bluuebunny/crossref_metadata_2025 huggingface dataset:
A candidate vaccine for hepatitis B containing the complete viral surface protein
Authors: Kniskern Peter J. , Hagopian Arpi , Burke Pamela , Dunn Nancy , Emini Emilio A. , Miller William J. , Yamazaki Shigeko , Ellis Ronald W.
Published: March 2007

The entire surface protein of hepatitis B virus sero-type ayw containing the preS (preS1+preS2) and S domains has been expressed in the yeast Saccharomyces cerevisiae. Yeast containing a recombinant plasmid utilizing a constitutive promoter did not express this gene successfully due to the toxicity of the protein. A plasmid using a regulatable promoter directed expression which initiated late in the exponential phase of growth and resulted in the accumulation of high intracellular levels of the complete surface protein. The purified polypeptide aggregates into a form which, although not comprised of typical 20 nm particles, displays antigenic determinants encoded by the preS1, preS2 and S domains. Immunization of rabbits elicited the formation of antibodies directed against all three domains. This candidate vaccine will be useful for studying the contributions to viral immunity of the host response to the preS1 and preS2 domains.
Digoxin-like immunoreactive substances in severe acute liver disease due to viral hepatitis and paracetamol overdose
Authors: Yang Sien-Sing , Hughes Robin D. , Williams Roger
Published: March 2007

The levels of endogenous serum digoxin-like immunoreactive substances were investigated during development of encephalopathy in patients with fulminant hepatic failure. The 67 patients studied had varying degrees of hepatic failure as a result of viral hepatitis or paracetamol overdose. Serum levels of digoxin-like immunoreactive substances were significantly increased in both viral hepatitis and paracetamol overdose, with mean values of 0.42 ± S.D. 0.25 ng per ml (n = 36) and 0.53 ± 0.19 ng per ml (n = 31), respectively, as compared to normal control subjects with mean values of 0.01 ± 0.02 ng per ml (n = 21, p < 0.001). A statistically significant correlation was found between serum digoxin-like immunoreactive substances and the degree of encephalopathy in the viral hepatitis patients and with the serum creatinine in the paracetamol overdose patients where renal failure was more severe. No correlation was found with liver damage as assessed by the prolongation of the prothrombin time, serum AST or bilirubin values. Experiments with ultrafiltration and heating showed that both free nonprotein-bound digoxin-like immunoreactive substances and the total digoxin-like immunoreactive substances measured were increased. Column chromatography of ultrafiltrates of fulminant hepatic failure serum on Sephadex G-25 demonstrated at least two peaks with digoxin-like immunoreactive activity. Reduced renal function is an important factor in the increased serum level of digoxin-like digoxin-like immunoreactive substances, but their presence due to liver failure, where there is increased permeability of the blood-brain barrier, could be relevant to the development of hepatic encephalopathy.
Validation of viscosity measurements for canine hepatic bile
Authors: Wilson David D. , Lowensohn Howard S.
Published: March 2007

This study developed the validated standards for a known viscosity method by obtaining consistent viscosity measurements with defined precision, reproducibility and sensitivity limits for canine hepatic bile. Size 75 Cannon-Manning semimicro viscometers yielded the most precise viscosity measurements. With the development of proper handling methods for fresh bile samples, a precision defined by a coefficient of variation of ≤ ± 0.3% was obtained. To maintain viscometer constancy, the viscometers must be cleaned with chromic acid after each bile test and pass reproducibility tests using defined distilled water viscosity tests.
Persistent measles virus genome in autoimmune chronic active hepatitis: Cause or coincidence?
Authors: Black Francis L.
Published: March 2007

A radiolabelled 50-base oligonucleotide complementary with the measles virus gene encoding the nucleocapsid was used as a probe to identify persistent measles virus genome in the lymphocytes from patients with autoimmune chronic active hepatitis (AICAH). Positive hybrids were found in 12 of 18 patients, and correlated strongly with high antibody titers to measles. Among the 45 controls, positive hybrids were found in one patient with measles, 1 of 3 patients with lupus erythematosis and 2 of 4 patients with cryptogenic cirrhosis. Persistence of part of the measles virus genome in AICAH may have important implications in the pathogenesis of the liver disease, and possibly in other disorders such as systemic lupus erythematosis, multiple sclerosis and Paget’s disease where an abnormal immune response to measles has been observed.
Reye’s syndrome: Are adults big children?
Authors: Latham Patricia S.
Published: March 2007

Reye’s syndrome (RS) is generally considered a childhood disease. We report our experience with RS in adults in the metropolitan Milwaukee area. Reye’s syndrome was diagnosed in seven 18- to 46-year-old adults. The diagnostic criteria were as follows: viral prodrome followed by vomiting and encephalopathy without focal neurological signs, normal cerebrospinal fluid values, increased levels of serum aminotransferases (transaminase), prolonged prothrombin time, elevated blood ammonia levels, and characteristic microvesicular fatty liver and mitochondrial changes. None of the patients was hypoglycemic. The diagnosis of RS was entertained in 22 but confirmed in only seven patients. In cases of non-Reye’s encephalopathy, drug ingestion presented as one of the most difficult differential diagnostic problems, which also included alcohol abuse, collagen vascular disease, and hepatitis B surface antigenemia. Clinical jaundice, distinctly uncommon in RS, was present in only one patient who presented to us in stage V coma. In adults, RS is more difficult to diagnose and should be suspected more frequently in patients with unexplained altered behavior following a viral illness and vomiting. Liver biopsy can be performed safely and is usually mandatory in adults. Patients with RS diagnosed during stage I or II coma and treated experienced an uneventful recovery.
Preoperative endoscopic sphincterotomy as an adjunct to cholecystectomy for common bile duct stones
Authors: Cotton Peter B.
Published: March 2007

