bluuebunny/crossref_metadata_2025 huggingface dataset:
Reactivation of Cytomegalovirus in Patients With Cirrhosis: Analysis of 122 Cases
Authors: Tanaka Shinji , Toh Yasushi , Minagawa Hiroko , Mori Ryoichi , Sugimachi Keizo , Minamishima Yoichi
Published: March 2007

Human cytomegalovirus causes severe and often fatal infections in immunocompromised patients. After organ transplantation cytomegalovirus in peripheral blood mononuclear cells is thought to be activated by alloreaction and to spread because of immunosuppression, and it may cause endogenous cytomegalovirus diseases. Patients with cirrhosis, one group of candidates for liver transplantation, often show various grades of immunosuppression before transplantation. To evaluate the status of cytomegalovirus infection in cirrhotic patients and its relevance to the degree of immunosuppression, we examined the presence of cytomegalovirus in mononuclear cells by polymerase chain reaction and immunocytochemical analysis. We studied 122 patients with definite cirrhosis and 43 normal volunteers. All cirrhotic patients (100%) and 40 (93%) of 43 normal controls were seropositive for cytomegalovirus. Cytomegalovirus DNA was detected by polymerase chain reaction in 77 (63.1%) of 122 seropositive cirrhotic patients, but in only 1 (2.5%) of 40 seropositive normal controls (p < 0.01). Cytomegalovirus antigen could not be detected in mononuclear cells by immunocytochemical staining with monoclonal antibodies. Cytomegalovirus DNA—positive patients have a greater impairment of liver function than do cytomegalovirus DNA—negative patients; this fact is manifested by delayed indocyanine green retention rates and elevated serum bilirubin levels (p < 0.05). Lymphocyte proliferative response induced by phytohemagglutinin and natural killer cell activity were also significantly lower in cytomegalovirus DNA—positive patients as compared with cytomegalovirus DNA—negative patients (p < 0.01). Our data suggest that the reactivation of cytomegalovirus may have already occurred in patients with cirrhosis before transplantation.
Preformed Lymphocytotoxic Antibodies: the Effects of Class, Titer and Specificity on Liver Vs. Heart Allografts
Authors: Furuya Tomoki , Murase Noriko , Nakamura Kenjiro , Woo Jacky , Todo Satoru , Demetris Anthony J. , Starzl Thomas E.
Published: March 2007

The effect on liver and heart allograft survival (ACI rats to Lewis rats) was studied after three methods of recipient presensitization and after different intervals between sensitization and transplantation. With comparable lymphocytotoxic antibody titers, liver allografts always survived longer than heart grafts. The titer, class and specificity of the antibodies varied with the method of sensitization. Four skin grafts produced IgG and IgM lymphocytotoxic antibody titers of 1:2,000 to 4,000. The IgG fraction was shown to have hepatic vascular endothelial specificity by indirect immunofluorescence. These primed recipients hyperacutely rejected both heart and liver allografts, which showed vascular deposition of IgG antibodies. Survival of either kind of graft was inversely proportional to the lymphocytotoxic antibody titer and length of time after placement of the last skin graft. Presensitization with a single heterotopic heart graft produced an even higher mixed IgG and IgM lymphocytotoxic antibody titer of 1:8,000 but with less IgG vascular endothelial specificity. These animals also hyperacutely rejected heart or liver grafts with tissue deposition of IgG but less consistently and with a weaker correlation with lymphocytotoxic antibody titers and time after sensitization. Sensitization with two pretransplant blood transfusions produced the lowest titer (1:500 to 1,000) and the least IgG vascular endothelial specificity. Liver allograft survival was routinely enhanced in these animals, and little effect was seen on heart grafts. Collectively, the experiments showed that the liver is not only resistant to antibody–mediated rejection relative to the heart but is more easily enhanced. A more precise characterization of preformed antibodies may increase the ability to predict the outcome of liver transplantation in sensitized recipients or guide pretransplant strategies to foster enhancing antibodies.
Increase of Cytokeratin D During Liver Regeneration: Association With the Nuclear Matrix
Authors: Bastos Ricardo , Engel Pablo , Pujades Cristina , Falchetto Rocco , Aligué Rosa , Bachs Oriol
Published: March 2007

An increase of a 45 kD protein (p45) in the nuclear matrix has been observed when rat liver cells were proliferatively activated in vivo by a partial hepatectomy. The maximal levels of the association of p45 with the nuclear matrix have been detected 24 hr after hepatectomy just at the time when DNA replication is also maximal. By amino acid sequence analysis, immunoblotting and immunocytochemical methods, it has been demonstrated that p45 is identical to rat cytokeratin D. Immunogold staining of nuclear matrixintermediate filament preparations from cultured hepatocytes indicated that p45 is associated with cytoskeletal filaments that are strongly interconnected to the lamina, whereas no intranuclear localization of the protein has been detected. With an overlay assay a specific binding of labeled p45 to two nonidentified high–molecular weight proteins and also to lamin B has been observed. Northern blot analysis revealed a biphasic pattern of expression of the messenger RNA for cytokeratin D during liver regeneration. A sharp increase in the messenger RNA levels occurred in the prereplicative phase of liver regeneration a few hours before the accumulation of the protein in the nuclear matrix fraction, and a second peak occurred 48 hr after partial hepatectomy.
Hemodynamic Effects of Calibrated Stenosis of the Superior Mesenteric Artery in Conscious Rats With Portal Vein Stenosis
Authors: Soubrane Olivier , Braillon Alain , Lin Han-Chieh , Kleber Gerhardt , Lebrec Didier
Published: March 2007

