasodilatation (P < .001). Compared with controls, cirrhotic patients had attenuated ET–1 responses (P < .001), augmented BQ–123 responses (P < .001), and similar BQ–788 responses (P = .62). Despite normal systemic hemodynamics and plasma ET–1 concentrations, forearm vascular responses to exogenous ET–1 are reduced in cirrhotic patients. The augmented vasodilatation to BQ–123 in cirrhotic patients is consistent with a compensated vasodilated state, and a greater contribution of ET–1 to the maintenance of basal vascular tone acting through the ETA receptor.
Heterogeneous Response of Antimitochondrial Autoantibodies and Bile Duct Apical Staining Monoclonal Antibodies to Pyruvate Dehydrogenase Complex E2: the Molecule Versus the Mimic
Authors: Migliaccio Chris , Van de Water Judy , Ansari Aftab A. , Kaplan Marshall M. , Coppel Ross L. , Lam Kit S. , Thompson Richard K. , Stevenson Freda , Gershwin Eric M.
Published: August 2002

The 2–oxo–acid dehydrogenase complexes and, in particular, the E2 component of the pyruvate dehydrogenase complex (PDC) are the target of antimitochondrial antibodies (AMA). More than 95% of primary biliary cirrhosis (PBC) patients have detectable levels of autoantibodies to PDC–E2 and in general these react with a region of the molecule that contains the prosthetic group lipoic acid (LA). LA is vital to the function of the enzyme, although there is conflicting evidence as to whether its presence is required for PDC–E2 recognition by AMA. Some, but not all, monoclonal antibodies (mAbs) to PDC–E2 produce an intense staining pattern at the apical surface of bile duct epithelial cells (BEC) in patients with PBC, and it has been argued that the molecule at the apical surface of PBC bile duct cells is a modified form of PDC–E2 or a cross–reactive molecule, acting as a molecular mimic. Herein, we characterize the epitopes recognized by 4 anti-PDC–E2 mAbs that give apical staining patterns (3 mouse and 1 human). In particular, by using a combination of recombinant antigens, competitive inhibition assays, and a unique peptide–on–bead assay, we determined that these apically staining mAbs recognize 3 or 4 distinct epitopes on PDC–E2. More importantly, this suggests that a portion spanning the entire inner lipoyl domain of PDC–E2 can be found at the BEC apical surface. In addition, competition assays with patient sera and a PDC–E2-specific mAb showed significant epitope overlap with only 1 of the 3 mouse mAbs and showed a differential response to the peptide bound to beads. These findings further highlight the heterogeneous response of patient autoantibodies to the inner lipoyl domain of PDC–E2. (Hepatology 2001;33:792–801.)
A Prospective, Randomized Trial of Butyl Cyanoacrylate Injection Versus Band Ligation in the Management of Bleeding Gastric Varices
Authors: Lo Gin-Ho , Lai Kwok-Hung , Cheng Jin-Shiung , Chen Mei-Hsiu , Chiang Hung-Ting
Published: August 2002

Gastric variceal bleeding is a catastrophic event. Both cyanoacrylate injection and banding ligation have been proven to be effective in the management of bleeding gastric varices. This study was performed to compare the efficacy and complications of both the modalities. Cirrhotic patients with a history of gastric variceal bleeding were randomized to 2 groups. The group receiving endoscopic obturation (group A) comprised 31 patients and the group receiving band ligation (group B) comprised 29 patients. Butyl cyanoacrylate and pneumatic–driven ligator were applied, respectively. Treatment was repeated regularly until obliteration of gastric varices. Active bleeding occurred in 15 patients in group A and 11 patients in group B. Initial hemostatic rate (defined as no bleeding for 72 hours after treatment) was 87% in group A and 45% in group B (P = .03). The sessions required to achieve variceal obliteration and obliteration rates were similar in both the groups. However, rebleeding rates were significantly higher in group B (54%) than group A (31%) (P = .0005). Treatment–induced ulcer bleeding occurred in 2 patients (7%) in group A and 8 patients (28%) in group B (P = .03). The amount of blood transfusions required were also higher in group B than group A (4.2 ± 1.3 vs. 2.6 ± 0.9 units, respectively) (P < .01). Nine patients of group A and 14 patients of group B died (P = .05). In conclusion, endoscopic obturation using cyanoacrylate proved more effective and safer than band ligation in the management of bleeding gastric varices.
Madcam–1 Expressed in Chronic Inflammatory Liver Disease Supports Mucosal Lymphocyte Adhesion to Hepatic Endothelium (Madcam–1 in Chronic Inflammatory Liver Disease)
Authors: Grant Allister J. , Lalor Patricia F. , Hübscher Stefan G. , Briskin Michael , Adams David H.
Published: August 2002

