bluuebunny/crossref_metadata_2025 huggingface dataset:
Prognostic Impact of Splenectomy on Gastric Cancer: Results of the Korean Gastric Cancer Study Group
Authors: Kwon Sung Joon ,   Members of the Korean Gastric Cancer Study Group
Published: August 2002

The relation between splenectomy and survival time after curative total gastrectomy for gastric cancer was reviewed retrospectively on 492 patients treated at nine hospitals between 1989 and 1993. Altogether 260 patients underwent splenectomy, and 232 patients did not. A univariate analysis revealed that the survival time of patients with splenectomy was significantly less than those without splenectomy (p= 0.0265). In a subgroup of our patients stratified to adjust for the stage of disease, there was no significant difference between the survival rates. Splenectomy remained insignificant according to the multivariate analysis using Cox's proportional‐hazard regression. The splenectomy group was associated with more risk factors (e.g., T3/T4 tumors, positive nodes, stage greater than III, large tumor size) that are powerful predictors of death due to gastric cancer. In a separate multivariate analysis after eliminating those who had a T4 tumor invasion or a N2 nodal positivity from the analysis (or both), splenectomy again remained insignificant. In conclusion, we could not find any beneficial effect of splenectomy in gastric cancer patients in this retrospective multivariate analysis. We can presume that splenectomy cannot increase the survival rate so long as the splenectomy group has more risk factors than the nonsplenectomy group. Therefore randomized prospective clinical trials using more precise criteria to indicate the need for splenectomy are needed to assess whether splenectomy is beneficial.
Bounded cohomology of lattices in higher rank Lie groups
Authors: Burger Marc , Monod Nicolas
Published: August 2002

We prove that the natural map

H^2_b(\Gamma)\to H^2(\Gamma)

from bounded to usual cohomology is injective if

\Gamma

is an irreducible cocompact lattice in a higher rank Lie group. This result holds also for nontrivial unitary coefficients, and implies finiteness results for

\Gamma

: the stable commutator length vanishes and any

C^1

-action on the circle is almost trivial. We introduce the continuous bounded cohomology of a locally compact group and prove our statements by relating

H^\bullet_b(\Gamma)

to the continuous bounded cohomology of the ambient group with coefficients in some induction module.
Effective Nullstellensatz for arbitrary ideals
Authors: Kollár János
Published: August 2002

Let

f_i

be polynomials in

n

variables without a common zero. Hilbert's Nullstellensatz says that there are polynomials

g_i

such that

\sum g_if_i=1

. The effective versions of this result bound the degrees of the

g_i

in terms of the degrees of the

f_j

. The aim of this paper is to generalize this to the case when the

f_i

are replaced by arbitrary ideals. Applications to the Bézout theorem, to Łojasiewicz-type inequalities and to deformation theory are also discussed.
Evaluation of a new hepatitis B triple-antigen vaccine in inadequate responders to current vaccines
Authors: Zuckerman Jane N. , Zuckerman Arie J. , Symington Ian , Du Wei , Williams Anthony , Dickson Brian , Young Michael D.
Published: August 2002

In this double-blind, randomized, controlled study, healthcare professionals with a history of inadequate response to currently available single-antigen hepatitis B vaccines confirmed by measuring hepatitis B surface antibody titer before entry to the study were revaccinated with a 20-μg dose either of a novel triple-antigen (S, pre-S1, and pre-S2) recombinant vaccine or of a present single-antigen (S only) vaccine. Hepatitis B surface antibody titers were measured 8 weeks' post revaccination. A total of 925 individuals were randomized and vaccinated, of whom 915 (98.9%) completed the study and were included in the efficacy analysis. A single dose of the new triple-antigen hepatitis B vaccine (Hepacare) produced a successful response in over three quarters of these subjects who had not mounted an adequate response to current vaccines. The antibody response was statistically significantly superior (P = .002) to that after a single dose of current vaccines. An evaluation of the overall response showed that only the triple-antigen vaccine was able to raise the average antibody response (geometric mean titer [GMT]) to over 100 IU/L. The superior effect of the new vaccine was most pronounced in subjects who were previously complete nonresponders to currently available hepatitis B vaccines. Both vaccines were well tolerated and had similar safety profiles. This study demonstrated that in healthcare workers who had responded inadequately to at least a full course of immunization (median, 5 doses), a single 20-μg dose of a new triple-antigen vaccine induced protective antibody level in more vaccinees (P = .002) and increased the average antibody titer (GMT) in those protected successfully to a greater degree (P < .001) than a further attempt with a current vaccine (Engerix-B).
Familial intrahepatic cholestasis 1: Studies of localization and function
Authors: Ujhazy Peter , Ortiz Daniel , Misra Suniti , Li Shohua , Moseley James , Jones Hugh , Arias Irwin M.
Published: August 2002

Mutations in the FIC1 gene constitute the molecular defect in familial intrahepatic cholestasis I (Fic1 [Byler's disease]) and benign recurrent intrahepatic cholestasis. This report describes the localization of Fic1 in rat liver and intestine, as well as biochemical and transfection studies that support its function as an energy-dependent aminophospholipid translocase. Immunocytochemistry of rat liver and immunoblotting of membrane fractions localized Fic1 to the canalicular, but not basolateral, plasma membrane domain. In the small intestine, Fic1 was localized to the apical membrane of epithelial cells. The distribution of Fic1 in liver plasma membrane fractions from control and taurocholate-treated rats correlated positively with adenosine triphosphate (ATP)-dependent aminophospholipid (phosphatidyl-serine) translocase activity. In canalicular membrane vesicles, translocase activity had an initial velocity of 3.3 nmol phosphatidylserine (PS) translocated per milligram of protein per minute and a K
m (ATP) = 1.2 mmol/L; was inhibited by vanadate, N-ethylmaleimide, sodium azide, and calcium; and was unidirectional (i.e., from the outer to the inner canalicular plasma membrane leaflet). Transient transfection of CHOK1 cells with FIC1 cDNA resulted in appearance of FIC1 in membrane preparations and energy-dependent PS translocation in cells. These studies indicate that FIC1 is a canalicular P-type ATPase that participates in maintaining the distribution of aminophospholipids between the inner and outer leaflets of the plasma membrane. How this process produces cholestasis is under study.
Enhanced expression of B7-1, B7-2, and intercellular adhesion molecule 1 in sinusoidal endothelial cells by warm ischemia/reperfusion injury in rat liver
Authors: Kojima Naosuke , Sato Mitsuru , Suzuki Akira , Sato Takeya , Satoh Shigeru , Kato Tetsuro , Senoo Haruki
Published: August 2002

