bluuebunny/crossref_metadata_2025 huggingface dataset:
Eosinophil cationic protein's role in human hepatic allograft rejection
Authors: Foster Preston F. , Bhattacharyya Achyut , Sankary Howard N. , Coleman James , Ashmann Marilyn , Williams James W.
Published: March 2007

Although it is known that eosinophils consistently infiltrate rejecting human liver allografts, their function is unknown. Infiltrating eosinophils can release a cytotoxic substance, eosinophil cationic protein. Furthermore, eosinophil cationic protein may be identified in biopsy specimens using immunoperoxidase staining of an eosinophil cationic protein-specific monoclonal antibody.

To study a possible effector role of eosinophils in rejecting liver allografts, 38 serial allograft biopsy specimens from 12 patients with acute rejection, 54 biopsy specimens from 11 patients with allograft dysfunction caused by other causes and 22 biopsy specimens from 8 patients without allograft dysfunction were stained for extracellular eosinophil cationic protein. In addition, the absolute blood eosinophil counts and the portal tract eosinophil percent of the total number of portal tract inflammatory cells were tabulated in these patients until 30 days after transplantation.

The blood absolute eosinophil count, portal tract eosinophil percent and incidence of positive extracellular eosinophil cationic protein staining were significantly increased in patients with rejection compared with patients with dysfunction from other causes (p < 0.05 to 0.005, t test). Furthermore, each of these parameters predicted rejection with excellent sensitivity (75% to 92%) and specificity (91% to 100%). Of patients with rejection, 59% had significant elevation of all three parameters before or during rejection, and 92% had at least two parameters elevated. Conversely, of the patients with dysfunction from other causes, 0% had elevations of any parameter.

The recognized cytotoxic properties of eosinophil cationic protein and its almost exclusive presence, along with eosinophils in the blood and allograft biopsy specimens of patients during acute rejection, support the role of the eosinophil as an effector cell in tissue injury during acute liver allograft rejection. (Hepatology 1991;13:1117-1125.)
Intralobular distribution and quantitation of cytochrome P-450 enzymes in human liver as a function of age
Authors: Ratanasavanh Damrong , Beaune Philippe , Morel Fabrice , Flinois Jean-Pierre , Guengerich Peter F. , Guillouzo Andre
Published: March 2007

We have used immunohistochemical, immunoblotting and messenger RNA blotting approaches to study the distribution and quantitation of three cytochrome P-450 enzymes, namely P-450 IA2, P-450 IIC and P-450 IIIA and, for comparison, epoxide hydrolase and NADPH-cytochrome P-450 reductase in human liver. Age-related changes in both the amounts and the intralobular distributions of these enzymes were demonstrated, and the enzymes differ in these regards: In fetal liver, P-450 IA2 and P-450 IIC were very low, when present at all, whereas P-450 IIIA, epoxide hydrolase and the reductase were already abundant and found in all the hepatocytes. During the postnatal period, P-450 IIC dramatically increased and was observed in all hepatocytes, the centriobular ones being more intensely stained. P-450 IIIA was restricted to centrilobular and midzonal hepatocytes in normal adult liver. P-450 IA2 showed this same intralobular distribution; however, its presence was detected only several weeks or months after birth as judged both by immunohistochemical and immunoblotting techniques. Epoxide hydrolase and NADPH-cytochrome P-450 reductase were easily visualized in all hepatocytes regardless of the age of the donor; in child and adult livers, centrilobular hepatocytes were more intensely stained. Immunoreactive protein contents and corresponding messenger RNA levels correlated well with immunohistochemical observations. No major modification was seen in fibrotic liver, whereas both positive and negative cells were observed in cirrhotic liver nodules for all enzymes studied. (Hepatology 1991;13:1142-1151.)
Ethanol-induced changes in hepatic free radical defense mechanisms and fatty-acid composition in the miniature pig
Authors: Zidenberg-Cherr Sheri , Olin Katherine L. , Villanueva Jesus , Tang Anna , Phinney Stephen D. , Halsted Charles H. , Keen Carl L.
Published: March 2007

In the miniature pig, ethanol consumption has been reported to induce alterations in hepatic antioxidant defense capacity, which could result in increased risk of peroxidative damage. However, ethanol may also induce changes in membrane fatty acid composition, which could reduce the risk of peroxidative damage. This study examined lipid peroxidation, antioxidant defense and fatty acid composition in livers from miniature pigs fed ethanol in diets containing 12% of their calories as fat for 20 mo. After 12 and 20 mo of feeding, ethanol-fed pigs had higher hepatic manganese-superoxide dismutase activity, lower hepatic copper concentrations and low hepatic copperzinc-superoxide dismutase and glutathione peroxidase activities compared with controls. Lipid peroxidation as assessed by thiobarbituric acid reacting substance assay was lower in liver homogenate and mitochondrial and microsomal fractions from ethanol-fed pigs than in controls. The percentage contribution of highly unsaturated fatty acids to total fatty acids in liver homogenates (after 12 mo of feeding) and microsome fractions (after 20 mo of feeding) was lower in the ethanol-fed pigs than in the controls, resulting in a lower peroxidizability index. Ethanol-fed pigs had minimal or no hepatic damage as assessed by histological methods. We suggest that the relative resistance of microsomes to lipid peroxidation is due to the lower peroxidizability index in the ethanol-fed pigs and may account in part for the absence of significant histopathological findings after 20 mo of ethanol feeding. (Hepatology 1991;13:1185-1192.)
Tissue distribution, quantitation and proliferation kinetics of fat-storing cells in carbon tetrachloride-injured rat liver
Authors: Geerts Albert , Lazou Jean-Marc , de Bleser Pieter , Wisse Eddie
Published: March 2007