One hundred and twenty patients with known common bile duct stones were entered into a prospective randomised study of preoperative endoscopic sphincterotomy and stone clearance (group 1) versus surgery alone (group 2). Five patients were incorrectly entered; the 55 patients randomised to group 1 and the 60 randomised to group 2 were well matched with respect to clinical features and biochemical and medical risk factors. In group 1 endoscopic stone clearance was successful in 50 patients (91%); five of these patients refused elective surgery, though this was subsequently necessary in one. In group 2 common bile duct stones were cleared surgically in 54 of 59 patients (91.5%); one patient was treated by endoscopic sphincterotomy alone because of a myocardial infarct. The overall major complication rate in group 1 was 16.4% and included two deaths; in group 2 this was 8.5% and included one death. The minor complication rate in group 1 was 16.4% and that in group 2, 13.6%. These differences in outcome were not significant.

Despite a significant reduction in total hospital stay of patients in group 1, these results do not support the routine use of preoperative endoscopic sphincterotomy in patients having biliary surgery for stones in the common bile duct.
Survival analysis of variceal hemorrhage: Does it matter when the meter is started?
Authors: Smith Lacey J. , Graham David Y.
Published: March 2007

Variation in time of patient admission to studies of prognosis after variceal hemorrhage has been proposed as a major factor in the wide range of reported results. A study of 144 unselected subjects with a low initial mortality (3% at two days) suggests that the effect has been overemphasized and studies in which time of entry is later than the date of bleeding may be usefully compared. Reanalysis of previous work suggests that even in populations with a high initial mortality limited comparisons between studies can still be usefully made. It is stressed that survival analysis must be started from the date of study entry and not from the date of the index bleed which involves incorporating a retrospective period of survivorship.
IgA deposition and synthesis in alcoholic liver injury
Authors: Triger D. R.
Published: March 2007

Immunoglobulin deposition in alcoholic and non-alcoholic liver disease was studied using an indirect immunoperoxidase technique. A continuous pattern of IgA deposition, with IgA outlining the sinusoids, was shown to be a specific and sensitive marker for liver disease caused by alcohol in both cirrhotic and non-cirrhotic livers. The sensitivity was lowest in cases of alcoholic disease showing fatty change alone. In one case it was possible to show the absence of IgA in liver disease caused by a drug, which was histologically indistinguishable from alcoholic hepatitis.
Large-volume paracentesis in nonedematous patients with tense ascites: Its effect on intravascular volume
Authors: Pinto Paul C. , Amerian Jim , Reynolds Telfer B.
Published: March 2007

In patients with portal hypertension and tense ascites, large-volume paracentesis improves patient comfort and may improve systemic hemodynamics. However, it has been avoided in nonedematous patients because of concern for complications, including intravascular volume depletion. In this study, 12 nonedematous patients with chronic liver disease, portal hypertension and tense ascites underwent 14 large-volume (5-liter) paracenteses for the relief of discomfort and/or respiratory distress. Plasma volume was measured directly by a dilution method with 125I-labeled human serum albumin prior to and at 24 or 48 hr after 13 of the paracenteses. All patients felt better postparacentesis. No dizziness, hypotension, tachycardia, encephalopathy or change in mean serum sodium, creatinine or blood urea nitrogen occurred. Two patients experienced a decrease in hematocrit, which was not explained by blood loss or increase in plasma volume. Mean plasma volume was 3,713 ± 129 ml (55.1 ± 1.5 ml per kg ideal body weight) preparacentesis and 3,684 ± 136 ml postparacentesis, the difference being −0.78% (p = 0.48, NS). Our results suggest that 5-liter paracentesis in nonedematous patients with tense portal hypertension-related ascites improves patient comfort and is not associated with a decrease in measured plasma volume.
Is the magnetic resonance imaging proton spin-lattice relaxation time a reliable noninvasive parameter of developing liver fibrosis?
Authors: Chamuleau Robert A. F. M. , De Nie Joris H. N. Creyghton Ineke , Moerland Marinus A. , Van der Lende Otto R. , Smidt Jaap
Published: March 2007

During the development of liver fibrosis in rats by an individual dose-titrated CCl4 administration, hepatic proton spin-lattice relaxation time (T1) has been measured in vivo every 2 weeks for 8 weeks. Liver content of collagen, triglycerides and water has been measured biochemically in biopsy material.

