bluuebunny/crossref_metadata_2025 huggingface dataset:
Increased galactose clearance after liver transplantation: A measure of increased blood flow through the denervated liver?
Authors: Henderson Michael J. , Millikan William J. , Hooks Michael , Noe Beverly , Kutner Michael H. , Warren Dean W.
Published: March 2007

This study measured the liver blood flow-dependent index of galactose clearance in patients after liver transplantation, to test the hypothesis that liver blood flow is increased in the denervated liver. Eight normal subjects and 16 patients 1 to 8 months after liver transplant were studied. All patients were stable with no evidence of severe rejection at the time of study. Galactose clearance was measured at steady state during continuous infusion of 75 mg per min of 5% galactose. The results show a statistically significant (p < 0.01) higher average galactose clearance in the transplant patients (1,187 ± 316 ml per min per m2) compared to the control group (709 ± 121 ml per min per m2). The major limiting factor in galactose clearance at low concentrations is liver blood flow, and we interpret these data as evidence for increased blood flow in the transplanted liver. Possible mechanisms for the increased galactose clearance are (i) loss of normal vasomotor tone in the denervated liver, or (ii) persistence of abnormal systemic hemodynamics after transplantation. Elucidation of these mechanisms awaits further study.
Reperfusion injury to endothelial cells following cold ischemic storage of rat livers
Authors: Caldwell-Kenkel Jane C. , Currin Robert T. , Tanaka Yukio , Thurman Ronald G. , Lemasters John J.
Published: March 2007

Storage of donor livers in Euro-Collins solution for human transplantation surgery is limited to about 8 hr. Here, tissue damage to isolated rat livers stored under the same conditions as human livers was characterized following reperfusion. The purpose of this work was to determine the importance of nutritional status on injury due to cold storage and reperfusion, to establish whether lethal injury occurs during cold storage or only after reperfusion, and to identify the cell types most vulnerable to damage. Rat livers were perfused with Krebs-Henseleit-bicarbonate buffer, stored 8 to 48 hr in Euro-Collins solution and reperfused with warm, oxygenated Krebs-Henseleit buffer for 15 min. Nuclear trypan blue uptake and lactate dehydrogenase release were used as indices of cell death. After 8 hr of cold storage and reperfusion, little loss of parenchymal or nonparenchymal viability occurred. After 24 or 48 hr, virtually all parenchymal cells remained viable. However, severe damage to nonparenchymal cells was observed, and about 40% of nonparenchymal cells were trypan blue positive. Nutritional status (fed vs. fasted) did not affect the extent of cell damage. Nonparenchyma cell killing was accompanied by cellular rounding, nuclear pyknosis and protrusion of cells into sinusoidal lumens. Scanning electron micrographs demonstrated denudation of the sinusoidal lining. Rounding and pyknosis were not observed in 24-hr-stored livers which were not reperfused, and trypan blue uptake did not occur in stored livers infused with cold, anoxic Euro-Collins solution. Based on cytochemistry and electron microscopy, lethal cell injury occurred predominantly to endothelial cells. Storage of livers in University of Wisconsin cold storage solution, which has been shown to extend preservation of livers for transplantation surgery, protected endothelial cells from reperfusion injury after cold ischemic storage. The data suggest that damage to stored livers leading to graft failure after transplantation involves a reperfusion injury to hepatic endothelial cells. Identification of this injury in isolated livers by trypan blue labeling provides a rapid and inexpensive means to evaluate and improve liver preservation solutions.
Thiopental infusion in the treatment of intracranial hypertension complicating fulminant hepatic failure
Authors: Forbes Alastair , Alexander Graeme J. M. , O’Grady John G. , Keays Richard , Gullan Richard , Dawling Sheila , Williams Roger
Published: March 2007

Intracranial hypertension complicating fulminant hepatic failure has a mortality in excess of 90% in the presence of renal failure if not rapidly responsive to mannitol and ultrafiltration. Based on data which suggest that barbiturates can be of value in controlling the intracranial hypertension of head injury, intravenous thiopental was assessed in 13 patients with fulminant hepatic failure. All had developed acute renal failure complicated by intracranial hypertension unresponsive to other modes of therapy and were likely by all published criteria to have little chance of survival. The dosage of thiopental was adjusted incrementally until intracranial pressure, measured by extradural transducers, fell to within normal limits or adverse hemodynamic changes occurred. The intracranial pressure was reduced, in each case, by 185 to 500 mg (median: 250 mg) thiopental given over 15 min, and in eight cases continuing infusion achieved stable normal intracranial pressure and cerebral perfusion pressure. Five of the patients made a complete recovery and there were only three deaths from intracranial hypertension. Side effects were few and included minor hypotension controlled by dose reduction. The response of otherwise intractable intracranial hypertension and the 38% survival rate are remarkable for a group of patients with such a poor prognosis.
Combined hepatitis B immune globulin and vaccine for postexposure prophylaxis of accidental hepatitis B virus infection in hemodialysis staff members: Comparison with immune globulin without vaccine in historical controls
Authors: Mitsui Takehiro , Iwano Keiko , Suzuki Shigeru , Yamazaki Chikao , Masuko Kazuo , Tsuda Fumio , Aihara Shinobu , Akahane Yoshihiro , Miyakawa Yuzo , Mayumi Makoto
Published: March 2007

