bluuebunny/crossref_metadata_2025 huggingface dataset:
Hepatitis B Virus Envelope Variation After Transplantation With and Without Hepatitis B Immune Globulin Prophylaxis
Authors: Carman W F , Trautwein C , van Deursen J , Colman K , Dornan E , McIntyre G , Waters J , Kliem V , Müller R , Thomas H C , Manns M P
Published: November 2004

Hepatitis B virus (HBV) replicates via an intermediate RNA step. High frequency of polymerase errors with additional selection pressure leads to mutations in the HBV genome. We investigated the number, type, and antigenic effects of mutations in the coding region of the HBV surface antigen in eight patients who underwent orthotopic liver transplantation (OLT) for HBV–related end–stage liver disease and were experiencing infection of the graft and who received hepatitis B surface antigen antibody (anti–HBs) prophylaxis (hepatitis B immune globulin [HBIG]) after OLT. Controls were chronic HBV patients who underwent kidney transplantation and received the same immunosuppressive regime but no HBIG. The S–gene was amplified from serum before and after transplantation, sequenced, and changes in the genome were analyzed. In the five patients who experienced reinfection while receiving anti–HBs, clear mutations occurred in the S–gene. In the patient who did not receive HBIG and those who experienced reinfection only after termination of HBIG, no mutations were found in the S–gene. In the kidney recipients, mutations in the S–gene occurred in only one of eight patients. Because the a determinant contains neutralizing epitopes, this region was chosen for antibody binding to quantify antigenic effects of the mutations. The two patients who selected mutations in the a determinant and became reinfected while receiving HBIG had reduced antibody binding after OLT. Our results suggest that HBIG after OLT imposes a selection pressure on the S–gene, and that mutations are one mechanism for reinfection while receiving HBIG.
The Role of Gallbladder Emptying in Gallstone Formation During Diet–Induced Rapid Weight Loss
Authors: Gebhard R L , Prigge W F , Ansel H J , Schlasner L , Ketover S R , Sande D , Holtmeier K , Peterson F J
Published: November 2004

Obese persons are at risk for cholesterol gallstones because their bile is saturated with cholesterol. The risk increases during rapid weight loss by means of certain very–low–calorie diets or gastric bypass surgery. Gallstone risk factors during rapid weight loss include increased bile cholesterol saturation index and gallbladder stasis. Obese subjects were randomized to one of two low–calorie liquid diets for rapid weight loss: a 520–kcal diet with less than 2 g fat/d, and a 900–kcal diet with 30 g fat/d (including one 10–g fat meal to stimulate maximal gallbladder emptying). Bile and blood lipids, saturation index, leukocyte 3–hydroxy–3–methylglutaryl coenzyme A (HMG CoA) reductase activity, and ultrasonographic gallbladder emptying were measured repeatedly during dietary treatment. Both diets produced comparable weight loss of 22%. Bile cholesterol saturation index increased during both diets (26%), but fell to 15% below prediet level after weight loss. Compared with subjects' maximal gallbladder emptying fraction of 66%, the 520–kcal diet provided poor gallbladder emptying (35%), whereas the 10–g fat meal of the 900–kcal diet provided maximal emptying. Gallstones developed in four of six 520–kcal subjects and none of seven 900–kcal subjects (

P

= .021), an unanticipated difference that resulted in premature study termination for ethical reasons. Blood lipids and HMG CoA reductase activity in mononuclear leukocytes fell at week 8 during both diets, but recovered while weight was still being lost. The findings suggest that gallstone risk during rapid weight loss may be reduced by maintenance of gallbladder emptying with a small amount of dietary fat. Ultimately, weight loss reduced bile cholesterol saturation and improved highdensity lipoprotein (HDL) levels.
Transjugular Intrahepatic Portosystemic Shunt for the Management of Severe Venoocclusive Disease Following Bone Marrow Transplantation
Authors: Fried M W , Connaghan D G , Sharma S , Martin L G , Devine S , Holland K , Zuckerman A , Kaufman S , Wingard J , Boyer T D
Published: November 2004

Hepatic venoocclusive disease (VOD) is a common, life–threatening complication of bone marrow transplantation (BMT). Portal hypertension is usually present and accounts for many of the clinical manifestations of this syndrome. We describe the results of transjugular intrahepatic portosystemic shunt (TIPS) for the management of VOD after BMT TIPS was performed in six patients with histologically confirmed VOD who had progressive jaundice and ascites. Portal hypertension was improved by TIPS in all patients (mean portal pressure gradient before TIPS, 20.2 +/– 4.6 vs. 6.7 +/– 1.9 mm Hg post–TIPS,

P

< .004). Three patients who underwent TIPS late in the course of VOD did not demonstrate any clinical improvement after TIPS and expired within 2 weeks of the procedure. The remaining three patients had less advanced disease and demonstrated decreases in serum bilirubin, improvement in coagulopathy, and decreased ascites after TIPS. Two patients subsequently expired, one with persistent histological changes of VOD. The lone survivor continues to do well with resolution of ascites, jaundice, and coagulopathy as of her last outpatient visit. TIPS was an effective method for portal decompression in patients with VOD after BMT, and was associated with clinical improvement in some patients. However, these effects may be transient and may not improve overall survival.
Selection of Mutations in the Hepatitis B Virus Polymerase During Therapy of Transplant Recipients With Lamivudine
Authors: Ling R , Mutimer D , Ahmed M , Boxall E H , Elias E , Dusheiko G M , Harrison T J
Published: November 2004