In this study, we have investigated the cell population kinetics of fat-storing cells in livers of rats intoxicated with CCl4. Fat-storing cells were identified in cryostat sections by immunoperoxidase staining of desmin. The peroxidase label was visualized using diaminobenzidine/hydrogen peroxide containing Ni2+ and Co2+-ions (Nico/diaminobenzidine method). In normal rats, we found 12.8 fat-storing cells/0.1 mm2 in periportal areas vs. 9.4 in pericentral fields. After one injection of CCl4, the number of pericentral cells increased gradually to reach a maximum of 39.4 cells/0.1 mm2 96 hr after injection. The desmin staining intensity of the pericentral fat-storing cells increased from 48 hr onward. At 72 to 120 hr, strongly stained cells were observed in pericentral areas and in bands of tissue between adjacent central veins, reminiscent of the connective tissue septa in fibrotic livers. In the periportal areas the number of fat-storing cells was not altered. After a second and third injection of CCl4, the number of cells increased further in the pericentral areas. When more than three injections were given, the pericentral fat-storing cell population reached a new steady state with the cell number being seven times higher than in control animals.

Proliferation of fat-storing cells at different stages of CCl4 intoxication was studied by intravenous administration of 3H-thymidine, followed by combined desmin staining and autoradiography. Autoradiographical labeling of fat-storing cells was nearly absent in control animals and at 24 hr after a single CCl4 injection. At 48 to 96 hr, labeling indices of pericentral fat-storing cells were significantly higher than in control animals, with a maximum at 72 hr when 22.9% of the cells were labeled. After multiple injections of CCl4, labeling indices between 4.9% and 8.4% were found.

We conclude that fibrogenesis is preceded by a strong expansion of the fat-storing cell population in the pericentral areas of the liver lobules and in bands of tissue between adjacent central veins. Local proliferation is an important mechanism underlying the expansion of this cell population. (Hepatology 1991;13:1193-1202.)
Glucuronidation of bile acids by their high-dose infusion into rats
Authors: Takikawa Hajime , Narita Tohru , Sano Naoyo , Yamanaka Masami
Published: March 2007

We previously reported that high-dose infusion of ursodeoxycholate into rats caused its extensive glucuronidation. In this study, the glucuronidation of various bile acids after high-dose infusion into rats was examined and the effects of coinfusion of bile acids on the glucuronidation of a trace dose of [14C]deoxycholate were also studied. Sixty minutes after infusion of 14C-bile acids at a rate of 1 μmol/min/100 gm, the glucuronidation of the labeled bile acid in the bile was 31%, 15%, 8% and 3% for deoxycholate, ursodeoxycholate, chenodeoxycholate and cholate, respectively. The infusion of a trace dose of [14C] deoxycholate resulted in only 2% glucuronidation, and coinfusion of taurochenodeoxycholate or tauroursodeoxycholate at a rate of 1 μmol/min/100 gm did not change the percentage of glucuronidation of [14C]deoxycholate. However, coinfusion of chenodeoxycholate, ursodeoxycholate or cholate at the same rate markedly increased the percentage of the [14C]deoxycholate-glucuronide in the bile (35%, 18% and 36%, respectively). Thus glucuronidation of bile acids by high-dose infusion into rats occurs predominantly with deoxycholate and is not specific for ursodeoxycholate, and glucuronidation depends on the unconjugated bile acid load, which might be regulated by the capacity of amidation by the liver. (Hepatology 1991;13:1222-1228.)
Liver transplantation restores female reproductive endocrine function
Authors: Brown Kimberly A. , Lucey Michael R.
Published: March 2007

The effect of successful liver transplantation on menstrual function was assessed by questionnaire in 44 women transplanted for various types of end stage liver disease, acute liver failure or malignant disease. Significant amenorrhoea (>one year) was present in 48% of women with chronic liver disease before transplantation, and was reversed within 10 months of surgery in all but one of the pre-menopausal patients who had primary amenorrhoea and hypogonadotrophic hypogonadism. Two patients became pregnant five months and 1-5 years after transplantation, but in one instance the pregnancy was unsuccessful, possibly as a consequence of cyclosporin related intrauterine growth retardation.

Seventeen female patients who underwent orthotopic liver transplantation between June 1973 and June 1987 became pregnant 5 months to 11 years after transplantation. Immunosuppression was maintained with combinations of prednisone, cyclosporine, and azathioprine prior to and during pregnancy. One patient discontinued immunosuppression after knowledge of pregnancy, taking only azathioprine sporadically. Mean age at time of delivery was 26 years. Twelve patients had no alteration in liver function studies; 7 patients demonstrated mild or moderate enzyme elevations prior to delivery, with one case of rejection confirmed by percutaneous liver biopsy. Major problems related to pregnancy were hypertension, anemia, and hyperbilirubinemia. Twenty live births occurred (2 patients had 2 separate pregnancies, one patient has a set of twins); 13 were by caesarian section, 7 by vaginal delivery. Eleven of the 13 caesarian births were premature by gestational age. All vaginal births were term. Toxemia of pregnancy and early rupture of membranes were the principal indications for caesarean section.

There were no congenital abnormalities or birth defects and all the children are surviving well. Fifteen of 16 children older than one year have normal physical and mental development, with one child manifesting immature speech development. Four children are under one year, all with normal milestones thus far. Sixteen of the 17 mothers are alive from 2-18 years after transplantation; the only death was from a lymphoma, almost 4 years after transplantation and 2 1/2 years after delivery. This experience suggests that women undergoing liver transplantation can safely bear children despite an increased risk of premature caesarian births. The effect of chronic immunosuppression of female pediatric patients on their reproductive potential later in adulthood remains to be fully evaluated but the results so far are favorable.
Ursodeoxycholic acid and taurine as therapy for cholestatic liver disease
Authors: Chan Mary F. , Lake John R.
Published: March 2007

Relatively hydrophobic bile acids have been shown to produce some hepatotoxicity, whereas treatment with a more hydrophilic bile acid, ursodeoxycholic acid, has improved liver function indices in patients with certain chronic liver diseases. Taurine-conjugated bile acids are more hydrophilic than glycine-conjugated bile acids, and thus, taurine administration has also been suggested for the treatment of chronic hepatitis. To determine if taurine and ursodeoxycholic acid are beneficial and if their effects are additive, this double-blind, randomized trial was conducted to compare the effects of ursodeoxycholic acid, taurine, and a combination of the two on indices of liver injury in 24 patients with chronic hepatitis.

