bluuebunny/crossref_metadata_2025 huggingface dataset:
Atrial natriuretic peptide inhibits growth of hepatoblastoma (HEP G2) cells by means of activation of clearance receptors
Authors: Rashed Hani M. , Sun Hui , Patel Tarun B.
Published: March 2007

To investigate whether atrial natriuretic factor regulates the growth of hepatocytes and to determine the receptor subtype involved in such modulation, we studied the effect of atrial natriuretic factor 103-126 and clearance receptor binding analogs of atrial natriuretic factor, (des-(Q116, S117, G118, L119, G120) atrial natriuretic factor 102-121 and des-(C105,121) atrial natriuretic factor 104-126) on growth of human hepatoblastoma cells. Atrial natriuretic factor 103-126 and des-(Q116, S117, G118, L119, G120) atrial natriuretic factor 102-121 inhibited thymidine incorporation into human hepatoblastoma cells cultured in the presence of bovine serum albumin and epidermal growth factor but not in cells cultured in bovine serum albumin alone. Moreover, atrial natriuretic factor 103-126, des-(Q116, S117, G118, L119, G120) atrial natriuretic factor 102-121 and des-(C105,121) atrial natriuretic factor 104-126, in a concentration-dependent manner, inhibited thymidine incorporation and cell proliferation. As monitored by the ability of des-(Q116, S117, G118, L119, G120) atrial natriuretic factor 102-121 to displace 125I-labeled atrial natriuretic factor, epidermal growth factor increased the expression of cell surface clearance receptors. Epidermal growth factor also transiently increased the cellular content of atrial natriuretic factor clearance receptor messenger RNA without altering the levels of guanylyl cyclase-linked atrial natriuretic factor receptor messenger RNA levels. Maximal increase in atrial natriuretic factor clearance receptor messenger RNA coincided with the maximal increase in des-(Q116, S117, G118, L119, G120) atrial natriuretic factor 102-121-displaceable 125I-atrial natriuretic factor binding sites. The ability of atrial natriuretic factor clearance receptor-binding ligands to inhibit thymidine incorporation and cell proliferation-coupled with the selective upregulation of clearance receptor expression by epidermal growth factor, which facilitates the growth modulatory actions of atriopeptins-indicates that the atrial natriuretic factor clearance receptors mediate the growth regulatory actions of atrial natriuretic factor. Additionally, the clearance receptor-binding ligands decreased cellular cyclic AMP content only under conditions in which clearance receptors are expressed, suggesting that modulation of cyclic AMP by activation of these receptors regulates growth. (Hepatology 1993;17:677-684.)
Immunoelectron microscopy identification of early proliferating cells in rat liver tissue during hyperplasia induced by lead nitrate
Authors: Rijhsinghani Koshilya , Choi Ho-Soon H. , Burton Leroy A. , Paronetto Fiorenzo , Tavoloni Nicola
Published: March 2007

Recent studies have suggested that hepatic stem cells may be involved in at least some forms of liver epithelial growth. To obtain further information on this controversial hypothesis, we treated rats with lead nitrate to induce liver growth and identified the cells undergoing early DNA synthesis by bromodeoxyuridine immunohistochemistry, using both light and electron microscopic detection methods. Eight hours after an intravenous injection of lead nitrate 100 μmol/kg, DNA synthesis was detected in a few scattered hepatocytes and in nonparenchymal cells in portal connective tissue. At the light microscopic level, identification of nonparenchymal cells was limited to bile duct epithelial cells. Other cell types were also labeled, but their identity could not be established. At the ultrastructural level, however, four types of nonparenchymal cells were identified as containing bromodeoxyuridine immunogold particles. These four types included bile duct epithelial cells, fibroblasts, macrophages and nondescript periductular cells. These periductular cells displayed certain ultrastructural features of bile duct cells but did not line a lumen or display microvilli on their apical membrane, nor did they reside within the bile duct basement membrane. Because proliferation of nonparenchymal cells in portal areas preceded that of hepatocytes, it is suggested that the former reaction reflects a direct mitogenic effect of lead nitrate and not an adaptive growth response secondary to parenchymal enlargement. However, whether DNA synthesis in periductular cells or bile duct cells reflects activation of hepatic stem cells cannot be established from the present morphological observations. If so, such a progenitor compartment must be dormant because it does not seem to play a functional role in this and other forms of adult liver epithelial growth. (Hepatology 1993;17:685-692.)
Administration of prostaglandin E1 analog reduces rat hepatic and ito cell collagen gene expression and collagen accumulation after bile duct ligation injury
Authors: Beno David W. A. , Espinal Ronald , Edelstein Brian M. , Davis Bernard H.
Published: March 2007

Recent studies suggest that prostaglandin E may have the ability to suppress cytokine responsiveness. We examined the effects of prostaglandin E administration on several parameters of acute and chronic liver injury induced by bile duct ligation. Enisoprost, a prostaglandin E1 analog, was found to suppress early hepatic and Ito cell type I collagen gene expression without-diminishing the induction of the fibrogenic cytokine transforming growth factor-β. Overall liver inflammation and cell proliferation were not altered, suggesting that prostaglandin E acts distal to the initial injurious event(s). During later phases, drug administration reduced total collagen accumulation and type I collagen periductular infiltration associated with early nodule formation. (Hepatology 1993;17:707-714.)
To ligate or sclerose: Beginning of a new era in the management of esophageal varices?
Authors: Sarin S. K. , Bhatia V.
Published: March 2007

Background.