We describe mutations in the hepatitis B virus (HBV) polymerase gene in viruses which reactivated in two patients during therapy with –2′–deoxy– 3′–thiacytidine, or lamivudine (3TC), and following orthotopic liver transplantation for chronic hepatitis B. Virus resistance to 3TC is associated with mutations which lead to amino acid substitutions in the highly conserved tyr–met–asp–asp (YMDD) motif, part of the active site of the polymerase, and which parallel those seen in resistant human immunodeficiency virus (HIV). Substitutions of

valine

and

isoleucine

for methionine were found in the two cases. The significance of single secondary mutations, which differ between viruses from the two patients, remains to be determined. Thus, viral resistance to lamivudine of hepatitis B virus mimics that of HIV and can occur in the setting of immunosuppression after liver transplantations.
Role of the Pituitary in Tumor Promotion With Ethinyl Estradiol in Rat Liver
Authors: Hällström I P , Liao D , Assefaw-Redda Y , Ohlson L C , Sahlin L , Eneroth P , Eriksson L , Gustafsson J , Blanck A
Published: November 2004

Synthetic estrogens act as tumor promoters in rat liver. Because estrogen treatment markedly increases the secretion of pituitary prolactin, also shown to be a tumor promoter in rat liver, the possibility of a pituitary influence in estrogen promotion was investigated in Wistar rats. In diethylnitrosamine (DEN)–initiated hypophysectomized (hx) female rats, 24 weeks of ethinyl estradiol (EE) administration (500 microg/kg/d, intraperitoneally) did not increase the number of hepatocyte nodules and did not induce hepatocellular carcinoma (HCC) in a 2–year study. Very few placental forms of glutathione–S–transferase (GST–P)–positive foci were observed at the end of EE administration.

Estrogen receptor (ER)

messenger RNA (mRNA) levels in hx females were 20% of the levels in intact females. EE administration (range, 160–210 microg/kg/d, subcutaneous release pellets) to DEN–initiated intact males and females increased the number and size of hepatocyte foci. A significant increase in HCC frequency was observed in EE–treated females compared with females receiving sham–release pellets, and the latency period for HCC induction was decreased by EE in both males and females. Inhibition of prolactin (PRL) secretion by bromocriptine (Brc) (ParlodelLAR, slow intramuscular release vehicles) during EE treatment decreased the number of foci without affecting their size and markedly prolonged the latency period in both sexes. EE treatment also significantly increased the expression of c–myc, and c–jun, enhanced the levels of growth hormone receptor (GHr) mRNA in females and the levels of ER mRNA in males and “feminized” the expression of the GH–regulated genes cytochrome P450 (CYP), 2C11, CYP 2C12, and GHr in male liver. Brc administration decreased the mRNA levels of the female–predominant CYP 2C12 in EE–treated males but otherwise had no effects. In conclusion, a decreased promotive effect of EE was obtained by decreasing the PRL levels, indicating that estrogens exert at least part of their promotion effects indirectly, by increasing the levels of pituitary PRL.
Neuroactive Amino Acids and Glutamate (Nmda) Receptors in Frontal Cortex of Rats With Experimental Acute Liver Failure
Authors: Michalak A , Rose C , Butterworth J , Butterworth R F
Published: November 2004

It has been proposed that alterations of excitatory and inhibitory amino acids play a role in the pathogenesis of hepatic encephalopathy in acute liver failure. To evaluate this possibility,

in vivo

cerebral microdialysis was used to sample extracellular concentrations of amino acids in the frontal cortex of unanesthetized rats at various times during the progression of encephalopathy resulting from acute liver failure. Liver failure was induced by portacaval anastomosis followed 24 hours later by hepatic artery ligation. Dialysate concentrations of amino acids were measured by high–performance liquid chromatography (HPLC) with fluorescence detection. Deterioration of neurological status was accompanied by two– to four–fold increases in extracellular glutamate, glutamine, and glycine; concentrations of gamma–aminobutyric acid (GABA) and taurine were unchanged. Densities of binding sites for the glutamate (n–methyl–d–aspartate [NMDA]) receptor ligand 3H–MK801, assessed using quantitative receptor autoradiography, however, were unchanged in the frontal cortex of rats at coma stages of ischemic liver failure. Increased extracellular glutamate concentrations were positively correlated with the severity of encephalopathy and with arterial ammonia concentrations. Such changes may result from an ammonia–induced reduction in the capacity for astrocytes to uptake glutamate. Increased extracellular glutamate in brain, together with increases in concentrations of glycine, a positive allosteric modulator of glutamate (NMDA) receptors, are consistent with increased NMDA–related glutamatergic neurotransmission in this model of acute liver failure. Increased extracellular glutamate, therefore, could contribute to the pathogenesis of hepatic encephalopathy and brain edema in acute liver failure.
Centrolobular Liver Fibrosis in the Hypercholesterolemic Rabbit
Authors: Buyssens N , Kockx M M , Herman A G , Lazou J , Van den Berg K , Wisse E , Geerts A
Published: November 2004

During a study on the development of atheromatous lesions in rabbits fed a diet with a low or high cholesterol supplement, we found a moderate to pronounced centrolobular liver fibrosis. This fibrosis developed in three stages. Early after supplementation of cholesterol, we observed increased immunoreactivity of collagen types I, III, and IV, and fibronectin, around central veins and in adjacent sinusoids. In the second stage, we observed further increase of collagen and fibronectin immunoreactivity, together with the appearance of α–smooth muscle actin (α–SM actin)–positive cells and anti–rabbit macrophage monoclonal antibody (RAM 11)–positive cells. In the third stage, we observed large numbers of α–SM actin–positive cells, together with heavy deposition of connective tissue proteins in pericentral sinusoids, in addition to focal atrophy of parenchymal cells. By transmission electron microscopy (TEM), fat–storing cells in the pericentral regions were shown to be enlarged, to lose their lipid–droplets, and to acquire dilated rough endoplasmic reticulum corresponding to an activated phenotype. Parenchymal cells were either normal or contained numerous small lipid–droplets. They sometimes were smaller and distorted. Northern hybridization performed on total RNA of whole liver showed an increased level of collagen α1(I), α1(III), and α1(IV) messenger RNA (mRNA) after 24 weeks of low dietary cholesterol supplementation. These data show enhanced expression of extracellular matrix proteins. We conclude that cholesterol overload induces pericentral liver fibrosis in rabbits. The diet clearly activates fat–storing cells to become fibrogenic effector cells. At present, we have no explanation why hypercholesterolemia induces phenotypic transition of fat–storing cells.
Performance Characteristics and Results of A Large–Scale Screening Program for Viral Hepatitis and Risk Factors Associated With Exposure to Viral Hepatitis B and C: Results of the National Hepatitis Screening Survey
Authors: Kaur S , Rybicki L , Bacon B R , Gollan J L , Rustgi V K , Carey W D
Published: November 2004