To elucidate a role of costimulatory molecule and cell adhesion molecule in hepatic ischemia/reperfusion injury, we examined an alteration in B7-1 (CD80), B7-2 (CD86), and intercellular adhesion molecule 1 (ICAM-1; CD54) expression in the rat liver after warm ischemia/reperfusion injury. To induce hepatic warm ischemia in a rat model, both portal vein and hepatic artery entering the left-lateral and median lobes were occluded by clamping for 30 minutes or 60 minutes, and then reperfused for 24 hours. B7-1, B7-2, and ICAM-1 expressions in the liver were analyzed by immunofluorescence staining and real-time reverse transcription polymerase chain reaction (RT-PCR). Although B7-1 and B7-2 expressions were at very low levels in the liver tissues from normal or sham-operated control rats, both B7-1 and B7-2 expressions were enhanced at protein and messenger RNA (mRNA) levels in the affected, left lobes after warm ischemia/reperfusion. ICAM-1 protein and mRNA were constitutively expressed in the liver of normal and sham-operated control rats, and further up-regulated after warm ischemia/reperfusion. Localization of increased B7-1, B7-2, and ICAM-1 proteins, as well as von Willebrand factor as a marker protein for endothelial cells, was confined by immunofluorescence staining to sinusoidal endothelial cells in hepatic lobules. Data from quantitative real-time RT-PCR analysis revealed that B7-1 and B7-2 mRNA levels were elevated in hepatic lobes after warm ischemia/reperfusion (5.13- and 52.9-fold increase, respectively), whereas ICAM-1 mRNA expression was rather constitutive but further enhanced by warm ischemia/reperfusion (4.24-fold increase). These results suggest that hepatic sinusoidal endothelial cells play a pivotal role as antigen-presenting cells by expressing B7-1 and B7-2 in warm hepatic ischemia/reperfusion injury, and that B7-1 and/or B7-2 might be the primary target to prevent early rejection and inflammatory reactions after hepatic ischemia/reperfusion injury associated with liver transplantation.
Targeting dexamethasone to Kupffer cells: Effects on liver inflammation and fibrosis in rats
Authors: Melgert Barbro N. , Olinga Peter , Van Der Laan Judith M.S. , Weert Betty , Cho Jaejin , Schuppan Detlef , Groothuis Geny M. M. , Meijer Dirk K.F. , Poelstra Klaas
Published: August 2002

Kupffer cells (KC) play an important role in the pathogenesis of inflammatory liver diseases leading to fibrosis. Anti-inflammatory drugs are only effective when administered at high doses that may cause side effects. Therefore, dexamethasone coupled to mannosylated albumin (Dexa5-Man10-HSA) was designed by us to selectively deliver this anti-inflammatory drug to the KC. The effectiveness of Dexa5-Man10-HSA was studied both in organ cultures and fibrosis induced by bile duct ligation (BDL) in rats. Dexa5-Man10-HSA accumulated in livers of both healthy and fibrotic rats (67% ± 5% and 70% ± 9% of the dose, respectively) and uptake was found almost exclusively in KC. Active dexamethasone was liberated from its carrier, because Dexa5-Man10-HSA could effectively inhibit nitric oxide (NO) and tumor necrosis factor α (TNF-α) release in endotoxin-activated liver slices. In vivo, however, this was associated with increased collagen I and III depositions and enhanced tissue inhibitor of metalloproteinase-1 (TIMP-1) mRNA expression. This was accompanied by a decreased influx of reactive oxygen species (ROS) producing cells in the livers of BDL animals treated with Dexa5-Man10-HSA as compared with untreated BDL rats. Dexa5-Man10-HSA treatment also replenished the depleted glycogen stores in hepatocytes of BDL livers. In conclusion, our studies showed selective delivery of dexamethasone to KC with Dexa5-Man10-HSA. This conjugate reduced intrahepatic ROS in vivo and TNF-α production in vitro and prevented glycogen depletion in vivo, indicating effective pharmacologic targeting. Dexa5-Man10-HSA, however, also accelerated fibrogenesis, which was paralleled by TIMP-1 mRNA induction. Targeting of dexamethasone to KC provides evidence for a dual role of this cell type in fibrogenesis of BDL rats.
The processing and utilization of hepatocyte growth factor/scatter factor following partial hepatectomy in the rat
Authors: Pediaditakis Peter , Lopez-Talavera Juan Carlos , Petersen Bryon , Monga Satdarshan P. S. , Michalopoulos George K.
Published: August 2002