Endoscopic sclerotherapy is an accepted treatment for bleeding esophageal varices, but it is associated with substantial local and systemic complications. Endoscopic ligation, a new form of endoscopic treatment for bleeding varices, may be safer. We compared the effectiveness and safety of the two techniques.

Methods.

In this randomized trial we compared endoscopic sclerotherapy and endoscopic ligation in 129 patients with cirrhosis who had proved bleeding from esophageal varices. Sixty-five patients were treated with sclerotherapy, and 64 with ligation. Initial treatment for acute bleeding was followed by elective retreatment to eradicate varices. The patients were followed for a mean of 10 months, during which we determined the incidence of complications and recurrences of bleeding, the number of treatments needed to eradicate varices, and survival.

Results.

Active bleeding at the first treatment was controlled by sclerotherapy in 10 of 13 patients (77 percent) and by ligation in 12 of 14 patients (86 percent). Slightly more sclerotherapy-treated patients had recurrent hemorrhage during the study (48 percent vs. 36 percent for the ligation-treated patients, P = 0.072). The eradication of varices required a lower mean (± SD) number of treatments with ligation (4 ± 2 vs. 5 ± 2, P = 0.056) than with sclerotherapy. The mortality rate was significantly higher in the sclerotherapy group (45 percent vs. 28 percent, P = 0.041), as was the rate of complications (22 percent vs. 2 percent, P < 0.001). The complications of sclerotherapy were predominantly esophageal strictures, pneumonias, and other infections.

Conclusions.

Patients with cirrhosis who have bleeding esophageal varices have fewer treatment-related complications and better survival rates when they are treated by esophageal ligation than when they are treated by sclerotherapy. N Engl J Med 1992;326:1527-1532.
Omeprazole induction of cytochrome P-450IA2: The importance of selecting the appropriate human model
Authors: Watkins Paul B.
Published: March 2007

Omeprazole has been shown to induce cytochrome P450IA1 and P450IA2 activity in vitro. To reflect cytochrome P450IA2 (CYPIA2) activity in vivo, the 13C-[N-3-methyl]-caffeine breath test was conducted in 18 volunteers: 12 extensive metabolizers, one intermediate metabolizer, and five poor metabolizers of S-mephenytoin. Breath tests were performed before treatment with an oral dose of 40 mg omeprazole, on the seventh day of treatment, and after a 7-day washout period. The mean percentage exhalation of the 13C test dose, as determined by 13CO2 in breath during 8 hours, was 23.0% ± 8.0% (n = 18) before treatment. The largest increases in exhalation rate of 13CO2 were observed in the poor metabolizers and the intermediate metabolizers (range, 12.8% to 62.9%; median, 38.9%); median area under the plasma concentration-time curves (AUC) of omeprazole was four times higher than in the extensive metabolizers. The change after omeprazole treatment in extensive metabolizers ranged from −9.8% to + 47.7% (median, 12.3%; n = 12) of pretreatment values. In both groups, exhalation rates of 13CO2 returned to near pretreatment values within the 7-day washout period (24.2% ± 7.8%; n = 17). Changes in the 13C-caffeine breath test correlated well with both the pretreatment value R = −0.67, p = 0.003; n = 18 and the plasma AUC of omeprazole (R = 0.61, p = 0.007; n = 18). Therapeutic doses of omeprazole seem to induce CYP1A2 activity in poor metabolizers, whereas they exert minor inducing effects in extensive metabolizers of S-mephenytoin. CLIN Pharmacol Ther 1992;52:170-180.
Expression of the terminal protein of hepatitis B virus is associated with failure to respond to interferon therapy
Authors: Foster Graham R. , Goldin Robert D. , Hay Andrew , McGarvey Michael J. , Stark George R. , Thomas Howard C.
Published: March 2007

The terminal protein domain of the hepatitis B viral polymerase can inhibit the cellular response to interferon. To clarify the clinical relevance of this inhibitory effect, we examined the expression of terminal protein in liver biopsy specimens from patients with chronic hepatitis B infection. We found that expression of terminal protein is associated with a failure of hepatocytes to respond to interferon, as assessed by expression of the interferon-inducible protein β2-microglobulin. Patients whose liver specimens contained large numbers of cells expressing terminal protein tended not to respond to treatment. During interferon therapy the percentage of cells expressing terminal protein remained constant, but treatment significantly reduced the number of cells that expressed the hepatitis B nucleocapsid protein. Hence expression of terminal protein in a cell may prevent elimination of the virus by interferon therapy. (Hepatology 1993;17:757-762.)
Characterization of hepatitis C virus structural proteins with a recombinant baculovirus expression system
Authors: Hsu Henry H. , Donets Mikhail , Greenberg Harry B. , Feinstone Stephen M.
Published: March 2007