The subjects were assigned at random to two of the four following treatments: ursodeoxycholic acid (600 mg/d), taurine (1.5 g/d), ursodeoxycholic acid plus taurine (600 mg and 1.5 g/d) or placebo, given in two successive cycles of 2 months each, according to a balanced incomplete block design.

As expected, ursodeoxycholic acid became the predominant bile acid in bile when administered alone or in combination with taurine, and taurine conjugate concentrations increased during taurine administration. Ursodeoxycholic acid reduced serum aminotransaminase and γ-glutamyl transpeptidase activities significantly, whereas taurine did not. The effects of taurine and ursodeoxycholic acid were not significantly different from those produced by ursodeoxycholic acid alone. It is concluded that ursodeoxycholic acid, but not taurine, improves biochemical indices of liver injury in patients with chronic hepatitis.
FK 506-A promise of good things to come?
Authors: Neuberger James
Published: March 2007

The new immunosuppressive drug FK 506 was used from the outset with low doses of prednisone to treat 120 recipients of primary liver grafts and 20 more patients undergoing liver retransplantation. The patient survival rate after 2 to 8 months in the primary liver transplantation series is 93.3%, with original graft survival of 87.5%. Of the 20 patients in the hepatic retransplant series, 17 (85%) are living. Almost all of the surviving patients have good liver function. In addition 11 hearts, 2 double lungs, and a heart-lung have been transplanted under FK 506, with survival of all 14 patients. With all of the organ systems so far tested, including the kidney (which has been reported elsewhere), rejection usually has been controlled without additional drugs and with lower average steroid doses than in the past. Nephrotoxicity has been observed, but not to an alarming degree, and there has been a notable absence of hypertension. There is a suggestion that serum cholesterol may be lowered by FK 506, but this is unproved. Although the adverse reactions of FK 506 and the immunosuppressive mechanisms resemble those of cyclosporine, our preliminary observations suggest that FK 506 may have a more advantageous therapeutic index.
Prevalence of antibody to hepatitis C virus among Saudi Arabian children: A community-based study
Authors: Al-Faleh Faleh Z. , Ayoola Ayobanji E. , Al-Jeffry Mohammed , Al-Rashed Rashed , Al-Mofarreh Mohammed , Arif Mohammed , Ramia Sami , Al-Karawi Mohammed , Al-Shabrawy Mohammed
Published: March 2007

In a population-based survey, 39 (0.90%) of 4,496 Saudi Arabian children (ages 1 to 10) were positive for antibody to hepatitis C virus. No significant difference was seen between the prevalence rate in males (0.9%) and females (0.8%) or between urban (0.7%) and rural dwellers (1.0%). A significant variation of rates (0% to 5.7%) was seen from one region to another. The Gizan population, noted for hyperendemic hepatitis B virus infection, had the highest prevalence of antibody to hepatitis C virus despite its cultural and socioeconomic similarities to other regions. In some regions of Saudi Arabia the prevalence of antibody to hepatitis C virus among children was 0% despite endemic rates for both hepatitis B virus and hepatitis A virus infections.

An inverse relationship between age and antibody to hepatitis C virus positivity was noted, suggesting an early acquisition of infection in the population studied. Although the overall prevalence of antibody to hepatitis C virus in Saudi children appears low, endemic foci exist where transmission of infection appears to occur early in childhood. The significance of this characteristic for the incidence of chronic sequelae of hepatitis C virus infection needs further evaluation. (HEPATOLOGY 1991;14:215-218.)
Association of a precore genomic variant of hepatitis B virus with fulminant hepatitis
Authors: Carman William F. , Fagan Elizabeth A. , Hadziyannis Stephanos , Karayianni Peter , Tassopoulos Nicolaos C. , Williams Roger , Thomas Howard C.
Published: March 2007

A variant of hepatitis B virus has been described recently in HBsAg+ Mediterranean patients who lack HBeAg and who have an unusual and severe form of chronic hepatitis. This variant is unable to produce HBeAg because of the presence of a novel translational stop codon at the end of the precore region of the genome. By direct sequencing of DNA, generated by the polymerase chain reaction, we have evaluated the association between infection with this variant and the fulminant course of hepatitis B. Eighteen patients with fulminant hepatitis B were studied. Of the 15 cases from whose serum viral DNA could be sequenced, the variant was found in the admission sera of 8 of 9 HBeAg—patients but in none of 6 HBeAg+ patients who had fulminant hepatitis B. Patients harboring the variant progressed more rapidly into hepatic encephalopathy, but those infected with the variant strain alone had a greater likelihood of survival than those infected with the normal strain or a mixture. The mutant strain may emerge spontaneously during fulminant hepatitis as occurs in chronic hepatitis B infection during seroconversion from HBeAg to antibody. Alternately, and perhaps less commonly, patients may be infected with the variant ab initio. (HEPATOLOGY 1991;14:219-222.)
A pathophysiological interpretation of unresponsiveness to spironolactone in a stepped-care approach to the diuretic treatment of ascites in nonazotemic cirrhotic patients
Authors: Gatta Angelo , Angeli Paolo , Caregaro Lorenza , Menon Francesca , Sacerdoti David , Merkel Carlo
Published: March 2007