Chronic viral hepatitis frequently goes undetected until cirrhosis develops. Although the effect of interferon on the natural history of hepatitis B virus (HBV) or hepatitis C virus (HCV) infection in asymptomatic persons is unknown, treatment may modify the course of the infection, producing cures in some. In September 1992, screening for HBV and HCV was offered in 40 centers throughout the United States. Demographic features, potential risk factors, and symptoms were studied. Blood samples were obtained for the determination of serum alanine aminotransferase levels and for markers of HBV and HCV infection. Thirteen thousand nine hundred ninety seven subjects were screened. The prevalence of infection with HBV or HCV was 24.8% (HBV 17.8%; HCV 7.0%; and both 2.8%). Hepatitis B and C disease was present in 0.7% and 4.4% of the population, respectively. Risk factors for HBV and HCV infection were similar in: blood transfusions, hemodialysis, IV drug use, and sex with an IV drug user. For HBV infection, sex with multiple partners, increasing age, and birth in South East Asia or Africa were additional risk factors. The cost to find a case of HCV infection is less than the costs for finding many other treatable diseases. Screening for HBV, though more costly, is reasonably efficient, and simultaneous screening for HBV and HCV provides greater efficiency. It is practical to consider screening for HBV and HCV in the United States, particularly if any risk factor is present. Improved treatment strategies will make screening even more cost effective.
Existence of A Platelet–Adhesion Defect in Patients With Cirrhosis Independent of Hematocrit: Studies Under Flow Conditions
Authors: Ordinas A , Escolar G , Cirera I , Vinas M , Cobo F , Bosch J , Teres J , Rodés J
Published: November 2004

A defect in hemostasis has been repeatedly reported in patients with cirrhosis. However, the nature of this defect has not been fully characterized. We explored adhesive and cohesive functions of platelets from cirrhotic patients at different stages of disease development. The response of platelets to standard activating agents was tested by aggregometric procedures. The interaction of platelets with subendothelial components was explored in a perfusion system in which blood was exposed (shear rate, 800/s; 10 minutes) to denuded segments of rabbit aorta. Platelet interactions in these perfusions were analyzed morphometrically. Results were always compared with those obtained in similar studies using blood obtained from healthy subjects. Aggregation studies showed abnormal responses for single or several agonists. Abnormalities in aggregation were more evident in patients with severe disease (Child–Pugh class C), although they occasionally were abnormal for single agonists (ADP or U46619) in patients with less severe disease (Child–Pugh classes A or B). All the patient classes showed impaired platelet–subendothelial interactions (

P

< .01 vs. healthy subjects) that were not justified by the relative thrombocytopenia present in the more severely affected patients. Experimental increases in hematocrit in patients at stages B and C did not improve platelet–subendothelial interactions. Platelets from cirrhotic patients interact defectively with subendothelial components under flow conditions. The adhesion defect is more evident and consistent than the aggregation defects and may already be present in patients with mild liver failure. This adhesion defect may contribute to the defective hemostasis observed in cirrhotic patients.
Transjugular Renal Biopsy in the Treatment of Patients With Cirrhosis and Renal Abnormalities
Authors: Jouet P , Meyrier A , Mal F , Callard P , Guettier C , Stordeur D , Trinchet J , Beaugrand M
Published: November 2004

When renal lesions are suspected in patients with cirrhosis, clotting disorders often preclude percutaneous renal biopsy. This study was undertaken to determine whether transjugular renal biopsy is possible, safe, and useful in such patients. From 1987 to 1994, 70 patients with cirrhosis and clotting disorders underwent transjugular renal biopsies, providing renal tissue in 55. Of these 55 patients, 41 were Child–Pugh class B or C, 35 were alcoholic, serum creatinine levels were ≥ 130 μmol/L in 46, and proteinuria was ≥ 0.5 g/d in 37. Clinically significant complications of transjugular renal biopsy were persistent hematuria in 4 and perirenal hematoma in 4, requiring blood transfusions in 1 and 2 cases, respectively. There were no deaths related to renal biopsy. Renal lesions were identified as glomerular in 41 (74.5%), interstitial in 7, and end–stage in 2 and were absent in 5. Transjugular renal biopsy influenced treatment in 21 patients (38%), including 11 who were proposed for liver transplantation and 4 who had chronic liver rejection. Decisions based on results of transjugular renal biopsy were to perform liver transplantation in 8 and combined renal and liver transplantation in 5, whereas 2 were refused. In 6 other patients, the results of renal biopsy modified the medical regimen. We conclude that transjugular renal biopsy may be a useful procedure in patients with cirrhosis and clotting disorders. This technique does not entail undue risks and may influence treatment decisions, particularly in patients proposed for liver transplantation.
The Proportion of Xanthine Oxidase Activity of Total Xanthine Oxidoreductase Activity In Situ Remains Constant in Rat Liver Under Various (Patho)Physiological Conditions
Authors: Frederiks W M , Bosch K S
Published: November 2004