After 4 weeks of CCl4 treatment, T1 increased signifcantly and remained at the same level, whereas liver collagen reached its maximum at 8 weeks. It is concluded that, under our experimental conditions, increased hepatic T1 represents drug-induced edema and that hepatic T1 is not a reliable noninvasive parameter for developing liver fibrosis in vivo.
Endotoxin levels measured by a chromogenic assay in portal, hepatic and peripheral venous blood in patients with cirrhosis
Authors: Lumsden Alan B. , Henderson Michael J. , Kutner Michael H.
Published: March 2007

Endotoxin concentrations were measured in the portal, hepatic and peripheral venous blood of two groups of patients with cirrhosis using a limulus-based chromogenic assay. The high sensitivity of chromogenic detection allowed measurement of endotoxin as low as 10 to 15 pg per ml, an order of magnitude greater than previously possible by gelation studies. Group 1 consisted of 56 patients with cirrhosis undergoing angiographic evaluation. In this group, there was wide variability in hepatic venous concentration [ 73 ± 110 pg per ml (mean ± S.D.)] and peripheral venous concentration [31 ± 58 pg per ml]. However, paired t test showed peripheral venous concentration was significantly (p < 0.001) lower than hepatic venous concentration. Neither hepatic or peripheral venous endotoxin levels correlated significantly with a variety of clinical, biochemical or radiological parameters. Group 2 consisted of 21 patients with cirrhosis undergoing shunt surgery. Endotoxin levels again showed a wide range, with portal venous concentration (142 ± 167 pg per ml) and simultaneous peripheral venous concentration (82 ± 150 pg per ml). Paired t test in this group showed a significant (p < 0.001) portal to peripheral venous gradient.

This study showed the feasibility of measuring endotoxin in plasma to low concentrations by a chromogenic assay technique. It supports the concept of relatively high levels of endotoxin in the portal circulation. In the presence of liver disease, systemic endotoxemia occurs, which is augmented by stressful situations.
Lobular distribution of alcohol dehydrogenase in the rat liver
Authors: Yamauchi Masayoshi , Potter James J. , Mezey Esteban
Published: March 2007

The hepatic lobular localization of alcohol dehydrogenase was determined in male, female and castrated male rats. Alcohol dehydrogenase immunoreactive protein and activity were increased in female and castrated rats as compared to normal male rats. By immunohistochemistry, alcohol dehydrogenase protein was found localized principally in the perivenous area of the hepatic lobule in all of the animals. Alcohol dehydrogenase activity eluted from the male rat liver, during bidirectional digitonin perfusion, exhibited a pattern characteristic of cytosolic enzymes predominantly localized to the perivenous area. The elution of the enzyme was more rapid during cava-porta than porta-cava perfusion occurring in close association with the elution of glucokinase, an enzyme localized principally in the perivenous area. By contrast, elution of lactate dehydrogenase, which is located predominantly in the periportal area, preceded elution of alcohol dehydrogenase during porta-cava perfusion, but followed it during cava-porta perfusion. These differences were less apparent in the cava-porta than in the porta-cava direction. The predominant localization of alcohol dehydrogenase immunoreactive protein and activity to the perivenous area of hepatic lobule was not affected by sexual difference or increase in the enzyme following castration.
Reduction by prostacyclin of acetaminophen-induced liver toxicity in the mouse
Authors: Guarner Francisco , Boughton-Smith Nigel K. , Blackwell Geoffrey J. , Moncada Salvador
Published: March 2007

The effect of prostacyclin on acetaminophen-induced liver injury has been investigated in the mouse. Two structurally unrelated thromboxane synthetase inhibitors, OKY 1581 and benzyl imidazole, were also examined in order to investigate the role of the prostacyclin-thromboxane balance in the development of hepatic lesions.

Whereas prostacyclin or OKY 1581 given shortly after acetaminophen prevented mortality and reduced liver necrosis, as assessed by serum ALT activity and histology, benzyl imidazole was only effective if given prior to acetaminophen.

Acetaminophen overdose resulted in an enhanced prostaglandin and thromboxane generation by liver homogenates. While OKY 1581 inhibited thromboxane production by the liver homogenates, prostacylcin synthesis was increased. Pretreatment with the cyclooxygenase inhibitor indomethacin blocked both the increase in prostacyclin generation and the protective effect of OKY 1581. Benzyl imidazole inhibited the synthesis of thromboxane but did not enhance prostacyclin production. In addition, the protective effect of benzyl imidazole was unaltered by indomethacin pretreatment. Furthermore, whereas benzyl imidazole interfered with hepatic drug metabolism, as assessed by prolongation of the pentobarbitone sleeping time, prostacylcin and OKY 1581 were without activity.

Prostacyclin treatment can prevent acetaminophen-induced liver necrosis in mice. Enhanced prostacyclin synthesis by the selective thromboxane synthetase inhibitor OKY 1581 also exerts a protective role in this model.
In vitro toxicity of polymorphonuclear neutrophils to rat hepatocytes: Evidence for a proteinase-mediated mechanism
Authors: Mavier Philippe , Preaux Anne-Marie , Guigui Bernard , Lescs Marie-Claude , Zafrani Elie-Serge , Dhumeaux Daniel
Published: March 2007