Mucosal addressin cell adhesion molecule (MAdCAM–1) plays a pivotal role in T–lymphocyte homing to the gut. Given the strong association between the autoimmune liver diseases primary sclerosing cholangitis and autoimmune hepatitis and inflammatory bowel disease, we investigated the role of MAdCAM–1 in recruiting mucosal lymphocytes to the liver. MAdCAM–1 was strongly expressed on inflamed portal vein/sinusoidal endothelium in autoimmune mediated liver disease. In modified Stamper–Woodruff assays, MAdCAM–1 on hepatic vessels supported adhesion of α4β7+ lymphocytes (i.e., gut–derived T cells) from patients with inflammatory bowel disease and primary sclerosing cholangitis. This adhesion was inhibited by pretreatment with blocking antibodies to MAdCAM–1, α4β7, or the integrin α4 chain indicating that MAdCAM–1 in inflamed liver is functionally active. Circulating lymphocytes from patients with primary sclerosing cholangitis showed rolling adhesion on MAdCAM–1 transfectants in a flow–based adhesion assay that could be blocked by anti–MAdCAM–1 or anti–α4β7 mAbs. These findings indicate that, under certain circumstances, vessels in the human liver support adhesion of α4β7+ mucosal lymphocytes via binding to aberrantly expressed MAdCAM–1 on liver endothelium. This provides a mechanism to explain the hepatic recruitment of mucosal lymphocytes in inflammatory liver disease complicating inflammatory bowel disease.
Prolonged, But Not Acute, Glutathione Depletion Promotes Fas–Mediated Mitochondrial Permeability Transition and Apoptosis in Mice
Authors: Haouzi Delphine , Lekehal Mounia , Tinel Marina , Vadrot Nathalie , Caussanel Laure , Lettéron Philippe , Moreau Alain , Feldmann Gérard , Fau Daniel , Pessayre Dominique
Published: August 2002

Glutathione depletion either decreased or increased death–receptor-mediated apoptosis in previous studies. Comparison of the durations of glutathione depletion before death–receptor stimulation in these studies might suggest a different effect of prolonged versus acute thiol depletion. We compared the effects of the prolonged glutathione depletion caused by a sulfur amino acid-deficient (SAA-) diet and the acute depletion caused by a single dose of phorone on hepatic apoptosis triggered by the administration of an agonistic anti–Fas antibody. The chronic SAA- diet did not affect hepatic Fas or Bcl–XL, but increased p53 and Bax, and exacerbated Fas–mediated mitochondrial membrane depolarization, electron–microscopy-proven outer mitochondrial membrane rupture, cytochrome c translocation to the cytosol, and caspase 3 activation. These effects were prevented by cyclosporin A, an inhibitor of mitochondrial permeability transition. The SAA- diet increased internucleosomal DNA fragmentation, the percentage of apoptotic hepatocytes, serum alanine transaminase (ALT) activity, and mortality after Fas stimulation. Despite a similar decrease in hepatic glutathione, administration of a single dose of phorone 1 hour before the anti–Fas antibody did not change p53 or Bax, and did not enhance Fas–induced mitochondrial permeability transition and toxicity. However, 4 repeated doses of phorone (causing more prolonged glutathione depletion) increased Bax and Fas–mediated toxicity. In conclusion, a chronic SAA- diet, but not acute phorone administration, increases p53 and Bax, and enhances Fas–induced mitochondrial permeability transition and apoptosis. Thiol depletion could cause oxidative stress that requires several hours to increase p53; the latter induces Bax, which translocates to mitochondria after Fas stimulation.
Etoposide Prevents Apoptosis in Mouse Liver With D–Galactosamine/Lipopolysaccharide–Induced Fulminant Hepatic Failure Resulting in Reduction of Lethality
Authors: Nakama Tetsufumi , Hirono Shuichi , Moriuchi Akihiro , Hasuike Satoru , Nagata Kenji , Hori Takeshi , Ido Akio , Hayashi Katsuhiro , Tsubouchi Hirohito
Published: August 2002