We cloned and expressed the sequences encoding the structural proteins of the hepatitis C virus in a baculovirus eukaryotic expression system. Four recombinant constructs expressed sufficient hepatitis C virus-specific proteins in insect cell culture to allow analysis of protein cleavage, glycosylation and immunoreactivity. Using immunoblot analysis, we detected a 22-kD protein corresponding to the hepatitis C virus capsid protein cleaved from a larger precursor. Recombinant constructs encoding the presumptive envelope (E1) protein produced products ranging from 30 to 35 kD, whereas constructs encoding the presumptive E2/NS1 protein expressed products ranging in size from 68 to 73 kD. The recombinant envelope proteins were glycosylated, as shown by sensitivity to endoglycosidase F digestion, whereas the capsid was not. We examined the immunoreactivity of these recombinant proteins using sera from 50 patients chronically infected with HCV. Forty-seven of 50 of these sera contained antibodies against the capsid, 14 (28%) also had antibodies against E1 and at least 5 (10%) had antibody against E2/NS1. Forty-seven of 50 sera (94%) were viremic, as determined on hepatitis C virus polymerase chain reaction. The three sera that were hepatitis C virus polymerase chain reaction negative did not have envelope antibodies, whereas all sera that had envelope antibodies were also hepatitis C virus polymerase chain reaction positive. Thus antibodies to baculovirus-expressed hepatitis C virus structural proteins, including E1 and E2/NS1, are found in the presence of viremia. (Hepatology 1993;17:763-771.)
Lack of mother-to-infant transmission of hepatitis C virus in human immunodeficiency virus-seronegative women: A prospective study with hepatitis C virus RNA testing
Authors: Roudot-Thoraval Françoise , Pawlotsky Jean-Michel , Thiers Valérie , Deforges Lionel , Girollet Pierre-Paul , Guillot François , Huraux Christiane , Aumont Pascale , Brechot Christian , Dhumeaux Daniel
Published: March 2007

The published risk of mother-to-infant transmission of hepatitis C virus varies according to the population studied and the tests used. In a prospective study we used the polymerase chain reaction to assess the risk of vertical transmission of hepatitis C virus in an unselected population of women uninfected by human immunodeficiency virus. Hepatitis C virus antibodies were sought with a second-generation enzyme-linked immunosorbent assay in 2,367 consecutive pregnant women. Forty-one were positive, and 17 consented to serological follow-up of their offspring (n = 18). A second-generation recombinant immunoblot assay, ALT determination and hepatitis C virus RNA testing were performed on maternal sera obtained during pregnancy and sera from the offspring at birth and thereafter. Five older brothers or sisters were also tested. Hepatitis C virus RNA sequences in serum were amplified with a modified nested polymerase chain reaction procedure with primers from the highly conserved 5′ noncoding region of the hepatitis C virus genome. All the neonates were positive for hepatitis C virus antibodies, with enzyme-linked immunosorbent assay titers and recombinant immunoblot assay patterns similar to those of their mothers. After birth hepatitis C virus antibodies gradually disappeared within 6 mo. Hepatitis C virus RNA was consistently negative in the 18 children from birth to 24 mo (range = 3 to 24 mo) and in the 5 older children, regardless of the hepatitis C virus polymerase chain reaction status of the mothers (8 of whom were positive). In conclusion, the lack of vertical transmission of hepatitis C virus in this study suggests that unselected and human immunodeficiency virus-negative women are at low risk of perinatal transmission of hepatitis C virus, even in the presence of active hepatitis C virus replication. (Hepatology 1993;17:772-777.)
Anionic polypeptide fraction in bile of patients with and without gallstones
Authors: Domingo Nicole , Lafont Huguette , Halpern Zamir , Peled Yohanan , Grosclaude Jean , Gilat Tuvia
Published: March 2007

With the demonstration of pronucleating and antinucleating proteins, the role of biliary proteins became of considerable research interest. Anionic polypeptide fraction is the third most abundant biliary protein; it is found in association with biliary lipids, has antinucleating properties for calcium and is found in gallstones. Its levels in various human biles have not been studied as of this writing. In this investigation the concentration of anionic polypeptide fraction in gallbladder bile was measured in 16 subjects without gallstones, 19 subjects with cholesterol stones and 15 subjects with pigment stones in Tel Aviv. Anionic polypeptide fraction concentrations in bile (mean ± S.D.) were 0.76 ± 0.09 gm/L in controls and 0.81 ± 0.25 gm/L (which was not significant) in patients with cholesterol gallstones. They were significantly higher 1.03 ± 0.23 (p < 0.05) in patients with pigment gallstones. The anionic polypeptide fraction/phospholipid ratio and the anionic polypeptide fraction/total lipid ratio were significantly higher in patients with pigment gallstones (p < 0.005 and 0.05, respectively). The anionic polypeptide fraction lipid ratios were insignificantly elevated in biles of patients with cholesterol stones compared with the ratios in biles of controls. Only the anionic polypeptide fraction/phospholipid ratio was significantly higher in biles of patients with pigment stones compared with those with cholesterol gallstones. The values were similar although higher in a small group of gallstone patients from Marseilles. The role of anionic polypeptide fraction in the pathogenesis of gallstones, particularly pigment gallstones, requires further study. (Hepatology 1993;17:778-780.)
Brachial and femoral artery blood flow in cirrhosis: Relationship to kidney dysfunction
Authors: Maroto Albert , Ginés Pere , Arroyo Vicente , Ginés Angels , Saló Joan , Clária Joan , Jiménez Wladimiro , Bru Concepció , Rivera Francisca , Rodés Joan
Published: March 2007