Human polymorphonuclear neutrophils, when exposed to soluble or particulate stimuli, can destroy various types of cells. The aim of this study was to investigate their toxicity against hepatocytes. Human polymorphonuclear neutrophils were incubated in basal conditions and after stimulation with 5 mg per ml opsonized zymosan in the presence of rat hepatocytes isolated by collagenase digestion. Cytotoxicity was quantified by the percentage of ALT activity released by hepatocytes in culture medium. Whereas unstimulated neutrophils exhibited only minor effects, opsonized zymosan-stimulated neutrophils induced, after 16 hr incubation, a 24.0 ± 4.1% (mean ± 1 S.E.) ALT activity release at a neutrophil/hepatocyte ratio of 5, and a 51.7 ± 6.8% ALT activity release at a ratio of 20. At this ratio of 20, the ALT activity release was 9.0% at 1 hr and 24.0% at 4 hr. Three proteinase inhibitors (i.e., soybean trypsin inhibitor, α1-proteinase inhibitor and fetal calf serum) decrease cytotoxicity by 78, 76 and 78%, respectively. The protective effect of proteinase inhibitors was not due to a nonspecific effect of proteins, since bovine serum albumin did not decrease the toxicity of stimulated polymorphonuclear cells. The supernatant of stimulated neutrophils was also found to be toxic against hepatocytes, and again, this effect was inhibited by soybean trypsin inhibitor, α1-proteinase inhibitor and fetal calf serum. Finally, the role of proteinases was supported by the demonstration of a cytotoxic effect of two purified proteinases: porcine pancreatic elastase and human neutrophil cathepsin G. The toxicity of these proteinases was also markedly reduced by the specific inhibitors used in the study. These results show that human polymorphonuclear neutrophils stimulated with opsonized zymosan may destroy hepatocytes through the release of proteinases. This might have important path-ophysiological implications, especially in alcoholic hepatitis in which polymorphonuclear neutrophils regularly infiltrate the liver and could therefore participate in the hepatocellular injury.
Changes in albumin, α-fetoprotein and collagen gene transcription in ccl4-induced hepatic fibrosis
Authors: Panduro Arturo , Shalaby Fouad , Biempica Luis , Shafritz David A.
Published: March 2007

In efforts to understand mechanisms of liver dysfunction in cirrhosis, transcription of specific genes important to liver function has been measured in the rat model of CCl4-induced hepatic fibrosis. The relative transcription rates of albumin, α-fetoprotein and pro-α1-collagen genes were studied during development of fibrosis and after fibrosis was established. During the initial phase of CCl4 administration, there was a decrease in albumin transcription associated with increased α-fetoprotein transcription, indicative of active liver regeneration. However, later during development of fibrosis, the response pattern of these genes was different, as albumin gene transcription was normal or increased and α-fetoprotein gene transcription was no longer increased. Three weeks after completion of CCl4 treatment (fully established cirrhosis), albumin genes responded normally or hypernormally to an acute regenerative stimulus, but the α-fetoprotein gene was again not measurably responsive. Pro-α1-collagen gene transcription increased during the entire fibrogenic process and remained elevated after cirrhosis was established. These studies suggest that a switch from albumin to α-fetoprotein gene transcription can serve as a marker of liver regenerative capacity, and that this process is altered during and after development of hepatic fibrosis. The fibrogenic process is also associated with elevated transcription of collagen genes.
Plasma levels of pipecolic acid in patients with chronic liver disease
Authors: Kawasaki Hironaka , Hori Tatsuaki , Nakajima Masako , Takeshita Kenzo
Published: March 2007

Plasma levels of pipecolic acid, which is a minor metabolite of lysine, were determined by high-performance liquid chromatography in 22 patients with chronic liver disease, composed of 6 patients with chronic active hepatitis, 11 with liver cirrhosis and 5 with hepatocellular carcinoma. The plasma levels of pipecolic acid, when compared to those in normal subjects (1.00 ± 0.08 nmoles per ml), were found to be significantly elevated (p < 0.01) in patients with liver cirrhosis (1.93 ± 0.24 nmoles per ml) and hepatocellular carcinoma (2.22 ± 0.49 nmoles per ml), but did not show any significant change in patients with chronic active hepatitis. Plasma levels of pipecolic acid correlated positively with serum bile acid and bilirubin, and negatively with indocyanine green disappearance rate, cholinesterase and prothrombin time but not with plasma lysine levels. These results suggest that plasma levels of pipecolic acid increase almost parallel to the severity of liver damage, and that this increase in pipecolic acid may reflect the injury of liver peroxisomes which appear to be related to the degradation of pipecolic acid.
The predominance of IgG3 and IgM isotype antimitochondrial autoantibodies against recombinant fused mitochondrial polypeptide in patients with primary biliary cirrhosis
Authors: Surh Charles D. , Cooper Anne E. , Coppel Ross L. , Leung Patrick , Ahmed Aftab , Dickson Rolland , Gershwin Eric M.
Published: March 2007