d–Galactosamine (GalN)/lipopolysaccharide (LPS)–induced liver injury is an experimental model of fulminant hepatic failure in which tumor necrosis factor α (TNF–α) plays a pivotal role. We examined the effects of etoposide on GalN/LPS–induced fulminant hepatic failure. Mice were given an intraperitoneal dose of GalN (800 μg/g body weight)/LPS (100 ng/g body weight) with and without intraperitoneal etoposide (10 μg/g body weight) treatment. Liver injury was assessed biochemically and histologically. TNF–α levels in the serum, and apoptosis of hepatocytes and CPP32/caspase–3 in the liver, were determined. GalN/LPS treatment caused lethal liver injury in 87% of animals (13 of 15). The effect was associated with significant increases in TNF–α and alanine transaminase (ALT) levels in serum, the number of apoptotic hepatocytes, CPP32/caspase–3 activity, and TNF receptor 1 (TNFR1) mRNA expression in the liver. Etoposide (10 μg/g body weight) was given 3 times (at 50, 26, and 4 hours before GalN/LPS administration). Treatment of GalN/LPS–treated mice with etoposide reduced apoptosis of hepatocytes, resulting in reduction of lethality (13% [2 of 15]), while another topoisomerase II inhibitor, IRCF–193, showed no significant effect. The antilethal effect of etoposide was also confirmed in GalN/TNF–α-induced fulminant hepatic failure. Etoposide treatment reduced CPP32/caspase–3 activity in the liver, although it did not alter the serum TNF–α levels or hepatic TNFR1 mRNA expressions. In addition, etoposide treatment enhanced the mRNA and protein expression of Bcl–xL, an antiapoptotic molecule in the liver. The present findings suggest that etoposide prevents endotoxin–induced lethal liver injury by up–regulation of Bcl–xL, and that etoposide could be useful for the treatment of TNF–α-mediated liver diseases.
Induction Of Mdr1b Expression by Tumor Necrosis Factor–α in Rat Liver Cells Is Independent of P53 But Requires Nf–κB Signaling
Authors: Ros Jenny E. , Schuetz John D. , Geuken Mariska , Streetz Konrad , Moshage Han , Kuipers Folkert , Manns Michael P. , Jansen Peter L.M. , Trautwein Christian , Müller Michael
Published: August 2002

The multidrug resistance protein Mdr1b in rats is up–regulated during liver regeneration after partial hepatectomy or after endotoxin treatment. We hypothesize that up–regulation of Mdr1b in these models is TNF–α-dependent. The mechanism of Mdr1b activation by TNF–α is unknown as TNF–α can signal through various pathways, including NF–κB and p53, transcription factors for which binding sites in the Mdr1b promoter have been identified. We aimed to elucidate the mechanism of up–regulation of Mdr1b by TNF–α. We selectively used constructs expressing dominant negative Fas–associated death domain protein (FADD), TNF receptor associated factor–2 (TRAF2) or IκB to inhibit pathways downstream of the TNF receptor. Further, the proteasome inhibitor MG–132 was used, which prevents the breakdown of IκB. We show a critical role for NF–κB in activation of Mdr1b gene expression both in primary rat hepatocytes and in rat hepatoma H–4–II–E cells. Because p53 is up–regulated by TNF–α in an NF–κB-dependent manner and the Mdr1b promoter contains a p53 binding site, we used liver cells expressing a dominant negative p53 to show that TNF–α up–regulation of Mdr1b is independent of functional p53. Using transient transfection assays, we show that Mdr1b up–regulation correlates with activation of the promoter. Mutation of the NF–κB site in the Mdr1b promoter prevents its induction by TNF–α. In conclusion our results show that activation of the rat Mdr1b gene by TNF–α is a result of NF–κB signaling and independent of p53. (Hepatology 2001;33:1425–1431.)
Extended Lamivudine Treatment in Patients With Chronic Hepatitis B Enhances Hepatitis B E Antigen Seroconversion Rates: Results After 3 Years of Therapy
Authors: Leung Nancy W.Y. , Lai Ching-Lung , Chang Ting-Tsung , Guan Richard , Lee Chuan-Mo , Ng Keng-Yeen , Lim Seng-Gee , Wu Pui-Chee , Dent Julie C. , Edmundson Sally , Condreay Lynn D. , Chien Rong-Nan
Published: August 2002