Because superior mesenteric arterial blood flow is increased in portal hypertension and plays a role in elevated portal pressure, mechanical reduction of artery diameter should induce decreases in portal pressure and superior mesenteric arterial blood flow. In this study, calibrated superior mesenteric artery stenosis (induced with a 22–gauge needle) was performed in rats simultaneously with portal vein stenosis or 2 wk after creation of portal vein stenosis. Hemodynamic studies were performed 3 wk after induction of portal vein stenosis in conscious, unrestrained rats. At that time, neither weight loss nor digestive tract alterations were observed in rats with arterial stenosis. In neither group of rats with arterial stenosis was portal tributary blood flow significantly different from that of normal rats; nor was it significantly lower than in rats with portal vein stenosis without arterial stenosis. In both groups of rats with arterial stenosis, portal pressure was significantly lower (12.1 ± 1.6 mm Hg and 12.5 ± 1.8 mm Hg, respectively) than in rats subjected to portal vein stenosis (15.4 ± 1.5 mm Hg) but significantly higher than in controls (7.2 ± 1.0 mm Hg). In rats with arterial stenosis, cardiac index was also significantly lower than that in rats with portal vein stenosis but higher than that in controls. In conclusion, this study shows that both early and late superior mesenteric artery stenosis significantly reduce the degree of portal hypertension and the hyperkinetic state of rats with extrahepatic portal hypertension. Thus we can speculate that superior mesenteric artery stenosis might provide a new therapeutic approach for portal hypertension.
Role of Mesenchymal Cell Populations in Porcine Serum–Induced Rat Liver Fibrosis
Authors: Bhunchet Ekapot , Wake Kenjiro
Published: March 2007

The role of liver mesenchymal cell populations in porcine serum–induced rat liver fibrosis were studied morphologically and immunohistochemically. Fiveweek–old rats were intraperitoneally injected with porcine serum twice a week and examined at various intervals between 3 and 24 wk after the initial injection. At an early phase, numbers of fibroblasts and extracellular matrix increased in the walls of central veins and in portal and capsular connective tissues. In the walls of central veins, the number of “second–layer cells” (i.e., the fibroblasts located at the second layer of the wall) increased. Connective tissue septa, accompanying some fibroblasts, extended from these interstitial tissues into the hepatic parenchyma, and their foremost edges came into direct contact with the perisinusoidal stellate cells. The sinusoids adjacent to the newly formed septa collapsed and later disappeared; this process resulted in the formation of hepatic limiting plates along the septa. At a more advanced stage, the interstitial fibroblasts and septal cells–which were derived from interstitial fibroblasts and the stellate cells – increased and became multilayered, constructing three–dimensional cell networks. These networks, together with increased collagen fibrils and elastic fibers, constitute the fibrotic dense connective tissue.

In the control rat, smooth muscle cells were positive on vimentin, desmin and smooth muscle–α–actin staining. The stellate cells, second–layer cells, capsular and portal fibroblasts were shown to be vimentin and desmin positive and smooth muscle–α–actin negative. In the fibrotic liver, septal(fibroblastic) cells were vimentin and desmin positive and smooth muscle–α–actin negative.

We conclude that not only the perisinusoidal stellate cells but also the interstitial fibroblasts, including the second–layer cells, play substantial role in the development of porcine serum–induced septal fibrosis in rat liver.
Cytoprotective Effect of Somatostatin in A Rat Model of Hepatic Ischemic Reperfusion
Authors: Landa Ignacio , Arias Javier , Gómez Manuel , Quadros Manuel , Moreno Ana , Balibrea José Luis
Published: March 2007

To evaluate the possible cytoprotective effect of somatostatin in hepatic ischemic reperfusion injury we used 75 adult male Wistar rats randomly separated into four groups. The rats in group 1 underwent sham operations, and those in group 2 underwent resection of the median and left lateral lobes. The rats in group 3 underwent a 90–min period of ischemia of the right lateral lobe, which we induced by temporarily occluding the right portal vein and the hepatic artery. On restoration of flow to the right lateral lobe, the median and left lateral lobes (about 80% of total liver mass) were excised (and later assayed for thymidine kinase basal activity). The rats in group 4 were given the same treatment as group 3 rats except that a saline solution of somatostatin was infused at a rate of 2 μg/min starting at laparotomy and lasting 24 hr. The rats in groups 1, 2 and 3 were infused with saline. Rats in groups 2, 3 and 4 were randomly assigned to two subgroups; one of these subgroups was observed until spontaneous death, and rats in the other group were killed 24 hr after the procedure for obtaining peripheral blood and liver samples. Somatostatin infusion improved the animals' survival rates from 0% (group 3) to 60% (group 4) (p < 0.05) and decreased bilirubin levels (0.78 ± 0.17 mg/dl, n = 15 [group 4] vs. 1.69 ± 0.04 mg/dl, n = 15 [group 3]; p < 0.05). Hepatectomy alone (group 2) increased thymidine kinase activity from a basal level of 164.4 ± 6.9 pmol/mg to a level of 253.6 ± 7.6 pmol/mg of protein after 24 hr (n = 10, p < 0.001). In ischemic reperfusion groups (3 and 4) thymidine kinase activity was not modified. Our results suggest a cytoprotective effect for somatostatin. Although the exact mechanism of this action at the cellular level is unknown, it seems to be unrelated to an early increment in hepatocyte regeneration.
Resident Mast Cells Are the Main Initiators of Anaphylactic Leukotriene Production in the Liver
Authors: Hagmann Wolfgang , Hacker Hans Jörg , Buchholz Ulrike
Published: March 2007