Autoantibodies against inner mitochondrial membrane proteins are a hallmark of primary biliary cirrhosis. Specifically, these antimitochondrial autoantibodies recognize two polypeptides of approximately 70 and 52 kD, respectively. Although the specificity of antimitochondrial autoantibodies has been studied for the past 2 decades, the complementary DNA encoding the major primary biliary cirrhosis-specific 70 kD antigen has only recently been cloned. The availability of the recombinant autoantigen has resulted in the development of a highly sensitive and specific ELISA to detect antimitochondrial autoantibodies and to determine their immu-noglobulin isotypes. We report herein that IgG3 is the predominant isotype of antimitochondrial autoantibodies in a group of 74 primary biliary cirrhosis patients. This finding is significant in light of the genomic im-munoglobulin in heavy chain gene arrangement. Ninety-three per cent of primary biliary cirrhosis patients possessed IgG3 antimitochondrial autoantibodies with ti-ters of 1:103 or higher; 32% of these patients possessed titers of 104, 29% at 103 and 7% at 106. IgM antimitochondrial autoantibodies were next most prevalent; 63% of the patients were positive and 50% of these patients showed titers of 103, 43% at 104 and 6% at 105. Other isotypes were present but in much lower titer and occurrence. Isotypes of antimitochondrial autoantibodies reactive to the 52 kD antigen were also determined using immunoblotting techniques. The predominance of IgG3 and IgM were similarly observed. Finally, the serum immunoglobulin isotype levels of primary biliary cirrhosis patients were compared with healthy normal adults by radial immunodiffusion. Serum IgG3 and IgM were very elevated in primary biliary cirrhosis; with IgG3 at 5.5-fold and IgM at 4.3-fold above normals. Moreover, IgG3 comprised an average of 17.4% of the total serum IgG in primary biliary cirrhosis compared to 4.5% in the normal population. These results are noteworthy because experimental and naturally occurring viral infections likewise lead to a predominance of IgG3 antibodies.
Regionality of glucose-6-phosphate hydrolysis in the liver lobule of the rat: Metabolic heterogeneity of “portal” and “septal” sinusoids
Authors: Teutsch Harald F.
Published: March 2007

To investigate intercellular compartmentation of liver metabolism, we have recently introduced new procedures for quantitative assessment of metabolic liver cell heterogeneity both along sinusoids of portal and septal origins as well as at the level of the parenchymal unit, and also for three-dimensional imaging of enzyme and metabolite distribution. As part of the evaluation of the role of metabolic liver cell heterogeneity for the regulation of net substrate flux in the glucose-6-phosphatase/glucokinase system, and for the reduction of glucose/glucose-6-P recycling through spatial separation of these antagonistic enzymes, these techniques were used on livers from male rats. They served to obtain distribution data on glucose-6-phosphatase (the hydrolytic component of the glucose-6-phosphatase/glucokinase system) and its substrate, glucose-6-P, during the postresorptive phase (i.e., a metabolic state of net glucose release). Glucose-6-phosphatase (Vmax) and glucose-6-P were shown to decrease along the sinusoidal axis, and values of both parameters were significantly higher along sinusoids of portal than septal origin. Distribution of in vivo rates of glucose-6-P hydrolysis indicates the importance of metabolite distribution for in vivo regulation of liver cell function, insofar as it considerably increases the degree of heterogeneity among hepatocytes over that of maximal rates of glucose formation. Histo- and microchemical data support the concept of a “lobular parenchymal unit” composed of “primary lobules,” and justify the conclusion that hepatocyte function, in addition to the hormonal and nutritional states of the animal, not only depends upon cell location along the sinusoidal axis, but also on the origin of sinusoids.
Diabetes-Induced cholestasis in the rat: Possible role of hyperglycemia and hypoinsulinemia
Authors: Garcia-Marin Jose Juan , Villanueva Gloria R. , Esteller Alejandro
Published: March 2007

In one of our earlier studies, an impaired biliary function in diabetes was suggested. We studied bile formation in rats with streptozotocin-induced diabetes (60 mg per kg body weight). Diabetic rats showed hyperglycemia and hypoinsulinemia, but no significant changes in hematocrit, plasma protein concentration or plasma osmolality. Bile flow was significantly (p < 0.05) reduced (-23%) as compared with control animals, despite a higher (p < 0.05) bile acid secretion rate (+56%).

The biliary responses to three choleretic compounds (taurocholate, ursodeoxycholate and insulin), acting in a very different way upon bile formation, were not impaired in diabetes. The study of the relationship between bile acid output and bile flow, after infusion of taurocholate at different doses (0.25 to 1.5 μmoles per min per 100 gm body weight) showed that diabetesinduced cholestasis in the rat is mainly related to a decreased bile acid-independent fraction of the bile flow.

We tested the possible role of hyperglycemia and hypoinsulinemia as cholestatic factors in diabetes. Glucose infusion [300 mM, 150 μ per min (Group G)] induced a significant (p < 0.05) reduction in bile flow (−0.33 μl per min per gm liver) as compared to the basal period. After acute pancreatectomy (P) or mannoheptulose treatment [0.14 mmole per 100 gm body weight (Group M)], similar cholestatic effects were observed (−0.29 and −0.27 μl per min per gm liver, respectively). However, plasma glucose and insulin concentrations were higher (p < 0.01) in Group G than in P or M.

Glucose infusion to acutely pancreatectomized (PG) or mannoheptulose-treated (MG) rats induced a similar and marked cholestasis (−0.46 and −0.51 μl per min per gm liver, respectively; both p < 0.001). The plasma insulin concentration was not different among the P, M, PG and MG. Nevertheless, a lower (p < 0.05) bile flow was observed in PG and MG, as compared to P and M, respectively. Plasma glucose concentrations were higher (p < 0.001) in PG and MG as compared to P and M.

Bile acid output and plasma osmolality were not significantly different in controls, P, M, PG and MG.

In summary, our results indicate that diabetes induces cholestasis in the rat. They suggest that the decrease in bile formation is not due to general damage to the hepatic secretory system but rather to the presence of additive cholestatic factors, such as hyperglycemia and hypoinsulinemia, which specifically reduce the bile acid-independent fraction of bile flow.
Prospective study of asymptomatic hbsag carrier children infected in the perinatal period: Clinical and liver histologic studies
Authors: Chang Mei-Hwei , Hwang Lu-Yu , Hsu Hey-Chi , Lee Chin-Yun , Beasley Palmer R.
Published: March 2007

Liver histologic findings were studied in 18 children who were 4 to 9 years old, and who had been HBsAg carriers since having been infected by their mothers in the perinatal period. All were born to HBeAg-HBsAg carrier mothers; the children were followed periodically from birth. Throughout their entire course, none developed symptoms or signs suggestive of liver disease.

