bluuebunny/crossref_metadata_2025 huggingface dataset:
Diagnosis of chronic hepatitis C after liver transplantation by the detection of viral sequences with polymerase chain reaction
Authors: Poterucha John J. , Rakela Jorge , Lumeng Lawrence , Lee Chao-Hung , Taswell Howard F. , Wiesner Russell H.
Published: March 2007

Chronic hepatitis frequently occurs after liver transplantation. The role of hepatitis C virus infection in patients after liver transplantation is unknown, although antibodies to HCV are detected in some of these cases. The use of polymerase chain reaction techniques for the detection of hepatitis C virus RNA should improve sensitivity and specificity, particularly in these immunosuppressed patients. Our goal was to further clarify the role of hepatitis C virus infection in chronic hepatitis occurring after liver transplantation. Patients with chronic hepatitis of uncertain origin after transplantation were identified. Serum samples taken at the time of the most recent liver biopsy that showed chronic hepatitis were tested for anti-hepatitis C virus using enzyme-linked immunoassay and supplemented by recombinant immunoblot assay (recombinant immunoblot assay I and recombinant immunoblot assay II). The samples were also tested for the presence of hepatitis C virus RNA using polymerase chain reaction. Of the 25 patients with chronic hepatitis, 15 (60%) had hepatitis C virus RNA present. Only seven (47%) of these 15 patients had anti-hepatitis C virus detected. Hepatitis C virus is a major cause of chronic hepatitis occurring after liver transplantation. The magnitude of hepatitis C virus infection will be underestimated if only currently available assays for anti-hepatitis C virus are used. (Hepatology 1992; 15:42-45).
Ultrastructural identification of light microscopic giant mitochondria in alcoholic liver disease
Authors: Inagaki Takao , Kobayashi Susumu , Ozeki Norio , Suzuki Masahiro , Fukuzawa Yoshitaka , Shimizu Kazuhito , Kato Katsuhisa , Kato Katsumi
Published: March 2007

Ultrastructural identification of light microscopic giant mitochondria was performed on the same specimens for light and electron microscopic observations. The liver tissue specimens were fixed in OsO4, embedded in epoxy resin, cut 4 μm thick and stained with polychrome. At the beginning of the study a light microscopic observation was made, and a microphotograph was taken. The identification of light microscopic giant mitochondria by conventional microscopy was identified by the occupation rate in liver cells, the negative findings of stainability and the morphological consistency (round, cigar-shaped and granular). The specimens were subsequently embedded again in epoxy resin and cut into ultrathin sections of 400 Å. A transillumination electron microscope was used for the observation, and ultrastructural images of light microscopic giant mitochondria revealed that they were crystalloid bodies with a crystalline latticelike structure. The occupation rates within liver cells and the morphological shapes of the crystalloid bodies corresponded with those of light microscopic giant mitochondria. The light microscopic giant mitochondria obviously had different features from those of electron microscopic giant mitochondria and Mallory bodies (Yokoo’s type II), although Mallory bodies showed the same staining properties as light microscopic giant mitochondria. (Hepatology 1992; 15:46-53).
Graft regeneration and host liver atrophy after auxiliary heterotopic liver transplantation for chronic liver failure
Authors: Willemse Pierre J. A. , Ausema Lambert , Terpstra Onno T. , Krenning Eric P. , Ten Kate Fibo W. J. , Schalm Solko W.
Published: March 2007

We studied the size of the liver graft and the host liver in six consecutive patients undergoing auxiliary heterotopic liver transplantation for chronic endstage liver disease. In all cases, a liver reduced in size by left lateral hepatectomy was inserted. The sizes of the graft and host liver were estimated by planimetry of two-dimensional di-isopropyl iminodiacetic acid scintigrams taken 3, 7, 21, 90 and 180 days after surgery.

Graft size increased from a mean of 12.2 cm2 (95% confidence interval = 10.2 to 14.1) on day 3 to a maximum of 14.8 cm2 (95% confidence interval = 13.4 to 16.1) on day 21 and remained stable thereafter; in contrast, the host liver decreased in size from 9.6 cm2 (95% confidence interval = 6.8 to 12.3) on day 3 to 3.9 cm2 (95% confidence interval = 3.0 to 4.8) at mo 6.

We conclude that in patients with chronic liver failure, an auxiliary allograft reduced in size and placed adjacent to the host liver shows regenerative growth within 3 wk, whereas the host liver atrophies in 3 to 6 mo. (Hepatology 1992;15:54-57).
Sclerotherapy vs. esophageal transection vs. distal splenorenal shunt for the clinical management of esophageal varices in patients with child class A and B liver function: A prospective randomized trial
Authors: Kitano Seigo , Iso Yasunori , Hashizume Makoto , Yamaga Hirohiko , Koyanagi Nobuhiro , Wada Hiroya , Iwanaga Tetsuya , Ohta Masayuki , Sugimachi Keizo
Published: March 2007

Ninety-six patients with good liver function (Child class A or B) and esophageal varices were randomly assigned to one of three groups given different treatments: endoscopic injection sclerotherapy (n = 32), esophageal transection (n = 32) or distal splenorenal shunt (n = 32). Five patients (5.2%) had to be excluded from this study because severe chronic pancreatitis made separation of the distal splenic vein from the pancreatic bed difficult. Esophageal transection was performed for these patients.