Brachial artery and common femoral artery blood flows and cardiac output were measured with duplex-Doppler ultrasonography in 12 normal subjects, 12 patients with compensated cirrhosis and 35 patients with cirrhosis and ascites (8 with functional kidney failure). The aim of this study was to investigate whether arteriolar vasodilation in these vascular territories contributes to hyperdynamic circulation in cirrhosis. Cardiac output was significantly increased and systemic vascular resistance significantly reduced in the three groups of cirrhotic patients. We found no significant differences between normal subjects and compensated cirrhotic patients in brachial artery (55 ± 7 vs. 57 ± 7 ml/min) and femoral artery (353 ± 20 vs. 310 ± 25 ml/min) blood flow. Nonazotemic cirrhotic patients with ascites showed significantly lower (p < 0.05) brachial artery blood flow (40 ± 3 ml/min) than healthy subjects and compensated patients. Femoral artery blood flow (327 ± 25 ml/min), however, was not significantly different. Brachial artery (25 ± 3 ml/min) and femoral artery (213 ± 22 ml/min) blood flows were markedly reduced in the patients with kidney failure (p < 0.05 with respect to the other three groups). Glomerular filtration rate correlated directly with brachial (r = 0.74, p = 0.0001) and femoral (r = 0.52, p = 0.03) artery blood flow in the cirrhotic patients. These results indicate that the arteriolar vasodilation causing hyperdynamic circulation in cirrhosis does not take place in the brachial and femoral vascular territories. (Hepatology 1993;17:788-793.)
Frequent loss of heterozygosity on chromosome 22 in hepatocellular carcinoma
Authors: Takahashi Kazuhiro , Kudo Jiro , Ishibashi Hiromi , Hirata Yasuhiko , Niho Yoshiyuki
Published: March 2007

We investigated 24 hepatocellular carcinomas in Japan to find loss of heterozygosity with 15 polymorphic DNA markers that detect allelic losses at specific chromosome loci. Loss of heterozygosity on chromosomes 10q, 17p and 22q was detected in 3 of 12 (25%), 9 of 21 (43%) and 5 of 15 (33%) informative cases of hepatocellular carcinoma, respectively. This is the first report of loss of heterozygosity on chromosome 22q in hepatocellular carcinoma; the newly recognized common chromosome loss was considered to exist between D22S9 and D22S10 on 22q11. On the basis of this and other studies, we believe it is likely that such a chromosome loss in hepatocellular carcinoma is a signal for malignant transformation and that loss of unknown genes on chromosomes 10q, 17p and 22q may contribute to tumor progression in hepatocellular carcinoma. (Hepatology 1993;17:794-799.)
Quantitative assessment of hepatocellular function through in vivo radioreceptor imaging with technetium 99m galactosyl human serum albumin
Authors: Kudo Masatoshi , Todo Akio , Ikekubo Katsuji , Yamamoto Kazutaka , Vera David R. , Stadalnik Robert C.
Published: March 2007

Technetium 99m diethylenetriaminepentaacetic acid-galactosyl human serum albumin is a newly developed analog ligand to asialoglycoprotein receptor, which is a hepatic cell surface receptor specific for galactose-terminated glycoproteins. Hepatic functional imaging, which yields estimates of asialoglycoprotein receptor concentration, was performed after intravenous injection of 3 mg technetium 99m diethylenetriaminepentaacetic acid-galactosyl human serum albumin. A total of 75 human subjects were studied: 6 controls without liver diseases, 51 patients with chronic liver diseases and 18 patients with acute liver diseases. In chronic liver disease the asialoglycoprotein receptor concentration significantly correlated with the clinical severity based on the criteria of the Liver Cancer Study Group of Japan (rs = −0.890, p = 0.0001). Good correlations between the asialoglycoprotein receptor concentration and conventional liver function tests were also observed. In acute liver disease the asialoglycoprotein receptor concentration correlated well with the normotest (r = 0.796, p = 0.0001), prothrombin time (r = 0.701, p = 0.0002) and total serum bilirubin (r = −0.642, p = 0.0007). We conclude that the parameter, asialoglycoprotein receptor concentration, obtained from the kinetic analysis of technetium 99m diethylenetriaminepentaacetic acid-galactosyl human serum albumin time-activity data, is a sensitive measure of functioning hepatocyte mass in acute and chronic liver disease. (Hepatology 1993;17:814-819.)
Changes in type IV collagen content in livers of patients with alcoholic liver disease
Authors: Tsutsumi Mikihiro , Urashima Sachio , Matsuda Yoshiro , Takase Shujiro , Takada Akira
Published: March 2007

An increase of serum type IV collagen levels in patients with liver disease has been reported; however, the mechanisms of this increase are not yet well known. We recently developed an assay system for type IV collagen content in liver biopsy specimens. In this study, type IV collagen content in the livers and sera of patients with alcoholic liver disease and nonalcoholic liver disease was determined. Serum and hepatic type IV collagen contents were measured with a one-step sandwich enzyme immunoassay system using monoclonal antibodies for human type IV collagen. Hepatic type IV collagen content increased significantly in liver disease. In alcoholic liver disease, type IV collagen content in patients with mild fibrosis was lower than that in advanced types of alcoholic liver disease. In nonalcoholic liver disease, hepatic type IV collagen content tended to increase with the progression of fibrosis. Type IV collagen content in alcoholic liver disease was significantly higher than that in the corresponding type of nonalcoholic liver disease. Hepatic total collagen content increased significantly in parallel with the progression of fibrosis in both alcoholic liver disease and nonalcoholic liver disease. The total collagen content in each type of alcoholic liver disease was significantly lower than that in the corresponding type of nonalcoholic liver disease. The ratio of type IV collagen to total collagen content was the highest in livers showing mild fibrosis, both in alcoholic liver disease and nonalcoholic liver disease, and decreased in parallel with the progression of fibrosis. The ratio in patients with alcoholic liver disease was significantly higher than that in those with the corresponding nonalcoholic liver disease. Hepatic type IV collagen content correlated with the intensity of the staining reactions for type IV collagen only around the sinusoidal walls in alcoholic liver disease, but not in nonalcoholic liver disease. A significant correlation was found between serum and liver type IV collagen content, although the coefficient value was not very high. These results indicate that the response of type IV collagen synthesis to liver injury is strong in mild fibrosis and reaches a plateau at a relativelyearly stage of fibrosis; then the content of the other types of collagen increases gradually with the progression of fibrosis. The stimulation for type IV collagen synthesis is more prominent in alcoholic liver disease than in nonalcoholic liver disease, especially at intralobular areas. (Hepatology 1993;17:820-827.)
Concordance of iron storage in siblings with genetic hemochromatosis: Evidence for a predominantly genetic effect on iron storage
Authors: Crawford Darrell H. G. , Halliday June W. , Summers Kim M. , Bourke Michael J. , Powell Lawrie W.
Published: March 2007