Hepatocyte growth factor/scatter factor (HGF/SF) is a pluripotent growth factor capable of acting as a motogen, a morphogen, and a mitogen. Originally, HGF/SF was found as a blood-borne mitogen for hepatocytes and has since been determined to be very important in liver repair. Previous studies have established that HGF/SF must be proteolytically cleaved to elicit its effects. After liver injury by toxins such as carbon tetrachloride or after surgical resection, partial hepatectomy (PHX), HGF/SF concentrations increase in the blood. The aims of this study were to examine (1) which form of HGF/SF is present in the normal liver, (2) which form is present in the regenerating liver after PHX, and (3) if the HGF/SF used after PHX is derived from existing liver reservoirs. Both single-chain HGF/SF and active two-chain HGF/SF are present in normal liver, with the former being the dominant form. After PHX, the liver can be described as having two phases with regard to the use of endogenous HGF/SF. The first phase from 0 to 3 hours is the consumptive phase and is characterized by a decrease in both single-chain HGF/SF and active two-chain HGF/SF. The second phase is the productive phase. It is characterized by a pronounced reappearance of both single-chain HGF/SF as well as two-chain HGF/SF. The activation index shows a 5-fold increase over sham operations during the productive phase. The use of radiolabeled HGF/SF showed that during the first 3 hours, HGF/SF is used in part from hepatic stores. Furthermore, during the first 3 hours after PHX, only active two-chain HGF/SF is seen in the plasma.
Oxidized low-density lipoproteins bind to the scavenger receptor, CD36, of hepatic stellate cells and stimulate extracellular matrix synthesis
Authors: Schneiderhan Wilhelm , Schmid-Kotsas Alexandra , Zhao Jinshun , Grünert Adolf , Nüssler Andreas , Weidenbach Hans , Menke Andre , Schmid Roland M. , Adler Guido , Bachem Max G.
Published: August 2002

Cumulating evidence suggests that oxidative stress resulting in lipid peroxidation and protein modification is involved in the pathogenesis of chronic liver injury and fibrogenesis. We investigated the effects of oxidized low-density lipoproteins (oxLDL) on collagen and fibronectin synthesis of cultured human and rat hepatic stellate cells (HSC). As shown on protein and mRNA levels, oxLDL dose-dependently stimulated the synthesis of collagen types I and III and fibronectin of cultured HSC. The effect was biphasic, with a maximum between 5 and 25 μg/mL oxLDL (c-fibronectin concentration in HSC supernatants increased 3.9-fold; collagen type I increased 4-fold). Higher oxLDL concentrations were cytotoxic. LDL modified with malondialdehyde (MDA) was not toxic, but stimulated extracellular matrix synthesis as well. As demonstrated by immunofluorescence microscopy (double staining of CD36 and iso-α-smooth muscle actin [iso-α-sm actin]), immunoblot, and reverse-transcription polymerase chain reaction (RT-PCR), respectively, cultured human HSC express the oxLDL receptor, CD36 (glycoprotein IIIb). Colocalization of CD36 and iso-α-sm actin on sinusoidal lining cells was further demonstrated using sections of human fibrotic liver. Preincubation of cultured human HSC with the monoclonal antibody, OKM5, known to block CD36-mediated oxLDL uptake, resulted in a reduction of the oxLDL-stimulated collagen type I synthesis by 56%. In summary, our results demonstrate that low concentrations of modified lipoproteins (oxLDL and MDA-LDL) represent fibrogenic mediators that bind to CD36 and stimulate matrix synthesis of HSC.
Treatment strategy for small hepatocellular carcinoma: Comparison of long-term results after percutaneous ethanol injection therapy and surgical resection
Authors: Yamamoto Junji , Okada Shuichi , Shimada Kazuaki , Okusaka Takushi , Yamasaki Susumu , Ueno Hideki , Kosuge Tomoo
Published: August 2002

This comparative study was conducted to clarify the efficacy of percutaneous ethanol injection (PEI) and surgical resection in the treatment of small hepatocellular carcinomas (HCC). Thirty-nine patients treated by PEI and 58 who underwent hepatic resection for small HCC (smaller than 3 cm and 3 or less in number) during the same period were enrolled. The surgery group included more patients with large and multiple bilobar nodules than the PEI group. The histological differentiation of the treated tumors became worse in the surgery patients than in those treated by PEI. On the other hand, the PEI group included more patients with a poor hepatic reserve, according to Child-Pugh grading, the ICG test, and the serum total bilirubin value. The 1-, 3-, and 5-year overall survival rates were almost identical between the 2 cohorts (100%, 82.1%, and 59.0%, respectively, in the PEI group; 96.6%, 84.4%, and 61.5%, respectively, in the surgery group) (P = .96). During the follow-up period, 33 of 39 (85%) and 41 of 58 (71%) patients developed tumor recurrence after PEI and surgery, respectively. Cumulative 1-, 3-, and 5-year tumor-free survival rates in the PEI group were 63.4%, 30.3%, and 9.7 %, whereas those in the surgery group were 75.5%, 44.7%, and 25.7%, respectively (P = .10). Our overall findings show that local therapy can achieve an actual 5-year survival rate of around 60% for patients with small HCC with the proper selection of treatment. A prospective randomized comparative trial is required to settle this longstanding issue.
Acute exacerbations of chronic hepatitis B are rarely associated with superinfection of hepatitis B virus
Authors: Kao Jia-Horng , Chen Pei-Jer , Lai Ming-Yang , Chen Ding-Shinn
Published: August 2002