During anaphylaxis the sensitized liver can have substantial capacity for leukotriene production. However, the intrahepatic cellular source for these potent eicosanoid mediators has been unclear so far. We therefore analyzed the appropriate role of resident liver cells in organ–specific generation of leukotrienes by immunohistochemical localization of 5–lipoxygenase, by measurement of cysteinyl leukotriene production in animals or isolated livers and by histochemical monitoring of mast cells in rat, guinea pig and mouse livers, respectively. During anaphylaxis in vivo, these species all generated large amounts of leukotrienes. Immunohistochemistry with rat liver demonstrated resident mast cells as the predominant cell type in liver containing 5–lipoxygenase. Rat and guinea pig livers contained numerous mast cells and produced substantial amounts of leukotrienes on antigen challenge; in contrast, mouse livers neither showed detectable mast cells nor generated leukotrienes when stimulated analogously. Infusion of histamine or serotonin (1 μmol/L each) or of the degranulating substance P (8 μmo/L) did not elicit leukotriene generation in rat livers. Furthermore, substantial degranulation of liver mast cells by compound 48/80 (0.5 mg/kg body mass) was paralleled by only modest leukotriene formation (63 ± 10 pmol in bile/kg body mass/30 min). These results indicate that during anaphylaxis mast cells are the main intrahepatic cells initiating leukotriene production and that such leukotriene generation is likely to be independent of mast cell degranulation or the release of histamine or serotonin.
Rapid and Marked Induction of Hepatocyte Growth Factor During Liver Regeneration After Ischemic or Crush Injury
Authors: Hamanoue Masahiro , Kawaida Kouichi , Takao Sonshin , Shimazu Hisaaki , Noji Sumihare , Matsumoto Kunio , Nakamura Toshikazu
Published: March 2007

Liver injuries induced by ischemia or physical trauma are characterized by noninflammatory damage frequently observed in a clinical setting. When the liver of rats was injured by ischemic treatment or physical crushing, necrotic tissue degeneration occurred in several sites of lobulus within 24 hr. Hepatocyte growth factor, a potent mitogen for adult rat hepatocytes in primary culture, was markedly induced in the livers of rats injured by ischemia or physical trauma. In both cases, the hepatocyte growth factor messenger RNA level in the injured liver reached about 10 to 20 times that of the normal level during 12 to 24 hr after liver injury. The increase in hepatocyte growth factor messenger RNA correlated well with the degree of liver damage as evaluated by serum ALT activity in the sera of rats. In situ hybridization showed that hepatocyte growth factor messenger RNA expression occurs in nonparenchymal liver cells, primarily in Kupffer cells of the ischemic liver. After the increase of hepatocyte growth factor messenger RNA in the injured liver, a marked compensatory hepatocyte DNA synthesis occurred 48 to 72 hr after these treatments. These results suggest that hepatocyte growth factor acts as a hepatotropic factor for liver regeneration after noninflammatory liver damage caused by ischemia and physical crush, probably through a paracrine mechanism.
Transmission of Hepatitis C: Sexual, Vertical or Exclusively Blood–Borne?
Authors: Bach Nancy , Bodenheimer Henry C.
Published: March 2007

Serum samples from eight pregnant women and their offspring were studied by nested polymerase chain reaction (PCR) for detection of hepatitis C virus (HCV) RNA to evaluate mother–to–child transmission of this virus. The mothers were all infected with human immunodeficiency virus (HIV); none showed symptoms of HCV infection. Anti–HCV antibodies were tested for by recombinant immunoblot assay. HCV viral sequences were found in five of the mothers and four of eight children, three of them at birth. Viremia was persistent in one infant who had chronic transaminase elevation and persistently remained anti–HCV–positive. The other three babies had intermittent viremia; all were asymptomatic and lost anti–HCV antibodies during follow–up. This loss of antibodies was also observed in PCR–negative infants. Thus, these results demonstrate transmission of HCV from mother to child by women coinfected with HCV and HIV. They indicate the usefulness of PCR for direct and early detection of HCV viremia in neonates.

Body fluids from 14 patients with chronic hepatitis C were analyzed for the presence of hepatitis C viral RNA using the polymerase chain reaction. Nucleic acids were extracted from serum, saliva, and semen in guanidinium thiocyanate, subjected to reverse transcription, and then amplified by a double polymerase chain reaction technique using “nested” primers from the highly conserved 5′ noncoding region of the hepatitis C virus genome. Hepatitis C viral RNA was found in the serum of all patients in titers ranging between 10-1 and 10-3. The hepatitis C viral genome was not detected in any saliva or semen sample. These findings suggest that body fluids of patients with chronic hepatitis C are rarely, if ever, contaminated with the hepatitis C virus. This may help to explain the infrequent transmission of this disease by sexual or close physical contact.
Adh1, 2 And 3: Genes Whose Times Have Come
Authors: Crabb David W.
Published: March 2007

The human class I alcohol dehydrogenase (ADH) gene family consists of ADH1, ADH2, and ADH3, which are sequentially activated in early fetal, late fetal, and postnatal liver, respectively. Analysis of ADH promoters revealed differential activation by several factors previously shown to control liver transcription. In cotransfection assays, the ADH1 promoter, but not the ADH2 or ADH3 promoter, was shown to respond to hepatocyte nuclear factor 1 (HNF–1), which has previously been shown to regulate transcription in early liver development. The ADH2 promoter, but not the ADH1 or ADH3 promoter, was shown to respond to CCAAT/enhancer–binding protein α (C/EBPα), a transcription factor particularly active during late fetal liver and early postnatal liver development. The ADH1, ADH2, and ADH3 promoters all responded to the liver transcription factors liver activator protein (LAP) and D–element–binding protein (DBP), which are most active in postnatal liver. For all three promoters, the activation by LAP or DBP was higher than that seen by HNF–1 or C/EBPα, and a significant synergism between C/EBPα and LAP was noticed for the ADH2 and ADH3 promoters when both factors were simultaneously cotransfected. A hierarchy of ADH promoter responsiveness to C/EBPα and LAP homo– and heterodimers is suggested. In all three ADH genes, LAP bound to the same four sites previously reported for C/EBPα (i.e., —160, — 120, — 40, and — 20 bp), but DBP bound strongly only to the site located at —40 bp relative to the transcriptional start. Mutational analysis of ADH2 indicated that the —40 bp element accounts for most of the promoter regulation by the bZIP factors analyzed. These studies suggest that HNF–1 and C/EBPα help establish ADH gene family transcription in fetal liver and that LAP and DBP help maintain high–level ADH gene family transcription in postnatal liver.
Prevalence of Hepatitis C Virus Infection in Hemodialysis Patients: A Longitudinal Study Comparing the Results of RNA and Antibody Assays
Authors: Chan Tak Mao , Lok Anna Suk Fong , Cheng Ignatius Kum Po , Chan Rachel Tzun
Published: March 2007