No deaths occurred during the 30 days of treatment. The 5-yr cumulative bleeding rates were 0%, 5.9% and 12.9% in the endoscopic injection sclerotherapy, esophageal transection and distal splenorenal shunt groups, respectively (no statistical significance). In no case in the three groups did death occur because of variceal bleeding. Sixteen patients died, mainly because of underlying liver disease; four were in the endoscopic injection sclerotherapy group, five were in the esophageal transection group and seven were in the distal splenorenal shunt group. No statistically significant difference in survival rate among the three groups was found.

These results show that endoscopic injection sclerotherapy is a satisfactory alternative to esophageal transection or distal splenorenal shunt for the clinical management of patients with esophageal varices. (Hepatology 1992;15:63-68).
Treatment of severe alcoholic hepatitis by infusion of insulin and glucagon: A multicenter sequential trial
Authors: Trinchet Jean-Claude , Balkau Beverley , Poupon Renée E. , Heintzmann François , Callard Patrice , Gotheil Cécile , Grange Jean-Didier , Vetter Denis , Pauwels Arnaud , Labadie Hélène , Chazouilleres Olivier , Mavier Philippe , Desmorat Hervé , Zarski Jean-Pierre , Barbare Jean-Claude , Chambre Jean-françois , Pariente Alexandre E. , Roulot Dominique , Beaugrand Michel
Published: March 2007

Severe alcoholic hepatitis is still a therapeutic challenge. It has been recently advocated that a 3-wk infusion with insulin and glucagon reduces its short-term mortality rate. A multicenter, randomized, single-blind, sequential trial was designed to compare this treatment with placebo. The triangular boundary was defined with α = 0.05, β = 0.10 and estimated survival at 4 wk of 50% with placebo, 75% with treatment. Patients with biopsy-proven severe alcoholic hepatitis (presence of one or more of three criteria: encephalopathy, prothrombin activity ≤ 50%, bilirubinemia ≥ 100 μmol/L) were randomized into two groups; one treatment group received an infusion (12 hr/day) of an association of insulin (30 IU) and glucagon (3 mg), and a control group received an infusion of glucose. Treatments were administered during a 3-wk period, and the mortality rate was noted at 4 wk.

The decision to discontinue the trial was reached on the basis of results from the first 44 patients. Overall results were assessed in the 72 patients included at the time of this decision (treatment group: n = 37; control group: n = 35). Fifty-three patients had cirrhosis. No significant differences were noted between the two groups at inclusion on the basis of clinical, laboratory and histological criteria. The mortality rate was not significantly different in the two groups; 10 patients (27%) in the treatment group and 5 patients (14%) in the control group died. Causes of death were similar in the two groups and consisted primarily of gastrointestinal hemorrhage, hepatic failure and infectious events. Only one minor case of hypoglycemia was observed.

Treatment by the infusion of an association of insulin and glucagon is not beneficial in patients with severe biopsy-proven alcoholic hepatitis. (Hepatology 1992;15:76-81).
d-penicillamine prevents the development of hepatitis in long-evans cinnamon rats with abnormal copper metabolism
Authors: Togashi Yuji , Li Yu , Kang Jong-Hon , Takeichi Noritoshi , Fujioka Yasunori , Nagashima Kazuo , Kobayashi Hiroshi
Published: March 2007

The Long-Evans Cinnamon rat is a mutant strain that contracts hereditary hepatitis and, eventually, spontaneous hepatocellular carcinoma. Because we found a corresponding gross copper accumulation in the liver of the rats, we examined whether the development of hepatitis in our rat system could be prevented by administration of D-penicillamine. D-Penicillamine is a copper-chelating agent and one of the drugs effective for human Wilson’s disease, in which abnormal copper metabolism is also observed. The results show that D-penicillamine treatment inhibited the elevation of serum transaminases, suppressed abnormal histological changes in the liver and completely prevented the onset of hepatitis in the Long-Evans Cinnamon rats. We further found that the copper concentration in the liver and serum copper and ceruloplasmin levels were decreased, whereas the urinary copper level was increased in the D-penicillamine—treated Long-Evans Cinnamon rats. These findings demonstrate that the pathogenesis of hereditary hepatitis in Long-Evans Cinnamon rats is due to abnormal copper accumulation in the liver. (Hepatology 1992;15:82-87).
The acute-phase response protects mice from D-galactosamine sensitization to endotoxin and tumor necrosis factor-α
Authors: Alcorn Joseph M. , Fierer Joshua , Chojkier Mario
Published: March 2007

D-Galactosamine is an hepatocyte-specific inhibitor of RNA synthesis. It has been used to sensitize animals both to the lethal effects of bacterial endotoxin (lipopolysaccharide) and to a principal lipopolysaccharide-induced mediator of shock, tumor necrosis factor-α. The mechanism by which this sensitization occurs is unknown. Because lipopolysaccharide, acting through a network of cytokines, provokes the transcription of a number of hepatic acute-phase proteins, we postulated that the lipopolysaccharide-sensitizing effect of D-galactosamine could be caused by its inhibition of acute-phase product transcription. We confirmed that the acute-phase response to lipopolysaccharide was attenuated by simultaneous administration of D-galactosamine. However, when the acute-phase response was induced by subcutaneous turpentine 24 hr before D-galactosamine administration, the effect of D-galactosamine on circulating acute-phase reactants was negligible. Furthermore, induction of an a priori acute-phase response protected mice from both D-galactosamine/lipopolysaccharide and D-galactosamine/tumor necrosis factor-α-induced death. The turpentine-induced acute-phase response did not decrease endogenous tumor necrosis factor-α production after lipopolysaccharide, nor did it affect the clearance of larger doses of injected tumor necrosis factor-α. Thus we suggest that the acute-phase response protects against death in D-galactosamine—sensitized mice through an interaction with mediators of shock subsequent to tumor necrosis factor-α release. (Hepatology 1992;15:122-129).
The effect of liver denervation on hepatic hemodynamics during hypovolemic shock in swine
Authors: Henderson Michael J. , Mackay Gregory J. , Lumsden Alan B. , Atta Hussein M. , Brouillard Richard , Kutner Michael H.
Published: March 2007