There are 7 genotypes of hepatitis B virus (HBV). Whether superinfection of HBV carriers with different HBV genotypes occurs remains unknown. We therefore determined the HBV genotype and association between superinfection and acute exacerbation of disease in a cohort of 244 patients with chronic HBV infection who had elevated serum aminotransferase levels for at least 1 year. Within this group, 103 patients experienced acute exacerbation with an annual incidence of 13%, and 20 of the 103 patients had IgM antibody to hepatitis B core antigen (IgM anti-HBc). These 20 patients had a higher prevalence of genotype C infection (65%) than the remaining 83 anti-core IgM-negative patients (40%) who also had acute exacerbations (P < .05). Detailed analysis of HBV genotypes and sequences of the variable pre-S gene were determined in serial samples from 20 patients with IgM anti-HBc-positive acute exacerbations (group A), 20 patients with IgM anti-HBc-negative acute exacerbations (group B), and 20 patients without exacerbations (group C). Two (10%) of the group A patients had virologic evidence of HBV superinfection during acute exacerbation, one superinfected with heterotypic virus and the other with homotypic virus. The newly introduced virus disappeared after the exacerbation and the original virus resumed thereafter. The calculated prevalence of HBV superinfection in the hepatitis B carriers and those with acute exacerbations was 0.8% (2 of 244) and 1.9% (2 of 103), respectively. In conclusion, superinfection of HBV on hepatitis B carriers indeed occurs and may cause acute exacerbations, albeit at a low frequency even in hyperendemic areas of HBV infection.
Differential expression of cyclooxygenase-2 (COX-2) in human bile duct epithelial cells and bile duct neoplasm
Authors: Hayashi Nobuyasu , Yamamoto Hirofumi , Hiraoka Nobuaki , Dono Keizo , Ito Yasuhiro , Okami Jiro , Kondo Motoi , Nagano Hiroaki , Umeshita Koji , Sakon Masato , Matsuura Nariaki , Nakamori Shoji , Monden Morito
Published: August 2002

It is well known that chronic inflammatory conditions involving the bile ducts predispose to the development of bile duct carcinoma, although the relationship between chronic inflammation and malignant transformation is unclear. In this study, by combining immunohistochemistry and computer imaging techniques, we quantified and compared the cyclooxygenase-2 (COX-2) protein expression levels of epithelial cells according with their histopathological backgrounds. This technique revealed that the highest levels of COX-2 were expressed in bile duct carcinoma cells, mainly in cytoplasm, and the expression pattern was homogenous and abundant. Moderate levels of COX-2 protein expression were also observed in noncancerous epithelial cells with inflammatory reaction, but the staining intensity was heterogeneous among the positive cells exhibiting inflammation. In contrast, only scattered weak reactivity of COX-2 protein was observed in the noncancerous bile duct epithelial cells without inflammatory reaction. Moreover, bile duct epithelial cells in primary sclerosing cholangitis (PSC) showed very strong expression of COX-2 protein, that was comparable with carcinoma cells. On the other hand, primary biliary cirrhosis (PBC) epithelial cells showed moderate levels of COX-2 expression. In addition, specific COX-2 inhibitors, JTE-522 and NS-398, directly inhibited the growth of 4 bile duct carcinoma and 1 gall bladder carcinoma cell lines that expressed COX-2 protein, in vitro. These data suggest that COX-2 expression might regulate carcinogenesis of bile duct epithelial cells in inflammatory regions and tumor progression in this cancer. The data also suggest that COX-2 selective inhibitors might have therapeutic effects not only on bile duct carcinoma, but other hepatobiliary carcinomas.
Prospective study on anti-hepatitis C virus-positive patients with persistently normal serum alanine transaminase with or without detectable serum hepatitis C virus RNA
Authors: Martinot-Peignoux Michelle , Boyer Nathalie , Cazals-Hatem Dominique , Pham Bach-Nga , Gervais Anne , Le Breton Véronique , Levy Stéphane , Degott Claude , Valla Dominique-Charles , Marcellin Patrick
Published: August 2002

A significant proportion of patients with detectable antibodies to hepatitis C virus have normal serum alanine transaminase levels. Our aim was to study the outcome of this group. Between 1992 and 1999, 135 consecutive anti-HCV-positive patients with persistently normal ALT were followed for 3.6 ± 2.3 years (0.5 to 8.5 years), 108 had a liver biopsy at inclusion, and 24 had a second liver biopsy 3.5 ± 1.0 years later. Serum HCV RNA was detectable with PCR in 94 patients (69%) and not detectable in 41 patients (31%). Patients with and without detectable serum HCV RNA had similar epidemiological characteristics. Serum ALT levels and anti-HCV ratio were lower (P = .001), and histological lesions had lower grade and stage in patients without detectable serum HCV RNA (P = .001). Liver HCV RNA was not detectable with PCR in the 12-serum HCV RNA-negative patients tested. During follow-up, all patients without detectable serum HCV RNA remained HCV RNA-negative and kept normal serum ALT; all patients with detectable serum HCV RNA remained HCV RNA-positive, 20 (21%) had a slight fluctuation of serum ALT above the upper limit of normal. No significant changes were observed in the liver lesions of the 24 patients who underwent a second liver biopsy. In anti-HCV-positive patients with persistently normal serum ALT, histological lesions are significantly lower in HCV RNA-negative than in HCV RNA-positive patients. During follow-up, the HCV RNA status of patients remained unchanged; 21% of the patients with detectable serum HCV RNA had slight increase in serum ALT levels, but histological lesions remained stable.
Serum alanine aminotransferase flares during interferon treatment of chronic hepatitis B: Is sustained clearance of HBV DNA dependent on levels of pretreatment viremia?
Authors: Nair Satheesh , Perrillo Robert P.
Published: August 2002