Phenotypic concordance between siblings has been demonstrated in some inherited conditions, and such data provide strong evidence that the severity of disease is affected by genetic factors. We assessed the concordance of liver iron stores between siblings in 22 sibling pairs (15 same-sex pairs and 7 opposite-sex pairs) with genetic hemochromatosis. In this study population a wide range was found in the hepatic iron concentration and the hepatic iron index (32 to 833 μmol/gm dry wt and 1.65 to 14.4, respectively), which could not be accounted for by differing exposure to the environmental factors that influence iron stores. Despite the large variation of hepatic iron concentration within the group, siblings of identical sex had accumulated similar amounts of liver iron. A highly significant correlation for hepatic iron concentration (r = 0.81) and hepatic iron index (r = 0.70) was found between siblings of the same sex. The hepatic iron concentration and the hepatic iron index of one sibling was less than 50% of the other in only three same-sex sibling pairs. In each instance, reasons existed (blood donation, age at diagnosis and human leukocyte antigen nonidentity) for this discordance. In six of the seven opposite-sex pairs, the woman had lower hepatic iron stores than her male sibling, consistent with previous studies on the extent of iron overload in women and its modification by physiological blood loss. The correlation coefficients for hepatic iron concentration and hepatic iron index between the male and female siblings within families were 0.73 and 0.63, respectively, suggesting that female hemochromatotic siblings of affected men with high levels of liver iron also have high liver iron stores relative to other affected women. These findings provide strong evidence that genetic factors are the principal determinants of the amount of iron that accumulates in patients with genetic hemochromatosis and that only major environmental factors, such as significant blood donation or blood loss, will modify hepatic iron stores. (Hepatology 1993;17:833-837.)
Tumor necrosis factor up-regulates expression of low-density lipoprotein receptors on HepG2 cells
Authors: Liao Wei , Florén Claes-Henrik
Published: March 2007

Tumor necrosis factor mediates most biological activities of endotoxin and also, in part, mediates endotoxin-induced disturbances in lipid metabolism. In this study, the effect of tumor necrosis factor on low-density lipoprotein receptor activity was investigated in cells of HepG2, a well-differentiated human hepatoma cell line. Pretreatment of the cells with tumor necrosis factor leads to enhanced binding, uptake and degradation of 125I-labeled low-density lipoprotein. This effect of tumor necrosis factor was dose and time dependent. Tumor necrosis factor-stimulated enhancement of low-density lipoprotein binding occurred at all stages of cell growth. However, addition of an excess of unlabeled low-density lipoprotein, to down-regulate low-density lipoprotein receptors before exposure to tumor necrosis factor of the cells, completely abolished the effects of tumor necrosis factor. Competition experiments using unlabeled low-density lipoprotein and blockage experiments with a monoclonal low-density lipoprotein receptor antibody showed that tumor necrosis factor-stimulated low-density lipoprotein binding takes place through stimulation of low-density lipoprotein receptors. Comparison of the kinetics of specific low-density lipoprotein binding in the unstimulated cells and in the tumor necrosis factor-stimulated cells indicated that tumor necrosis factor caused a 30% increase in maximum velocity with no significant change in Michaelis constant, suggesting that tumor necrosis factor increases the number of low-density lipoprotein receptors on the cells rather than changing binding affinity. Preincubation of the cells with cycloheximide or actinomycin D totally abolished the up-regulatory effect of tumor necrosis factor on low-density lipoprotein receptors. Tumor necrosis factor did not stimulate proliferation of HepG2 cells, as judged by cell protein determination or by [3H]thymidine incorporation. In conclusion, this study suggests that tumor necrosis factor up-regulates expression of low-density lipoprotein receptors on HepG2 cells by stimulation of de novo synthesis of receptors, independent of cell growth. (Hepatology 1993;17:898-907.)
Increased neutrophil function induced by bile duct ligation in a rat model
Authors: Levy Rachel , Schlaeffer Francisc , Keynan Arie , Nagauker Ofra , Yaari Arie , Sikuler Emanuel
Published: March 2007