Twenty-three staff members serving in a hemodi-alysis unit were exposed accidentally to needlestick contaminated with blood containing hepatitis B surface antigen and hepatitis B e antigen, as well as high levels of DNA polymerase activity (< 100 cpm). They received hepatitis B vaccine (20 μg) simultaneously with hepatitis B immune globulin (5 ml, 200 IU per ml) within 48 hr after the exposure, and the vaccination was repeated at 1 and 3 months. The protective efficacy was compared with that in a past study in the same unit in which 33 members were given hepatitis B immune globulin alone within 48 hr after the exposure to blood with similarly high levels of DNA polymerase activity. No differences were noted in age or sex between the staff members who were vaccinated and those who were not, nor were there any differences between their inocula in the titers of hepatitis B virus markers. During 12 months after the accident, only one (4%) of the 23 vaccinated members contracted hepatitis B virus infection, at a frequency significantly lower than 11 (33%) of the 33 members who did not receive vaccine (p < 0.02). These results indicate that hepatitis B vaccine, when given in combination with hepatitis B immune globulin, is efficacious for postexposure immunoprophylaxis of accidental infection.
A controlled trial of human lymphoblastoid interferon in chronic hepatitis B in Italy
Authors: Saracco Giorgio , Mazzella Giuseppe , Rosina Floriano , Cancellieri Claudio , Lattore Valter , Raise Enzo , Rocca Giuseppe , Giorda Laura , Verme Giorgio , Gasbarrini Giovanni , Barbara Luigi , Bonino Ferruccio , Rizzetto Mario , Roda Enrico
Published: March 2007

Sixty-four heterosexual Italian carriers of HBsAg with chronic HBeAg and hepatitis B virus DNA-positive hepatitis were assigned randomly either to receive human lymphoblastoid interferon (injections of 5 million units per m2 three times per week for 6 months) or to serve as untreated controls. After 18 months of followup evaluation, 26 of the 33 treated patients (79%) had cleared hepatitis B virus DNA, 23 (70%) had lost HBeAg and 20 (61%) had seroconverted to anti-HBe. Fifteen of the 31 controls (48%) had cleared hepatitis B virus DNA (p = 0.01), 12 (39%) had lost HBeAg and nine (29%) had seroconverted to anti-HBe (p = 0.002). Eight treated patients but only one control had lost HBsAg and seroconverted to anti-HBs (24% vs. 3%, p = 0.01). Treated patients cleared hepatitis B virus markers after a mean interval of 4 months, compared with 8 months in the controls.

All responders to interferon cleared intrahepatic HBcAg, and 50% showed histological improvement. The baseline hepatitis B virus DNA levels and the original histology were not predictive of a response to therapy; women appeared to respond better than men. Lymphoblastoid interferon provides an effective therapy in the heterosexual Italian patient with chronic hepatitis B.
Adoptive immunotherapy with lymphokine-activated killer cells plus recombinant interleukin 2 in patients with unresectable hepatocellular carcinoma
Authors: Onishi Saburo , Saibara Toshiji , Fujikawa Masanao , Sakaeda Hiroshi , Matsuura Yasushi , Matsunaga Yoichi , Yamamoto Yasutake
Published: March 2007

Ten patients with hepatocellular carcinoma, three of whom had pulmonary metastasis, were treated with adoptive immunotherapy using autologous lymphokine-activated killer cells plus recombinant interleukin 2. Patients received 15 μg per day of recombinant interleukin 2 consecutively (for 14 to 64 days), from Day 7 prior to the first leukapheresis, and received 109 to 1010 lymphokine-activated killer cells once or twice per week intravenously; the lymphokine-activated killer cells had been generated from mononuclear cells obtained through leukapheresis. Preadministration of recombinant interleukin 2 prior to the first leukapheresis resulted in a remarkable increase of lymphokine-activated killer activity in seven of nine cases in whom lymphokine-activated killer activity had been poorly inducible even at high concentrations of recombinant interleukin 2. At the end of the treatment, liver tumor regression (34 and 63%, respectively, of two-dimensional size) was observed in two of two patients with a solitary tumor; no increase of liver tumor size was observed in seven patients with massive or multiple tumors, and no changes in the size or number of pulmonary metastatic tumors in any patients were observed. More than a 35% decrease in serum α-fetoprotein level was noted in four of nine α-fetoprotein-positive patients. However, Child’s grades, performance status and lymphokine-activated killer activity on entry into the study could not be used as parameters to predict therapy responsiveness. Neither serious side effects nor significant changes of serum bilirubin, ALT and creatinine were noted. Thus, this treatment seems to be well tolerated even in advanced hepatocellular carcinoma with poor liver function reserve, and tumor regression could be expected in small-burden hepatocellular carcinoma. The assessment of the therapeutic effects and application in hepatocellular carcinoma awaits the development of this trial.
Antimitochondrial antibodies in primary biliary cirrhosis recognize both specific peptides and shared epitopes of the M2 family of antigens
Authors: Flannery Graham R. , Burroughs Andrew K. , Butler Patrice , Chelliah Jeyananthan , Hamilton-Miller Jeremy , Brumfitt William , Baum Harold
Published: March 2007