We longitudinally studied 51 patients from two hemodialysis centers to determine the prevalence of hepatitis C virus infection in hemodialysis patients. Serum samples were tested for antibody to HCV by first- and second- generation enzyme immunoassays and for hepatitis C virus RNA by nested polymerase chain reaction assay. Antibody to hepatitis C virus was detected in the initial serum samples by first-generation enzyme immunoassay and second-generation enzyme immunoassay in 6 (11.8%) and 11 (21.6%) patients, respectively. First-generation enzyme immunoassay had a false-positive rate of 33.3% and a false-negative rate of 63.6%. Hepatitis C virus RNA was found in eight second-generation enzyme immunoassay-positive patients (72.7%) and in one patient negative for antibody to hepatitis C virus (2.5%) giving an overall positivity rate of 17.6%. After 19 mo, antibody to hepatitis C virus was detected in 15 patients (29.4%) on second-generation enzyme immunoassay; hepatitis C virus RNA was found in 13 patients (25.5%). Hepatitis C virus markers persisted in all 12 patients with initial evidence of hepatitis C virus infection. Three patients acquired hepatitis C virus infection during the interim, giving a new infection rate of 4.9% per patient-year. Antibody to hepatitis C virus, hepatitis C virus RNA or both was detected in 55.6% of patients with biochemical changes suggestive of non-A, non-B hepatitis. Of the 15 antibody to hepatitis C virus, second-generation enzyme immunoassay-positive patients, 66.7% had persistently normal serum transaminase levels. In summary, hepatitis C virus infection is common among hemodialysis patients. First-generation enzyme immunoassay is an unreliable assay for antibody to hepatitis C virus in these patients. We found good correlation between the results of antibody to hepatitis C virus detection on second-generation enzyme immunoassay and of hepatitis C virus RNA by nested polymerase chain reaction and found that serum transaminase level is a poor indicator of hepatitis C virus infection in hemodialysis patients. (Hepatology 1993;17:5-8.)
The Alcohol-altered Liver Membrane Antibody and Hepatitis C Virus Infection in the Progression of Alcoholic Liver Disease
Authors: Takase Shujiro , Tsutsumi Mikihiro , Kawahara Hiromu , Takada Nobuo , Takada Akira
Published: March 2007

Progression of alcoholic liver disease is closely related to drinking habits. However, prognosis of alcoholic liver disease is not determined just by drinking habits, but also by other factors. In this study, the roles of alcohol-altered liver membrane antibody and hepatitis C virus infection were analyzed in alcoholic patients who were followed up for various lengths of time. Serial changes of liver histological appearance were analyzed in 39 patients with alcoholic liver disease who were followed for long periods (49.7 ± 34.3 mo) and who underwent liver biopsy at least two times. Prognoses of 35 patients with alcoholic cirrhosis who were followed for more than 1 yr were also evaluated. Development of cirrhosis in alcoholic liver disease was significantly higher in the alcohol-altered liver membrane antibody-positive patients than in the patients negative for this antibody. On the other hand, hepatitis C virus markers were not related to development of cirrhosis. However, hepatocellular carcinoma developed more frequently in the hepatitis C virus marker-positive patients. In patients with cirrhosis, the cumulative rates of hepatocellular carcinoma development were significantly higher in the hepatitis C virus marker-positive patients than in the marker-negative patients. Cumulative survival rates in the hepatitis C virus marker-positive patients were significantly lower than rates in the hepatitis C virus marker-negative patients, even in noncancer patients. However, such differences were not observed in the alcohol-altered liver membrane antibody-positive and alcohol-altered liver membrane antibody-negative cirrhotic patients. These results suggest that alcohol altered liver membrane antibody is a factor related to the progression of alcoholic liver disease and that hepatitis C virus infection is a determining factor for development of hepatocellular carcinoma and for prognosis of cirrhosis in patients who continue to drink. (Hepatology 1993;17:9-13.)
Experimental Hepatitis Induced by Ethanol After Immunization with Acetaldehyde Adducts
Authors: Yokoyama Hirokazu , Ishii Hiromasa , Nagata Shigeyuki , Kato Shinzo , Kamegaya Kiyotaka , Tsuchiya Masaharu
Published: March 2007