Activity of xanthine oxidoreductase (total xanthine dehydrogenase plus xanthine oxidase) and xanthine oxidase was determined cytophotometrically in periportal and pericentral areas of livers of rats under various (patho)physiological conditions that are known to affect the content of reduced glutathione. For this purpose, rats were either normally fed or fasted for 24 hours, fasted for 24 hours, and treated with diethylmaleate that depleted glutathione or treated by

in vivo

ischemia for 2 hours in the livers. Xanthine oxidoreductase activity was shown histochemically with the use of a tetrazolium salt procedure, and xanthine oxidase activity was localized with a cerium– diaminobenzidine–cobalt–hydrogen peroxide technique in unfixed cryostat sections of the livers. Cytophotometric measurements showed that total xanthine oxidoreductase activity was decreased after fasting and ischemia, whereas only ischemia caused reduced xanthine oxidase activity. Moreover, the percentage of xanthine oxidase of total xanthine oxidoreductase activity was constant in both periportal and pericentral areas at the level of approximately 4% in normally fed and 24–hour fasted and diethylmaleate–treated rats. Ischemia reduced this percentage in both areas of the liver to 2%. It was concluded that the amount of endogenous reduced glutathione did not affect the percentage of xanthine oxidase. The low percentage of xanthine oxidase as determined in the present

in situ

histochemical study indicates that

in vivo

the percentage oxidase in rat liver is lower than is assumed on the basis of biochemical assays in liver homogenates even after strictly controlled homogenization procedures. Apparently, conversion of xanthine dehydrogenase into xanthine oxidase may occur

in vitro

to yield percentages of xanthine oxidase of 10%–20% as are reported in the literature. The latter increase in the percentage of xanthine oxidase may be caused by changes in the local environment of the enzymes, which is left completely intact in histochemical assays. The finding of this low percentage of xanthine oxidase further stresses that the main function of xanthine oxidoreductase in the liver is not the production of superoxide anion radicals and/or hydrogen peroxide but rather the metabolism of xanthine to uric acid, which can act as a potent antioxidant.
Increased Nitric Oxide Synthase Activity As A Cause of Mitochondrial Dysfunction in Rat Hepatocytes: Roles for Tumor Necrosis Factor α
Authors: Kurose I , Miura S , Higuchi H , Watanabe N , Kamegaya Y , Takaishi M , Tomita K , Fukumura D , Kato S , Ishii H
Published: November 2004

Kupffer cells have been implicated in playing an important role in the pathogenesis of endotoxemia–associated liver injury. The present study was designed to investigate whether Kupffer cell–derived mediators alter the mitochondrial oxidative phosphorylation of hepatocytes in the endotoxemic condition. Liver cells were isolated from male Wistar rats. Oxidative phosphorylation was monitored as the fluorescence of rhodamine 123 (Rh123), which is the fluorescent cationic dye used to indicate mitochondrial energy synthesis. Two hours after coculture of hepatocytes with lipopolysaccharide (LPS)–pretreated Kupffer cells, a marked decrease in hepatocyte rhodamine 123 fluorescence was observed. The hepatocyte mitochondrial dysfunction was attenuated by the addition of either NG–monomethyl–l–arginine (l–NMMA), an inhibitor of nitric oxide (NO) synthesis, or aminoguanidine, an inducible–type of NO synthase inhibitor, to the culture medium of cocultures, to the pretreatment of LPS–activated Kupffer cells with antisense oligodeoxynucleotides against iNOS messenger RNA (mRNA), or to tumor necrosis factor α (TNF–α) mRNA. Four hours after the coculture, hepatocyte Rh123 fluorescence further decreased, and an iNOS induction as well as an increased NO production were observed in hepatocytes that were cocultured with LPS–pretreated Kupffer cells. The membrane barrier dysfunction of hepatocytes, indicated by propidium iodide staining, was also induced by a 4–hour coculture with LPS–pretreated Kupffer cells. These late–phase changes were inhibited either by the pretreatment of hepatocytes with antisense oligodeoxynucleotides against iNOS mRNA or by treatments that are effective in the early phase (within 2 hours). Incubation with recombinant rat TNF–α decreased hepatocyte Rh123 fluorescence within 2 hours. Thus, the present study suggests that NO and TNF–α released from LPS–pretreated Kupffer cells directly inhibit the hepatocyte mitochondrial function in the early phase, and then NO synthesized by TNF–α–induced hepatocyte iNOS causes lethal hepatocyte injury, characterized by diminished mitochondrial energization and membrane barrier function in the late phase.
The Central Role of Sinusoidal Endothelial Cells in Hepatic Hypoxia–Reoxygenation Injury in the Rat
Authors: Samarasinghe D A , Farrell G C
Published: November 2004