Sera from patients with primary biliary cirrhosis exhibit variable autoantibody reactivity against mitochondria, the commonest antigen (designated M2) including three structures of approximate M.W. 70, 50 and 40 kD. The nature of these antigens has only recently been established; the 70 and 50 kD are the transacetylase E2 and component X, respectively, of the pyruvate dehydrogenase complex and are distinct polypeptides. We have demonstrated, by immunoblotting, elution and rebinding of antibodies, unequivocal cross-reactivity between the major bands of the M2 antigen. In addition, cross-reactivity has been shown between antibodies binding to each of the three M2 bands of mitochondria and two major antigenic bands of both Gram-negative and Gram-positive bacteria. Conversely, antibodies eluted from these two bands of Escherichia coli were found to bind all three M2 bands of mitochondria. These results suggest that the antibodies of primary biliary cirrhosis contain both peptide-specific and cross-reacting antibodies, the latter recognizing a common “M2 epitope” that might include nonprotein components of the peptides. However, direct and competitive enzyme-linked immunosorbent assays failed to implicate the coenzyme of the pyruvate dehydrogenase complex, lipoic acid or its amide, as the common antigenic moiety.
Identity of the M2 autoantigens in primary biliary cirrhosis
Authors: Mackay Ian R. , Rowley Merrill J. , McD. Armstrong John
Published: March 2007

Primary biliary cirrhosis (PBC)-specific antigens were purified from beef heart mitochondria by immunoaffinity chromatography. Three major polypeptides (75, 60, and 40 kDa) were detected in the purified antigen fraction both by Coomassie blue staining and by western blot analysis. The 75 kDa antigen was identified as a subunit of Complex I (NADH-ubiquinone reductase) by the following criteria: (1) antibodies against the purified 75 kDa subunit of beef heart Complex I react with the immunoaffinity-purified 75 kDa antigen, (2) the 75 kDa subunit present in isolated Complex I, like that in the immunoaffinity-purified antigen, reacts with PBC sera only after reduction with mercaptoethanol, and (3) the 75 kDa antigen is enriched in isolated Complex I. A relationship between the 75 kDa and the 60 and 40 kDa antigens is suggested, since optimal binding of anti-mitochondrial autoantibodies (AMA) to the latter antigens also requires prior reduction with mercaptoethanol. A fourth major antigen (70 kDa) was also detected by western blot analysis, but only in samples that had not been boiled prior to electrophoresis. This antigen, which is also present in isolated Complex I, resembles the 75, 60, and 40 kDa antigens in its response to mercaptoethanol and its reaction with antibodies against the 75 kDa subunit of Complex I. A scheme is presented which relates all of the PBC antigens to the parent 75 kDa subunit of Complex I, probably as proteolytic products of the latter.
Drug-binding proteins after liver transplantation: Are they significant?
Authors: Tredger Michael J. , Williams Roger
Published: March 2007

In patients with liver disease, the synthesis of drug-binding proteins may be impaired. After liver transplantation, levels of drug-binding proteins are unknown. Consequently, concentrations of albumin and α-acid glycoprotein (AAG) were measured in stable patients after liver transplantation. Albumin levels were decreased from normal (4.5 ± 3 gm per dl) in patients with liver disease before (3.4 ± 0.7) and after transplantation (3.4 ± 0.8). AAG levels were decreased from normal (67 ± 20 mg per dl) in patients with liver disease (46 ± 22) but were higher than normal after transplantation (121 ± 28). AAG is an acutephase reactant, the synthesis of which may have been stimulated by the surgical procedure. The effect of these changes on drug metabolism was not studied.
Frequency of IgG and IgM autoantibodies to four specific M2 mitochondrial autoantigens in primary biliary cirrhosis
Authors: Mutimer David J. , Fussey Shelley P. M. , Yeaman Stephen J. , Kelly Peter J. , James Oliver F. W. , Bassendine Margaret F.
Published: March 2007

We have previously identified four of the M2 antigens in primary biliary cirrhosis as the E2 components (dihydrolipoamide acyltransferases) of pyruvate dehy-drogenase complex, branched-chain 2-oxo acid dehy-drogenase complex and 2-oxoglutarate dehydrogenase complex and the protein X component of pyruvate dehydrogenase complex (approximate molecular masses: 74, 50, 50 and 52 kD, respectively). In the present study, we have examined by immunoblotting the frequency of IgG and IgM autoantibodies to these four proteins in 129 patients with primary biliary cirrhosis (36 histological Stage I, 42 Stage II/III, 51 Stage IV) and 77 controls (49 non-primary biliary cirrhosis chronic liver disease, 16 primary Sjögren’s syndrome, 12 healthy normal women). One hundred twenty-seven of 129 (98%) primary biliary cirrhosis patients had antibodies against at least one of the four M2 polypeptides, compared to 2/77 controls (both had autoimmune chronic active hepatitis and were antimitochondrial antibody positive by indirect immunofluorescence). One hundred twenty-one of 129 (94%) primary biliary cirrhosis sera reacted with the E2 component and protein X of pyruvate dehydrogenase complex, 69/129 (53%) primary biliary cirrhosis sera reacted with E2 of branched-chain 2-oxo acid dehydrogenase complex and 113/129 (88%) reacted with E2 of 2-oxoglutarate dehydrogenase complex. Primary biliary cirrhosis patients with histological Stage I disease had a lower incidence of autoantibodies to each M2 protein, compared to more advanced disease (IgG, p < 0.05) but only 2/36 Stage I patients had no anti-M2 antibodies. There was no correlation between the presence of IgG or IgM antibodies to the M2 polypeptides and established prognostic markers in primary biliary cirrhosis (serum bilirubin and albumin levels). The specificity of autoantibodies to the E2 components of all three 2-oxo acid dehydrogenase complexes for primary biliary cirrhosis suggests that a common mechanism or immunological defect underlies the development of this autoimmune disease.
Defective immunoregulation in primary biliary cirrhosis: CD4+, Leu-8+ T cells have abnormal activation and suppressor function in vitro
Authors: Suou Takeaki , Civeira Maria P. , Kanof Marjorie E. , Moreno-Otero Ricardo , Jones Anthony E. , James Stephen P.
Published: March 2007