This study tested the hypothesis that the denervated liver is more susceptible to hypovolemic shock than the normal liver. Fourteen swine, seven nondenervated and seven after liver denervation, were studied during hypovolemic shock to 50% of baseline blood pressure. Hepatic artery and portal vein flows were measured using transonic flow probes, and cardiac output and central venous pressure were measured using Swan-Ganz catheters. Hepatic artery flow fell equivalently in the two groups, from 132 ± 71 to 94 ± 17 ml/min in the nondenervated group compared with 149 ± 56 to 91 ± 55 ml/min in the denervated group. In contrast, portal flow in the denervated group (276 ± 71 to 119 ± 53 ml/min) fell significantly (p < 0.001) more than in the nondenervated group (289 ± 135 to 194 ± 70 ml/min). The 58% reduction from baseline in portal flow in the denervated group compared with the 30% reduction in the nondenervated group suggests that the normal compensatory mechanism to maintain portal flow during hypovolemic shock is neurally mediated. It can be hypothesized that sensory afferent fibers might initiate a feedback to splanchnic vasodilatation in response to reduced portal flow. This study supports the hypothesis that the denervated liver is more susceptible to hypovolemic shock. (Hepatology 1992;15:130-133).
Intracellular calcium-mediated activation of hepatic Na+/H+ exchange by arginine vasopressin and phenylephrine
Authors: Anwer Sawkat M. , Atkinson James M.
Published: March 2007

The effect of Ca+ + mobilizing agonists arginine vasopressin and phenylephrine on Na+/H+ exchange was studied in freshly isolated hepatocytes and isolated perfused rat livers. The activity of Na+/H+ exchange was determined from the rate of H+ efflux, 22Na uptake and pHi recovery. Arginine vasopressin and phenylephrine stimulated H+ efflux and 22Na uptake in isolated rat hepatocytes and increased the rate of pHi recovery from acid-loaded hepatocytes. These effects were inhibited by amiloride. Arginine vasopressin- and phenylephrine—induced increases in H+ efflux were also dependent on extracellular Na+. Arginine vasopressin- and phenylephrine—induced increases in intracellular Ca+ + concentration, H+ efflux, 22Na uptake and intracellular pH recovery were decreased in hepatocytes preloaded with the Ca+ +-buffering agent [bis-(2-amino-5-methylphenoxy)-ethane-N,N,N′,N′-tetraacetic acid] (MAPTA). Na+/H+ exchange-dependent intracellular pH recovery from cytosolic acidification was stimulated by thapsigargin, which increases intracellular calcium concentration by inhibiting endoplasmic reticulum Ca+ + ATPase. Arginine vasopressin- and phenylephrine—induced increases in intracellular pH recovery were not dependent on extracellular Ca+ + and were inhibited by calmidazolium, a calmodulin inhibitor. Arginine vasopressin and phenylephrine also increased H+ efflux in the absence but not in the presence of amiloride in perfused rat livers without affecting biliary HCO3
− excretion. These results indicate that arginine vasopressin and phenylephrine activate Na+/H+ exchange in rat hepatocytes, an effect mediated in part by intracellular Ca+ + and calmodulin kinase. Furthermore, sinusoidal Na+/H+ exchange does not appear to be involved in biliary HCO3
− excretion. (Hepatology 1992;15:134-143).
The clinical significance of molecular variation within the hepatitis B virus genome
Authors: Brown Jonathan L. , Carman William F. , Thomas Howard C.
Published: March 2007

Although HBV has a circular DNA genome that is partially double stranded, it replicates by means of an RNA intermediate. The process is catalyzed by a translation product of the polymerase open reading frame that has reverse transcriptase activity. The enzyme is found in association with the virion and achieves a high rate of nucleotide misincorporation during transcription because such enzymes lack proofreading activity. The virus is remarkable for its efficient use of nucleic acid because the genome is only 3.2 kb long and yet it encodes four groups of proteins and their regulatory elements (1). This is achieved in some regions by reading the sequence through different frames to direct the synthesis of distinct proteins from the same genetic material. Only a few of the mutations that occur during the normal replication cycle therefore permit the entry of a new virus to the pool for natural selection. Nevertheless, patients with chronic hepatitis have been shown to have viruses with different sequences cocirculating, and some regions of the genome are poorly conserved between different isolates (2).

The existence of patients with evidence of HBV replication but no evidence of liver disease, both in the early phase of acute infection (3) and in some chronic infections (4), has led to the suggestion that the virus is not directly cytopathic but that it is the immune response to infected liver cells that causes the hepatitis (5). The development of polymerase chain reaction (PCR) sequencing techniques has allowed us to determine whether sequence variation occurs under host selection and offers an explanation for the variable outcome of HBV infection.
Further insights into sinusoidal organic anion uptake
Authors: Gumucio Jorge J. , Moseley Richard H.
Published: March 2007