We produced hepatitis in guinea pigs by immunization with acetaldehyde adducts and ethanol treatment. Human hemoglobin-acetaldehyde adducts were prepared without any reducing agents and affinity purified with polyclonal antibodies against acetaldehyde adducts. Female guinea pigs were immunized with the adducts and were simultaneously given ethanol for 40 days. These treatments induced hepatic necrosis with infiltration of mononuclear cells in the hepatic lobules. The formation of the lymphoid follicle was also observed in severe cases. These changes were accompanied by the elevation of serum AST and lactic dehydrogenase activities and titers of circulating antibodies against acetaldehyde adducts. By contrast, the combination of ethanol and immunization with unmodified hemoglobin produced only fatty change of the liver, and animals immunized with the adducts alone had minimal inflammatory changes of the liver. Peripheral blood lymphocytes obtained from the animals with hepatitis were shown to be stimulated by acetaldehyde adducts to a significantly greater degree than those from control animals who received nothing, ethanol alone or ethanol and unmodified hemoglobin. These results suggest that the immune response to acetaldehyde adducts may be involved, at least partly, in the pathogenesis of inflammation observed in alcoholic liver disease. (Hepatology 1993;17:14-19.)
Persistence of Hepatitis B and Hepatitis C Viral Genomes in Primary Liver Cancers from HBsAg-Negative Patients: A Study of a Low-endemic Area
Authors: Paterlini Patrizia , Driss Françoise , Nalpas Bertrand , Pisi Emilio , Franco Dominique , Berthelot Pierre , Bréchot Christian
Published: March 2007

The role of HBV and HCV in the course of primary liver cancer in patients who are negative for HBsAg has been debated. Using a combination of serological and polymerase chain reaction assays, we investigated the association between HCV and HBV infections and primary liver cancer in 24 HBsAg-negative patients living in France. The presence of HCV RNA and HBV DNA sequences was tested for in serum and in tumorous and nontumorous liver samples. Twelve patients had anti-HCV, and 11 patients had anti-HBs and/or anti-HBc. HCV RNA sequences were found in the serum samples of all anti-HCV-positive patients and none of the patients who were negative. Patients with HCV viremia had HCV RNA genomic sequences and presumed replicative intermediates in both tumorous and nontumorous specimens. Sequence analysis of a hypervariable region in the E2/NS1 gene of HCV showed significant variations between the viral molecules isolated from the nontumorous, tumorous and serum samples. This eliminated the hypothesis of the contamination of the tumor by nontumorous cells and serum particles and assessed that liver tumor cells did contain HCV RNA genomes.

Eleven of 22 patients tested had HBV DNA in the serum; 5 patients were anti-HBc positive and anti-HBs positive. Patients with HBV viremia had HBV DNA sequences in both tumorous and nontumorous liver specimens. Selective loss of part of the HBV genome in the tumorous tissue of two of these patients suggested HBV DNA persistence in clonally expanded malignant cells. Only 4 of the 22 patients were negative for both viruses. Our results show that HBsAg-negative hepatocellular cancer in France is associated with chronic HBV or HCV infection and, in some cases, both; these findings are consistent with an etiological role for HBV and HCV in HCC that develops in cirrhotic patients living in areas of low prevalence. (Hepatology 1993;17:20-29.)
Expression and Hypomethylation of α-Fetoprotein Gene in Unicentric and Multicentric Human Hepatocellular Carcinomas
Authors: Peng Shian-Yang , Hsu Hey-Chi , Lai Po-Lin , Tsung Po-Tah , Chu Juan-Shiu , Lee Po-Huang , Chen Ding-Shin
Published: March 2007

The messenger RNA and DNA methylation of the α-fetoprotein gene were studied in 101 resected primary hepatocellular carcinomas, of which 93 were unicentric and 8 were multicentric. Fifty-five were 5 cm or less in diameter (small) and 46 were more than 5 cm in diameter (large). In 48.5% of the cases, we detected α-fetoprotein messenger RNA in hepatocellular carcinomas, more frequently in large (60.9%) than in small (38.2%; p < 0.00001) but not in any of the nontumorous livers. The α-fetoprotein messenger RNA was detected in 83%, 70% and 6.8% of patients with serum α-fetoprotein levels of 320 ng/ml or more, 100 to 319 ng/ml and less than 100 ng/ml, respectively. This finding suggests that α-fetoprotein gene expression in hepatocellular carcinoma contributes to the serum α-fetoprotein elevation in patients with hepatocellular carcinoma. α-Fetoprotein messenger RNA appeared as a major band of 2.4 kb, with two minor species of about 6.5 and 3.6 kb in the hepatocellular carcinoma and the fetal liver. Hypomethylation of the 5′ end of the α-fetoprotein gene was detected in 78.3% of hepatocellular carcinomas expressing α-fetoprotein messenger RNA but infrequently (16.7%) in hepatocellular carcinomas with no detectable α-fetoprotein messenger RNA (p < 0.0003). This finding suggests that hypomethylation at the 5′ region of the gene is associated with α-fetoprotein gene reexpression in hepatocellular carcinoma. The α-fetoprotein gene expression helped to differentiate unicentric from multicentric hepatocellular carcinomas and to identify other hidden α-fetoprotein-secreting hepatocellular carcinomas. The α-fetoprotein gene expression occurred more often in patients younger than 30 yr old (100% vs. 41.2%; p < 0.002), in HBsAg-seropositive patients (53.2% vs. 33.3%; p < 0.03) and in patients with poorly differentiated hepatocellular carcinoma (56% vs. 23.1%; p < 0.003). Patients with unicentric small hepatocellular carcinomas expressing α-fetoprotein messenger RNA or serum α-fetoprotein elevation had a worse 2-yr survival rate than those with neither α-fetoprotein messenger RNA expression nor serum α-fetoprotein elevation (70.6% vs. 94.7%; p < 0.02). We conclude that the α-fetoprotein gene expression in hepatocellular carcinoma possesses biological significance. (Hepatology 1993;17:35-41.)
Orthotopic Liver Transplantation in Two Adults with Niemann-Pick and Gaucher's Diseases: Implications for the Treatment of Inherited Metabolic Disease
Authors: Smanik Elizabeth J. , Tavill Anthony S. , Jacobs Gretta H. , Schafer Irwin A. , Farquhar Lou , Weber Fredrick L. , Mayes James T. , Schulak James A. , Petrelli Mary , Zirzow Gregory C. , Oliver Katharine L. , Miller STEPHEN P. F. , Brady Roscoe O.
Published: March 2007