A study in Chinese patients with chronic hepatitis B showed that treatment with lamivudine for 1 year significantly improves liver histology and enhances hepatitis B e antigen (HBeAg) seroconversion compared with placebo. Fifty–eight patients from this 1–year study have received long–term treatment with lamivudine 100 mg; the outcome of 3 years of lamivudine is reported here. Before treatment, all patients had detectable HBeAg. HBeAg seroconversion (HBeAg–negative, anti–HBe-positive), hepatitis B virus (HBV)–DNA suppression, alanine transaminase (ALT) normalization, emergence of YMDD variant HBV, liver histology, and long–term safety were assessed. After 3 years of continuous treatment with lamivudine 100 mg daily, 40% (23 of 58) of patients achieved HBeAg seroconversion. In patients with baseline serum ALT >2× upper limit of normal (ULN), the rate of HBeAg seroconversion was 65% (17 of 26). Median serum HBV–DNA concentrations were below the level of detection, and median ALT concentrations were within the normal range throughout 3 years of treatment. YMDD variant HBV emerged in 33 of 58 (57%) patients during the 3 years, of whom 9 (27%) achieved HBeAg seroconversion (6 after emergence of YMDD variant HBV). ALT levels and histologic scores after emergence of YMDD variant HBV did not show major deterioration. Lamivudine was well tolerated during 3 years of therapy. In conclusion, these data in Chinese patients with chronic hepatitis B show enhanced seroconversion rates with extended lamivudine treatment. Up to two thirds of patients with moderately elevated pretreatment ALT achieved HBeAg seroconversion after 3 years of therapy.
Increased Density of Brain Histamine H1 Receptors in Rats With Portacaval Anastomosis and in Cirrhotic Patients With Chronic Hepatic Encephalopathy
Authors: Lozeva Violina , Tuomisto Leena , Sola David , Plumed Carme , Hippeläinen Mikko , Butterworth Roger
Published: August 2002

The binding properties and the regional densities of histamine H1 receptors were studied in brain of rats with portacaval anastomosis (PCA) and in autopsied brain tissue from cirrhotic patients with hepatic encephalopathy (HE). Receptor binding studies and quantitative receptor autoradiography were performed, employing [3H]mepyramine. Histamine H1 receptors in rat brain displayed a higher density and a lower affinity compared with control human frontal cortex. Specific [3H]mepyramine binding was heterogeneously distributed throughout the brain in both species. In human brain, binding was highest in the parietal and temporal cortices and lowest in caudate–putamen. In rat brain, binding was highest in the suprachiasmatic nucleus, dentate gyrus of the hippocampus, ventromedial hypothalamus, and nucleus accumbens. Cortical tissue from PCA rats and frontal cortical tissue from HE patients contained significantly increased densities (B
max) of H1 receptors. A selective increase in H1 receptor density was also observed in parietal and insular cortices of HE patients. Results of the present study suggest a selective up–regulation of brain H1 receptors in PCA rats and in patients with HE. The central histaminergic system is implicated in the control of arousal and circadian rhythmicity. Previous studies have shown that blockade of H1 receptors in PCA rats results in improved locomotor activity and circadian rhythmicity scores. The present findings suggest that cortical histaminergic hyperactivity could contribute to the neuropsychiatric symptoms characteristic of human HE, and that selective histamine H1 receptor antagonists could be beneficial in the prevention and treatment of some of the symptoms of HE in cirrhotic patients.
Identification of Immunodominant Hepatitis C Virus (Hcv)–Specific Cytotoxic T–Cell Epitopes by Stimulation With Endogenously Synthesized Hcv Antigens
Authors: Urbani Simona , Uggeri Jacopo , Matsuura Yoshiharu , Miyamura Tatsuo , Penna Amalia , Boni Carolina , Ferrari Carlo
Published: August 2002