Previous studies in cultured rat hepatocytes revealed that initial uptake of sulfobromophthalein (BSP) was markedly reduced upon removal of Cl− from the medium. In the present study, unidirectional Cl− gradients were established in short-term cultured rat hepatocytes and their effect on BSP uptake was determined. These investigations revealed that BSP uptake requires external Cl− and is not stimulated by unidirectional Cl− gradients, suggesting that BSP transport is not coupled to Cl− transport. In contrast, BSP transport is stimulated by an inside-to-outside OH− gradient, consistent with OH− exchange or H+ cotransport. As the presence of Cl− is essential for but not directly coupled to BSP transport, binding of 35S-BSP to hepatocytes was determined at 4° C. This revealed an ˜ 10-fold higher affinity of cells for BSP in the presence as compared to the absence of Cl− (Ka + 3.2 ± 0.8 vs. 0.42 ± 0.09 μM−1; P < 0.02). Affinity of BSP for albumin was Cl−-independent, and was ˜ 10% of its affinity for cells in the presence of Cl−. These results indicate that extracellular Cl− modulates the affinity of BSP for its hepatocyte transporter.
Fragmentation of bile duct stones by extracorporeal shock-wave lithotripsy: A five-year experience
Authors: Sauerbruch Tilman , Holl Joseph , Sackmann Michael , Paumgartner Gustav
Published: March 2007

Over 5 yr, 103 elderly patients (mean age = 70 yr) with bile duct stones (mainly not amenable to endoscopic extraction) underwent adjuvant extracorporeal shock-wave lithotripsy using a first-generation kidney lithotripter. Disintegration of stones was achieved after a mean of 1.4 sessions in 92% of the patients. Spontaneous passage of fragments into the duodenum occurred in one fourth of the patients, and endoscopic extraction of fragments was necessary in 75% of the patients, resulting in complete clearance of the bile duct stones in 91 (88%) of 103 patients. The most important adverse effect was septic disease after extracorporeal shock-wave lithotripsy in 4% of the patients. The 30-day mortality rate was 1% (one patient), and another 15 patients died during a mean follow-up of 26 ± 14 mo (mainly of causes unrelated to biliary tract disease). Two of 91 patients who had been rendered stone free were readmitted because of recurrent stone disease during the follow-up period. Of the 43 patients who still had their gallbladders during extracorporeal shock-wave lithotripsy, 14% subsequently underwent cholecystectomy.

These data show that extracorporeal shock-wave lithotripsy of bile duct stones is a useful and safe adjunct to nonsurgical procedures for the removal of calculi in the biliary tree. (Hepatology 1992;15:208-214).
Prognostic features and role of liver transplantation in severe corticosteroid-treated autoimmune chronic active hepatitis
Authors: Sanchez-Urdazpal Luis , Czaja Albert J. , van Hoek Bart , Krom Ruud A. F. , Wiesner Russell H.
Published: March 2007

To identify prognostic features and to define the role of liver transplantation in severe autoimmune chronic active hepatitis, findings before and after corticosteroid therapy in 111 patients were correlated with outcome and compared with the findings in 24 patients who had been selected independently for liver transplantation. Patients whose condition deteriorated during corticosteroid treatment were younger (32 ± 3 yr vs. 43 ± 2 yr; p < 0.02) than those who experienced remission, but no individual features predicted outcome. Patients in whom therapy failed required longer durations of continuous treatment than did those who experienced remission (60 ± 14 mo vs. 20 ± 12 mo; p = 0.001). Of 13 patients who did not experience remission within 4 yr, 9 (69%) ultimately deteriorated. Ascites developed more often in those patients whose therapy failed and who died of liver failure than in counterparts who survived (86% vs. 33%). Patients undergoing transplantation were similar to those whose treatment failed, but they died less frequently (8% vs. 56%, p < 0.01). Indeed, the 5-yr survival rate after transplantation was comparable to that of patients who had entered remission (92% vs. 100%). Successive biopsy samples failed to disclose recurrent autoimmune hepatitis after transplantation. Human leukocyte antigens Al, B8 occurred more commonly in patients in whom treatment failed or who underwent transplantation (70% vs. 41%, p < 0.05). We conclude that failure to achieve remission within 4 yr and the human leukocyte antigen Al, B8 phenotype are associated with poor prognosis. Manifestations of liver decompensation, such as ascites, in patients who have been unable to experience remission justify consideration of transplantation. Transplantation improves the survival of patients with features of treatment failure, and it is not associated with recurrent disease. (Hepatology 1991;15:215-221).
Isolated hepatic lipocytes and kupffer cells from normal human liver: Morphological and functional characteristics in primary culture
Authors: Friedman Scott L. , Rockey Don C. , McGuire Richard F. , Maher Jacquelyn J. , Boyles Janet K. , Yamasaki Glenn
Published: March 2007