Two adults were seen with cirrhosis caused by different lipid storage diseases. A 42-yr-old woman with Niemann-Pick disease type B had marked hepatomegaly, ascites and recent variceal bleeding. Her evaluation showed chronic bilateral pulmonary infiltrates, multiple stigmata of chronic liver disease including the recent cessation of menses, diuretic-resistant sterile ascites, hepatic encephalopathy and variceal bleeding. Five percent of normal sphingomyelinase activity was measured in peripheral leukocytes. A 42-yr-old man with Gaucher's disease and a history of bilateral hip replacements presented with hepatomegaly, jaundice, refractory ascites and renal insufficiency. His evaluation showed 20% to 23% of normal glucocerebrosidase activity in peripheral leukocytes. Both patients underwent orthotopic liver transplantation with resolution of all aspects of decompensated liver function. Assessment of the underlying metabolic defect before and 6 to 14 mo after transplantation showed that after transplantation the patient with Niemann-Pick disease had above normal hepatic sphingomyelinase activity, a less-marked increase in peripheral leukocyte enzyme activity and lower than normal hepatic sphingomyelin and cholesterol content. In contrast, the patient with Gaucher's disease had only a 61% increase in hepatic glucocerebrosidase activity but had an elevated hepatic glucocerebroside content that was only 15% of the pretransplant level and decreased peripheral leukocyte enzyme levels. These findings suggest that variable relationships may exist between posttransplant hepatic and peripheral leukocyte enzyme activities in the different lipidoses, which may have implications for recurrence of glycolipid-induced liver damage. (Hepatology 1993;17:42-49.)
Fucosylation Index of α-Fetoprotein, a Possible Aid in the Early Recognition of Hepatocellular Carcinoma in Patients with Cirrhosis
Authors: Aoyagi Yutaka , Saitoh Atsushi , Suzuki Yasufumi , Igarashi Kentarou , Oguro Makoto , Yokota Tsuyoshi , Mori Shigeki , Suda Takeshi , Asakura Hitoshi , Isemura Mamoru
Published: March 2007

We report here on three patients with cirrhosis for whom an early recognition of hepatocellular carcinoma was made possible by the measurement of the degree of fucosylation (fucosylation index) of α-fetoprotein. Increased levels of this index associated with a moderate increment of serum concentration of α-fetoprotein were observed in three patients with cirrhosis who showed no indication of hepatocellular carcinoma by several imaging modalities. Four years after the onset of an increase in the fucosylation index, small hepatocellular carcinoma with a tumor diameter less than 2 cm was revealed in case 1. In cases 2 and 3, small hepatocellular carcinomas were detected 24 mo and 9 mo, respectively, after the first sign of the increase in the index. However, the development to hepatocellular carcinoma was not detected in five patients with cirrhosis in whom continuous increments of serum concentration of α-fetoprotein with low levels of fucosylation index were observed during the prospective follow-up from 3 to 9 yr. These findings indicated that the fucosylation index of α-fetoprotein can be used as an aid in an early recognition of hepatocellular carcinoma, especially in patients with cirrhosis during the follow-up process in which the moderate increment of serum concentration of α-fetoprotein is noted. (Hepatology 1993;17:50-52.)
Effect of Dipyridamole on Kidney Function in Cirrhosis
Authors: Llach Josep , Ginès Pere , Arroyo Vicente , Salmerón Joan Manuel , Ginès Angels , Rodés Joan , Jiménez Wladimiro , Gaya Joan , Rivera Francisca
Published: March 2007

Adenosine is a potent endogenous renal vasoconstrictor. To investigate the sensitivity of the renal circulation to adenosine in cirrhosis, we evaluated kidney function and vasoactive hormones in 20 patients with cirrhosis before and after administration of dipyridamole (0.4 mg/kg, intravenously), a drug that increases extracellular levels of adenosine. In patients with ascites and increased plasma renin activity (6.9 ± 4.0 ng/ml hr [mean ± S.D.]) (n = 7), dipyridamole induced marked reductions in renal plasma flow (from 623 ± 294 to 374 ± 188 ml/min, p = 0.03), glomerular filtration rate (from 89 ± 22 to 48 ± 16 ml/min, p = 0.009), urine volume (from 7.1 ± 2.1 to 1.5 ± 1.1 ml/min, p = 0.0001), free water clearance (from 4.0 ± 1.7 to 0.4 ± 0.6 ml/min, p = 0.001) and sodium excretion (from 28 ± 36 to 7 ± 15 μEq/min, p = 0.05) in the absence of changes in arterial pressure, plasma renin activity and levels of aldosterone, norepinephrine and antidiuretic hormone. In patients without ascites (n = 5) and in patients with ascites and normal plasma renin activity (0.9 ± 0.5 ng/ml hr) (n = 8), renal plasma flow and glomerular filtration rate did not change significantly after dipyridamole administration, whereas excretion of sodium and free water was reduced. These results indicate that in cirrhotic patients with ascites and overactivity of the renin-angiotensin system, dipyridamole induces renal vasoconstriction in the absence of changes in systemic hemodynamics, suggesting that these patients are particularly sensitive to the renal vasoconstrictor effect of endogenous adenosine. (Hepatology 1993;17:59-64.)
Vanishing Bile Duct Syndrome: A Possible Mechanism for Intrahepatic Cholestasis in Hodgkin's Lymphoma
Authors: Hubscher Stefan G. , Lumley Matthew A. , Elias Elwyn
Published: March 2007