To determine whether abnormalities of lymphocyte function in primary biliary cirrhosis are due to altered function of immunoregulatory T cell subpopulations, phenotypic and functional characteristics of CD4+ T cells were examined. The proportion of CD4+ T cells expressing the Leu-8 and CD45R antigens was normal in patients with primary biliary cirrhosis. The capacity of CD4+, Leu-8-T cells to provide helper function for pokeweed mitogen-stimulated immunoglobulin synthesis by B cells in vitro was similar in patients and controls. However, in contrast to normal individuals and patients with other liver diseases, CD4+, Leu-8+ T cells from six of 10 patients with primary biliary cirrhosis did not suppress, but enhanced immunoglobulin synthesis. Whereas treatment of CD4+ T cells from normal individuals with anti-Leu-8 monoclonal antibody enhanced their suppressor function, similar treatment of CD4+ T cells from patients with primary biliary cirrhosis did not increase their suppressor function. To determine whether the abnormal regulatory function of CD4+, Leu-8+ T cells was due to a defect of cell activation, the proliferative response of CD4+ T cell subpopulations to mitogenic stimulation was examined. The proliferative responses of CD4+, Leu-8-T cells from patients with primary biliary cirrhosis and controls were similar, but the proliferative responses of CD4+, Leu-8+ T cells from patients with primary biliary cirrhosis were lower than those of control cells. Since the CD4+, Leu-8+ T cell population plays a role in suppressing immunoglobulin synthesis and is contained within the autoreactive T cell population, the abnormal function of this T cell subpopulation in some patients with primary biliary cirrhosis may play a role in defective immunoregulation found in this disease.
A pilot, double-blind, controlled 1-year trial of prednisolone treatment in primary biliary cirrhosis: Hepatic improvement but greater bone loss
Authors: Mitchison Harriet C. , Bassendine Margaret F. , Malcolm Archie J. , Watson Alex J. , Record Christopher O. , James Oliver F. W.
Published: March 2007

A randomized, double-blind, 1-year pilot study of prednisolone treatment for primary biliary cirrhosis was undertaken. Nineteen patients received 30 mg prednisolone per day initially, with a maintenance dose of 10 mg per day. Seventeen patients received placebo. The groups were matched for age, menopausal status, hepatic histological stage and bilirubin.

Treatment was well tolerated without dropouts. Two patients receiving prednisolone developed diabetes, one a duodenal ulcer and one depression. One patient receiving placebo died of liver failure after 3 months.

Cholestatic symptoms (itch and fatigue) improved on prednisolone. There was significant (prednisolone vs. placebo) improvement in transaminase (p = 0.0214), alkaline phosphatase (p = 0.0032), procollagen III peptide (p = 0.0103), immunoglobulin G (p = 0.0012) and liver histology (p = 0.016); these changes were greatest among noncirrhotic patients.

No patient developed skeletal symptoms. Fifty-seven per cent had abnormal triolein breath tests prior to treatment, and 65% had abnormally low calcium absorption tests. Calcium absorption increased significantly in the treated group vs. placebo at 2 weeks (p < 0.02), but not at 1 year. Femoral photon absorptiometry fell in the prednisolone group after 1 year (-3.5% vs. placebo +0.5%, p < 0.05), as did trabecular bone volume (-6% vs. -2.8%, p < 0.005) and resorption surface (-11% vs. +2%, p < 0.02) on serial bone biopsy.

Prednisolone seems to exert a favorable hepatic effect in primary biliary cirrhosis but at the expense of increased bone loss to approximately twice the expected rate. Prednisolone treatment merits further assessment in primary biliary cirrhosis over a longer period, with attention to selection of patients most likely to benefit and continuing observation of bone mass to better establish the “cost/benefit” ratio.
Portal hypertension and ascites in acute hepatitis: Clinical, hemodynamic and histological correlations
Authors: Valla Dominique , Flejou Jean-François , Lebrec Didier , Bernuau Jacques , Rueff Bernard , Salzmann Jean-Louis , Benhamou Jean-Pierre
Published: March 2007

We attempted to ascertain the mechanism of portal hypertension and ascites complicating acute hepatitis in 66 patients who underwent transvenous liver biopsy and measurement of hepatic venous pressure gradient. Increase in hepatic venous pressure gradient was related to the severity of acute hepatitis, as indicated by the significant correlation between the values for hepatic venous pressure gradient and serum bilirubin, serum albumin or coagulation factor V, and by its higher value in patients with, than in patients without, encephalopathy. Hepatic venous pressure gradient was higher in patients with, than in patients without, ascites (12.5 ± 3.4 vs. 8.4 ± 3.6 mmHg, respectively; p < 0.001). No ascites was clinically detectable in the patients in whom hepatic venous pressure gradient was below 6 mmHg.

We tested the hypothesis that sinusoidal collapse due to liver cell dropout was a major factor in portal hypertension. Semiautomatic determination of the fractional area of sinusoidal collapse on chromotrope-stained sections and automatic measurement of Sirius red-stained collagen fiber density were performed. Hepatic venous pressure gradient significantly correlated with fractional sinusoidal collapse area (r = 0.61, p < 0.001) and with Sirius red-stained collagen fiber density (r = 0.43, p < 0.01).