All of the 18 children showed mild but definite liver histologic changes: 15 had nonspecific histologic changes, and three had chronic persistent hepatitis. In 13 of 18 children, follow-up aminotransferase activities were abnormal, but none exceeded 100 KU. At the time of biopsy, ALTs on four children were above the upper limit of normal. All children were HBeAg-positive in early infancy, but five lost this antigen and developed antibody during follow-up. The histologic findings in HBeAg-positive children did not differ from those in children with antibody. Perinatal hepatitis B virus infection has been thought to play an important role in chronic liver disease, including hepatocellular carcinoma. This study indicates that some pathologic changes following perinatal infection begin very early.
Large granular lymphocytes in the liver
Authors: James Stephen P.
Published: March 2007

Considerable numbers of large granular lymphocytes (LGL) were isolated from rat liver by a simple method consisting of sinusoidal lavage at elevated (50 cm water column) perfusion pressure. This method gave a yield comparable with the enzymatic dissociation method commonly used for the isolation of nonparenchymal liver cells, but was shorter in time and had the advantage of avoiding the potentially harmful effects of the dissociating enzymes. The isolated LGL were highly cytotoxic against YAC-1 lymphoma cells and this cytolytic activity was blocked by treatment of the effector cells with an antibody against natural killer cells (anti-asialo GMI). We characterized the hepatic LGL as nonphagocytic, nonadherent, per-oxidase-negative and acid phosphatase-positive cells which could be enriched in the low-density fraction of a Percoll gradient. At the light micro- scopic level, they showed characteristic azuro- philic granules, which corresponded to strongly osmiophilic granules with a specific morphology in electron microscopy. It is concluded that these LGL are identical to the “pit cells” which were formerly described by electron microscopy in situ as normal components of the liver sinusoids and which are easily recognized by their fine structure. It is also proposed that the liver may represent one of the major natural killer organs.
Selenium deficiency in search of a disease
Authors: Burk Raymond F.
Published: March 2007

Serum selenium concentrations were found to be significantly lower in women with intrahepatic cholestasis of pregnancy than in women with normal pregnancies during the last trimester of pregnancy and post partum. The activity of the seleno-enzyme glutathione peroxidase had a significant positive correlation with selenium concentration and it was also significantly lower in women with the disease.

These findings suggest that selenium deficiency and reduced glutathione peroxidase activity are associated with the aetiopathogenesis of intrahepatic cholestasis of pregnancy.
Neonatal hepatitis in Taiwan
Authors: Mowat Alex P.
Published: March 2007

Fifty-six patients with moderate to severe neonatal hepatitis were followed for 12 to 78 months. Two died from causes other than hepatitis itself and were free from liver disease at the time of death. Of the remaining 54 patients, seven died of hepatitis, two are living with chronic liver disease and psychomotor retardation, and 45 are living without liver disease. High peak bilirubin levels and liver histologic findings of periportal fibrosis, moderate to severe portal inflammation, and/or diffuse giant cell transformation appear to be major factors predictive for poor outcome. Cytomegalovirus (CMV) infection was a common associated infection. Evidence of CMV infection was found in 22 (49%) of the 45 patients studied. Three of them died, and one is still living with cirrhosis of the liver. Metabolic disorders such as alpha-1-anti-trypsin deficiency, galactosemia, and aminoaciduria and/or aminoacidemia were carefully screened but were not found in these cases. A fatal case had a sibling who had died of a similar disease course. Chinese infants may have metabolic and familial cholestasis diseases requiring further investigation.
Expression of class I and class II major histocompatibility complex antigens on human hepatocytes
Authors: Franco Alessandra , Barnaba Vincenzo , Natali Piergiorgio , Balsano Clara , Musca Antonino , Balsano Francesco
Published: March 2007

We analyzed whether normal human hepatocytes, which normally do not display Class II major histocompatibility complex antigens, can be induced to express them in vitro, and whether this induction has an in vivo counterpart in chronic liver diseases. While both α- and γ-interferon induced expression of Class I antigens, only γ-interferon induced expression of Class II antigens on hepatocytes in vitro. Recombinant interleukin 2 had no effect on major histocompatibility complex antigen expression. Both Class I and Class II antigens could be detected by indirect immunofluorescence on hepatocytes from patients with various forms of chronic liver disease, regardless of etiology. These findings suggest that γ-interferon produced by T lymphocytes that infiltrate the liver during the course of chronic hepatitis induces Class II major histocompatibility complex antigen expression and may endow the hepatocytes with the capacity to perform accessory (antigen-presenting) cell functions.
Histocompatibility antigens: Markers of susceptibility to and protection from alcoholic liver disease in a portuguese population
Authors: Monteiro Estela , Alves Patricia M. , Santos Livia M. , Quintas Isabel , Baptista Amelia , Galvao-Teles Alberto , Gavaler Judith S.
Published: March 2007