The role of individual cell types in hepatic hypoxia–reoxygenation (reperfusion) injury has not been completely defined. We therefore examined the effects of hypoxia and hypoxia–reoxygenation on the viability of rat hepatocytes, Kupffer cells, and sinusoidal endothelial cells (SECs) in primary culture and whether direct exposure to hypoxia followed by reoxygenation activated Kupffer cells. Cultures of hepatocytes (purity > 99%), Kupffer cells (97%), and endothelial cells (> 93%) were established as single–cell types and as cocultures. Hypoxia was achieved by culturing cells under 95% N2/5% CO2, and cell viability was estimated by lactate dehydrogenase (LDH) leakage and Trypan blue exclusion. Kupffer cells and endothelial cells were more resistant to hypoxia than hepatocytes. Following 4–8 hours of hypoxia, reoxygenation accentuated cell death in endothelial cells. In contrast, reoxygenation did not accentuate cell death in hepatocytes or in resting Kupffer cells. The activation of Kupffer cells by the addition of lipopolysaccharide failed to alter their response to hypoxia–reoxygenation. The addition of phorbol myristate acetate to Kupffer cells stimulated the production of superoxide as expected, and the medium from these activated cells augmented the cellular injury of hypoxic hepatocytes. In contrast, hypoxia–reoxygenation did not stimulate Kupffer cells to produce superoxide or other hepatotoxic products. Moreover, Kupffer cells in coculture with hepatocytes did not augment hepatocyte injury after hypoxia–reoxygenation. Likewise, in cocultures of Kupffer cells and SECs, the presence of the Kupffer cell failed to enhance endothelial injury following hypoxia–reoxygenation, and these cocultures did not produce superoxide after reoxygenation. Thus, despite other evidence that Kupffer cells are activated in the intact liver during reperfusion injury, when present in isolation, only endothelial cells possess the innate capacity to undergo hypoxia–reoxygenation injury. Furthermore, changes in oxygen tension alone are not sufficient to activate Kupffer cells to secrete superoxides or other cell products that are toxic to hepatocytes or endothelial cells. It is concluded that SECs play a central role in hypoxia–reoxygenation injury, and the factors that activate Kupffer cells in vivo require further study.
Low Lipoprotein (A) Levels During Acute Viral Hepatitis
Authors: Geiss H C , Ritter M M , Richter W O , Schwandt P , Zachoval R
Published: November 2004

High serum concentrations of lipoprotein (a) [Lp(a)] are considered a risk factor for premature atherosclerosis. Besides apolipoprotein B–100, Lp(a) consists of apolipoprotein (a) [apo(a)], which shows a remarkable size polymorphism. The serum concentration of Lp(a) is considerably influenced by this apo(a) phenotype. Because Lp(a) is synthesized in the liver, we wondered whether and to what extent Lp(a) levels might be affected by acute liver disease. We compared Lp(a) serum concentrations in 74 patients (54% male, 46% female; mean age, 46 years) with acute viral hepatitis (32, 28, and 14 with hepatitis A, B, and C, respectively) with those in 404 healthy controls (57% men, 43% women; mean age, 47 years). In addition, the intraindividual course of Lp(a) concentration during and after acute hepatitis was followed in a subgroup of 23 patients (15, 6, and 2 with hepatitis A, B, and C, respectively). During acute hepatitis, median Lp(a) concentrations in the patient group were significantly diminished compared with controls (7 vs. 17 mg/dL;

P

< .0001, Mann–Whitney test). Any bias by an unequal isoform distribution was excluded because there was no significant difference in the isoform distribution between patients and controls (

P

> .10, chi2 test). Furthermore, the decrease in Lp(a) concentration during acute hepatitis was independent of the molecular weight of the apo(a) isoform. Longitudinally observed patients showed a marked increase in Lp(a) concentration during convalescence (7 to 32 mg/dL;

P

< .0001, Wilcoxon test). Our results show that acute hepatitis is associated with decreased Lp(a) serum levels. Further studies are needed to evaluate whether Lp(a) serum concentration might be clinically useful as a parameter of liver function.
Prevalence of Herpesviridae and Hepatitis B Virus Dna in the Liver of Patients With Non–A, Non–B Fulminant Hepatic Failure
Authors: Mason A , Sallie R , Perrillo R , Rayner A , Xu L , Dohner D E , Dehner M , Naoumov N , Gelb L , Saha B , O'Grady J , Williams R
Published: November 2004

Members of the herpes virus family and hepatitis B virus (HBV) have been implicated as etiologic agents in non–A, non–B (NANB) fulminant hepatic failure (FHF), but the frequency of infection with these agents has not been established using appropriate controls. To examine this issue, we studied 50 NANB FHF patients and 104 liver transplant recipients from North America and Europe. Hepatic DNA was analyzed by polymerase chain reaction (PCR) for evidence of Epstein–Barr virus (EBV), cytomegalovirus (CMV), herpes simplex virus I (HSV I) and II (HSV II), varicella–zoster virus (VZV), and human herpes virus–6 (HHV–6) nucleic acid sequences. The prevalence of HBV was assessed in North American subjects only. HSV I, HSV II, VZV, and HHV–6 viral sequences were not observed in any samples. Three of 50 FHF (6%) and 14 of 104 control patients (13%) were positive for CMV DNA. Two of 50 FHF (4%) and 10 of 104 control patients (10%) had EBV DNA, and HBV DNA was observed in 3 of 10 North American FHF patients (30%) and 3 of 59 controls (5%) without serum markers for HBV infection. The finding of HBV DNA in the liver of seronegative controls from North America but not Europe suggests that occult hepatitis B sequences in patients with NANB FHF may simply reflect geographic differences. The majority of cryptogenic FHF cases cannot be attributed to infection with herpes viruses or HBV.
A Prospective, Randomized Trial Comparing Lymphoblastoid to Recombinant Interferon Alfa 2A As Therapy for Chronic Hepatitis C
Authors: Rumi M , Del Ninno E , Parravicini M L , Romeo R , Soffredini R , Donato M F , Wilber J , Russo A , Colombo M
Published: November 2004

To compare the long–term effectiveness and tolerability of lymphoblastoid interferon (IFN–αN1) and recombinant interferon alfa 2a (IFN–α2a) in patients with chronic hepatitis caused by hepatitis C virus (HCV), 234 consecutive patients with HCV–related chronic hepatitis were randomized prospectively to receive titrated doses (starting dose = 6 million units [MU]) of IFN–α2a (n = 118) or IFN–αN1 (n = 116) for 12 months. HCV RNA was detected by reverse– transcription polymerase chain reaction (RT–PCR), quantified by branched–DNA (bDNA) assay, and genotyped by reverse hybridization assay. Thirty–one patients in the IFN–α2a group and 28 in the IFN– αN1 group (total, 59 [25%]) had normal transaminases and undetectable HCV RNA by RT–PCR after 12 months of therapy, but only 19 in the first group and 20 in the second group (total, 39 [17%]) had biochemical and virological responses 12 months after treatment was discontinued. The two treatment groups differed in terms of prevalence of major drug–related adverse reactions (23% vs. 37%,