We conclude that portal hypertension in the course of acute hepatitis is related to the severity of liver damage and is a major factor in the development of ascites. Portal hypertension is mainly determined by intrahepatic vascular space being reduced by the collapse of sinusoids.
Successful endoscopic obturation of gastric varices with butyl cyanoacrylate
Authors: Ramond Marie-Jose , Valla Dominique , Mosnier Jean-François , Degott Claude , Bernuau Jacques , Rueff Bernard , Benhamou Jean-Pierre
Published: March 2007

In 27 patients who had bled from esophagogastric varices, large-sized and/or actively bleeding gastric varices were endoscopically obturated with the tissue adhesive butyl cyanoacrylate. Active bleeding was stopped in six patients. Rebleeding occurred in 10 patients; in four patients, rebleeding was due to ruptured gastric varices, occurred early and was successfully treated by reinjection of gastric varices; in one patient, rebleeding was attributed to ulceration on an injected gastric varix. Eight patients died: two of rebleeding (from esophageal varices or undetermined source), four of sepsis and/or liver failure and two at home of undetermined cause. No specific complication due to injection of gastric varices was observed. The results obtained in this series of patients with gastric varices obturated by injection of butyl cyanoacrylate are much more satisfactory than those obtained in previously published series of patients with gastric varices treated by injection of sclerosants.
Ubiquitin—a common denominator in intermediate filament pathology of brain and liver?
Authors: Denk Helmut , Zatloukal Kurt , Preisegger Karl-Heinz
Published: March 2007

Polyclonal antibodies were raised which have a high affinity for conjugated ubiquitin. Immuno-cytochemistry was performed on paraffin sections of tissues showing well-characterized inclusion bodies. Ubiquitin was found as a component of the intermediate filament inclusion bodies characteristic of several major diseases including Lewy bodies of Parkinson’s disease, Pick bodies of Pick’s disease, Mallory bodies of alcoholic liver disease, cytoplasmic bodies of a specific myopathy, and Rosenthal fibres within astrocytes. Ubiquitin was also present in the three histological lesions characteristic of Alzheimer’s disease. These observations suggest a fundamental role for ubiquitin in the formation of intermediate filament inclusion bodies in man, and have implications regarding the pathogenesis of these important diseases.
Aplastic anemia after liver transplantation for fulminant viral hepatitis: Black boX or bag of worms?
Authors: Zeldis Jerome B.
Published: March 2007

Aplastic anemia developed in 9 of 32 patients (28 percent) undergoing orthotopic liver transplantation for acute non-A, non-B hepatitis, at one to seven weeks after the procedure. No patient previously had evidence of hematologic dysfunction or conditions known to be associated with aplastic anemia. No other cases of aplastic anemia were identified among 1463 patients undergoing liver transplantation for all other indications at the four centers participating in the study (chi-square = 415, P < 0.001; 95 percent confidence interval for the incidence of aplastic anemia after transplantation for non-A, non-B hepatitis, 13 to 44 percent, vs. 0.00 to 0.13 percent for all other indications).

The operative and postoperative treatment of these patients was not otherwise different, indicating that the aplastic anemia was a complication of the hepatitis, not of the transplantation proce- dure. Four of the nine patients died of complications due to infections. Three of the surviving patients have been followed for less than six months, one for one year, and one for two years. The two patients followed the longest have recovered marrow function to an appreciable degree, and two of the others have evidence of early recovery.

We concluded that patients undergoing ortho-topic liver transplantation for non-A, non-B hepatitis are at a high risk for the development of aplastic anemia.
Which Patients With Chronic Hepatitis B Virus Infection Will Respond to α–Interferon Therapy? A Statistical Analysis of Predictive Factors
Authors: Brook Gary M. , Karayiannis Peter , Thomas Howard C.
Published: March 2007

Twenty–one pretreatment variables were assessed for their significance in response prediction using data from 114 patients given α–interferon for chronic hepatitis B virus infection. In those patients who had received a minimum of 90 million units per m2 total dose over 12 weeks, a negative anti–human immunodeficiency virus antibody status (p < 0.001), chronic active hepatitis on liver biopsy (p < 0.005), high AST level (p < 0.001), low hepatitis B virus DNA level (p < 0.001) and a history of acute hepatitis (p < 0.005) were all associated with an increased likelihood of response on univariate analysis. On stepwise logistic regression analysis, hepatitis B virus DNA, AST and a history of acute hepatitis predicted response independently (p < 0.05). The most reliable combination of predictive factors was a negative anti–human immunodeficiency virus antibody status, with either a positive history of acute icteric hepatitis and AST > 45 IU per liter or no history of acute icteric hepatitis and AST > 85 IU per liter, which predicted response in 77% with a specificity of 79% (p < 0.001). The loss of HBsAg in addition to HBeAg and hepatitis B virus DNA was more likely to occur in patients with chronic infection of <2 years duration (p < 0.001).
Tissue–Specific Activity of Heterologous Viral Promoters in Primary Rat Hepatocytes and Hep G2 Cells
Authors: Xian-Jun Fang , Keating Armand , de Villiers Jean , Sherman Morris
Published: March 2007

In preparation for studies using gene transfer, we have identified transcriptional control elements which are active in primary rat hepatocytes. We used plasmids which were constructed so that the promoter or enhancer of interest initiated transcription of the bacterial chloramphenicol acetyltransferase (CAT) gene. Plasmids were introduced into primary rat hepatocytes in culture, into Hep G2 cells and other human and animal cell lines and into bone marrow stromal cells, and CAT activity was assayed after 48 hr.