Hepatitis C virus (HCV)–specific CD8+ cytotoxic T lymphocytes (CTL) are believed to play an important role in the pathogenesis of liver cell injury and viral clearance in HCV infection. Because HCV does not efficiently infect human cells in vitro and primary infected hepatocytes cannot be used as stimulator/target cells for CTL analysis, development of efficient systems to activate and expand CTL in vitro, reproducing antigen presentation to CTL occurring during natural infection, is mandatory to study CTL activity and to define the hierarchy of immunodominance of CTL epitopes. To achieve this goal, 5 different defective adenoviruses carrying structural and nonstructural HCV genes (core, core–E1–E2, E2, NS3–NS4A, NS3–NS5A) were used to induce the endogenous synthesis of HCV proteins in human adherent mononuclear cells in vitro and to allow their entry into the HLA class I cytosolic pathway of antigen processing. The cytolytic activity of peripheral blood lympho–mononuclear cells (PBMC) from HLA–A2+ HCV–infected patients stimulated with recombinant adenovirus–infected cells was tested against target cells either pulsed with a panel of synthetic peptides containing the HLA–A2 binding motif or infected with recombinant vaccinia viruses carrying HCV genes. Our study defines a reproducible system to stimulate and expand HCV–specific CTL in vitro that mimics the conditions of antigen encounter in vivo. By this approach, we have identified several HLA–A2-restricted epitopes that should correspond to immunodominant HCV sequences recognized by CTL during natural infection. Therefore, these amino acid sequences represent ideal candidates for the design of therapeutic vaccines for chronic HCV infection.
Long–Term Follow–Up of Interferon Alfa Treatment in Chinese Patients With Chronic Hepatitis B Infection: the Effect on Hepatitis B E Antigen Seroconversion and the Development of Cirrhosis–Related Complications
Authors: Yuen Man-Fung , Hui Chee-Kin , Cheng Chi-Chung , Wu Chi-Hang , Lai Yim-Ping , Lai Ching-Lung
Published: August 2002

The long–term effect of interferon alfa (IFN–α) in Chinese patients with chronic hepatitis B infection is unknown. A total of 411 chronic hepatitis B patients (208 treated with IFN–α and 203 as control) were followed up for hepatitis B serology and the development of hepatoma and other cirrhosis–related complications. The hepatitis B e antigen (HBeAg) seroconversion rate in the IFN–α-treated group, though significantly greater at 6 and 24 months, was comparable with the control group on subsequent follow–up, irrespective of pretreatment alanine transaminase (ALT) levels. HBeAg seroreversion rate was higher in the IFN–α group compared with the control group (21.1% vs. 2.2%; P = .001). Loss of hepatitis B surface antigen (HBsAg) occurred in 2.4% of the IFN–α-treated patients and 0.49% of the control patients (P = NS). Around 90% of the anti–HBe-positive patients in both groups were still hepatitis B virus (HBV)–DNA-positive by polymerase chain reaction (PCR) assay. Two patients suffered from hepatic reactivation during the course of treatment. Nine (4.3%) patients in the IFN–α group and 2 (1.0%) in the control group developed complications of cirrhosis and hepatoma (P = .062). In Chinese HBsAg carriers, IFN–α was of no long–term benefit in inducing HBeAg seroconversion or in the prevention of hepatoma and other cirrhosis–related complications.
The Role of Smad3 in Mediating Mouse Hepatic Stellate Cell Activation
Authors: Schnabl Bernd , Kweon Young O. , Frederick Joshua P. , Wang Xiao-Fan , Rippe Richard A. , Brenner David A.
Published: August 2002

Transforming growth factor β (TGF–β) is the most potent profibrogenic mediator in liver fibrosis. Although Smad proteins have been identified as intracellular mediators in the TGF–β signaling pathway, the function of individual Smad proteins remains poorly understood. The aim of this study was to explore the contribution of Smad3 in mediating TGF–β responses in a model of acute liver injury in vivo and in culture–activated hepatic stellate cells (HSCs). Wild–type, Smad3 heterozygous or Smad3 homozygous knockout mice were treated with a single intragastric administration of CCl4. After 72 hours, the induction of hepatic collagen α1(I) and α2(I) messenger RNA (mRNA) levels in Smad3 knockout mice was only 42% and 64%, respectively, of the levels induced in wild–type mice. However, smooth muscle α–actin (α–SMA) was expressed at a slightly higher level in livers from knockout mice compared with wild–type mice. In culture–activated HSCs from Smad3 knockout mice, collagen α1(I) mRNA was 73% of wild–type HSCs, but α–SMA expression was the same. HSCs from knockout mice showed a higher proliferation rate than wild–type HSCs. Smad3–deficient HSCs did not form TGF–β1-induced Smad–containing DNA–binding complexes. In conclusion, (1) maximal expression of collagen type I in activated HSCs requires Smad3 in vivo and in culture; (2) Smad3 is not necessary for HSC activation as assessed by α–SMA expression; (3) Smad3 is necessary for inhibition of proliferation of HSCs, which might be TGF–β-dependent; and (4) Smad3 is required for TGF–β1-mediated Smad–containing DNA–binding complex formation in cultured HSCs.
Restoration of Cerebral Blood Flow Autoregulation and Reactivity to Carbon Dioxide in Acute Liver Failure by Moderate Hypothermia
Authors: Jalan Rajiv , Olde Damink Steven W.M. , Deutz Nicolaas E.P. , Hayes Peter C. , Lee Alistair
Published: August 2002