A syndrome of idiopathic intrahepatic cholestasis occurs in some patients with Hodgkin's lymphoma. The underlying mechanism is poorly understood. In this paper we describe three patients with Hodgkin's lymphoma in whom severe intrahepatic cholestasis of unknown pathogenesis developed. In two cases jaundice was the presenting symptom; all three patients died with intractable liver damage. The three patients were initially thought to have idiopathic Hodgkin's-associated cholestasis, but subsequent review of histological material revealed advanced vanishing bile duct syndrome in addition to severe cholestasis. Ten liver specimens were obtained from 4 to 97 wk after the onset of jaundice (seven needle biopsies, one wedge biopsy, two postmortem livers). In seven liver specimens taken within 30 wk of the onset of jaundice, portal tracts characteristically had a “hurned-out” appearance without secondary periportal changes related to chronic cholestasis. Three biopsy specimens obtained from one of the patients more than 1 yr after the onset of jaundice showed evidence of progressive periportal damage in the form of fibrous expansion, marginal ductular proliferation and copper-associated protein deposition. More than 80% of small portal tracts lacked recognizable bile ducts in the final liver specimens obtained from the three patients. These observations suggest that Hodgkin's lymphoma should be included in the list of diseases associated with loss of intrahepatic bile ducts. The possibility of a vanishing bile duct syndrome should be considered in the differential diagnosis of unexplained intrahepatic cholestasis in patients with Hodgkin's disease. (Hepatology 1993;17:70-77.)
Nω-Nitro-L-arginine Administration Corrects Peripheral Vasodilation and Systemic Capillary Hypotension and Ameliorates Plasma Volume Expansion and Sodium Retention in Portal Hypertensive Rats
Authors: Lee Fa-Yauh , Colombato Luis A. , Albillos Agustin , Groszmann Roberto J.
Published: March 2007

In portal hypertensive states, peripheral vasodilation leads to sodium retention and plasma volume expansion. Nω-nitro-L-arginine, a specific biosynthesis inhibitor of the vasodilator nitric oxide, has been shown to acutely reverse peripheral vasodilation and the vascular hyporesponsiveness to endogenous and exogenous vasoconstrictors observed in portal hypertensive rats. This study investigated whether Nω-nitro-L-arginine treatment in portal hypertensive rats prevents peripheral vasodilation and therefore ameliorates plasma volume expansion and sodium retention. For 2 days before partial portal vein ligation or sham operation and then continuously for 4 days after the operation, animals received either placebo (0.9% saline) or Nω-nitro-L-arginine (˜2 μg/kg/min) intravenously through a subcutaneously implanted Alzet osmotic pump (model 2ML1; Alza, Palo Alto, CA). In portal hypertensive rats, Nω-nitro-L-arginine treatment significantly increased mean arterial pressure (placebo vs. Nω-nitro-L-arginine, 123 ± 4 vs. 150 ± 2 mm Hg, respectively; p < 0.001) and systemic vascular resistance (3.8 ± 0.2 vs. 5.6 ± 0.3 mm Hg/ml/min/100 gm body weight; p < 0.001), associated with a decrease in the cardiac index (33.5 ± 1.0 vs. 27.0 ± 1.1 ml/min/100 gm body weight; p < 0.001). Nω-nitro-L-arginine treatment also induced a decrease in plasma volume (4.6 ± 0.1 vs. 4.1 ± 0.1 ml/100 gm body weight; p < 0.001) and extracellular sodium space (39.4 ± 0.7 vs. 37.4 ± 0.4 ml/100 gm body weight; p < 0.05) without changes in serum sodium. In addition, Nω-nitro-L-arginine corrected the decreased capillary pressure observed in portal hypertensive rats. Capillary pressure negatively correlated with plasma volume but not with sodium space. In contrast, Nω-nitro-L-arginine infusions in sham-operated rats significantly elevated mean arterial pressure without modifying plasma volume and sodium space. These results demonstrate that correction of peripheral vasodilation and capillary hypotension by Nω-nitro-Larginine ameliorates plasma volume expansion and sodium retention in portal hypertensive rats. (Hepatology 1993;17:84-90.)
Increase in Ornithine Decarboxylase Activity Caused by Hepatocyte Growth Factor in Primary Cultured Adult Rat Hepatocytes
Authors: Higaki Ikko , Matsui-yuasa Isao , Terakura Masanobu , Otani Shuzo , Kinoshita Hiroaki
Published: March 2007

The effect of hepatocyte growth factor on ornithine decarboxylase activity was studied in primary cultured adult rat hepatocytes. Ornithine decarboxylase activity was increased 3 hr after the addition of hepatocyte growth factor and remained at a high level until 12 hr; thereafter it decreased, and it returned to the control level by 24 hr. Enzyme activity began to increase with 1 ng/ml hepatocyte growth factor and reached its maximum with 5 ng/ml hepatocyte growth factor. When insulin or epidermal growth factor was added with hepatocyte growth factor, enzyme activity was further stimulated. The level of ornithine decarboxylase messenger RNA did not increase with addition of hepatocyte growth factor. The half-time of ornithine decarboxylase activity was prolonged about twofold by hepatocyte growth factor treatment. These results suggest that hepatocyte growth factor treatment of cells enhanced ornithine decarboxylase activity posttranslationally (Hepatology 1993;17:99-102.)
Cross-linked Cytokeratin Polypeptides in Liver and Hepatoma Cells: Possible Association with the Process of Cell Degeneration and Death
Authors: Fukuda Kazunori , Kojiro Masamichi , Chiu Jen-Fu
Published: March 2007