Neutrophil function was studied in rats with common bile duct ligation. Superoxide production stimulated by phorhol myristate acetate, opsonized zymosan or formyl-methionyl-leucyl-phenylalanine; phagocytosis; and chemotaxis were significantly greater in neutrophils from rats with common bile duct ligation than in sham-operated control rats. Enhanced neutrophil activity was observed within 12 hr of bile duct ligation; it remained increased during the 15-day study. Preincubation of neutrophils from control rats with sera of rats with common bile duct ligation did not increase superoxide generation. This suggests that the high superoxide production observed in neutrophils of rats with common bile duct ligation was not an immediate effect of the serum. Neutrophils of rats with portal vein ligation exhibited normal activity, indicating that portal systemic shunting per se is not the underlying mechanism for increased activity. The elevated levels of AST and alkaline phosphatase, indicating liver damage, that appeared within 12 hr of bile duct ligation correlated with the increased superoxide generation. (Hepatology 1993;17:908-914.)
Changes in hepatocyte water volume affect protein synthesis
Authors: Wondergem Robert
Published: March 2007

Protein synthesis in isolated rat hepatocytes was determined from the incorporation of [3H]leucine (4 mM) into acid-precipitable material in the presence of amino acids at twice their physiological concentration. Protein synthesis increased linearly with time and incubated cell protein, and was inhibited by cycloheximide by more than 95%. In normo-osmotic incubations containing amino acids at twice the physiological concentrations the rate of [3H]leucine incorporation was 5.8 ± 0.2 nmol/h per mg cell protein (n = 26). Hyperosmotic cell shrinkage due to addition of 60 mM-NaCl or 120 mM-raffinose inhibited [3H]leucine incorporation into acid-precipitable material by 60% and 74%, respectively, whereas hypo-osmotic cell swelling was ineffective. Inhibition of protein synthesis by adding 120 mM-raffinose was largely counteracted by simultaneous lowering of the NaCl concentration by 60 mM. Glutamine (10 mM) had no effect on protein synthesis in normo-osmotic incubations (320 mosm), but stimulated protein synthesis in hyperosmotically (440 mosm) pre-shrunken cells almost to rates found in normo-osmotic (320 mosm) control incubations. Cyclic AMP and vasopressin inhibited protein synthesis by 23% and 8%, respectively, whereas insulin and phenylephrine were ineffective. However, inhibition of protein synthesis by cyclic AMP was about twice as strong in the presence of vasopressin or phenylephrine. When protein synthesis was preinhibited by cyclic AMP, [3H]leucine incorporation was stimulated by glutamine (10 mM), insulin or hypoosmotic exposure. There was a close relationship between the inhibition of protein synthesis and the extent of hepatocyte shrinkage induced by the abovementioned effectors, suggesting a role of cell volume in the regulation of hepatic protein synthesis.
Quantitative analysis of antibodies to hepatitis C virus during interferon-α therapy
Authors: Yuki Nobukazu , Hayashi Norio , Hagiwara Hideki , Takehara Tetsuo , Katayama Kazuhiro , Kasahara Akinori , Fusamoto Hideyuki , Kamada Takenobu
Published: March 2007

We quantified IgG antibodies to structural (core) and nonstructural (C100-3) hepatitis C virus proteins in 42 patients with chronic hepatitis C treated with a 6-mo course of interferon-α Sera were drawn before and at the end of therapy and also 6 mo after therapy withdrawal; they were stored for later analysis of antibodies and serum hepatitis C virus RNA. Sustained virus clearance was observed at the end of therapy and 6 mo after therapy withdrawal in nine cases; it was accompanied with sustained reductions of antibody to hepatitis C virus core protein and antibody to C 100-3 protein. A sustained reduction of antibody to hepatitis C virus core protein was specific to sustained virus clearance, although that of antibody to C 100-3 protein was not. None of the patients who did not show reductions of levels of both antibodies at the end of therapy displayed sustained virus clearance. Five patients showed hepatitis C virus RNA negativity and normal aminotransferase levels at the end of therapy without reduction of antibody to hepatitis C virus core protein levels. Of these five patients, relapse of hepatitis occurred in four, and viremia was present 6 mo after therapy withdrawal in all cases. These results demonstrate that testing for antibody titers may add information for evaluating virus clearance after interferon therapy. (Hepatology 1993;17:960-965.)
Excess HBcAg in HBc antibody-negative chronic hepatitis B virus carriers
Authors: Lazizi Yamina , Dubreuil Pascal , Pillot Jacques
Published: March 2007

HBcAg and antibody to HBcAg were assayed in chronic hepatitis B virus carriers who were not reactive for HBc antibodies on available commercial tests. HBc antibody-negative sera, collected before the onset of the acute phase in recovering patients, were used as controls. A high level of HBcAg was detected in HBc antibody-negative chronic hepatitis B virus carriers after dissociative treatment. HBcAg levels were correlated with serum hepatitis B virus DNA levels. Precipitation of immune complexes increased the amount of detected HBcAg. HBc antibodies were detected in some patients only after sucrose gradient fractionation of serum and dissociative treatment. All HBsAg-positive chronic carriers who lacked HBc antibody were immunocompromised. Our results show that in HBc antibody-negative chronic hepatitis B virus carriers with active replication, HBc antibodies may be complexed by the excess of antigen and become undetectable by the available commercial tests. Unresponsiveness to HBcAg cannot always be ascribed to infection by another hepatitis B virus-related virus or hepatitis B virus variant. (Hepatology 1993;17:966-970.)
Passage of amino acids and glucose across the blood-brain barrier in patients with hepatic encephalopathy
Authors: Knudsen Gitte M. , Schmidt Jes , Almdal Thomas , Paulson Olaf B. , Vilstrup Hendrik
Published: March 2007