During interferon treatment of chronic hepatitis B, an alanine aminotransferase (ALT) flare may herald a sustained loss of viral replication, but the relationship between virologic response, the extent of a flare, and pretreatment hepatitis B virus (HBV) DNA level has not been defined. We retrospectively examined the impact of an ALT flare on sustained virologic response in 121 interferon-treated patients and 42 untreated controls with either low-level (<100 pg/mL) or high-level (≥100 pg/mL) viremia. The degree of ALT flare was classified as mild (increase in ALT of 86-171 IU/L above baseline), moderate (increase of 172 to 343 IU/L above baseline), and severe (increase of ≥344 IU/L above baseline). Undetectable serum HBV DNA and hepatitis B e antigen (HBeAg) loss were significantly more likely at the end of follow-up in patients having a flare (P = .0001 and .001, respectively). In the high viremia group, a proportionate increase in virologic response was observed as the degree of flare increased. By multivariate analysis, high baseline HBV DNA, high pretreatment ALT, and both moderate and severe ALT flare were independently predictive of a virologic response with severe flare being the most powerful predictor for a sustained loss of serum HBV DNA (odds ratio, 5.3; P = .004). Severe flare was predictive of a virologic response in the high but not low viremia group. We conclude that a virologic response in patients with high-level viremia is dependent on the degree of ALT flare. Induction of a robust flare may enhance virologic response when high-level viremia is detected.
Relationship of serum leptin concentration and other measures of adiposity with gallbladder disease
Authors: Ruhl Constance E. , Everhart James E.
Published: August 2002

Obesity increases the risk of gallstones, especially in women. Most gallbladder disease studies have used body mass index (BMI) as a measure of overall adiposity, although BMI does not distinguish between fat and lean body mass. Central adiposity may also increase gallstone risk, although this is less well studied. Leptin is a peptide whose serum concentration is highly correlated with total body fat mass. We examined the relationship of gallbladder disease with anthropometric measures and serum leptin concentration in a large, national, population-based study. A total of 13,962 adult participants in the Third National Health and Nutrition Examination Survey underwent gallbladder ultrasonography and anthropometric measurements of BMI, body circumferences, and skinfold thicknesses, and a random subgroup of 5,568 had measures of fasting serum leptin concentrations. Gallstone-associated gallbladder disease was defined as ultrasound-documented gallstones or evidence of cholecystectomy. When controlling for BMI and other gallbladder disease risk factors in multivariate analysis, a test for trend for increasing waist-to-hip circumference ratio and risk of gallbladder disease was statistically significant among women (P = .043) and men (P = .007). BMI remained strongly associated with gallbladder disease among women (P < .001), but was unrelated among men (P = .46). Leptin concentration was associated with gallbladder disease in both sexes (P < .001), but not after controlling for BMI and waist-to-hip circumference in either women (P = .29) or men (P = .65). In conclusion, waist-to-hip circumference ratio was related to gallbladder disease among women and men. Serum leptin concentration was not a better predictor of gallbladder disease than anthropometry.
Transforming growth factor β and activin tonically inhibit DNA synthesis in the rat liver
Authors: Ichikawa Takeshi , Zhang You-Qing , Kogure Kimitaka , Hasegawa Yoshihisa , Takagi Hitoshi , Mori Masatomo , Kojima Itaru
Published: August 2002

The present study was conducted to assess the role of transforming growth factor β (TGF-β) and activin(s) in the regulation of the mass of the liver. To this end, we eliminated TGF-β or activin signaling in intact rat liver by adenovirus-mediated transfer of the gene encoding truncated type II TGF-β receptor (AdextTR) or truncated type II activin receptor (AdextAR). In intact rat liver that received a single application of either AdextTR or AdextAR via the portal vein, DNA synthesis as assessed by bromodeoxy uridine (BrdU) labeling was induced. In AdextTR- or AdextAR-treated rats, nuclear labeling was significantly higher than that in AdexLacZ, adenovirus vector encoding Escherichia coli β-galactosidase gene, or saline-treated rats at 3, 5, 7, and 9 days of infusion. The peak of the BrdU labeling was observed after 7 days of infusion and the labeling decreased thereafter. Apoptosis of hepatocytes, assessed by the terminal deoxynucleotidyl transferase (TdT)-mediated, dUTP-biotin nick-end labeling method was detected after 9 days of infusion. Immunoreactivity of TGF-β and activin A increased in the liver after the blockade of the activin or TGF-β signaling. TGF-β and activin A may have been up-regulated when the action of these ligands was blocked. These results indicate that blockade of the action of either TGF-β or activin leads to the initiation of DNA synthesis in intact liver. TGF-β and activin tonically inhibit hepatocyte growth even in intact liver and may play a critical role in the maintenance of constant liver mass.
Propranolol for the prevention of first esophageal variceal hemorrhage: A lifetime commitment?
Authors: Abraczinskas Diane R. , Ookubo Rie , Grace Norman D. , Groszmann Roberto J. , Bosch Jaime , Garcia-Tsao Guadalupe , Richardson Caroline R. , Matloff Daniel S. , Rodés Juan , Conn Harold O.
Published: August 2002

Although β blockers have had significant impact in the treatment of portal hypertension, the question of how long they should be continued for prevention of variceal hemorrhage remains unknown. Prospective studies on β blockers to prevent variceal hemorrhage lack long-term follow-up, and indefinite administration of β blockers for primary prevention of variceal bleeding has become standard practice. The aim of this study was to determine the outcomes of patients in whom β blocker therapy was discontinued. Patients completing a prospective, randomized, double-blind, placebo-controlled trial of propranolol for the primary prevention of variceal hemorrhage were tapered off of propranolol and placebo and followed prospectively for subsequent events. Of the 49 patients in the follow-up study (25 former propranolol, 24 former placebo), 9 experienced variceal hemorrhage (6 former propranolol, 3 former placebo). Following withdrawal of propranolol, the freedom from variceal bleeding was not significantly different between these 2 groups of patients, suggesting that the protective effect of propranolol against variceal hemorrhage, noted previously, was no longer present. Seventeen patients died (12 former propranolol, 5 former placebo) during the follow-up study. Cumulative survival was longer in the placebo group. These trends for EVH and survival were opposite to those observed in the original study population while patients were taking medication. When propranolol is withdrawn, the risk of variceal hemorrhage returns to what would be expected in an untreated population. Patients who discontinue β blockers experience increased mortality compared with an untreated population. These observations support the current practice of indefinite prophylactic therapy.
Delivery of IκB superrepressor gene with adenovirus reduces early alcohol-induced liver injury in rats
Authors: Uesugi Takehiko , Froh Matthias , Arteel Gavin E. , Bradford Blair U. , Gábele Erwin , Wheeler Michael D. , Thurman Ronald G.
Published: August 2002