The development of techniques for isolating hepatic lipocytes (Ito, stellate or fat-storing cells) from rodents has been instrumental in defining their role in hepatic vitamin A storage and fibrogenesis. In this study, we developed a method for the purification of lipocytes and Kupffer cell from wedge sections of normal human liver and examined their properties in primary culture. Sections of donor liver (400 to 600 gm) harvested but not used for transplantation were perfused in situ with University of Wisconsin solution and used for lipocyte isolation within 48 hr. Cells were isolated by catheter perfusion of the wedge through several large vessels with L-15 salts, Pronase and collagenase, followed by Larex density gradient centrifugation. Lipocytes were plated on either uncoated plastic or a basement membrane-like gel. Lipocyte and Kupffer cell yields were 2.3 ± 0.6 × 105 and 8.6 ± 1.4 × 105 cells, respectively, per gram of liver (n = 5). Lipocyte purity was 91% as assessed by vitamin A autofluorescence, and Kupffer cell purity was 83% as determined by uptake of fluorescinated staphylococci. Lipocytes cultured on the plastic spread within 48 to 72 hr, displaying slightly more heterogeneous retinoid droplet size than comparable rat cells; on a basement-membrane gel, the cells remained aggregated and spherical with occasional spindlelike extensions. Lipocytes on plastic expressed procollagens I and III, collagen IV and laminin by immunocytochemistry, and types I, III and IV procollagen messenger RNAs by RNAse protection, Northern blot and polymerase chain reaction, respectively. Transmission electron microscopy of lipocytes at 7 days demonstrated a prominent rough endoplasmic reticulum and contractile filaments. Scanning electron microscopy revealed a smooth cell surface with perinuclear droplets beneath the cell membrane. With continued primary culture on plastic (more than 7 days), cells appeared “activated” (i.e., increased spreading and diminished retinoid droplets) and began proliferating as assessed by nuclear autoradiography and [3H]thymidine incorporation. Kupffer cells observed by scanning electron microscopy in early primary culture displayed prominent membrane ruffling and lamellipodia. In summary, we have established a reproducible method for the isolation and primary culture of human lipocytes and Kupffer cells. (Hepatology 1992;15:234-243).
Treatment of hepatocellular carcinoma associated with advanced cirrhosis by transcatheter arterial chemoembolization using autologous blood clot: A preliminary report
Authors: Gunji Toshiaki , Kawauchi Nobuo , Ohnishi Shin , Ishikawa Takashi , Nakagama Hitoshi , Kaneko Takashi , Moriyama Takashi , Matsuhashi Nobuyuki , Yazaki Yoshio , Imawari Michio
Published: March 2007

Twenty-two patients with hepatocellular carcinoma were treated by a new method of transcatheter arterial chemoembolization using an autologous blood clot as an embolizing agent. All had underlying advanced cirrhosis (14 Child’s class B and 8 Child’s class C patients). The median follow-up interval was 11 mo (range = 2 to 30 mo). The results of the treatment were compared with those of conventional chemoembolization using gelatin sponge particles for 19 Child’s class B patients as historical controls. The survival rate for Child’s class B patients treated by the new procedure estimated by the Kaplan-Meier method was 100% at 2 yr, whereas the survival rate for Child’s class B patients treated by conventional chemoembolization was 89% at 1 yr and 72% at 2 yr. The survival rate for Child’s class C patients was 75% at 1 yr and 50% at 2 yr. Side effects such as pyrexia of more than 38° C or an elevation of the serum bilirubin level of more than 1.5-fold were less common in patients treated by the new method than in those treated by conventional chemoembolization, and thus the new procedure could be performed even for Child’s class C patients. The autologous blood clot did not collapse the hepatic arteries even when the embolization was performed repeatedly, and thus fine collateral vessels feeding recurrent hepatocellular carcinoma did not develop. The results suggest that the new chemoembolization using an autologous blood clot is a promising therapeutic procedure in the management of hepatocellular carcinoma associated with advanced cirrhosis.
Vascular adhesion molecules in acute and chronic liver inflammation
Authors: Volpes Riccardo , van den Oord Joost J. , Desmet Valeer J.
Published: March 2007

Adhesion to and penetration through the sinusoidal vascular endothelium is a mandatory step for leukocyte migration and accumulation at sites of liver inflammation. This leukocyte trafficking is controlled by interactions between adhesion molecules on leukocytes and corresponding ligands on endothelial cells.

We have analyzed the in situ distribution of two recently described vascular adhesion molecules (i.e., endothelial leukocyte adhesion molecule-1 and vascular cell adhesion molecule-1) and of the lymphocyte “homing” receptor cluster of differentiation antigen-44 in normal and inflamed liver biopsy specimens. Endothelial leukocyte adhesion molecule-1 and vascular cell adhesion molecule-1 were absent from normal liver tissue, but they were strongly expressed on sinusoidal lining cells in inflammatory liver diseases. Endothelial leukocyte adhesion molecule-1 expression predominated diffusely throughout the liver parenchyma in acute hepatitis; in contrast, vascular cell adhesion molecule-1 was mainly expressed in areas of periportal and intralobular inflammation in chronic active and persistent hepatitis. The “homing” receptor cluster of differentiation antigen-44 was weakly expressed on scattered mononuclear cells and on sinusoidal lining cells in normal liver tissue, but it was strongly up-regulated on mononuclear inflammatory cells and sinusoidal lining cells in acute and chronic hepatitis. In addition, reactivity for the cluster of differentiation antigen-44 was found on the membranes of variously sized clusters of hepatocytes in biopsy specimens with acute hepatitis.

De novo or up-regulated expression of these adhesion molecules on sinusoidal lining cells in inflamed liver biopsy specimens indicates that these cells actively modulate their phenotype in response to environmental factors, thus playing a key role in the recruitment of leukocytes in acute and chronic liver inflammation. (Hepatology 1992;15:269-275).
Evidence that an iron chelator regulates collagen synthesis by decreasing the stability of procollagen mRNA
Authors: Ikeda Hitoshi , Wu George Y. , Wu Catherine H.
Published: March 2007

Iron chelation has been shown previously to decrease collagen synthesis at a posttranslational level by inhibiting prolyl 4-hydroxylase, one of the key enzymes in collagen metabolism. On the other hand, recent in vivo studies of iron overload in rats suggest that iron could specifically activate collagen gene expression in liver tissues. These findings led us to investigate whether iron chelation might also affect collagen gene expression and posttranslational modification. Our data indicate that α,α′-dipyridyl, an iron chelator, at a concentration of 1 mmol/L, decreased steady-state levels of type I procollagen messenger RNA by 42% (p < 0.001) without affecting β-actin messenger RNA levels. Nuclear runoff studies demonstrated that transcription of the type I procollagen gene was unchanged by α,α′-dipyridyl. However, the turnover rate of type I procollagen messenger RNA was increased by 30%. This pretranslational inhibition of collagen synthesis was not due to decreased lipid peroxidation, because thiobarbituric acid-reactive substances were unchanged by α,α′-dipyridyl. However, cycloheximide totally abolished the effect, indicating that de novo protein synthesis was required. (Hepatology 1992;15:282-287).
The effect of bile salts on carbonic anhydrase
Authors: Milov David E. , Jou Wou-Seok , Shireman Rachel B. , Chun Paul W.
Published: March 2007