It has been hypothesized that the magnitude of proximal sodium reabsorption affects the response to aldosterone antagonists in nonazotemic cirrhotic patients with ascites. To verify this hypothesis, we evaluated intrarenal sodium handling by lithium clearance in 51 nonazotemic ascitic cirrhotic patients and in 23 controls who were maintained on the same low-sodium diet (80 mmol/day). Seven of 51 cirrhotic patients underwent spontaneous diuresis, whereas 44 required diuretic treatment. Treatment was started with spironolactone at a dose of 150 mg once daily. The dose was increased to 300 mg and then to 500 mg once daily if no response ensued. Cirrhotic patients who did not experience ascites mobilization with 500 mg spironolactone were then treated with a combined diuretic regimen that included spironolactone at a fixed dose (500 mg once daily) and furosemide at an initial dose of 50 mg once daily. The dose was increased to 100, 150 and 200 mg once daily if no response was noticed. Response to diuretic treatment was defined as body weight loss greater than 700 gm every 3 days until ascites became clinically undetectable. Nonresponders (43%) to spironolactone showed lower sodium fractional excretion (0.34% ± 0.28% vs. 0.80% ± 0.50%; p < 0.001) because of a lower fractional sodium delivery to the distal tubule (18.2% ± 5.8% vs. 23.4% ± 7.2%; p < 0.025) than responders. Moreover, nonresponders showed lower distal sodium reabsorption, both in absolute terms (2,360 ± 723 μEq/min vs. 3,221 ± 960 μEq/min; p < 0.01) and as a percentage of filtered sodium load (17.5% ± 5.7% vs. 23.1% ± 7.6%; p < 0.01) despite higher values of plasma aldosterone (524 ± 542 pg/ml vs. 136 ± 213 pg/ml; p < 0.025).

We conclude that unresponsiveness to adequate doses of spironolactone in nonazotemic ascitic cirrhotic patients is related to a pathophysiological condition in which the role of aldosterone in renal sodium retention is limited by markedly enhanced proximal sodium reabsorption. (HEPATOLOGY 1991;14:231-236.)
Detection of fibronectin receptor in sera: Its clinical significance as a parameter of hepatic fibrosis
Authors: Yamauchi Masayoshi , Nakajima Hisato , Ohata Mitsuru , Hirakawa Junnichi , Mizuhara Yuji , Nakahara Masao , Kimura Kazuo , Fujisawa Kiyoshi , Kameda Haruo
Published: March 2007

Pooled sera collected from cirrhotic patients was fractionated by affinity chromatography with a fibronectin receptor monoclonal antibody against the β-subunit of fibronectin receptor. Eluates were assayed using Western immunoblotting. The relative mobility of the protein reactive with fibronectin receptor antibody was nearly identical to that of the β-subunit of fibronectin receptor, confirming that fibronectin receptor is present in human serum. Serum levels of the β-subunit of fibronectin receptor were analyzed by sandwich enzyme-linked immunosorbent assay in patients with various liver diseases. The serum level of fibronectin receptor (μg/ml) was significantly higher in patients with chronic hepatitis (inactive, 2.59 ± 0.04; active, 3.45 ± 0.13), cirrhosis (4.77 ± 0.30), alcoholic liver disease (2.96 ± 0.16) and hepatocellular carcinoma (4.71 ± 0.49) than in normal subjects (2.11 ± 0.08). Strong positive correlation was observed between serum levels of fibronectin receptor and histological findings, particularly in the degree of hepatic fibrosis. Immunohistochemical studies with fibronectin receptor antibody revealed that the β-subunit of fibronectin receptor was present on the plasma membrane of hepatocytes and sinusoidal lining cells in the normal liver and was increased in fibrotic areas and on the plasma membrane of hepatocytes and sinusoidal lining cells of fibrotic liver. The serum level of fibronectin receptor in patients with chronic liver diseases may therefore be a useful marker of hepatic fibrosis. (HEPATOLOGY 1991;14:244-250.)
Antithrombin III supplementation reduces heparin requirement and platelet loss during hemodialysis of patients with fulminant hepatic failure
Authors: Langley Peter G. , Keays Rick , Hughes Robin D. , Forbes Alastair , Delvos Ullrich , Williams Roger
Published: March 2007

Previous studies have shown that antithrombin III levels are low in fulminant hepatic failure, and heparin kinetics are abnormal, making control of heparinization difficult during hemodialysis of these patients who are at risk of bleeding. In this study, we have performed a controlled, randomized trial of antithrombin III supplementation on heparin activity, occurrence of bleeding and the platelet count and activation during hemodialysis in 24 patients with fulminant hepatic failure. The treated group of 12 patients was given 3,000 units of antithrombin III before hemodialysis. Antithrombin III supplementation was shown to normalize antithrombin III levels during hemodialysis (prelevels: 0.22 ± 0.03 U/ml S.E.; at 1 hr 0.99 ± 0.06 U/ml; p <0.001; control prelevels: 0.24 ± 0.03 U/ml; at 1 hr 0.23 ± 0.04 U/ml). Total heparin usage was significantly decreased by antithrombin III supplementation (median 5,200 U; range = 2,005 to 13,000) as compared with the control group (median 10,200 U; range = 5,000 to 16,500; p <0.005). Blood heparin level (antifactor Xa activity) after the initial bolus was significantly greater in the antithrombin III—supplemented subjects (0.40 ± 0.07 U/ml compared with 0.22 ± 0.05 U/ml in the control group; p < 0.05). The significant reduction in platelet count observed in the control patients (18% ± 6% at 1 hr; p < 0.05) did not occur in antithrombin III patients (6% ± 4% at 1 hr), which was reflected by a lower release of the platelet-specific protein β-thromboglobulin. Two of 12 patients in both groups showed minor bleeding around vascular access sites during the first hemodialysis. Over the course of the study, no significant difference was seen in the frequency of bleeding from vascular access sites, gastrointestinal tract or other locations.

