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Shiesh, Shu‐Chu; Chen, Chiung‐Yu; Lin, Xi‐Zhang; Liu, Zher‐Ann; Tsao, Hui‐Chen
doi: 10.1053/jhep.2000.16332pmid: 10960434
Free radical‐mediated oxidative stress has been implicated in the genesis of gallstone in vitro. This study was designed to examine the oxidative stress changes during pigment gallstone formation and to investigate whether melatonin (MLT) could act as a chemopreventive agent for cholelithiasis in a guinea pig model. The common bile duct of guinea pigs was ligated with or without MLT pretreatment. Animals were studied on day 7, 9, 12, and 14 after surgery. Stone and/or sludge developed in ligated guinea pigs without MLT. Fourier transform infrared spectra of the sludge showed the presence of calcium bilirubinate, whose peak height per milligram of sludge gradually increased with time after ligation. Total antioxidant activity (TAA) in bile of guinea pigs at day 14 after ligation reduced to one third of the level in sham‐operated controls (P < .001). In addition, the bile of ligated guinea pigs had increased pH (P < .001), bile salts (P < .01), and malondialdehyde (MDA) (P < .05), compared to sham controls. Pretreatment of guinea pigs with MLT at a dose of 1,000 μg/kg significantly decreased the incidence of pigment gallstone formation at day 14 after ligation, as compared to no pretreatment (0/7 vs. 8/10). MLT also reverted the ligation‐induced changes in biliary bile salts, pH, MDA, and TAA to control levels. These in vivo findings support a causative role of oxidative stress in the bile duct ligation–induced pigment gallstone formation. Antioxidants may prove useful in preventing pigment gallstone formation in humans.
Lo, Gin‐Ho; Lai, Kwok‐Hung; Cheng, Jin‐Shiung; Chen, Mei‐Hsiu; Huang, Hui‐Chun; Hsu, Ping‐I; Lin, Chiun‐Ku
doi: 10.1053/jhep.2000.16236pmid: 10960435
Both β‐blockers and endoscopic variceal ligation (EVL) have proven to be valuable alternatives to sclerotherapy in the prevention of variceal rebleeding. Sucralfate is a mucosal protector. The effects of combinations of β‐blocker, band ligation, and sucralfate (triple therapy) remain unknown. A total of 122 patients with a history of esophageal variceal bleeding were randomized to receive EVL only (group A, 62 patients) or triple therapy (group B, 60 patients). The procedure for the triple therapy included ligation with the addition of sucralfate granules until variceal obliteration. In addition, nadolol was administered during the course of the study or until death. After a median follow‐up of 21 months, recurrent upper gastrointestinal bleeding developed in 29 patients (47%) in group A and 14 patients (23%) in group B (P = .005). Recurrent bleeding from esophagogastric varices occurred in 18 patients in group A and 7 patients in group B (P = .001). Twenty‐one patients in group A (50%) and 12 patients (26%) in group B experienced variceal recurrence after variceal obliteration (P < .05). Treatment failure occurred in 11 patients (18%) in group A and in 4 patients (7%) in group B (P = .05). Twenty patients from group A and 10 patients from group B died (P = .08); 9 and 4 of these deaths, respectively, were attributed to variceal hemorrhage (P = .26). The combination of ligation, nadolol, and sucralfate (triple therapy) proved more effective than banding ligation alone in terms of prevention of variceal recurrence and upper gastrointestinal rebleeding as well as variceal rebleeding.