Chronic alcohol administration increases gut-derived endotoxin in the portal blood, which activates Kupffer cells through nuclear factor κB (NF-κB) to produce toxic mediators such as proinflammatory cytokines, leading to liver injury. Therefore, a long-term intragastric ethanol feeding protocol was used here to test the hypothesis that NF-κB inhibition would prevent early alcohol-induced liver injury. Adenoviral vectors encoding either the transgene for IκB superrepressor (AdIκB-SR) or the bacterial β-galactosidase reporter gene (AdlacZ) were administered intravenously to Wistar rats. Animals were fed a high-fat liquid diet with either ethanol or isocaloric maltose-dextrin (control) for 3 weeks. There was no significant difference in mean urine alcohol concentrations between the groups fed ethanol. IκB-SR expression was increased for up to 2 weeks after injection, but was undetectable at 3 weeks. NF-κB activation was increased by ethanol and associated with up-regulation of tumor necrosis factor α (TNF-α). These increases were blunted significantly up to 2 weeks by AdIκB-SR. Dietary alcohol significantly increased liver to body weight ratios and serum alanine transaminase (ALT) levels in AdlacZ-treated animals, effects that were blunted significantly in AdIκB-SR-treated rats. Ethanol caused severe steatosis, inflammation, and focal necrosis in AdlacZ-treated animals. These pathologic changes were significantly decreased by AdIκB-SR. The protective effects of IκB-SR were significant 2 weeks after injection, but were lost at 3 weeks when IκB-SR was no longer expressed. Ethanol increased 4-hydroxynonenal as a maker of oxidative stress in both AdlacZ and AdIκB groups. These data support the hypothesis that NF-κB inhibition prevents early alcohol-induced liver injury even in the presence of oxidative stress.
Interleukin-1 receptor type I gene-deficient bile duct-ligated mice are partially protected against endotoxin
Authors: Sewnath Miguel E. , Van Der Poll Tom , Ten Kate Fiebo J. W. , Van Noorden Cornelis J. F. , Gouma Dirk J.
Published: August 2002

Cholestatic liver injury is associated with an increased susceptibility toward endotoxin-induced toxicity. To determine the role of interleukin 1 (IL-1) herein, extrahepatic cholestasis was induced by bile duct ligation (bdl) in IL-1 receptor type I gene-deficient (IL-1R−/−) mice, which are unresponsive to IL-1α and IL-1β, and normal IL-1R+/+ mice. Bdl elicited increases in hepatic IL-1α and IL-1β messenger RNA (mRNA) and protein. Hepatocellular injury at 2 weeks after bdl was similar in IL-1R−/− and IL-1R+/+ mice as shown by clinical chemistry and histopathology. Administration of endotoxin to cholestatic mice at 2 weeks after bdl was associated with enhanced cytokine release, more severe liver damage, and occurrence of death when compared with sham-operated mice. Endotoxin effects in sham-operated IL-1R−/− and IL-1R+/+ mice were largely similar, but cholestatic IL-1R−/− mice were better protected against toxic effects of endotoxin, as reflected by lowered cytokine release, less profound liver injury, and reduced mortality. These data indicate that IL-1α and IL-1β are produced in the liver after bdl, but that these cytokines do not play a significant role in cholestatic liver damage; however, endogenous IL-1 activity is an important denominator of enhanced endotoxin sensitivity that is observed during cholestasis induced by bdl.
TIPS versus drug therapy in preventing variceal rebleeding in advanced cirrhosis: A randomized controlled trial
Authors: Escorsell Àngels , Bañares Rafael , García-Pagán Juan Carlos , Gilabert Rosa , Moitinho Eduardo , Piqueras Belén , Bru Concepció , Echenagusia Antonio , Granados Alicia , Bosch Jaume
Published: August 2002

Prevention of variceal rebleeding is mandatory in cirrhotic patients. We compared the efficacy, safety, and cost of transjugular intrahepatic portosystemic shunt (TIPS) versus pharmacologic therapy in preventing variceal rebleeding in patients with advanced cirrhosis. A total of 91 Child-Pugh class B/C cirrhotic patients surviving their first episode of variceal bleeding were randomized to receive TIPS (n = 47) or drug therapy (propranolol + isosorbide-5-mononitrate) (n = 44) to prevent variceal rebleeding. Mean follow-up was 15 months. Rebleeding occurred in 6 (13%) TIPS-treated patients versus 17 (39%) drug-treated patients (P = .007). The 2-year rebleeding probability was 13% versus 49% (P = .01). A similar number of reinterventions were required in the 2 groups; these were mainly angioplasty ± restenting in the TIPS group (90 of 98) and endoscopic therapy for rebleeding in the medical group (45 of 62) (not significant). Encephalopathy was more frequent in TIPS than in drug-treated patients (38% vs. 14%, P = .007). Child-Pugh class improved more frequently in drug-treated than in TIPS-treated patients (72% vs. 45%; P = .04). The 2-year survival probability was identical (72%). The identified cost of therapy was double for TIPS-treated patients. In summary, medical therapy was less effective than TIPS in preventing rebleeding. However, it caused less encephalopathy, identical survival, and more frequent improvement in Child-Pugh class with lower costs than TIPS in high-risk cirrhotic patients. This suggests that TIPS should not be used as a first-line treatment, but as a rescue for failures of medical/endoscopic treatments (first-option therapies).
Effect of liver transplantation on inflammatory bowel disease in patients with primary sclerosing cholangitis
Authors: Dvorchik Igor , Subotin Michael , Demetris Jake A. , Fung John J. , Starzl Thomas E. , Wieand Samuel , Abu-Elmagd Kareem M.
Published: August 2002