We repeatedly measured blood-brain barrier passage of phenylalanine, leucine, glucose and GABA in nine patients with hepatic encephalopathy using the intravenous double-indicator technique. Controls were four patients without liver disease and two of the patients who had recovered completely from their hepatic encephalopathy. The corrected cerebral venous output curves were fitted by use of a three-compartment model with four parameters. In the patients with hepatic encephalopathy, the permeability-surface area products for phenylalanine and leucine from the blood to the brain and from the brain interstitial fluid to the intracellular compartment, the unidirectional extraction and the brain amino acid influx were similar in the two groups. The permeability from the brain back to blood for phenylalanine was decreased by 72% in patients with hepatic encephalopathy compared with that in the control group (p < 0.05), whereas no difference was seen for leucine. The permeability from the brain back to the blood for phenylalanine decreased with coma grade and normalized in the two patients who recovered. Correspondingly, the calculated brain interstitial fluid concentration of phenylalanine was increased in the patients with hepatic encephalopathy. The transfer variables for bloodbrain barrier passage of glucose were similar in the two groups. The permeability from the blood to the brain for GABA was very low in both the patients with hepatic encephalopathy and the control group. We conclude that in hepatic encephalopathy the permeability from brain to blood for phenylalanine decreases with coma grade. The decrease is caused by an increased interstitial fluid concentration of the amino acid. No evidence was found of general or selective blood-brain barrier disturbance in hepatic encephalopathy. (Hepatology 1993;17:987-992.)
A macroregenerative nodule containing multiple foci of hepatocellular carcinoma in a noncirrhotic liver
Authors: Theise Neil D. , Lapook Jonathan D. , Thung Swan N.
Published: March 2007

We report an incidental small hepatocellular carcinoma in a patient with chronic hepatitis C infection without cirrhosis. The existence of portal triads and the Meyenburg complexes within the lesion and atypical subnodules suggests that the carcinoma has arisen in the context of a macroregenerative nodule rather than the whole nodule being an early, spreading carcinoma. A growing body of evidence supports macroregenerative nodules as being precursor lesions in the development of hepatocellular carcinoma. Although they are generally thought of as being large cirrhotic nodules, this case suggests that they may be lesions that develop in the context of chronic liver disease, parallel to, but independently of, cirrhosis. Moreover, the development of carcinoma within the nodule suggests that macroregenerative nodules may play a role in carcinogenesis in noncirrhotic livers. (Hepatology 1993;17:993-996.)
Hyperglycemia reduces gallbladder emptying and plasma hormone secretion to modified sham feeding and regular feeding
Authors: de Boer Sybrand Y. , Masclee Ad A. M. , Lam Wai Fan , Schipper Jaap , Jansen Jan B. M. J. , Lamers Cornelius B. H. W.
Published: March 2007

The purpose of this study was to investigate the effect of acute stable hyperglycemia on gallbladder motility, plasma cholecystokinin level and pancreatic polypeptide secretion. Gallbladder emptying in response to modified sham feeding and regular feeding was determined in six healthy subjects on two separate occasions during normoglycemia (serum glucose = 5 mmol/L) and during hyperglycemia (serum glucose = 15 mmol/L). Pancreatic polypeptide secretion was determined as an indirect measure of cholinergic tone. Gallbladder contraction in response to sham feeding during hyperglycemia (9% ± 2%) was significantly (p < 0.05) reduced compared with that in normoglycemia (22% ± 1%). During hyperglycemia, gallbladder emptying after meal ingestion (29% ± 9%) was significantly (p < 0.05) less than that in normoglycemia (60% ± 10%). Sham feeding did not affect plasma cholecystokinin levels. Regular feeding induced significant (p < 0.05) increases in plasma cholecystokinin levels in both experiments. However, integrated postprandial plasma cholecystokinin secretion was significantly (p < 0.05) reduced during hyperglycemia compared with that in normoglycemia (29 ± 5 pmol ± 60 min vs. 58 10 pmol ± 60 min). Modified sham feeding-and feeding-stimulated pancreatic polypeptide secretion during hyperglycemia (235 ± 95 pmol ± 90 min and 1,035 ± 267 pmol ± 60 min, respectively) were significantly (p < 0.05) less than levels seen in normoglycemia (434 ± 71 pmol ± 90 min and 1,961 ± 219 pmol · 60 min, respectively). This study indicates that gallbladder emptying and plasma hormone secretion in response to sham feeding and regular feeding are affected by blood glucose levels. (Hepatology 1993;17:1022-1027.)
Brain indoles in human hepatic encephalopathy
Authors: Al Mardini Hanan , Harrison Emma J. , Ince Paul G. , Bartlett Kim , Record Christopher O.
Published: March 2007

The neurotransmitter serotonin has a profound effect on the control of sleep; thus excess serotonin activity in the brain could be responsible for impaired consciousness in hepatic encephalopathy. Furthermore, an increased brain level of 5-hydroxyindoleacetic acid has been a consistent finding in various animal models of the condition. In this study, using high-performance liquid chromatography with fluorometric detection, we examined levels of brain serotonin (5-hydroxytryptamine) and its precursors and metabolites in 16 patients dying with hepatic encephalopathy complicating acute and chronic liver disease and 9 control subjects matched for age, sex, postmortem delay in brain retrieval and length of frozen tissue storage. In patients with chronic liver disease, serotonin level was significantly increased in thalamus (p < 0.02); levels of its metabolite 5-hydroxyindoleacetic acid were increased in frontal cortex (p < 0.05), globus pallidus (p < 0.05) and putamen (p < 0.01). Levels of the precursor amino acid tryptophan were increased in thalamus (p < 0.01) and globus pallidus (p < 0.01); in both patient groups levels of 5-hydroxytryptophan and the tryptamine metabolite indoleacetic acid were increased in all brain areas studied. 5-Hydroxytryptamine levels were also increased in thalamus, frontal cortex and globus pallidus in the three patients with fulminant liver failure. Our findings are consistent with disordered neurotransmission, especially in the thalamus, an area of particular importance in the regulation of consciousness, alertness and attention in human beings. (Hepatology 1993;17:1033-1040.)
Hepatic 60-kD heat-shock protein responses in alcoholic hepatitis
Authors: Koskinas John , Winrow Vivienne R. , Bird George L. A. , Lau Johnson Y. N. , Portmann Bernard C. , Blake David R. , Alexander Graeme J. M. , Williams Roger
Published: March 2007