Bile salts are potent inhibitors of bovine carbonic anhydrase and human carbonic anhydrase I and human carbonic anhydrase II. To further characterize the binding of bile salts to carbonic anhydrase, rate constants for the CO2 hydration reaction in the presence of deoxycholate, cholate, glycocholate and taurocholate were determined using stop-flow experments. Values for the Michaelis-Menton dissociation constant for bovine carbonic anhydrase, human carbonic anhydrase I and human carbonic anhydrase II were found to be 5.2, 9.2 and 13.2 mmol/L, respectively. The inhibition constant values for the various bile salts tested ranged from 0.1 to 1 mmol/L for bovine carbonic anhydrase, 1.6 to 2.4 mmol/L for human carbonic anhydrase I and 0.09 to 0.7 mmol/L for human carbonic anhydrase II. Our results suggest a mechanism of noncompetitive carbonic anhydrase inhibition for bile salts.

Bile-salt binding to carbonic anhydrases as measured by scanning molecular sieve chromatography resulted in an increase in partition radius, molecular volume and surface area. The partition radius increased from 24 Å to 28 Å in the presence of 2.5 mmol/L sodium deoxycholate at critical micelle concentration. As determined by sedimentation equilibrium measurements, approximately 1 gm of carbonic anhydrase will bind 0.03 gm of deoxycholate, suggesting three to six binding sites for bile salt on the carbonic anhydrase molecule. The conformational changes and inhibition of carbonic anhydrases resulting from bile-salt binding may be important to the regulation of enzymatic activity in tissues along the enterohepatic circulation; by limiting bicarbonate availability this interaction may also contribute to the metabolic derangements seen in patients with cholestatic liver disease. (Hepatology 1992;15:288-296).
Changes in transcripts of basement components during rat liver development: Increase in laminin messenger RNAs in the neonatal period
Authors: Reif Shimon , Sykes Donald , Rossi Thomas , Weiser Milton M.
Published: March 2007

The expression of laminin and type IV collagen messenger RNA in rat liver was investigated in relation to liver development. Levels of messenger RNA for laminin chains A, B1 and B2, and α1 and α2 chains of type IV collagen were studied by Northern-blot and dot-blot analysis. Although the expression of messenger RNAs for laminin B1 and B2 chains was higher in 19-day gestational fetal liver when compared with the adult, the highest level was detected in 15-day newborns. This finding coincides with the final establishment of the mature liver. Laminin A messenger RNA was not detected in the 19-day gestational fetus or in the neonatal period. In contrast, α1-(IV) and α2-(IV) collagen messenger RNAs maintained high levels in the early neonate and then decreased gradually after 15 days. Our findings suggest that during late stages of liver ontogeny the main components of liver basement membrane proteins undergo a significant alteration in their synthesis. The data further suggest that laminin may play a role in the final stages of hepatic differentiation.
Regulation of perfluorooctanoic acid-induced peroxisomal enzyme activities and hepatocellular growth by adrenal hormones
Authors: Thottassery Jaideep , Winberg Lloyd , Youssef Jihan , Cunningham Michael , Badr Mostafa Z.
Published: March 2007

A wide variety of compounds, including hypolipidemic drugs, plasticizers and other industrial chemicals, have been found to cause liver enlargement and hepatic peroxisome proliferation by mechanisms that are unclear. Although thyroid and sex hormones have been shown to modulate the hepatic response to these chemicals, the role of adrenal hormones in these phenomena is not clear, and a few studies have produced conflicting data. Therefore this study was undertaken to investigate the role of adrenal hormones in hepatomegaly and peroxisomal enzyme induction caused by peroxisomal proliferators and to further delineate the interrelationship between these parameters. Because adrenalectomy alters hepatic drug metabolism, we have used the nonmetabolizable proliferator perfluorooctanoic acid. Our data show that hepatomegaly caused by perfluorooctanoic acid depends on corticosterone, the major glucocorticoid in rodents. Liver growth caused by perfluorooctanoic acid appears to be predominantly hypertrophic in nature, and DNA synthesis in response to perfluorooctanoic acid predominates in periportal regions of the liver lobule. Data also show that although induction of peroxisomal β-oxidation by perfluorooctanoic acid is independent of adrenal hormones, induction of catalase is dependent on the presence of these hormones. This study supports the contention that induction of activities of various peroxisomal enzymes is controlled by different regulatory mechanisms.
Temporal relationship of peripheral vasodilatation, plasma volume expansion and the hyperdynamic circulatory state in portal-hypertensive rats
Authors: Colombato Luis A. , Albillos Agustin , Groszmann Roberto J.
Published: March 2007

Peripheral vasodilatation and plasma volume expansion are required to generate the hyperdynamic circulatory state observed in portal hypertension. To determine which of these factors is the initial event and to assess their temporal relationship with the development of hyperdynamic circulation, we sequentially measured plasma volume (by125I-albumin dilution), cardiac index (by thermodilution), mean arterial pressure (by catheterization), superior mesenteric and iliac arterial flows (by Doppler flowmetry) and calculated total and regional peripheral resistances in portal-hypertensive rats.