Thus in a controlled study, supplementation of antithrombin III markedly reduced the amount of heparin required during hemodialysis of patients with fulminant hepatic failure and also reduced platelet losses. Antithrombin III supplementation may be of benefit in hemodialysis, continuous arteriovenous hemofiltration or other invasive techniques requiring anticoagulation in these patients at particular risk of bleeding. (HEPATOLOGY 1991;14:251-256.)
Prognosis of unresectable hepatocellular carcinoma: An evaluation based on multivariate analysis of 90 cases
Authors: Akashi Yuka , Koreeda Chizu , Enomoto Shigeki , Uchiyama Shozo , Mizuno Takako , Shiozaki Yasuko , Sameshima Yoshiko , Inoue Kyoichi
Published: March 2007

A multivariate analysis of data from 90 patients with unresectable hepatocellular carcinoma was performed using Cox’s regression model to identify factors possibly affecting their prognoses. Thirty-one patients underwent arterial anticancer chemotherapy, and the remaining 59 patients received transcatheter arterial embolization with anticancer agents. Four of 27 variables tested for all the patients (i.e., encapsulation [p < 0.05], gross appearance of hepatocellular carcinoma [p < 0.01], clinical stage [p < 0.01] and therapy [p < 0.01]) were found to be prognostically significant. Five of 27 variables tested were prognostically significant for the transcatheter arterial embolization group; they were an extension rate of hepatocellular carcinoma (p < 0.01), encapsulation (p < 0.01), α-fetoprotein (p < 0.01), prothrombin time (p < 0.01) and serum sodium (p < 0.01). Regression equations were used to describe a prognostic index. A prognostic index was defined as the regression equation derived from the results of a total of 90 patients; PI-1 = eY, where PI-1 = prognostic index 1 Y = 1.549 (gross appearance of hepatocellular carcinoma −1.344) + 0.778 (encapsulation − 1.622) + 0.818 (clinical stage − 1.800) + 1.760 (therapy − 1.344) and prognostic index 2, the regression equation derived from the results of the transcatheter arterial embolization group of patients; PI-2 = eY, where PI-2 = prognostic index 2 Y = 1.210 (extension rate of hepatocellular carcinoma − 1.576) + 1.179 (encapsulation − 1.475) + 0.0001277 (α-fetoprotein − 1420.792) −0.039 (prothrombin time − 72.237) − 0.214(serum sodium − 138.427). According to the prognostic index, the patients were divided into two groups (i.e., those with the good prognoses and those with bad prognoses). According to prognostic index 1, the prognosis of the patient who did not undergo transcatheter arterial embolization therapy was 5.8 times poorer than that of the patient who underwent transcatheter arterial embolization. One-year survival rates of the former and the latter were 66% and 9.4%, respectively. According to prognostic index 2, the prognosis of the patient whose extension rate of hepatocellular carcinoma was greater than 60% of the entire liver was 38 times poorer than that of the patient whose extension rate of hepatocellular carcinoma was less than 20% of the entire liver. This study demonstrated that prognostic indexes can be used to predict the survival time of a group of patients with unresectable hepatocellular carcinoma and that prognostic indexes can be used to predict those who have better prognosis in the transcatheter arterial embolization group. (HEPATOLOGY 1991;14:262-268.)
Immunohistochemical detection of transforming growth factor-β1 in fibrotic liver diseases
Authors: Nagy Peter , Schaff Zsuzsa , Lapis Károly
Published: March 2007

Transforming growth factor-β1 was localized by means of immunohistochemical reaction in liver biopsy specimens taken from patients having different chronic liver diseases with extending fibrosis. Two polyclonal antibodies that were produced in rabbits were directed against the amino terminal of transforming growth factor-β1.

Staining by anti-CC(1-30) was primarily extracellular and located in the portal and periportal fibrotic areas of all seven cases with chronic active hepatitis. No staining was noted in the four chronic persistent cases studied. A strong reaction was seen with the antibody in nine of the ten cirrhotic samples, whereas it was negative in one inactive cirrhosis case and in all five cases with normal liver histological findings. No positive staining could be detected by the anti-LC(1-30) in any of the liver tissues.

Detection of transforming growth factor-β1 in active liver diseases at the site of fibrosis suggests that transforming growth factor-β1 might have a role in the process and progression of fibrosis during the development of the disease. (HEPATOLOGY 1991;14:269-273.)
Graft vs. host disease after liver transplantation in humans: A report of four cases
Authors: Roberts John Paul , Ascher Nancy L. , Lake John , Capper Jan , Purohit Sarla , Garovoy Marvin , Lynch Roy , Ferrell Linda , Wright Teresa
Published: March 2007

Four cases of patients in whom graft vs. host disease developed after liver transplantation are described. The clinical course of each patient was similar with fever, pancytopenia, diarrhea and a skin rash developing 1 or 2 mo after liver transplantation. The clinical diagnosis was made from skin or colon biopsy specimens. Liver dysfunction did not occur in the patients at the time of diagnosis. Extrahepatic donor DNA was identified in the three patients it was tested for. Three patients died from the complications of the disease primarily related to sepsis. The other patient recovered from the graft vs. host disease but died from lymphoproliferative disease. (HEPATOLOGY 1991;14:274-281.)
Prevention of portal hypertension and portosystemic shunts by early chronic administration of clonidine in conscious portal vein-stenosed rats
Authors: Lin Han-Chieh , Soubrane Olivier , Lebrec Didier
Published: March 2007