Condat, Bertrand; Pessione, Fabienne; Helene Denninger, Marie; Hillaire, Sophie; Valla, Dominique
doi: 10.1053/jhep.2000.16597pmid: 10960436
Characteristics and outcomes of recent portal or mesenteric venous thrombosis are ill‐known. We intended to compare these features with those of patients with portal cavernoma, and also to assess the incidence of recanalization of recent thrombosis on anticoagulation therapy. All patients seen between 1983 and 1999 were enrolled into this retrospective study if recent portal or mesenteric venous thrombosis or portal cavernoma had been documented, and if cancer of the liver, pancreas, or bile duct, intrahepatic block including cirrhosis, and obstruction of the hepatic veins had been ruled out. The proportion of recent thrombosis was 7% in patients seen before 1990 and 56% after 1994 (P < .05). Patients with recent thrombosis (n = 33) or cavernoma (n = 108) did not differ with regard to age, sex ratio, or prevalence of prothrombotic states and of previous thrombotic events. In patients with recent thrombosis, septic pylephlebitis was more common and the incidence of gastrointestinal bleeding was lower (2.4 vs. 12.7/100 patient‐years). Recanalization occurred in 25 of 27 patients given anticoagulation and 0 of 2 patients not given anticoagulation. The probability of recanalization was related to the extent of thrombosis (P = .003). In conclusion, mesenteric or portal venous thrombosis is increasingly recognized at an early stage. The features differentiating recent thrombosis and cavernoma are related to silent onset precluding early recognition and therapy in the latter. Frequent association with prothrombotic states and frequent recanalization on anticoagulation support the recommendation of early anticoagulation therapy in all patients with recent portal vein thrombosis.
Escorsell, Àngels; Ruiz Del Arbol, Luis; Planas, Ramon; Albillos, Agustín; Bañares, Rafael; Calès, Paul; Pateron, Dominique; Bernard, Brigitte; Vinel, Jean‐Pierre; Bosch, Jaume
doi: 10.1053/jhep.2000.16601pmid:
Cadranel, Jean‐François; Rufat, Pierre; Degos, Françoise
doi: 10.1053/jhep.2000.16602pmid: 10960438
A nationwide prospective study was conducted in France in 89 university and primary referral hospitals' liver units to evaluate practices of liver biopsy and the occurrence of complications. A total of 2,084 biopsies were analyzed, recording the indication, hemostasis parameters, experience of operator, route of biopsy, use of ultrasonography (US), type of hospitalization, side effects, and complications. Pain, anxiety, and discomfort were evaluated by patients by visual analogue scale (VAS). Biopsies were performed by experienced physicians (>150 procedures performed) in 72%, and hepato‐gastroenterologists in 89% of the cases. Hepatitis C was the indication in 54%. Sedation or premedication (atropine) was given in 46%. US‐guidance was used in 56% of the cases. A day‐care procedure was used in 27%. No deaths occurred, but severe complications were observed in 0.57% and increased with the number of passes and decreased with experience of operator, use of atropine, and US‐guidance. Pain was independently related to general anesthesia, experience of the operator, female sex, and hepatitis C. Anxiety was increased in women. Discomfort was increased by venous access and decreased with an experienced operator. Acceptance of additional biopsies was related to a day‐care procedure and independently related to general anesthesia and multiples passes. This study showed that (1) liver biopsy procedures vary greatly in France, (2) hepatitis C is the main indication for liver biopsy at present, (3) US‐guidance should be developed to reduce severe complications, and (4) day‐care procedures increase acceptance of a future biopsy and should also be used more often.