In patients with acute liver failure (ALF) and uncontrolled intracranial hypertension, moderate hypothermia (32°C) reduces intracranial pressure (ICP) and cerebral blood flow (CBF), and can be used as a bridge to liver transplantation. The purpose of this study was to test the hypothesis that moderate hypothermia reduced ICP by restoring CBF autoregulation. Nine patients with uncontrolled intracranial hypertension and ALF who fulfilled the criteria for poor prognosis were studied. CBF autoregulation and reactivity to carbon dioxide were evaluated before and 4 hours after cooling (32°C). Significant reductions were observed in the ICP (median, 46 [range, 27–54] mm Hg to 19 [15–22] mm Hg; P < .01) and CBF (median, 111 [69–134] to 56 [38–67] mL/100 g/min; P < .05). The defective CBF autoregulation and the absence of reactivity to carbon dioxide that was observed in all patients was restored with cooling. The results of our study suggest that the improvement in ICP observed with hypothermia may be the result of its effects on CBF autoregulation and provides a tool to explore the mechanisms associated with the deranged CBF autoregulation in ALF.
High Amino Acid Variability Within the Ns5a of Hepatitis C Virus (Hcv) Is Associated With Hepatocellular Carcinoma in Patients With Hcv–1B-Related Cirrhosis
Authors: Giménez-Barcons Mireia , Franco Sandra , Suárez Yanette , Forns Xavier , Ampurdanès Sergi , Puig-Basagoiti Francesc , Sánchez-Fueyo Alberto , Barrera Josep-Maria , Llovet Josep-Maria , Bruix Jordi , Sánchez-Tapias José-María , Rodés Juan , Saiz Juan-Carlos
Published: August 2002

Interferon therapy may decrease the risk of hepatocellular carcinoma in patients with hepatitis C virus (HCV)–related liver cirrhosis. Interaction of the cellular protein kinase PKR with the PKR–binding domain (PKR–bd) of HCV–NS5A protein may affect cellular growth control and viral resistance to interferon therapy. Mutations within the PKR–bd, which comprises the interferon sensitivity determining region (ISDR), have been associated with interferon sensitivity. To determine whether or not there is an association between HCV heterogeneity and the presence of hepatocellular carcinoma, HCV–1b genomic regions were amplified and directly sequenced from serum samples obtained from 82 patients with liver cirrhosis, 53 with, and 29 without hepatocellular carcinoma. None of them had received antiviral therapy. When compared with the deduced consensus sequence, the median number of amino acid changes in the PKR–bd was higher among samples from patients with (4.22) than from those without hepatocellular carcinoma (1.62; P < .001), and isolates with 3 or more amino acid changes were significantly more common among the former (60%) than among the later (6%, P < .001). No such differences were observed in other viral regions, including Core, E2–HVR–1, E2–PePHD, NS3, and the 5′ and 3′ PKR–bd flanking regions. In addition, amino acid variation in viral regions other than HVR–1 did not accumulate over time in the analyzed sequential serum samples obtained from patients with or without hepatocellular carcinoma. Therefore, a mutated HCV–PKR–bd phenotype is very common in cirrhotic patients with hepatocellular carcinoma.
A Randomized 4–Arm Multicenter Study of Interferon Alfa-2B Plus Ribavirin in the Treatment of Patients With Chronic Hepatitis C Not Responding to Interferon Alone
Authors: Saracco Giorgio , Ciancio Alessia , Olivero Alda , Smedile Antonina , Roffi Luigi , Croce Guido , Colletta Cosimo , Cariti Giuseppe , Andreoni Massimo , Biglino Alberto , Calleri Guido , Maggi Giovanni , Tappero Gian Franco , Orsi Pier Giulio , Terreni Natalia , Macor Antonio , Di Napoli Angelo , Rinaldi Enrico , Ciccone Giovannino , Rizzetto Mario
Published: August 2002