Experimental groups were studied from day 1 through day 4 after portial portal-vein ligation (n = 110) or sham operation (n = 111). Decreased total peripheral resistance was detected within a day of portal-vein ligation (4.18 ± 0.21 mm Hg · min · ml−1.·100 gm vs. 5.19 ± 0.16 mm Hg · min · ml−1100 gm; p <0.01). Plasma volume increased significantly on day 2 (4.31 ± 0.07 ml · 100 gm−1vs. 3.86 ± 0.04 ml · 100 gm−1; p <0.05). Cardiac index and regional blood flows increased in parallel with plasma volume elevation. On day 4, maximum values of plasma volume (4.49 ± 0.08 ml · 100 gm−1vs. 3.73 ± 0.03 ml · 100 gm−1) coincided with fully developed hyperdynamic circulation, as shown by a significant elevation in cardiac index (32.3 ± 0.6 ml · min−1.100 gm−1vs. 25.5 ± 1.2 ml · min−1· 100 gm−1), iliac and mesenteric blood flow.

On day 1, vasodilatation was present in the iliac arterial circulation. In contrast, the superior mesenteric artery vascular bed showed vasoconstriction in response to the portal outflow block. Vasodilatation of the superior mesenteric artery bed was delayed until day 4, the time point at which plasma volume is maximally expanded.

In portal hypertension, peripheral vasodilatation is the first hemodynamic event in the development of hyperdynamic circulation. Vasodilatation is detectedfirst in the nonsplanchnic circulatory bed and precedes plasma volume expansion, which is then required for the development of the hyperdynamic circulatory state.
Pathogenesis of arterial hypotension in cirrhotic rats with ascites: Role of endogenous nitric oxide
Authors: Clària Joan , Jiménez Wladimiro , Ros Josefa , Asbert Mónica , Castro Anna , Arroyo Vicente , Rivera Francisca , Rodés Joan
Published: March 2007

Nitric oxide is a vasodilator tonically secreted by endothelial cells that is involved in the regulation of arteriolar tone. This study, which includes two protocols, was performed to investigate whether nitric oxide plays a role in the pathogenesis of arterial hypotension in cirrhosis with ascites. In protocol 1, the administration of increasing doses (25, 50, 250, 500 and 1,000 μg · kg−1 · min−1) of the nitric oxide biosynthesis inhibitor Nω-nitro-L-arginine to 18 conscious rats with cirrhosis and ascites produced, at each dose tested, a significantly greater increase in arterial pressure than in 17 conscious control rats. At the lowest dose of Nω-nitro-L-arginine, arterial pressure significantly rose in cirrhotic rats but not in controls. In protocol 2, arterial pressure, estimated renal plasma flow, glomerular filtration rate and sodium excretion were measured in 12 cirrhotic rats with ascites and 10 control rats before and during the sequential infusion of previously selected doses of Nω-nitro-L-arginine (25, 50 and 250 μg · kg−1 · min−1). Changes in arterial pressure reproduced those observed in protocol 1. In control rats, Nω-nitro-L-arginine caused a decrease in estimated renal plasma flow without affecting glomerular filtration rate or sodium excretion. In contrast, Nω-nitro-L-arginine administration to cirrhotic animals did not produce any appreciable renal vasoconstrictor effect, and it increased glomerular filtration rate and sodium excretion. These results, which indicate that cirrhotic rats show enhanced sensitivity to the pressor effect of nitric inhibition, support the contention that an increased systemic release of nitric oxide in cirrhosis with ascites contributes to the arterial hypotension present in this condition. In addition, they suggest that nitric oxide does not play a major role in the maintenance of renal hemodynamics in cirrhosis. (Hepatology 1992;15:343-349).
Treatment of refractory ascites: Is dialytic ultrafiltration better than paracentesis?
Authors: Badalamenti Salvatore , Salerno Francesco
Published: March 2007

We compared the clinical efficacy and safety of large-volume paracentesis and dialytic ultrafiltration in the treatment of refractory ascites in cirrhotic patients. A group of cirrhotic subjects (age 49-80 years) were randomly allocated to either continuous paracentesis (1-1.5 l/hour) or dialytic ultrafiltration until disappearance of ascites. Each patient was maintained on bed rest, fluid restriction (1 l/day) and a low (25 mmol/day) sodium diet for 14 days. Five patients (three in the paracentesis group and two in dialytic ultrafiltration group) developed massive ascites 3-5 months later, and received the crossover treatment. The average volume of fluid removed was similar in the two groups (4.70 ± 1.47 l for dialytic ultrafiltration versus 4.69 ± 1.84 l for paracentesis), but the treatment period was significantly shorter with dialytic ultrafiltration. The plasma creatinine significantly increased three days after paracentesis but did not increase in patients treated with dialytic ultrafiltration. There was an initial fall in mean arterial pressure during the first two hours of either treatment; a further fall in blood pressure was observed with paracentesis but not with dialytic ultrafiltration. Pretreatment plasma renin activity was elevated, but was not altered by either treatment. Plasma atrial natriuretic peptide levels were in the high-normal range before treatment. Paracentesis was associated with a delayed fall in plasma atrial natriuretic peptide, while dialytic ultrafiltration induced a modest but significant rise. No complication was experienced with dialytic ultrafiltration in the two weeks following treatment, but four of the eight patients who underwent paracentesis had developed severe complications. Dialytic ultrafiltration of ascitic fluid is a safe procedure in cirrhotic patients. Large-volume paracentesis without intravenous colloid reinfusion causes complications and carries the potential risk of reducing the effective intravascular volume.
Polyunsaturated lecithin prevents acetaldehyde-mediated hepatic collagen accumulation by stimulating collagenase activity in cultured lipocytes
Authors: Li Jianjun , Kim Cho-Il , Leo Maria A. , Mak Ki M. , Rojkind Marcos , Lieber Charles S.
Published: March 2007