The precise mechanism of the pathogenesis of alcoholic hepatitis is unknown, but immune involvement may perpetuate and exacerbate the process. Heatshock proteins, normally protective, may be immunogenic and have been shown to induce antibody formation in some inflammatory conditions. Alcohol, cellular hypoxia and tumor necrosis factor, all involved in alcoholic hepatitis, are potent inducers of heatshock protein. In this study, we sought 60-kD heatshock protein in liver tissue with a murine monoclonal antibody and measured circulating antibody to 60-kD heat-shock protein on ELISA. Fourteen of 20 livers from patients with acute alcoholic hepatitis expressed 60-kD heat-shock protein in hepatocyte cytoplasm in a diffuse pattern with superimposed clusters; other cell types were occasionally positive. Twelve of these patients had high-titer IgA 60-kD heat-shock protein antibody in serum. In contrast, 60-kD heat-shock protein was identified in only 2 of the 10 patients with alcoholic cirrhosis without hepatitis (p = 0.013). These two patients had severe liver disease, and one patient in this group was seropositive for IgA 60-kD heat-shock protein antibody. Eight alcoholic patients with fatty liver alone were negative for antigen, and all but one were negative for antibody. The 10 patients without liver damage were negative for antigen and antibody. The findings that 60-kD heat-shock protein is present in liver tissue of patients with acute alcoholic liver damage and that circulating IgA 60-kD heat-shock protein antibody levels are increased may point to one pathogenetic mechanism underlying development and progression of liver damage in alcoholic hepatitis. (Hepatology 1993;17:1047-1051.)
The role of 16, 16-dimethyl prostaglandin E2 on the intrahepatic biliary branches in dogs
Authors: Ohta Tetsuo , Nagakawa Takukazu , Yoshimitsu Yutaka , Sanada Hiromi , Fonseca Luis , Miyazaki Itsuo , Terada Tadashi
Published: March 2007

We studied the effects of the oral administration of a stable prostaglandin E2 analog, 16,16-dimethyl prostaglandin E2, on the intrahepatic biliary branches in a canine model. Obstructive cholestasis with a bacterial infection was induced surgically in two liver lobes in healthy mongrel dogs, and 16,16-dimethyl prostaglandin E2 was administered orally. We examined the morphological changes in the intrahepatic biliary branches and quantitatively estimated density of mucus-producing glandular elements in the ductal wall by counting these glands per unit area. Dogs treated with 16,16-dimethyl prostaglandin E2 (group 1) demonstrated fibrous thickening of the ductal wall, moderate infiltration by inflammatory cells and severe adenomatous hyperplasia of the bile duct epithelium, including striking proliferation of the mucous glands. The mean number of these mucous glands per unit area (4 mm2) was 43.0 ± 9.0 (mean ± S.D.; range = 36 to 56). In contrast, in a control group whose members did not receive 16,16-dimethyl prostaglandin E2 (group 2), the mean number of mucous glands per unit area was 19.4 ± 8.0 (range = 10 to 29), significantly lower than that in group 1, although histological examination revealed chronic inflammation in the region of the large bile duct similar to that in group 1. These findings suggest that the increase in the number of mucous glands that typically occur in the setting of bile stasis and biliary infection is enhanced by 16,16-dimethyl prostaglandin E2. (Hepatology 1993;17:1062-1065.)
Potential role of hepatic macrophages in neutrophil-mediated liver injury in rats with sepsis
Authors: Doi Fukashi , Goya Tomomochi , Torisu Motomichi
Published: March 2007

We investigated the pathogenesis of septic liver injury in rats caused by cecal ligation and puncture. In this model, numerous neutrophils accumulated in the liver in parallel with the development of liver dysfunction. The supernatants of hepatic macrophages isolated from these septic rats 24 hr after cecal ligation and puncture had enhanced chemotactic activities for human neutrophils. These results suggest that in sepsis, hepatic macrophages attract neutrophils to the liver. Human neutrophils preincubated in this macrophage supernatant had the following biological activities not seen in the sham-operated controls. (a) They became more adherent to cultured endothelial cells through up-regulation of adhesion molecules such as CD11b/CD18, (b) their chemiluminescence was markedly elevated. These functional changes of cecal ligation and puncture hepatic macrophages were the same as those in endotoxin-pretreated hepatic macrophages after isolation from normal rats. Therefore we suspect that hepatic macrophages are activated by portal vein endotoxin in sepsis. These activated hepatic macrophages secreted chemical mediators of inflammation, including leukotriene B4 and tumor necrosis factor. In conclusion, hepatic macrophages seem to interact closely with neutrophils and play an important role in the pathogenesis of septic liver injury. (Hepatology 1993;17:1086-1094.)