In primary rat hepatocytes, the highest CAT activity was obtained with plasmids carrying the Rous sarcoma virus long terminal repeat (pRSVCAT), or the SV40 early region promoter and enhancer (pSV2CAT). Hepatocytes carrying the murine cytomegalovirus immediate early promoter (pUCRNmCMVX/HCAT) also had appreciable CAT activity. No CAT activity was detected in rat hepatocytes carrying pSVOCAT (a promoterless construct), pUCRNtKCAT (herpes simplex thymidine kinase gene promoter), pLPVCAT (lymphocytotrophic papovavirus promoter) and pHBV1CAT (hepatitis B virus enhancer and core gene promoter). Therefore, for future studies of gene transfer in primary rat hepatocytes, the Rous sarcoma virus long terminal repeat or the SV40 early region promoter and enhancer can be effectively used to drive gene expression.

Hep G2 cells carrying pHBV1CAT had high CAT activity. Hep G2 cells carrying pHBV2CAT (similar to pHBV1CAT, but with the hepatitis B virus sequences in reverse orientation with respect to the CAT sequences) and pHBV3CAT (similar to pHBV2CAT, but hepatitis B virus sequences are separated from the CAT sequences by about 700 bases) also expressed CAT activity, but not as strongly as with pHBV1CAT. The hepatitis B virus enhancer and core gene promoter were also active in human nonliver cell lines but were virtually inactive in nonhuman cell lines.
Endotoxin–Induced Ascites Formation in the Rat: Partial Mediation by Platelet–Activating Factor
Authors: Guarner Francisco , Wallace John L. , Macnaughton Wallace K. , Ibbotson Geoffrey C. , Arroyo Vicente , Rodés Joan
Published: March 2007

Systemic endotoxemia has been observed in patients with acute and chronic liver failure, and bacterial endotoxin is known to increase vascular permeability. We investigated in the normal rat the effects of intraportal endotoxin administration and the possible mediation of these effects by platelet–activating factor. Injection of endotoxin lipopolysaccharide (10 and 25 mg per kg) in the rat resulted in rapid ascites formation, as well as systemic hypotension, hemoconcentration and acute erosions of the gastrointestinal mucosa. These effects were significantly attenuated by pretreatment with L652,731 and CF–3988, specific platelet–activating factor antagonists. Administration of 25 mg per kg endotoxin also resulted in significant elevations of plateletactivating factor biosynthesis in vitro by samples of duodenum, liver and lung. The effects of endotoxin were mimicked by intraportal infusion of platelet–activating factor (50 ng per kg per min), which induced ascites and gastrointestinal lesions. Platelet–activating factor reduced circulating plasma volume and increased peritoneal permeability to albumin as assessed by the ascites to plasma ratio of labeled albumin. These results, therefore, support a role for platelet–activating factor in mediating endotoxin–induced ascites and gastrointestinal erosions.
Assessment of Mitochondrial Function in Vivo With A Breath Test Utilizing α—Ketoisocaproic Acid
Authors: Michaletz Patrice A. , Cap Ludèk , Alpert Elliot , Lauterburg Bernhard H.
Published: March 2007

A breath test to assess hepatic mitochondrial function in vivo was evaluated in rats. Following the i.p. administration of [1–14C]–α–ketoisocaproic acid, 14CO2 exhalation reached a peak within 10 to 20 min and then declined exponentially, with a half–life of 14.3 min. Control animals exhaled 38.6% of the administered radioactivity within 1 hr. In functionally anhepatic animals, 14CO2 in breath amounted to 23% of that in control animals, indicating that α–ketoisocaproic acid decarboxylation reflects mainly hepatic mitochondrial function in vivo. Ethanol (3 gm per kg) significantly decreased α–ketoisocaproic acid decarboxylation (21.8% of the dose appearing in breath in 1 hr), probably due to the ethanol–induced shift in the NAD+:NADH ratio. In contrast, an uncoupler of mitochondrial respiration, sodium salicylate (375 mg per kg), increased the decarboxylation of α—ketoisocaproic acid (56.3% of the dose recovered as 14CO2 in 1 hr). Mitochondrial damage induced by 4–pentenoic acid decreased the decarboxylation of α–ketoisocaproic acid but did not affect the microsomal metabolism of antipyrine. The present data indicate that the α–ketoisocaproic acid breath test provides a noninvasive estimate of hepatic mitochondrial function in vivo which, when applied to man, might yield clinically useful information.
Presymptomatic Wilson's Disease: Further Questions and Comments
Authors: Conn Harold O. , Epstein Owen
Published: March 2007

In ninety families with at least one proven case of Wilson's disease, seen over 32 years, all close relatives were examined and “presymptomatic” disease was diagnosed in 30.11 had one or more abnormal physical signs when examined and 7 of these had Kayser Fleischer rings. In a further 10 patients the abnormalities of copper metabolism were so pronounced as to leave no doubt as to the diagnosis. 6 patients were not seen until they had been on treatment for 2 years or more; in some, much of the evidence on which the diagnosis was based is not available. In 3 patients there were only minor histological abnormalities in the liver and no increase in urinary copper but other indices of copper metabolism pointed to a diagnosis of Wilson's disease. 2 patients had transient neurological signs after starting treatment; otherwise, all but one (who died in an accident) have remained well for up to 26 years.
99MTc–Disida Vs. Endoscopic Biliary Manometry in Assessing Sphincter of Oddi Function
Authors: Bar-Meir Simon , Chamovitz David
Published: March 2007