The hemodynamic effects, including mesentericsystemic shunts of early chronic administration of clonidine, were studied in conscious, unrestrained, portal vein-stenosed rats. In rats receiving early chronic clonidine (600 μg · kg−1 · day−1 by gavage), begun 3 days before portal vein stenosis and then administered continuously for 10 consecutive days, portal pressure (10.0 ± 1.5 mm Hg) and degree of mesenteric-systemic shunts (58% ± 25%) were significantly lower than in the placebo group (15.2 ± 1.5 mm Hg and 83% ± 7%, respectively). The effects were observed either 2 to 3 hr or 18 to 24 hr after the last dose of clonidine. In rats receiving clonidine continuously for 5 days, starting 5 days after portal vein stenosis, portal pressure (11.0 ± 1.3 mm Hg) was significantly lower than in the placebo group, but mesenteric-systemic shunts (82% ± 8%) were not significantly different. In rats receiving a single oral dose of clonidine (600 μg/kg) 10 days after portal vein stenosis, portal pressure (11.8 ± 2.1 mm Hg), measured 2 to 3 hr after clonidine administration, was significantly lower than in the placebo group. Mesenteric-systemic shunts (83% ± 8%), however, were not significantly different from the placebo group. In addition, 18 to 24 hr after a single dose of clonidine, hemodynamic values returned to basal conditions. We also demonstrated that chronic clonidine administration begun before portal vein stenosis can reduce the initial increase in portal pressure after this procedure. We concluded that early chronic clonidine administration reduces the severity of portal hypertension and the development of portosystemic shunts in portal vein-stenosed rats. These beneficial effects are probably due to a limitation of the initial increase in portal pressure that follows portal vein stenosis (HEPATOLOGY 1991;14:325-330.)
A comparison of lipoprotein secretion, bile production and hepatic morphology in isolated rat livers perfused with a perfluorocarbon emulsion or rat erythrocytes
Authors: Felker Tünde E. , Gantz Donald , Tercyak Anna M. , Oliva Cheryl , Clark Susanne Bennett , Small Donald M.
Published: March 2007

Isolated rat livers were perfused with an oxygenated perfluorocarbon emulsion, FC-43 emulsion for 1 to 4 hr. FC-43 emulsion contained 20% FC-43 (wt/vol) perfluorotributylamine (the fluorocarbon component for the transport of oxygen and carbon dioxide) emulsified with 2.56% Pluronic F-68 (a nonionic surfactant) in Krebs-Ringer bicarbonate buffer. FC-43 emulsion also contained 3% hydroxyethyl starch as an oncotic agent and 1.8 mg/ml glucose. The viability (oxygen consumption), bile secretion, structural integrity and secretion of nascent lipoproteins by FC-43-perfused rat livers was compared with livers perfused with Krebs-Henseleit bicarbonate buffer that contained rat erythrocytes (25% hematocrit) and 1.5 mg/ml glucose (red blood cell medium). Oxygen consumption was somewhat higher in livers perfused with FC-43 emulsion. Bile secretion of livers perfused with FC-43 emulsion for 4 hr was reduced significantly to 40% of that by red blood cell medium. The structural integrity of livers perfused with FC-43 emulsion varied from normal to marked cellular damage. Lightmicroscopical examination of rat livers perfused with FC-43 emulsion showed ballooning of sinusoids, presence of vacuoles in sinusoidal lining cells in some hepatocytes and detachment of endothelium in sinusoids. The number of vacuoles progressively increased in longer perfusions. Electron-microscopical studies showed the presence of small (60 to 100 nm) vesicles of varying electron density, presumably fluorocarbon particles inside the vacuoles in sinusoidal lining cells (Kupffer and endothelial) and hepatocytes. After 4 hr of perfusion with FC-43 emulsion, most of the sinusoidal endothelia were denuded, and the microvilli of the hepatocytes all but disappeared. In contrast, the ultrastructure of rat livers perfused with red blood cell medium for 4 hr was unaltered. The accumulation of nascent lipoproteins in perfusates of FC-43-perfused livers was markedly reduced, and no normal very-low-density lipoprotein, low-density lipoprotein or high-density lipoprotein were isolated. Chemical analysis showed the presence of Pluronic F-68 in all lipoprotein fractions. Our data strongly suggest that, during recirculating liver perfusions with FC-43 emulsion (between 1 and 4 hr), the nonionic surfactant detergent Pluronic F-68 dissociated from the emulsion and markedly affected hepatic structure, lipoprotein secretion and the composition of lipoproteins isolated from perfusate. Therefore FC-43 emulsion is not a suitable liver-perfusion medium for studies of lipoprotein metabolism. (HEPATOLOGY 1991;14:340-351.)
Biliary excretion of bile acid conjugates in a hyperbilirubinemic mutant sprague-dawley rat
Authors: Takikawa Hajime , Sano Naoyo , Narita Tohru , Uchida Yoshinobu , Yamanaka Masami , Horie Tohru , Mikami Takashi , Tagaya Osamu
Published: March 2007