To determine whether a higher dosage of interferon (IFN) associated with ribavirin and/or prolonged time of administration may improve therapeutic efficacy, we conducted a 4–arm randomized trial on patients with chronic hepatitis C not responding to one or more previous treatment courses with IFN monotherapy. Group 1 (n = 139) received 3 million units (MU) IFN–α2b 3 times a week (t.i.w.) plus ribavirin 1,000 mg/d for 12 months; group 2 (n = 162) received 5 MU t.i.w. plus ribavirin for 12 months; group 3 (n = 142) received 3 MU t.i.w. plus ribavirin for 6 months; and group 4 (n = 151) received 5 MU t.i.w. plus ribavirin for 6 months. The primary end point was hepatitis C virus (HCV)–RNA clearance at the end of 6–month follow–up. HCV–RNA was negative in 15% of group 1, 23% of group 2, 11% of group 3, 16% of group 4 (group 2 vs. group 3, P = .04). Among patients with genotypes 1 and 4, sustained response was significantly higher in group 2 vs. group 3 (18% vs. 7%, P = .03; group 1 = 9%, group 4 = 12%, P = not significant [NS]). In patients with genotypes 2 and 3, sustained virologic response was not affected by the different regimens (group 1 = 32%, group 2 = 30%, group 3 = 30%, group 4 = 35%, P = NS). In conclusion, about 23% of nonresponders to IFN monotherapy may achieve a sustained response if re–treated by 5 MU t.i.w. IFN plus ribavirin 1,000 mg/d for 1 year. Patients with genotype 1 should receive a high dosage of IFN plus ribavirin for 12 months, whereas therapy for patients with genotype 2 or 3 should be less aggressive.
Hemodynamic, Renal, and Endocrine Effects of Acute Inhibition of Nitric Oxide Synthase in Compensated Cirrhosis
Authors: La Villa Giorgio , Barletta Giuseppe , Pantaleo Pietro , Del Bene Riccarda , Vizzutti Francesco , Vecchiarino Sabrina , Masini Emanuela , Perfetto Federico , Tarquini Roberto , Gentilini Paolo , Laffi Giacomo
Published: August 2002

To assess whether an increased production of nitric oxide is involved in the circulatory and renal alterations of cirrhosis, we evaluated systemic hemodynamics (echocardiography), renal hemodynamics, and sodium handling (lithium clearance method), plasma renin activity (PRA), aldosterone (PAC), and norepinephrine in 7 patients (3 men, mean age 65 ± 2 years) with compensated cirrhosis, portal hypertension, and hyperdynamic circulation during intravenous N
G–monomethyl–l–arginine (L–NMMA) (3 mg/kg bolus plus 0.05 mg/kg · min for 120 minutes) or placebo (the vehicle) in a randomized, placebo–controlled, crossover study. Administration of l–NMMA resulted in significant reductions in plasma and urinary nitrite levels and plasma cyclic guanosine monophosphate (cGMP), indicating effective inhibition of nitric oxide synthase. l–NMMA also significantly reduced cardiac index (-13%) and increased systemic vascular resistance (+26%), arterial pressure (+9%), renal blood flow (+12%), glomerular filtration rate (+12%), and sodium excretion (+25%). Changes in sodium excretion were caused by both enhanced filtered sodium load and reduced sodium reabsorption in the proximal tubule. Plasma norepinephrine significantly decreased in response to l–NMMA, and there was a trend for reductions in PRA and PAC. Placebo had no appreciable effect on any of the measured parameters. These results indicate that in patients with compensated cirrhosis, portal hypertension and hyperdynamic circulation inhibition of nitric oxide synthase corrects the altered systemic hemodynamics and improves renal function and sodium excretion.
Peroxisome Proliferator-Activated Receptor–α-/- Mice Show Enhanced Hepatocyte Proliferation in Response to the Hepatomitogen 1,4–Bis[2–(3,5–Dichloropyridyloxy)] Benzene, A Ligand of Constitutive Androstane Receptor
Authors: Columbano Amedeo , Ledda-Columbano Giovanna M. , Pibiri Monica , Concas Danilo , Reddy Janardan K. , Rao Sambasiva M.
Published: August 2002