Sphincter of Oddi (SO) dysfunction is a recognised cause of postcholecystectomy pain, but a difficult condition to diagnose, requiring endoscopic biliary manometry (EBM) to confirm sphincter motor abnormalities. We have assessed quantitative cholescintigraphy in 19 postcholecystectomy (PC) patients with clinical and manometric evidence of SO dysfunction, 10 PC patients with non–biliary type abdominal pain and 10 asymptomatic PC volunteers acting as controls to determine its value as a non–invasive screening test. Quantitative 99mTc–DISIDA scans lasted 60 minutes, activity/time curves being created by computer analysis using the entire hepatobiliary system as region–of–interest (ROI). Scintigraphic analysis demonstrated that the time in minutes to maximum counts (Tmax) was significantly increased in the SO dysfunction group compared with the non–biliary pain group and the asymptomatic volunteers (p < 0.001). The per cent of biliary tracer emptied was also significantly less in the SO dysfunction group than either of the other groups at both 45 minutes (p < 0.01) and 60 minutes (p < 0.02). We conclude that quantitative cholescintigraphy may be a valuable non–invasive screening test in clinically suspected SO dysfunction.
Soluble Interleukin 2 Receptor in Acute Viral Hepatitis and Chronic Liver Disease
Authors: Müller Christian , Knoflach Peter , Zielinski Christoph C.
Published: March 2007

Serum levels of soluble interleukin 2 receptor were determined in patients with acute viral hepatitis and patients with various chronic liver diseases. In addition, the ability of peripheral blood mononuclear cells of patients with alcoholic cirrhosis to generate soluble interleukin 2 receptor following mitogenic stimulation was studied in vitro. Serum soluble interleukin 2 receptor concentrations in all patients with acute viral hepatitis were found to be significantly elevated (1,319 ± 527 units per ml) during the first week after onset of disease, as compared to healthy control individuals (375 ± 102 units per ml; p < 0.0005) and declined toward normal levels during the course of the illness. Similarly, patients suffering from chronic liver disease such as alcoholic liver cirrhosis (1,172 ± 507 units per ml), primary biliary cirrhosis (619 ± 190 units per ml) or chronic active HBsAg+ hepatitis (941 ± 357 units per ml) showed increased serum soluble interleukin 2 receptor concentrations (p < 0.0005 vs. controls, respectively). In vitro mitogen stimulation of peripheral mononuclear cells derived from patients with alcoholic cirrhosis resulted in a soluble interleukin 2 receptor production not different from that seen in healthy individuals, suggesting that elevated soluble interleukin 2 receptor production not different from that seen in healthy individuals, suggesting that elevated soluble interleukin 2 receptor serum levels seen in this disease are not the result of an increased synthesis by circulating lymphocytes. Due to the ability of soluble interleukin 2 receptor to bind free interleukin 2—thus making it a potential immunoregulatory molecule—its high serum levels could explain some of the immunologic abnormalities observed in acute and chronic liver disease.
Effect of Ethanol on Splanchnic Hemodynamics in Awake and Unrestrained Rats With Portal Hypertension
Authors: Verma-Ansil Bikram , Carmichael Frederick J. , Saldivia Victor , Varghese George , Orrego Hector
Published: March 2007

Alcoholic liver disease is frequently accompanied by portal hypertension. We have previously shown that alcohol intake in awake, unrestrained rats is followed by an increase in portal tributary blood flow. In this study, the effect of ethanol on splanchnic hemodynamics in rats with portal hypertension was analyzed. Portal hypertension was induced by partial ligation of the portal vein. This procedure resulted in an increase in portal tributary and hepatic arterial blood flows compared to sham–operated animals. Ethanol (2 gm per kg, oral) increased portal tributary blood flow in both sham–operated and portal vein–ligated rats (sham + water = 37.6 ± 1.4; sham + ethanol = 63.1 ± 1.9; p < 0.01; partial portal vein stenosis + water = 53.2 ± 3.3; partial portal vein stenosis + ethanol = 69.5 ± 2.2 ml · kg-1. min-1; p < 0.01). In sham–operated rats, hepatic artery blood flow was unchanged following ethanol (sham + water = 6.6 ± 0.7; sham + ethanol = 7.1 ± 1.0 ml · kg-1. min-1), whereas in portal vein–ligated rats, flow was increased (partial portal vein stenosis + water = 13.7 ± 1.4; partial portal vein stenosis + ethanol = 19.8 ± 1.1 ml · kg-1 · min-1; p < 0.025). The adenosine receptor blocker 8–phenyltheophylline suppressed only the ethanol–induced increase in both portal tributary and hepatic artery blood flows in portal vein–ligated rats. The increases in hepatic artery and portal tributary blood flows observed in portal vein–ligated rats without ethanol were not influenced by 8–phenyltheophylline. In conclusion, the increase in portal tributary and hepatic artery blood flow following partial portal vein ligation is not adenosine mediated. We have now shown that, in portal hypertension, ethanol further increases portal tributary blood flow. Contrary to what is seen in normal and sham–operated rats, in portal hypertension, ethanol also increases hepatic arterial blood flow. Both the portal and arterial blood flow effects of ethanol appear to be adenosine mediated.
Fasting Plasma Caffeine Level in Cirrhotic Patients: Relation to Plasma Levels of Catecholamines and Renin Activity
Authors: Hasegawa Mayumi , Yamada Sadako , Hirayama Chisato
Published: March 2007