This report investigates the influence of liver transplantation and concomitant immunosuppression on the course of progression of inflammatory bowel disease (IBD) and discusses statistical methodology appropriate for such settings. The data on 303 patients who underwent liver transplantation for primary sclerosing cholangitis (PSC) were analyzed using person-time analysis and Cox regression, with the duration of IBD as the time variable and transplantation as a segmented time-dependent covariate, to take into account both posttransplant and pretransplant history of IBD. The need for colectomy and appearance of colorectal cancer were taken as outcome measures. The only significant risk factor in the multivariate model for colectomy was transplantation itself, which increased the risk of colectomy due to intractable disease (Wald statistic; P = .001). None of the variables available for analysis were found to influence the risk of colon cancer significantly. Graphs showing the dependence of the instantaneous risk of cancer on the time from onset of IBD and its independence from the latter in the case of colectomy are presented. The use of a unique statistical methodology described for the first time in this setting led us to the somewhat surprising conclusion that transplantation and concomitant use of immunosuppression accelerate the progression of IBD. At the same time, transplantation does not affect the incidence of colorectal cancer. These results confirm the findings of some recent studies and can potentially shed new light on the disease pathogenesis.
Phosphorylation of retinoid X receptor suppresses its ubiquitination in human hepatocellular carcinoma
Authors: Adachi Seiji , Okuno Masataka , Matsushima-Nishiwaki Rie , Takano Yukihiko , Kojima Soichi , Friedman Scott L. , Moriwaki Hisataka , Okano Yukio
Published: August 2002

Retinoid X receptor α (RXRα) has emerged as an important nuclear receptor involved in hepatocarcinogenesis, because its ligand suppresses the development of hepatocellular carcinoma (HCC) in both experimental and clinical studies. We have demonstrated that phosphorylation of RXRα at serine 260 interferes with its function and delays its degradation in cultured human HCC, leading to enhanced cellular proliferation. Here, we show that in normal liver and in nonproliferating hepatocyte cultures, RXRα is unphosphorylated and highly ubiquitinated, rendering it sensitive to proteasome-mediated degradation. On the other hand, phosphoserine 260 RXRα is resistant to ubiquitination and proteasome-mediated degradation in both human HCC tissues and a human HCC cell line, HuH7. In these tissues and cells, serine 260 is phosphorylated by mitogen-activated protein (MAP) kinase. In proliferating normal hepatocytes, similar to HCC cells, RXRα is also phosphorylated at serine 260 and resistant to ubiquitin-mediated degradation by proteasome, but this ubiquitination of RXRα is differentially regulated between HCC cells and normal hepatocytes. In proliferating hepatocytes, 9-cis retinoic acid (9cRA), a ligand to RXRα, suppresses MAP kinase-mediated phosphorylation and thereby enhances ubiquitination of RXRα, whereas it fails to exert these effects in HCC cells. In conclusion, switching of the ubiquitin/proteasome-dependent degradation of RXRα by phosphorylation at serine 260 may be responsible for the aberrant growth of HCC and its suppression by retinoids.
A20 protects mice from D-galactosamine/lipopolysaccharide acute toxic lethal hepatitis
Authors: Arvelo Maria B. , Cooper Jeffrey T. , Longo Christopher , Daniel Soizic , Grey Shane T. , Mahiou Jerome , Czismadia Eva , Abu-Jawdeh Graziella , Ferran Christiane
Published: August 2002

Apoptosis of hepatocytes is a seminal feature of fulminant hepatic failure. We show that the anti-apoptotic protein A20 is upregulated in hepatocytes by pro-inflammatory stimuli and functions to protect from apoptosis and limit inflammation by inhibiting NF-κB. Adenoviral mediated hepatic expression of A20 in BALB/c mice yields an 85% survival rate in the D-galactosamine (D-gal)/lipolysaccharide (LPS) model of acute toxic hepatitis compared with 15% to 20 % in control mice. Expression of A20 preserves normal liver function as assessed by prothrombin time. The protective effect of A20 is independent of tumor necrosis factor (TNF) inhibition. Maintaining high circulating TNF levels may be advantageous for liver regeneration. Our data supports this hypothesis as evidenced by increased proliferating cell nuclear antigen (PCNA) expression in the livers of mice expressing A20 compared with a dominant negative mutant of the TNF receptor (TNF-R), 6 hours following D-gal/LPS administration. In conclusion, these results qualify A20 as part of a physiologic, protective response of hepatocytes to injury and a promising gene therapy candidate for clinical applications aimed at preventing and treating viral and toxic fulminant hepatic failure.
Leptin in hepatic fibrosis: Evidence for increased collagen production in stellate cells and lean littermates of ob/ob mice
Authors: Saxena Neeraj K. , Ikeda Kazuo , Rockey Don C. , Friedman Scott L. , Anania Frank A.
Published: August 2002