The hepatic transport of bile acid conjugates was studied in the Eisai hyperbilirubinuria rat, a Sprague-Dawley mutant rat with conjugated hyperbilirubinemia. Serum bile acid levels were increased, bile acid-independent bile flow was decreased and biliary glutathione concentrations were markedly decreased in the Eisai hyperbilirubinuria rat. Biliary excretion of sulfobromophthalein was markedly impaired and almost no glutathione conjugate was excreted in the bile of the Eisai hyperbilirubinuria rat. Biliary excretion of lithocholate-3-O-glucuronide and lithocholate-3-sulfate in the Eisai hyperbilirubinuria rat was markedly delayed, whereas that of lithocholate was only slightly delayed. After [14C]chenodeoxycholate infusion (1 μmol/min/100 gm for 60 min), the increases in bile flow and biliary excretion of isotope in the Eisai hyperbilirubinuria rat were not so prominent as those observed in control rats, and the glucuronide of chenodeoxycholate, which constituted about 15% of biliary chenodeoxycholate in control rats, was not observed in the Eisai hyperbilirubinuria rat. Initial uptake of lithocholate and its glucuronide and sulfate by isolated hepatocytes was not impaired in the Eisai hyperbilirubinuria rat; the profiles of cytosolic bile acid binding proteins in Eisai hyperbilirubinuria rat liver were identical to those in control liver. These data indicate that the Eisai hyperbilirubinuria rat has excretory impairment of organic anions, bile acid glucuronide and sulfate and that it has characteristics very similar to those of the hyperbilirubinemic mutant Wistar rats TR− and GY. (HEPATOLOGY 1991;14:352-360.)
Minor contribution of hepatocytes to collagen production in normal and early fibrotic rat livers
Authors: Ogata Itsuro , Mochida Satoshi , Tomiya Tomoaki , Fujiwara Kenji
Published: March 2007

Hepatocyte contribution to hepatic collagen production in vivo was estimated in rats, based on the fact that ornithine is used for protein synthesis in the liver as arginine after conversion by way of the urea cycle only by hepatocytes. From rats given a mixture of [14C] ornithine and [3H]arginine, hepatic collagen and serum albumin were obtained. The hepatocyte contribution was calculated from the 14C and 3H in arginine purified from collagen and albumin by high performance liquid chromatography. The contribution was less than 10% of total collagen production in normal and early fibrotic livers induced by a single dose of carbon tetrachloride or dimethylnitrosamine. We conclude that hepatocytes may play a minor role in collagen production in normal and early fibrotic rat livers. (HEPATOLOGY 1991;14:361-367.)
Kupffer cell prostaglandin-E2 production is amplified during hepatic regeneration
Authors: Callery Mark P. , Mangino Martin J. , Flye Wayne M.
Published: March 2007

Prostaglandin-E2 increases in liver tissue after partial hepatectomy and stimulates DNA synthesis in primary cultures of hepatocytes. This study evaluated the capacity of Kupffer cells isolated at various intervals after partial hepatectomy to produce prostaglandin E2 in response to bacterial endotoxin. This stimulator of Kupffer cells is a normal endogenous component of portal venous blood. After partial hepatectomy (6 to 48 hr), when hepatic regeneration rates were greatest, regenerating liver Kupffer cells demonstrated a significantly greater capacity to produce prostaglandin E2 in response to bacterial endotoxin than did equal numbers of Kupffer cells from timematched, sham-operated control animals. However, by 12 days after partial hepatectomy, when liver mass had been more than 83% restored, regenerating liver Kupffer cell prostaglandin E2 production had decreased to levels produced by sham KC. We postulate that high levels of Kupffer cell—derived prostaglandin E2 provide a critical paracrine signal fundamental to the initiation and control of growth by neighboring hepatocytes during liver regeneration. (HEPATOLOGY 1991;14:368-372.)
Facilitated diffusion and sodium-dependent transport of purine and pyrimidine nucleosides in rat liver
Authors: Holstege Axel , Gengenbacher Heide-Maria , Jehle Linda , Hoppmann Johannes
Published: March 2007

In mammalian cells, nucleoside transport usually is mediated by facilitated diffusion. In addition, a Na+-dependent, concentrative nucleoside transport system has been detected in several tissues but not the liver. To further clarify hepatic nucleoside transport mechanisms, we measured the uptake of [2-14C]uridine (2 to 100 μmol/L) and of [8-14C]adenosine (10 to 75 μmol/L) by the isolated perfused rat liver in the presence or absence of extracellular sodium or specific inhibitors of facilitated nucleoside diffusion. Uridine transport and metabolism were monitored by the release of labeled catabolites including 14CO2, which indicated complete degradation of the pyrimidine. Adenosine, uridine and uridine catabolites were measured in the effluent perfusate by reversed-phase high-performance liquid chromatography and a radioactivity flow monitor. The existence of a Na+-dependent nucleoside transport system could be inferred from the following observations: (a) Sodium depletion caused a strong inhibition of nucleoside transport reflected by an up to threefold and 15-fold increase in extracellular uridine and adenosine, respectively. The sodiumdependent transport of uridine was saturated when the influent uridine concentration was raised beyond 20 μmol/L. No such saturation was observed for much higher concentrations of adenosine used (10 to 75 μmol/L). (b) Na+-free perfusion resulted in a strong suppression of the release of uridine catabolites by the liver. Complete uridine breakdown was depressed to 7% of the amount of 14CO2 released in the presence of sodium and at influent uridine concentrations below 20 μmol/L. (c) Inhibition of uridine (10 μmol/L) transport and degradation was observed after coperfusion with adenosine, deoxyadenosine, guanosine and deoxyguanosine. No effect was obtained with cytidine, deoxycytidine, thymidine or hypoxanthine (100 μmol/L each), indicating a specificity identical to that reported for one of the sodium-dependent transport systems from other tissues. (d) Na+-free perfusion further enhanced the effects on nucleoside uptake of specific inhibitors of the nucleoside facilitateddiffusion transporter (dipyridamol, S-(4-nitrobenzyl)-6-thioinosine; 50μmol/L). The results of our experiments demonstrate the presence of a sodiumdependent and a sodium-independent nucleoside transport system in the isolated perfused rat liver. (HEPATOLOGY 1991;14:373-380.)
Elsewhere reviews. Interferon signalling through arachidonic acid-dependent pathways: A clue to adjuvant therapy for chronic viral hepatitis?
Authors: Baskin Gordon
Published: March 2007