The distribution of six HLA antigens in a population of 88 Portuguese chronic alcohol abusers with biopsy-proven liver disease was compared to that in 66 Portuguese normal controls. Among the group of 88 alcohol abusers, the presence of HLA antigens A1, A9, A28 and Bw35 marked a significant 2.5- to 3-fold increased estimated risk for the development of alcohol-induced cirrhosis, while the presence of HLA B5 was found to be associated with a significantly decreased risk of alcohol-induced cirrhosis. Further, compared to controls, the estimated risk of any stage of alcohol-induced liver disease was significantly increased in alcoholic individuals with HLA A28 and Bw35, and the protective effect of HLA B5 was again observed. The findings of this study suggest that at least in a relatively homogeneous population group such as the Portuguese, the presence of HLA B5 may confer protection against alcohol-induced liver disease, including cirrhosis. The presence of HLA Bw35 and A28 appear to mark susceptibility to all histologic manifestations of alcohol-induced liver disease, while in addition to Bw35 and A28, A1 and A9 may mark increased risk for cirrhosis in particular.
Differential expression of MHC class II subregion products on bile duct epithelial cells and hepatocytes in patients with primary biliary cirrhosis
Authors: Spengler Ulrich , Pape Gerd R. , Hoffmann Robert M. , Johnson Judith P. , Eisenburg Josef , Paumgartner Gustav , Riethmüller Gert
Published: March 2007

To study the expression of MHC Class II subregion gene products on biliary epithelial cells in primary biliary cirrhosis, frozen sections from liver biopsies of 15 patients with primary biliary cirrhosis were studied immunohistochemically using HLA-D subregion specific monoclonal antibodies L243 (HLA-DR), Leu10 (HLA-DQ) and B7/21 (HLA-DP). Patients with early stages of primary biliary cirrhosis showed expression of HLA-DP, HLA-DR and HLA-DQ subregion gene products on bile duct epithelial cells. In advanced stages of disease, no MHC Class II antigens or only HLA-DR and HLA-DP were expressed on bile duct cells. While normal hepatocytes did not express detectable amounts of MHC Class II antigens, hepatocytes from liver biopsies of four patients with primary biliary cirrhosis showed a distinct staining exclusively with monoclonal antibodies specific for HLA-DR. The expression of MHC Class II antigens on parenchymal cells was independent of a lymphocytic infiltration into the tissue. This study demonstrates that bile ductular cells, but not hepatocytes, express a full set of MHC Class II molecules at least during the early stages of primary biliary cirrhosis. We propose, therefore, that the expression of both HLA-DR and HLA-DQ subregion products on bile duct epithelial cells may be a necessary, although not sufficient, condition for the initiation of an autoimmune process leading to the destruction of intrahepatic bile ducts in primary biliary cirrhosis.
Ectopic soft tissue calcium deposition following liver transplantation
Authors: Munoz Santiago J. , Nagelberg Steven B. , Green Paul J. , Angstadt John D. , Yang Shuin L. , Jarrell Bruce E. , Maddrey Willis C.
Published: March 2007

We observed ectopic soft tissue calcification affecting seven patients following orthotopic liver transplantation. The cause of such calcification is unknown, but potential pathogenetic factors include hyperparathyroidism, calcium administered during and following surgery, renal failure, acid-base changes and citrate in fresh frozen plasma. To investigate some of the mechanisms underlying ectopic calcification following liver transplantation, we determined preoperative levels of ionized serum calcium, phosphate, magnesium, parathyroid hormone (midmolecule assay) and 1,25-(OH)2 vitamin D in 20 patients who underwent 24 liver transplants. In addition, these parameters were measured weekly in 15 patients during the first month after liver transplantation.

Preoperatively, 5 of the 20 patients had elevated serum levels of parathyroid hormone, and 9 others had low levels of 1,25-(OH)2 vitamin D. After liver transplantation, ectopic calcification was found in seven patients (47%). The organs affected in order of frequency were lungs, liver graft, colon, vascular walls, kidneys, adrenal glands and gastric mucosa. One patient with ectopic calcification of both lungs had markedly restricted pulmonary function as well as radiologic evidence of osteopenia and pathologic fractures of three vertebrae. Postoperatively, increased parathyroid hormone levels were found in all patients who developed soft tissue calcification. Parathyroid hormone levels peaked during the second week after transplantation and were higher at all times compared to subjects without calcification. Five of the seven patients with ectopic calcification had associated renal failure. Individuals who developed calcification had received significantly more fresh frozen plasma, red blood cells and elemental calcium postoperatively, but showed no difference in serum levels of calcium, magnesium, vitamin D, total plasma CO2 or phosphate levels when compared to patients without calcification.