Previously, we have suggested that liver cell proliferation induced by certain mitogens is dependent on their binding and activation of nuclear receptors of the steroid/thyroid superfamily. More recently, it was shown that absence of the nuclear receptors peroxisome proliferator-activated receptor–α (PPARα) and constitutive androstane receptor (CAR) completely abolishes the proliferative response of hepatocytes to the mitogenic stimulus exerted by their specific ligands, peroxisome proliferators (PPs) and 1,4–bis[2–(3,5–dichloropyridyloxy)] benzene (TCPOBOP), respectively. Here we show that deletion of the PPARα gene accelerates and enhances the proliferative response evoked by the xenobiotic 1,4–bis[2–(3,5–dichloropyridyloxy)] benzene (TCPOBOP), a powerful mouse–liver mitogen and a ligand of the nuclear receptor CAR. Indeed, the number of hepatocytes entering S phase 24 hours after mitogen treatment was much greater in PPARα-/- mice compared with that of wild type mice (labeling indices 21.4% and 7.5%, respectively). Labeling index of hepatocytes from PPARα-/- mice was found to be higher than that of wild type mice up to 36 hours after treatment, indicating that lack of PPARα not only accelerated but also enhanced the overall proliferative response of the liver. The accelerated entry into S phase observed in hepatocytes from PPARα-/- mice was associated with a very rapid induction of cyclin D1. No major differences between TCPOBOP–treated PPARα-/- and wild type mice were observed in the expression of the 2 inhibitors of cyclin/CDKs complexes, p27 and p21. The results suggest that PPARα may play a role in modulating CAR–signaling pathways in the cell, in particular those leading to hepatocyte proliferation.
Beneficial Effects of Silymarin on Estrogen–Induced Cholestasis in the Rat: A Study In Vivo And in Isolated Hepatocyte Couplets
Authors: Crocenzi Fernando A. , Sánchez Pozzi Enrique J. , Pellegrino José M. , Favre Cristín O. , Rodríguez Garay Emilio A. , Mottino Aldo D. , Coleman Roger , Roma Marcelo G.
Published: August 2002

The effect of silymarin (SIL) on 17α–ethynylestradiol (EE)–induced cholestasis was evaluated in rats. EE (5 mg/kg, subcutaneously, daily, for 5 days) decreased both the bile–salt-dependent and the bile–salt-independent fractions of the bile flow. The decrease in the former was associated to a reduction in the bile salt pool size (-58%), and this effect was completely prevented by SIL. This compound also counteracted the inhibitory effect induced by EE on HCO3
– but not glutathione output, 2 major determinants of the bile–salt-independent bile flow. EE decreased the secretory rate maximum (Srm) of tauroursodeoxycholate, (-71%) and bromosulfophthalein (BSP; -60%), as well as the expression of the BSP canalicular carrier, mrp2; SIL failed to increase mrp2 expression, and had only a marginal beneficial effect on both tauroursodeoxycholate and BSP Srm values. However, the two–compartment model–based kinetic constant for BSP canalicular transfer was significantly improved by SIL (+262%). SIL decreased rather than increased CYP3A4, the cytochrome P450 isoenzyme involved in the oxidative metabolism of EE, and had no inhibitory effect on the UDP–glucuronosyltrasferase isoforms involved in the formation of its 17β–glucuronidated, more cholestatic metabolite. Pretreatment of isolated rat hepatocyte couplets with silibinin, the major, active component of SIL, counteracted the estradiol 17β–glucuronide–induced decrease in the percentage of couplets secreting apically the fluorescent bile acid analogue, cholyl–lysyl–fluorescein. These results show that SIL protects against EE–induced cholestasis by normalizing mainly the decrease in the bile salt pool size and HCO3
– output, and probably by counteracting the cholestatic effect of its cholestatic, glucuronidated metabolite.
A Comparison of the Mechanical Strength of Two Stapled Anastomosis Techniques for Equine Small Intestine
Authors: Bickers R. Jay , Blackford James T. , Eiler Hugo , Rohrbach Bart
Published: August 2002

Objective— To compare bursting strength, time of construction, and cost of a closed one‐stage, stapled functional end‐to‐end jejunojejunostomy (FEE) with a stapled side‐to‐side jejunojejunostomy (STS).

Study design— Experimental, randomized block design.

Animals— Seven adult horses without gastrointestinal disease.

Methods— The jejunum was isolated, and three FEE, three STS, and three control segments were created in each horse using a randomized block design. Anastomosis time was recorded. The intraluminal pressure at failure and mode of failure were recorded. Length at failure was measured on digitized images. Bursting pressure (BP), bursting wall tension (BWT), anastomosis time, and cost were compared.

Results— Control jejunal segments were stronger (P≤ .0001) in bursting strength and bursting wall tension (P≤ .0001) than either anastomosis type; no difference was found between anastomosis types for either variable. Functional end‐to‐end jejunojejunostomy was significantly quicker and less costly than STS (P≤ .0001).

Conclusions— Mechanically there were no significant differences between the FEE and STS techniques. The FEE technique maintained the physiologic direction of peristalsis of the segments, required less tissue manipulation, and was faster and more economical to create.

Clinical relevance— The FEE is a clinically viable technique.