We investigated transglutaminase-induced crosslinking of cytokeratin polypeptides in liver and hepatoma cells. To overcome the difficulties in the biochemical analysis of highly cross-linked polymers and aggregates of cytokeratins, cross-linked cytokeratin dimers were analyzed by immunoblotting to evaluate the degree of cross-linking of cytokeratins. Covalently cross-linked cytokeratin dimers were not detectable in normal rat liver cells. However, cytokeratin dimers and high-molecular-weight cytokeratin polymers were detected in liver tissue with histological evidence of coagulative necrosis induced by ischemia or carbon tetrachloride. Treatment of cultured hepatoma cells with the Ca2+ ionophore A23187 showed a dosedependent, time-dependent decrease of cell viability. The appearance of cytokeratin dimers was shown to be correlated with cell death. These results suggest that the transglutaminase-induced cross-linking of cytokeratin polypeptides in liver and hepatoma cells is closely associated with the process of cell degeneration and death. (Hepatology 1993;17:118-124.)
Transforming growth factor-β1: There is regulation beyond transcription
Authors: Brenner David A.
Published: March 2007

Since many lines of evidence suggest that expression of the transforming growth factor-β1 (TGF-β1) gene may be regulated post-transcriptionally, we examined the effect of the 5′-untranslated region (UTR) of this gene on TGF-β1 expression. For this purpose, fragments of the 840-nucleotide highly GC-rich TGF-β1 5′-UTR were inserted into the 5′-UTR of the structural gene for human growth hormone driven by the simian virus 40 early promoter. A portion of the 5′-UTR of TGF-β1 mRNA spanning the sequences from +11 to + 147 was shown to inhibit growth hormone expression by as much as 22-fold. This effect was cell-specific; growth hormone production was inhibited in PC-3 human prostate adenocarcinoma and A-549 human lung adenocarcinoma cells, while no effect was seen in rat pheochromocytoma PC12 cells, which show efficient translation of endogenous TGF-β1 mRNA. Computer analysis showed that this region of the 5′-UTR contained a stable secondary stem-loop structure spanning sequences +49 to + 76. This stem-loop region alone is sufficient to inhibit expression of the growth hormone gene, suggesting that it plays an important role in post-transcriptional regulation of TGF-β1 gene expression.
Patterns of antibodies to hepatitis C virus in patients with chronic non-A, non-B hepatitis and their relationship to viral replication and liver disease
Authors: Chemello Liliana , Cavalletto Daniela , Pontisso Patrizia , Bortolotti Flavia , Donada Carlo , Donadon Valter , Frezza Mario , Casarin Pietro , Alberti Alfredo
Published: March 2007

Patients with hepatitis C virus infection may have circulating antibodies to various structural and nonstructural antigens of the virus. To assess whether the antibody profile is related to epidemiological or clinical features of chronic infection or to viral replication, sera from 172 consecutive patients with biopsyproven chronic non-A, non-B hepatitis were studied for antibodies to nonstructural and structural hepatitis C virus antigens and for serum hepatitis C virus RNA with the polymerase chain reaction using primers derived from the 5′ noncoding region. Three subgroups could be identified on the basis of their seroreactivity to hepatitis C virus: 133 cases (77.3% [group A]) were positive on first- and second-generation assays and had antibodies to C100-3 and to C22, C33c or both identified on recombinant immunoblot assay; 23 cases (13.4% [group B]) were positive only on second-generation assay and reacted with C22, C33c or both but not with C100-3; and 26 cases (9.3% [group C]) were negative for all hepatitis C virus antibodies. Mean age and sex distributions were similar among the three groups; a history of transfusion was more frequent among cases in group B (p = 0.06). These patients also had the highest serum aminotransferase values (p = 0.001). Liver histological studies showed active necroinflammatory changes in 69.2% of patients in group A and 52.2% of those in group B but only in 25% of cases in group C. Serum hepatitis C virus RNA was frequently detected in patients of groups A and B, independent of their recombinant immunoblot assay profiles. Hepatitis C virus RNA was also detected in 57% of cases with indeterminate patterns of reactivity on recombinant immunoblot assay. However, none of the patients without hepatitis C virus antibody reactivity had detectable hepatitis C virus RNA in serum. These results identify different subgroups of patients with chronic hepatitis C and indicate that chronic non-A, non-B, non-C hepatitis does exist in our region and that it appears to cause less severe liver injury than does documented hepatitis C. (Hepatology 1993;17:179-182.)
Risk factors for hepatitis C virus infection in hepatitis C virus antibody ELISA-positive blood donors according to RIBA-2 status: A case-control survey
Authors: Serfaty Lawrence , Giral Philippe , Elghouzzi Marie Hélène , Jullien Anne Marie , Poupon Raoul
Published: March 2007

Studies of blood donors positive for antibody to hepatitis C virus on enzyme-linked immunosorbent assay are probably biased by the large number of false-positive results. We evaluated the epidemiological and biological characteristics of 177 such donors with regard to the confirmatory secondgeneration RIBA test (Ortho Diagnostic Systems) and have compared the results to those from an age- and sex-matched control group of 177 donors negative for antibody to hepatitis C virus on enzyme-linked immunosorbent assay. Second-generation recombinant immunoblot assay was positive in 38% of cases, indeterminate in 6% and negative in 56%. The case-control study showed a significantly higher frequency of intravenous drug abuse (27% vs. 0%), blood transfusion (22% vs. 9%), history of jaundice (21% vs. 7%), elevated ALT level (49% vs. 4%) and HBc antibody positivity (32% vs. 7%) in second-generation recombinant immunoblot assay-positive donors. No such differences were found between the second-generation recombinant immunoblot assay-negative donors and their controls. The 35 second-generation recombinant immunoblot assay-positive donors without histories of transfusion or intravenous drug abuse had a significantly higher frequency of surgery with major blood loss or prolonged stays in areas of hepatitis B virus endemicity than did their controls (20% vs. 0% and 49% vs. 26%, respectively). In conclusion, at least one risk factor for HCV infection was identified in 82% of the secondgeneration recombinant immunoblot assay-positive donors, 91% of whom could have been identified on the basis of these risk factors, ALT level and presence of HBc antibody. (Hepatology 1993;17:183-187.)