We conclude that multiorgan ectopic soft tissue calcification may complicate the postoperative course following liver transplantation. In one patient, calcifications were associated with respiratory insufficiency and bone fractures. Renal failure, secondary hyperparathyroidism and large amounts of transfused blood-derived products appear to be major factors associated with ectopic calcification. We speculate that renal failure and the citrate contained in massive fresh frozen plasma transfusions lead to transient hypocalcemia, which in turn stimulates parathyroid hormone secretion and secondary hyperparathyroidism. Under these conditions, local tissue injury and concomitant administration of exogenous calcium may result in soft tissue calcium deposition.
Identification of biliprotein as a liver growth factor
Authors: Díaz-Gil Juan J. , Sánchez Gonzalo , Trilla Carolina , Escartín Pedro
Published: March 2007

We determined the concentration of biliprotein in plasma of rats at different times after partial hepatectomy. From the same plasma samples, we purified a liver growth factor previously characterized by our group. When we plotted the 14 points studied, a linear relationship was obtained (r = 0.999; p < 0.001). This result, in addition to our group’s recent identification of this liver growth factor as an albumin-bilirubin complex, strongly suggests that biliprotein is a liver growth factor.
Absence of seroconversion following treatment with hepatitis B immune globulin containing antibody to human immunodeficiency virus
Authors: Phillips Michael , Cummins Laurence M.
Published: March 2007

Recent studies have demonstrated that commercial preparations of hepatitis B immune globulin often contain antibody to the human immunodeficiency virus. The presence of this antibody has aroused concerns that treatment with hepatitis B immune globulin might passively induce human immunodeficiency virus antibody seropositivity, leading to incorrect diagnoses of human immunodeficiency virus exposure. We studied a group of 16 normal volunteers who received an intramuscular dose of hepatitis B immune globulin (0.06 ml per kg) which was later discovered to contain human immunodeficiency virus antibody. None of the subjects had human immunodeficiency virus antibody before receiving hepatitis B immune globulin. Serum specimens collected at 1 to 4, 6, 8,12,16, 20 and 24 weeks after the injection were consistently negative for human immunodeficiency virus antibody. There was no detectable human immunodeficiency virus antibody in any specimen from any subject. We conclude that intramuscular therapy with hepatitis B immune globulin in the recommended dose not appear to place patients at risk of passive seroconversion to human immunodeficiency virus antibody positivity, despite the presence of antibody in the injected material.
Interaction of woodchuck hepatitis virus surface antigen with hepatocyte plasma membrane in woodchuck chronic hepatitis
Authors: Michalak Tomasz I. , Churchill Norma D.
Published: March 2007

The extent of association between woodchuck hepatitis virus surface antigen and host hepatocyte plasma membrane in chronic hepatitis was studied. Purified membranes containing the antigen were treated with various agents which perturb plasma membrane constituents to elute woodchuck hepatitis virus surface antigen. The products from disrupted membranes were analyzed by sedimentation in sucrose gradients and tested to identify the antigen reactivity.

The results indicated that membrane-bound wood-cauck hepatitis virus surface antigen was partially released by 4M potassium chloride, potassium thiocyanate and guanidine, 6M urea or 0.1 N sodium hydroxide (pH 13.5), but not in the presence of low concentrations of these reagents or by 10% 2-mercaptoethanol and 1% sodium dodecyl sulfate. No more than 15% of the total membrane-associated woodchuck hepatitis virus surface antigen was eluted by 0.1 N NaOH, which was found to be the most effective eluent among tested agents at the antigen removal. The remaining woodchuck hepatitis virus surface antigen was resistant to further extraction with sodium hydroxide, as expected for an integral membrane protein. Treatment of the infected membranes with 1% Triton X-100 or 50 mM deoxy-cholic acid, that solubilize the membrane lipid bilayer releasing most of the integral membrane proteins, resulted in the sedimentation of almost all detectable woodchuck hepatitis virus surface antigen reactivity with the detergent-insoluble membrane residues, suggesting a firm interaction of the antigen with the plasma membrane matrix. Partition of the membrane peripheral and integral proteins in 1% Triton X-114 into hy-drophilic and hydrophobic protein fractions, respectively, provided additional evidence that most of the detectable woodchuck hepatitis virus surface antigen reactivity within the infected membranes was associated with their integral proteins.

The results demonstrate that woodchuck hepatitis virus surface antigen found in hepatocyte plasma membrane behaves as a peripheral and an integral membrane protein. It was shown that most of the woodchuck hepatitis virus surface antigen behaving as an integral membrane protein interacts extremely extensively with the membrane. This unexpectedly strong membrane binding of woodchuck hepatitis virus surface antigen may be irreversible in naturally occurring conditions and could be eliminated only by lysis of infected hepatocyte membranes. Viral envelope material firmly associated with hepatocyte plasma membrane may constitute an important element of a complex mechanism leading to persistence of the virus infection that could also be responsible for preservation of hepatocytes with integrated viral genome.
Detection of hepatitis B virus dna in hepatocellular carcinoma: Analysis by hybridization with subgenomic dna fragments
Authors: Chen Jen-Yang , Harrison Tim J. , Lee Chue-Shue , Chen Ding-Shinn , Zuckerman Arie J.
Published: March 2007

We have previously reported an analysis of DNA extracted from 31 primary liver tumors where, in 25 cases, we found chromosomal integration of hepatitis B virus DNA sequences. We describe here an investigation of the extent of the viral genome at each integration site in 15 of the hepatitis B virus DNA-positive tumors using subgenomic fragments of the viral genome as probes. Probes were roughly equivalent to the pre-S region, the surface antigen gene, the region containing the enhancer, the x gene and the core antigen gene. We found the core antigen gene to be that most underrepresented in the tumors and speculate that, since cells which express core antigen in the infected liver may be targeted for lysis by the immune system, modifications of the integrated viral DNA which prevent core antigen expression may be selected. Conversely, the region of the genome present in the greatest number of integrations was the surface antigen gene and, because it is known that the major surface antigen promoter is active in the integrated state, we find promoter insertion an attractive hypothesis to explain oncogenesis by hepatitis B virus.