P

= .025). The mean total dose per patient was similar for the two groups, i.e., 502 MU IFN–α2a vs. 496 MU IFN–αN1, and the cost of each sustained response was $31,800 and $32,440, respectively. By multivariate analysis, pretreatment viremia higher than 0.2 MEq/mL and infection with genotype 1 were independently associated to treatment failure. The outcome of treatment in chronic hepatitis C patients was not improved by the administration of high cumulative doses of lymphoblastoid IFN.
Mutations in the Hepatitis B Virus Precore/Core Gene and Core Promoter in Patients With Severe Recurrent Disease Following Liver Transplantation
Authors: McMillan J S , Bowden D S , Angus P W , McCaughan G W , Locarnini S A
Published: November 2004

Recurrent hepatitis B virus (HBV) infection is a major problem in patients undergoing liver transplantation. Previously, we reported that infection with HBV strains containing a mutation in the precore region (G–to–A at nucleotide 1896) was associated with severe recurrent disease posttransplantation. In this study we investigated other mutations in the precore/core gene and core promoter which may be associated with this severe recurrence. The precore/core gene and core promoter of HBV from pre and posttransplantation sera of 15 patients with HBV recurrence were amplified by polymerase chain reaction (PCR) and sequenced. Pre and posttransplant sequences were very similar for each patient. HBV from patients who developed severe recurrence had significantly more mutations in both the nucleotide (

P

< .05) and predicted amino acid (

P

< .05) sequences of the precore/core gene, but not in the core promoter, than virus from patients with mild recurrence. There was also an apparent link between severe disease and HBV strains of genotype D (

P

< .05). The number of nucleotide and amino acid mutations in the precore/core gene was strongly associated with the presence of the precore mutation (

P

< .01). Mutations were found throughout the entire gene, however, at the amino acid level clustering was observed in the B– and helper T–cell epitopes as well as nuclear localization signals. In the encapsidation signal, nucleotide mutations were found that were predicted to increase the stability of the stem–loop structure. Overall, our data shows that genotype D and accumulated mutations throughout the HBV precore/core gene, but not core promoter, were associated with severe recurrent disease posttransplantation. These mutations were strongly linked to the presence of the precore mutation at nucleotide position 1896 and may contribute to the poor outcome in these patients.
Serum Hyaluronate Reflects Hepatic Fibrogenesis in Alcoholic Liver Disease and Is Useful As A Marker of Fibrosis
Authors: Pares A , Deulofeu R , Gimenez A , Caballeria L , Bruguera M , Caballeria J , Ballesta A M , Rodes J
Published: November 2004

The high levels of hyaluronic acid (HA), a glycosaminoglycan of the liver extracellular matrix, which is synthesized and degraded in the liver sinusoidal cells, have been related with a decreased function of the endothelial sinusoidal cells. The relevance of HA in alcoholic liver disease has not been sufficiently evaluated, and therefore the current study was addressed to assess whether serum HA reflects the severity of liver fibrosis and fibrogenesis as well as the potential usefulness of hyaluronic acid as a marker of early fibrosis in alcoholics with liver damage. Serum HA and aminoterminal propeptide of collagen III (PIIIP) levels, a marker of liver fibrogenesis in alcoholics with liver disease, were assessed in 45 chronic alcoholic patients (31 men and 14 women, age: 44.1 ± 1.5 years) (normal liver = 7; fatty changes = 8; fibrosis = 7; alcoholic hepatitis = 6; cirrhosis = 6; and cirrhosis plus alcoholic hepatitis = 11). The severity of liver inflammation and fibrosis were scored in liver specimens as: 0, no lesion; 1+ mild; 2+ moderate; and 3+ severe. Twenty–seven patients (60%) had HA above normal values (1 patient with fatty changes, 3 patients with fibrosis, and all patients with alcoholic hepatitis or cirrhosis). Hyaluronic acid and (PIIIP) levels increased in parallel with the severity of liver damage. Hyaluronic acid levels were higher in those patients with more liver inflammation (0, 128 ± 38; 1+, 553 ± 141; 2+, 668 ± 259; 3+, and 1,073 ± 419 microg/L; P = .004) and of fibrosis (0, 79 ± 32; 1+, 156 ± 70; 2+, 219 ± 105; and 3+, 695 ± 114 microg/L;

P

< .001). Procollagen III peptide levels were related with fibrosis (0, 17 ± 1; 1+, 25 ± 6; 2+, 47 ± 13; 3+, and 55 ± 9 ng/mL;

P

= .002) but not with inflammation (0, 29 ± 7; 1+, 45 ± 7; 2+, 54 ± 9; 3+, and 66 ± 30 ng/mL,

P

: not significant). Moreover, a direct linear correlation was observed between HA and PIIIP (r = .72,

P

< .001). A receiver operating characteristic (ROC) curve analysis revealed that HA was similar to PIIIP levels in discriminating between alcoholics without fibrosis and those with fibrosis (area under the ROC curves) (.913 ± .042 vs. .867 ± .054;