Fasting plasma caffeine concentrations, plasma levels of catecholamines and plasma renin activity were measured in patients with cirrhosis and control patients without hepatic dysfunction. A careful dietary history showed no significant difference in caffeine consumption (mean ± S.E.) among 46 cirrhotics (86 ± 7 mg per day) vs. 34 control patients (91 ± 8 mg per day). Fasting plasma caffeine concentrations, however, were significantly higher (7.68 ± 1.42 μg per ml) in cirrhotics than in controls (1.01 ± 0.20 μg per ml) (p < 0.01). Fasting plasma caffeine concentrations in cirrhotics varied significantly with Child's criteria, namely Child's A patients (2.06 ± 0.38 μg per ml); Child's B patients (6.92 ± 1.86 μg per ml), and Child's C patients (17.70 ± 3.65 μg per ml) (p < 0.001). In 44 cirrhotics, fasting plasma caffeine concentrations were compared with plasma levels of catecholamines and plasma renin activity. Plasma epinephrine concentrations were normal; however, plasma norepinephrine concentrations were increased in six cirrhotics, and plasma renin activities were increased in 28 cirrhotics. After a 3–day caffeine abstinence, plasma caffeine concentration and renin activity were significantly decreased (p < 0.01), and high plasma norepinephrine levels were also decreased in 12 cirrhotics. Plasma caffeine concentration, renin activity and norepinephrine level did not change in a control group of cirrhotics who continued to receive caffeine for 3 days (n = 6). After abstinence from caffeine, the decrease of fasting plasma caffeine concentration correlated well with the decrease of plasma renin activity (r = +0.746, p < 0.01). These results suggest that high levels of plasma renin activity and norepinephrine in cirrhosis are in part related to habitual intake of beverages with caffeine.
Bile Concentration Is A Key Factor for Nucleation of Cholesterol Crystals and Cholesterol Saturation Index in Gallbladder Bile of Gallstone Patients
Authors: Van Erpecum Karel J. , Berge Van Henegouwen Gerard P. , Stoelwinder Bregt , Schmidt Yvonne M.G. , Willekens Frans L.H.
Published: March 2007

We investigated whether bile concentration influenced cholesterol saturation index or nucleation time of cholesterol monohydrate crystals in a large number of gallbladder bile samples. Pigment stone patients never had cholesterol crystals in their fresh biles, and nucleation time was always longer than 20 days. Of the cholesterol stone patients 79% had cholesterol crystals in their fresh biles. Long nucleation times were generally found in cholesterol stone patients with dilute biles despite a high cholesterol saturation index. Nucleation time was usually short if bile was well concentrated depite a relatively low saturation index. Serial in vitro dilution of concentrated biles from cholesterol gallstone patients resulted in progressively prolonged nucleation times. Patients with solitary cholesterol stones had longer nucleation times than patients with multiple cholesterol stones. This study indicates that bile concentration is an important factor for nucleation time and cholesterol saturation index. Moreover, solitary and multiple cholesterol stones may have a different pathogenesis. (HEPATOLOGY 1990; 11: 1-6.)
Hepatic Expression of Class I and Class Ii Major Histocompatibility Complex Molecules in Primary Biliary Cirrhosis: Effect of Ursodeoxycholic Acid
Authors: Calmus Yvon , Gane Pierre , Rouger Philippe , Poupon Raoul
Published: March 2007

Aberrant hepatic expression of HLA molecules has been shown to be present in primary biliary cirrhosis and may play a determining role in the pathogenesis of the disease. We have studied the effect of the long–term administration of ursodeoxycholic acid on hepatic HLA expression. Nine untreated patients with primary biliary cirrhosis, eight patients treated for at least a year with ursodeoxycholic acid and eight control subjects without hepatobiliary disease were compared. HLA expression was studied on liver biopsy sections using a direct immunofluorescence technique with specific monoclonal antibodies directed against class I or class II HLA molecules. Aberrant biliary HLA class II expression was not modified by chronic administration of ursodeoxycholic acid. In contrast, aberrant hepatocyte HLA class I expression was markedly reduced. Reduction in HLA class I expression may lead to decreased cytotoxic T cell–dependent lobular necrosis, which is thought to contribute to the progression of primary biliary cirrhosis to advanced stages. These findings suggest that the beneficial effect of ursodeoxycholic acid treatment in primary biliary cirrhosis could result not only from a reduction in the intrahepatic accumulation of cytotoxic bile acids but also from a reduction in immunological injury.(HEPATOLOGY 1990; 11: 12-15.)
Experimental Autoimmune Hepatitis: Disease Induction, Time Course and T–Cell Reactivity
Authors: Lohse Ansgar W. , Manns Michael , Dienes Hans-Peter , Zum Büschenfelde Karl-Hermann Meyer , Cohen Irun R.
Published: March 2007

This study describes a murine model of autoimmune hepatitis: experimental autoimmune hepatitis. Experimental autoimmune hepatitis could be induced most effectively in male C57BL/6 mice by intraperitoneal immunization with the 100,000 g superantant of syngeneic liver homogenate (S–100) in complete Freund's adjuvant. BALB/C and C3H mice were less susceptible than C57BL/6 mice. Experimental autoimmune hepatitis could not be induced in Lewis rats. Intraperitoneal immunization was more effective than intramuscular or subcutaneous injections, and the amount of protein administered above a threshold was of little influence. A single intraperitoneal injection of S–100 in complete Freund's adjuvant resulted in hepatitis of at least 6 mo duration. Histological changes were most marked 4 wk after disease induction. The histological findings were characterized mainly by perivascular inflammatory infiltrates and hepatocyte necroses. The histological changes were accompanied by biochemical evidence of liver cell death. Passive transfer of experimental autoimmune hepatitis with concanavalin. A-activated splenocytes was possible. Specific T–cell reactivity against fractions of S–100 could be demonstrated in vitro. Thus experimental autoimmune hepatitis is a murine model of autoimmune hepatitis probably mediated by autoreactive T cells. It will allow studies of the pathogenesis of autoimmune hepatitis. (HEPATOLOGY 1990; 11: 24-30.)