Molecular mechanisms that mediate signal transduction by growth inhibitory cytokines are poorly understood. Type I (α and β) interferons (IFNs) are potent growth inhibitory cytokines whose biological activities depend on induced changes in gene expression. IFN-α induced transient activation of phospholipase A2 in 3T3 fibroblasts and rapid hydrolysis of [3H]-arachidonic acid (AA) from prelabeled phospholipid pools. The phospholipase inhibitor, bromophenacyl bromide (BPB), specifically blocked IFN-induced binding of nuclear factors to a conserved, IFN-regulated enhancer element, the interferonstimulated response element (ISRE). BPB also caused a dose-dependent inhibition of IFN-α-stimulated ISRE-dependent transcription in transient transfection assays. Specific inhibition of AA oxidation by eicosatetraynoic acid prevented IFN-α induction of factors binding to ISRE. Treatment of intact cells with inhibitors of fatty acid cyclooxygenase or lipoxygenase enzymes resulted in amplification of IFN-α-induced ISRE binding and gene expression. Thus, IFN-α receptor-coupled AA hydrolysis may function in activation of latent factors by IFN-α and provides a system for studying the role of AA metabolism in transduction of growth inhibitory signals.
Predicting drug interactions using cultured human hepatocytes
Authors: Lown Kenneth S. , Watkins Paul B.
Published: March 2007

In previous papers we demonstrated that cyclosporin A (CsA) was specifically oxidized in rabbit and human liver by cytochrome P-450IIIA. We therefore anticipated that any drug that is an inducer or an inhibitor of this cytochrome should lead to interaction with CsA when given in association with it. In order to confirm this hypothesis, primary cultures of human hepatocytes and human liver microsomes were used to “reproduce” in vitro clinically significant interactions observed between CsA and drugs known either as specific inducers (i.e., rifampicin) or as specific inhibitors (i.e., erythromycin) of P-450IIIA. Our results were in close agreement with the clinical reports. Human hepatocytes maintained in primary cultures for 72 hr in the presence of 50 μM rifampicin exhibited increased levels of P-450IIIA, determined by Western blot using specific antibodies, and concomitant increase in CsA oxidase activity, determined by HPLC analysis of extra and intracellular media. Conversely, these cultures exhibited erythromycin concentrationdependent decreases in CsA oxidase activity when incubated in the presence of 5, 20, and 100 μM erythromycin. In addition, a Lineweaver-Burk analysis of the erythromycin-mediated inhibition of CsA oxidase activity in human liver microsomes revealed competitive inhibition (with Ki
of 75 μM) as expected, this macrolide being a specific substrate of P-450IIIA. Using this experimental approach, 59 molecules representative of 17 different therapeutic classes were screened for inducers and inhibitors of CsA oxidase activity. Our results allowed us to elucidate the molecular mechanism of previously observed, but unexplained, drug interactions involving CsA, and to detect drugs that should interfere with CsA metabolism as inducers or inhibitors. Drugs detected as potential inducers of CsA oxidase included: rifampicin, sulfadimidine, phenobarbital, phenytoin, phenylbutazone, dexamethasone, sulfinpyrazone, and carbamazepine. Drugs detected as potential competitive inhibitors included: triacetyloleandomycin, erythromycin, josamycin, midecamycin, ketoconazole, miconazole, midazolam, nifedipin, diltiazem, verapamil, nicardipine, ergotamine, dihydroergotamine, glibenclamide, bromocryptine, ethynylestradiol, progesterone, cortisol, prednisone, prednisolone, and methylprednisolone. Finally cefoperazone, cefotaxime, ceftazidime, isoniazide, doxycycline, spiramycin, sulfamethoxazole, norfloxacin, pefloxacin, vancocin, trimethoprime, amphotericine B, valproic acid, quinidine, cimetidine, ranitidine, omeprazole, diclofenac, aspirin, paracetamol, debrisoquine, guanoxan, captopril, furosemide, acetazolamide, sparteine, gliclazide, and imipramine were found not to interfere with the hepatic metabolism of CsA.
Thymosin treatment of chronic hepatitis B: A placebo-controlled pilot trial
Authors: Mutchnick Milton G. , Appelman Henry D. , Chung H. T. , Aragona Emma , Gupta Tej P. , Cummings Glen D. , Waggoner Jeanne G. , Hoofnagle Jay H. , Shafritz David A.
Published: March 2007

Chronic hepatitis B is a severe and frequently progressive disease. We assessed the safety and efficacy of thymosin fraction 5 and thymosin-α1 in a prospective, placebo-controlled trial in 12 patients with chronic hepatitis B. All patients had histological and biochemical evidence of active liver disease for at least 6 mo before treatment and were positive for serum hepatitis B virus DNA and HBsAg. Seven patients received thymosin fraction 5 or thymosin-α1 and five patients received placebo twice weekly for 6 mo. By the conclusion of the study (1 yr), serum aminotransferase levels had improved significantly in thymosin-treated patients, but not in the placebo group. Six (86%) of the thymosin treated patients and one (20%) patient given placebo cleared hepatitis B virus DNA from serum (p < 0.04, Fisher’s exact test). After treatment, replicative forms of hepatitis B virus DNA were present in the liver specimens of four of five placebo-treated patients but in only one of seven thymosin-treated patients (p < 0.04, Fisher’s exact test). Response to thymosin therapy was associated with significant improvements in peripheral blood lymphocyte and CD3 and CD4 counts and in in vitro production of interferon-γ over initial values. No significant side effects were observed in patients given thymosin or in placebo-treated patients. Clinical, biochemical and serological improvement in patients responding to thymosin were sustained during 26 ± 3 mo of follow-up. The results of this pilot trial suggest that thymosin therapy promotes disease remission and cessation of hepatitis B virus replication in patients with chronic viral infection.