P

: n.s). In conclusion, serum HA reflects the severity of liver inflammation, fibrosis, and fibrogenesis in patients with alcoholic liver disease and is useful as a marker of precirrhotic and cirrhotic stages.
Kan–1 (Bile Acid Coa:Amino Acid N –Acyltransferase) Messenger Rna As A Novel Predictive Indicator for Prognosis of Hepatocellular Carcinoma Patients After Partial Hepatectomy
Authors: Furutani M , Arii S , Higashitsuji H , Mise M , Niwano M , Harada T , Nakayama H , Fukumoto M , Imamura M , Fujita J
Published: November 2004

We identified

kan–1

complementary DNA (cDNA), the sequence of which is identical to bile acid CoA:amino acid N–acyltransferase (BAT), a liver enzyme that catalyzes the conjugation of bile acids with glycine or taurine.

kan–1

(BAT) messenger RNA (mRNA) levels of the resected specimens obtained from 37 hepatocellular carcinoma (HCC) patients were studied in an attempt to evaluate prognostic significance in HCC patients after partial hepatectomy. Using Northern blot hybridization,

kan–1

(BAT) mRNA levels were quantified in tumorous and nontumorous tissues, and the ratio of the former to the latter was defined as the

kan–1

(BAT) ratio. Twelve patients had a

kan–1

(BAT) ratio < 0.5 (low kan– 1[BAT] ratio), and 25 patients had a ratio >0.5 (high

kan–1

[BAT] ratio). The patients with a low

kan–1

(BAT) ratio demonstrated poorer survival than the patients with a high

kan–1

(BAT) ratio (

P

= .0013). The overall estimated hazard ratio for death in patients with a low kan–1(BAT) ratio was 68.05 according to a multivariate model (

P

= .0005). Thus, the

kan–1

(BAT) ratio may serve as a new molecular prognostic marker in HCC patients, following hepatic resection.
Pilot–Controlled Trial of the Extracorporeal Liver Assist Device in Acute Liver Failure
Authors: Ellis A J , Hughes R D , Wendon J A , Dunne J , Langley P G , Kelly J H , Gislason G T , Sussman N L , Williams R
Published: November 2004

The objective of this pilot controlled study was to evaluate the extracorporeal liver assist device (ELAD) in patients with acute liver failure who were judged to still have a significant chance of survival (approximately 50%) and in those who had already fulfilled criteria for transplantation. Twenty–four patients were divided into two groups, 17 with a potentially recoverable lesion (group I) and 7 listed for transplantation (group II), and then randomly allocated to ELAD haemoperfusion or control. The median period of ELAD haemoperfusion was 72 hours (range 3–168 h). Biocompatibility of the device was good, with no acceleration in platelet consumption, and haemodynamic stability was maintained. Two patients were withdrawn from the study because of worsening of preexisting disseminated intravascular coagulation in one case and a hypersensitivity reaction in the other. Deterioration with respect to encephalopathy grade was more frequent in the control patients, 7 of 12 (58%), than in the ELAD–treated patients, 3 of 12 (25%). In group I where survival for the ELAD cases was 7 of 9 (78%), there was a higher than expected survival in the controls, 6 of 8 (75%). For group II cases, survival was 1 of 3 (33%) for the ELAD– treated patients, and 1 of 4 (25%) for the controls. Both of the survivors underwent transplantation. Assessment of additive function for the device revealed an improvement in galactose elimination capacity after 6 hours of haemoperfusion. Based on the results of this pilot–controlled trial, better indices of prognosis will be required, in addition to those used to select for transplantation, if patients at an earlier stage of clinical deterioration are to be included in future studies.
Failure to acquire new semantic knowledge in patients with large medial temporal lobe lesions
Authors: Bayley Peter J. , Squire Larry R.
Published: November 2004

We examined new semantic learning in two profoundly amnesic patients (E.P. and G.P.) whose lesions involve virtually the entire medial temporal lobe (MTL) bilaterally. The patients were given five tests of semantic knowledge for information that could only have been acquired after the onset of their amnesia in 1992 and 1987, respectively. Age‐matched and education‐matched controls (n = 8) were also tested. On tests of recall, E.P. and G.P. each scored 10% correct on a test of 20 easy factual questions (controls = 90%), 2% and 4% correct on 55 questions about news events (controls = 85%), and 0% and 4% correct on a test of 24 famous faces. On three tests of recognition memory for this same material, the patients scored at chance levels. Similarly, the patients were unable to judge whether persons who had been famous for many decades were still living or had died during the past 10 years (E.P. = 53%; G.P. = 50%; controls = 73%; chance = 50%). Lastly, neither patient E.P. nor patient G.P. could draw an accurate floor plan of his current residence, despite having lived there for 10 years and 1 year, respectively. The results demonstrate that the capacity for new semantic learning can be absent, or nearly absent, when there is virtually complete damage to the MTL bilaterally. Accordingly, the results raise the possibility that the acquisition of conscious (declarative) knowledge about the world cannot be supported by structures outside the MTL, even with extended exposure. Published 2004 Wiley‐Liss, Inc.
A model for valuation of the branch offices of a savings bank based on rough sets
Authors: Pérez‐Llera C. , Fernández‐Baizán C. , Fanjul J. L. , Feito J.
Published: November 2004

This work proposes a model for the valuation of branch ofﬁces of banks based on the rough set theory, which could be used as the basis for a decision‐making system for dimensioning strategies of a ﬁnancial entity. It compares the rough set approach with the competitive discriminant analysis methodology using a common set of data from 421 branches. We pay special attention to data reduction and the creation of decision rules that will allow future branches to be classiﬁed. These rules could constitute the basis for the evaluation of the viability of dimensioning strategies for a ﬁnancial entity. In order to evaluate the predictive capabilities of the decision rules, we present the results of cross‐validation tests to evaluate the ability of the model to classify new branches. It appears that the rough sets approach provides a favourable tool for the valuation of branch ofﬁces. Copyright © 2004 John Wiley & Sons, Ltd.
Artificial neural networks with feature transformation based on domain knowledge for the prediction of stock index futures
Authors: Kim Kyoung‐Jae
Published: November 2004