Leptin is a 16-kd hormone that mediates a range of metabolic effects by using a transduction pathway from the long form of the leptin receptor, OB-RL, through Janus kinase-signal transducer and activator of transcription (Jak-Stat) signaling components. Leptin is produced by hepatic stellate cells (HSCs) but only following their “activation.” Because activation of stellate cells is a central event in the fibrotic response to liver injury, we hypothesized that leptin may directly stimulate fibrogenesis in activated stellate cells via OB-RL. We analyzed leptin receptors and their signaling partners in a stellate cell line (HSC-T6) as well as in primary stellate cell isolates. We also examined the effect of leptin on stellate cell expression of α2(I) collagen messenger RNA (mRNA) levels by ribonuclease protection analysis (RPA). Finally, we examined the role of leptin in in vivo fibrogenesis by inducing a wounding response in ob/ob mice, which lack functional leptin. HSC-T6 and culture-activated stellate cells expressed OB-RL. Scatchard analysis verified specific binding of leptin to HSCs, with an association constant (Kd) equal to 660 ± 5.8 pmol/L. Exposure of HSCs to leptin resulted in significant increases in α2(I) collagen mRNA expression. Transient transfection with a promoter reporter construct showed a 3-fold increase in α2(I) collagen transgene activity. Leptin stimulated activation of Stat3 in activated HSCs. Finally, lean animals, but not ob/ob littermates, had significant fibrosis as assessed by picrosirius red staining and abundant α-smooth muscle actin staining. In conclusion, these results indicate that leptin is profibrogenic in activated HSCs and can signal via the Jak-Stat pathway. Up-regulation of leptin signaling in liver injury could contribute to enhanced fibrogenesis, particularly in states in which leptin levels are high.
Sustained remission after corticosteroid therapy for type 1 autoimmune hepatitis: A retrospective analysis
Authors: Czaja Albert J. , Menon Narayanan K. V. , Carpenter Herschel A.
Published: August 2002

Autoimmune hepatitis commonly relapses after corticosteroid therapy, and long-term management strategies have been proposed based on the premise that repeated relapses after drug withdrawal are inevitable. Our goal was to determine the frequency that remission can be sustained after its induction and termination of therapy. A total of 107 patients who had entered remission on conventional regimens were assessed for sustained remission after initial treatment and after relapse and re-treatment. Re-treatment strategies included conventional regimens and long-term maintenance schedules. Twenty-two patients (21%) achieved a sustained remission after initial treatment, and 24 of 85 patients who relapsed and were re-treated (28%) had a similar outcome. The probability of a sustained remission was 47% after 10 years of follow-up. Patients who sustained remission after initial therapy were distinguished only by a lower serum γ-globulin level at entry. Conventional re-treatment schedules after relapse were able to induce a sustained remission more commonly then long-term maintenance schedules (59% vs. 12%, P = .00002). In conclusion, patients who respond to initial corticosteroid therapy can achieve a sustained remission after treatment withdrawal or after relapse and re-treatment. All patients are candidates for this outcome, and withdrawal of medication, even during maintenance schedules, is necessary to assess its likelihood.
Bone marrow transplantation in mice leads to a minor population of hepatocytes that can be selectively amplified in vivo
Authors: Mallet Vincent O. , Mitchell Claudia , Mezey Eva , Fabre Monique , Guidotti Jacques-Emmanuel , Renia Laurent , Coulombel Laure , Kahn Axel , Gilgenkrantz Hélène
Published: August 2002

Cell-based therapy may some day be a therapeutic alternative to liver transplantation. Recent observations indicating that hematopoietic stem cells can differentiate into hepatocytes have opened new therapeutic prospects. However, the clinical relevance of this phenomenon is unknown. We have previously developed a strategy based on the protective effect of Bcl-2 against Fas-mediated apoptosis to selectively amplify a small number of hepatocytes in vivo. We now show that this approach can be used to amplify a minor population of bone marrow-derived hepatocytes. Normal mice were transplanted with unfractionated bone marrow cells from transgenic animals expressing Bcl-2 under the control of a liver-specific promoter. Recipients were then submitted to weekly injections of the anti-Fas antibody, Jo2. Upon sacrifice, the liver of the recipients showed bone marrow-derived clusters of mature hepatocytes expressing Bcl-2, which showed that the hepatocyte progeny of a genetically modified bone marrow can be selectively expanded in vivo. In contrast, no Bcl-2 expression could be detected without the selective pressure of Jo2, suggesting that differentiation of bone marrow cells into mature hepatocytes is very inefficient under physiologic conditions. We conclude that a selection strategy will be required to achieve a therapeutic level of liver repopulation with bone marrow-derived hepatocytes.
Synergistic effect of basic fibroblast growth factor and vascular endothelial growth factor in murine hepatocellular carcinoma
Authors: Yoshiji Hitoshi , Kuriyama Shigeki , Yoshii Junichi , Ikenaka Yasuhide , Noguchi Ryuichi , Hicklin Daniel J. , Huber James , Nakatani Toshiya , Tsujinoue Hirohisa , Yanase Koji , Imazu Hiroo , Fukui Hiroshi
Published: August 2002

The growth of any solid tumor depends on angiogenesis. Among the known angiogenic factors, basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF), are potent and representative factors involved in tumor development. It has been reported that bFGF and VEGF showed a synergistic effect in both in vitro and in vivo angiogenesis. However, the interaction of these factors on tumor development and angiogenesis, including hepatocellular carcinoma (HCC), has not yet been elucidated. In this study, we examined the combined effect of bFGF and VEGF overexpression by means of a combination of a retroviral tetracycline (tet)-regulated (Retro-Tet) gene expression system, which can manipulate the gene expression in vivo by providing tet in the drinking water, and a conventional plasmid gene expression system. In an allograft study, bFGF and VEGF overexpression synergistically increased tumor growth and angiogenesis in the murine HCC cells. This synergistic effect also was found in established tumors. VEGF messenger RNA (mRNA) expression in the tumor was increased 3.1-fold by bFGF-overexpression, and the bFGF-induced tumor development was significantly attenuated by treatment with KDR/Flk-1 neutralizing monoclonal antibody. In conclusion, these results suggest that bFGF synergistically augments VEGF-mediated HCC development and angiogenesis at least partly by induction of VEGF through KDR/Flk-1.