We recently found that polyunsaturated lecithin prevents ethanol from causing cirrhosis in the baboon. Because transformation of lipocytes to transitional cells plays a key role in hepatic fibrogenesis in vivo, and because this process in alcohol-fed baboons was found to be attenuated by polyunsaturated lecithin, we focused on lipocytes to study the mechanism of the protective effect. Rat lipocytes cultured on plastic undergo spontaneous activation, accompanied by expression of α-smooth muscle actin isoform and production of substantial amounts of type I collagen. The latter was further increased on incubation with acetaldehyde. This in vitro model was used here to study how acetaldehyde-mediated collagen production and accumulation can be turned off. Addition of polyunsaturated lecithin (10 μmol/L) was found to prevent the acetaldehyde-induced increase in collagen accumulation by 83% (p < 0.001). By contrast, a saturated phospholipid (10 μmol/L dilauroyl phosphatidylcholine), a monounsaturated one (10 μmol/L linoleoylpalmitoyl phosphatidylcholine) or linoleic acid (20 μmol/L bound to albumin) had no such effect. Incorporation of [3H]proline into collagen and the expression of ä-1 (I) procollagen mRNA were increased by acetaldehyde; the latter was not significantly affected by polyunsaturated lecithin. Polyunsaturated lecithin increased lipocyte collagenase activity by 100% (p < 0.001), whereas dilauroyl phosphatidylcholine, linoleoyl-palmitoyl phosphatidylcholine and linoleic acid had no such action. We concluded that (a) polyunsaturated lecithin selectively prevents the acetaldehyde-induced increase in collagen accumulation in lipocyte cultures, whereas other phospholipids or linoleate have no such effect; and (b) polyunsaturated lecithin does not modify the acetaldehydemediated increase in ä-1 (I) procollagen mRNA, but it increases collagenase activity, suggesting that the protective effect exerted by polyunsaturated lecithin against alcohol induced fibrosis in vivo is due at least in part to stimulation of collagenase activity, which may prevent excess collagen accumulation by offsetting increased collagen production. (Hepatology 1992;15:373-381).
Improved serodiagnosis of non-A, non-B hepatitis by an assay detecting antibody to hepatitis C virus core antigen
Authors: Katayama Tohru , Mazda Toshio , Kikuchi Shu , Harada Shizuko , Matsuura Yoshiharu , Chiba Joe , Ohba Hiroyoshi , Saito Izumu , Miyamura Tatsuo
Published: March 2007

We examined sequential serum samples from 12 patients with well-characterized posttransfusion non-A, non-B hepatitis who had an acute, resolving self-limited type of clinical course for the presence of antibody to the hepatitis C virus nucleocapsid (core) protein (p22) expressed by a recombinant baculovirus. These sera were simultaneously examined for antibody to the hepatitis C virus nonstructural protein (C 100-3) that is presently used for blood screening worldwide. In three patients, both anti-p22 and anti-C 100-3 antibodies were detected, but anti-p22 was detected much earlier. In four patients, only anti-p22 was detected. Two other patients were considered to be hepatitis C virus carriers who had been already infected with hepatitis C virus. In one patient, only anti-C 100-3 was detected, and it was transient. In two patients, neither antibody was detected. Anti-p22 was detected in at least one of eight samples of transfused blood. Of the nine samples of donated blood that were positive for anti-p22, only four were positive for anti-C 100-3. This new assay detecting the antibody to the p22 protein is thus useful for the serodiagnosis of non-A, non-B hepatitis in the acute phase and for blood screening. (Hepatology 1992;15:391-394).
Differences in the abundance of variably spliced transcripts for the second asialoglycoprotein receptor polypeptide, H2, in normal and transformed human liver
Authors: Paietta Elisabeth , Stockert Richard J. , Racevskis Janis
Published: March 2007

The human hepatic asialoglycoprotein receptor comprises two homologous polypeptides designated H1 and H2. Two distinct complementary DNA clones encoding these receptor subunits have been previously isolated from the human hepatoblastoma cell line HepG2. We discovered that multiple variants of H2 transcripts exist both in HepG2 cells and in the normal human liver that, at least in part, appear to be the result of alternative splicing events. We have found that (a) the complementary DNA clone for H2 previously isolated from HepG2 cells, characterized by a 57-nucleotide insertion within the 5′ end of the complementary DNA that is absent from H1, represented only one third of H2-related sequences in an unamplified normal human liver complementary DNA library and less than 10% of H2 clones in HepG2 cells; (b) the predominant message for H2 expressed in the liver and HepG2 cells, designated L-H2, appeared to represent the fully processed product of the gene encoding both L-H2 and H2; and (c) a variant H2 transcript existed in HepG2 cells, designated H2′, that contained a novel, 5′ 88-bp nucleotide insertion. Poly(A+) RNA analysis of the normal liver and HepG2 cells by complementary RNA hybridization and ribonuclease protection corroborated the observations made during the screening of complementary DNA libraries regarding the abundance of the various messages. A striking incongruity was found between the levels of messenger RNA containing the H2-specific 57-nucleotide sequence and the levels of polypeptide expressed in the liver and HepG2 cells as recognized by antiserum specifically raised against this sequence. (Hepatology 1992;15:395-402).