A feature transformation method based on domain knowledge for artiﬁcial neural networks (ANNs) is proposed. The method of feature transformation based on domain knowledge converts continuous values into discrete values in accordance with the knowledge of experts in speciﬁc application domains. This approach effectively ﬁlters data, trains the classiﬁer, and extracts the rules from the classiﬁer. In addition, it reduces the dimensionality of the feature space, which not only decreases the cost and time in the operation but also enhances the generalizability of the classiﬁer. The experimental results of the proposed approach will be compared and tested statistically with the results of the linear transformation method. The results show that the method of feature transformation based on domain knowledge outperforms the linear transformation in modelling of ANNs. Copyright © 2004 John Wiley & Sons, Ltd.
Novel polyelectrolyte carboxymethyl konjac glucomannan–chitosan nanoparticles for drug delivery. II. Release of albumin in vitro
Authors: Du Jian , Zhang Sheng , Sun Rui , Zhang Li‐Fang , Xiong Cheng‐Dong , Peng Yu‐Xing
Published: November 2004

Carboxymethyl konjac glucomannan–chitosan (CKGM‐CS) nanoparticles were spontaneously prepared under very mild conditions via polyelectrolyte complexation. Bovine serum albumin (BSA), as a model protein drug, was incorporated into the CKGM‐CS nanoparticles. The physicochemical properties of the BSA‐loaded nanoparticles were identified by Zetasizer 3000 and FTIR spectrophotometry. Their sizes were from 330 nm to 900 nm; zeta potentials were positive according to varies CKGM/CS ratios. The encapsulation efficiency was up 20%. The release behavior in vitro of BSA from the nanoparticles was also investigated. We could find that the BSA release from the CKGM‐CS nanoparticles is much more influenced by the CS coating layer than by the CKGM inner structure. And the CKGM‐CS matrices not only exhibited pH‐responsive properties, but ionic strength‐sensitive properties. These systems may present a potential for pulsatile protein drug delivery. © 2004 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater 72B: 299–304, 2005
Histone acetyltransferase activity of p300 enhances the activation of IL‐18 promoter
Authors: Sun Haijing , Lu Jun , Xu Xin , Jin Shunzi , Wang Xiuli , Wei Liang , Dong Mei , Huang Baiqu
Published: November 2004

Interleukin‐18 (IL‐18), an important regulator of innate and acquired immune responses expressed from a variety of cell types, is a pleiotropic cytokine in the development of T helper type 1 (Thl) cells. The p300/CBP (CREB‐binding protein) coactivator proteins are important histone acetyltransferases (HATs) that regulate the transcription of many genes. Whether p300/CBP play a role in the IL‐18 expression has not been investigated previously. In this study, we analyzed the roles of p300 in the regulation of mouse IL‐18 by using RT‐PCR and a series of co‐transfection studies. We showed that p300 had a stimulating effect on the endogenous IL‐18 mRNA synthesis and on the activity of IL‐18 p1 promoter. The results also showed that IL‐18 p1 promoter activity was enhanced by p300 in a dose‐dependent manner. Moreover, the p300‐mediated activation function can be suppressed by the adenovirus E1A protein, which inhibits the HAT function of p300. Also, a mutation in p300 HAT region abolished the effect of p300 on IL‐18 activation. These data further indicate that the acetylase activity of p300 was indispensable to its function. Furthermore, we found that p300 was able to enhance the effect of the transcription factor c‐Fos on activation of the IL‐18 promoter. Data presented in this paper implicate important roles of p300 in the transcriptional regulation of IL‐18. © 2004 Wiley‐Liss, Inc.
Bone morphogenetic protein‐2 induces expression of murine zinc finger transcription factor ZNF450
Authors: Edgar Alasdair J. , Dover Sharon L. , Lodrick Melanie N. , McKay Ian J. , Hughes Francis J. , Turner Wendy
Published: November 2004

The bone morphogenetic protein‐2 (BMP‐2) is a potent secreted factor that promotes osteoblast differentiation during development. Exposure to BMP‐2 is sufficient to cause a lasting change in cell fate presumably by activating specific target genes. To identify genes downstream of BMP‐2 we treated the murine pluripotent embryonic cell line, C3H10T1/2 that can be induced to form an osteoblastic phenotype, with 100 ng/ml BMP‐2 for 24 h. Using suppression subtractive hybridisation we found the novel zinc finger transcription factor, ZNF450 was upregulated. The single‐copy ZNF450 gene spans 15.6 kb on chromosome 10B1 and consists of seven exons, the first of which is untranslated. The open reading frame encodes a 710 reside protein. Analysis of the protein sequence reveals a highly conserved amino‐terminal BTB/POZ dimerisation domain, an AT‐hook motif, and eight C2H2 zinc fingers. Library screening identified a second mRNA isoform encoding a short protein isoform with one zinc finger. Using reverse transcriptase‐real time PCR to measure mRNA expression we found that ZNF450, Runx2/Cbfa‐1, and Sp7/osterix were induced by BMP‐2 after 4 h in C2C12 myoblast cells. Treatment of C2C12 cells with BMP‐2 causes a shift from a myoblastic to osteoblastic phenotype. ZNF450 was upregulated three to fivefold after 24 h in C3H10T1/2 cells and required 100 ng/ml BMP‐2. Expression of the 3 kb major transcript was highest in liver, testis, and kidney. However, ZNF450 mRNA was found also in a wide range of adult tissues. The consistent induction of ZNF450 by BMP‐2 after 4 h in three murine pluripotent cell lines suggests that ZNF450 may play a role in the BMP‐2 signalling pathway. © 2004 Wiley‐Liss, Inc.