Yamanaka, Takenari; Shiraki, Katsuya; Sugimoto, Kazushi; Ito, Takeshi; Fujikawa, Katsuhiko; Ito, Masaaki; Takase, Koujiro; Moriyama, Masami; Nakano, Takeshi; Suzuki, Atsushi
doi: 10.1053/jhep.2000.16266pmid: 10960439
Nagao, Mitsuo; Nakajima, Yoshiyuki; Kanehiro, Hiromichi; Hisanaga, Michiyoshi; Aomatsu, Yukio; Ko, Saiho; Tatekawa, Yukihiro; Ikeda, Naoya; Kanokogi, Hideki; Urizono, Yasuyuki; Kobayashi, Tsunehiro; Shibaji, Takamune; Kanamura, Tetsuhiro; Ogawa, Sanehito;
Moennikes, Oliver; Buchmann, Albrecht; Willecke, Klaus; Traub, Otto; Schwarz, Michael
doi: 10.1053/jhep.2000.16598pmid: 10960441
Mice deficient for connexin32 (Cx32), the major gap junction forming protein in liver, are highly susceptible to hepatocarcinogenesis. Because the Cx32 gene is located on the X‐chromosome, heterozygous females show mosaicism with respect to Cx32 expression; this enables their use in studying the effect of Cx32‐deficiency in a mixed Cx32‐plus/Cx32‐minus environment in vivo. Female C3H/He mice (Cx32+/+) were crossed with Cx32‐deficient C57BL/129Sv males (Cx32Y/‐) to yield F1 females heterozygous with respect to Cx32 (Cx32+/−). Patches of hepatocytes were observed in normal liver that either expressed Cx32 or failed to express the protein. The mean fraction of Cx32‐negative tissue in liver was about 60% and did not change significantly with age of mice. Neoplastic liver lesions, induced in weanling mice, were identified in serial liver sections by their deficiency in glucose‐6‐phosphatase staining. Parallel sections were used for immunohistochemical demonstration of Cx32 protein. Smaller lesions were either homogenously Cx32‐negative or showed unchanged to slightly elevated levels of Cx32 protein. There were no major differences in number and size distribution between lesions of these 2 phenotypes. In addition, larger lesions were mostly Cx32‐negative but often contained embedded patches of Cx32‐positive cells. Staining for the proliferation‐associated nuclear antigen Ki‐67 did not reveal significant differences between Cx32‐negative and Cx32‐positive hepatocytes in Cx32‐mosaic tumors. This suggests that expression of Cx32 within a subpopulation of tumor cells does not negatively regulate their growth nor does it seem to affect the proliferation of their directly neighboring Cx32‐negative counterparts.
Terabe, Masaki; Shimizu, Masumi; Mabuchi, Ayako; Matui, So; Morikawa, Hiroyasu; Kaneda, Kenji; Kakiuchi, Terutaka; Yokomuro, Kozo
doi: 10.1053/JHEP.2000.9875pmid: 10960442
We previously found that a small dose (2 μg per mouse) of staphylococcal enterotoxin B (SEB) induced early emerging unresponsiveness in intrahepatic‐lymphocyte populations (IHLs). The purpose of this study was to reveal the inducing role of accessory cells involved in IHLs in this phenomenon. IHLs prepared at 3 to 24 hours after SEB injection failed to proliferate in response not only to SEB but also to SEA, representing ligand‐nonspecific unresponsiveness, whereas spleen cells (SPCs) and mesenteric lymph‐node cells showed transient proliferation. Unresponsiveness in IHLs was related to a deficit of their accessory cell function as measured by coculture of irradiated IHLs and antigen‐specific, type 1 T‐helper (Th1) clone cells. High levels of nitrite were detected in the culture supernatant. Supplement of NG‐monomethyl‐l ‐arginine lowered nitrite levels and concurrently restored the proliferative response of Th1 cells, indicating the involvement of nitric oxide in suppression. Adherent cells prepared from IHLs well reproduced these results. As shown by flow cytometry, Mac‐1high Ia+ cells, which mainly included F4/80+ cells (macrophages) and a minor population of CD11c+ cells (dendritic cells), increased in proportion in IHLs but not in SPCs at 6 to 24 hours. Depletion of Mac‐1high cells from IHLs with antibody‐coated magnetic beads recovered the proliferative response. Depleted Mac‐1high cells had a monocytoid appearance. In immunostained sections, Kupffer cells came to highly express both Mac‐1 and Ia at 12 hours. These results indicate that Mac‐1highIa+ adherent cells, largely Kupffer cells activated by SEB, nonspecifically suppress the proliferation of Th1 cells via nitric oxide production before manifestation of ligand‐specific unresponsiveness.
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Failure to control bleeding and early rebleeding account for the high mortality associated with variceal hemorrhage in cirrhosis. We compared endoscopic sclerotherapy to terlipressin, a drug that effectively controls acute bleeding while reducing in‐hospital mortality. This multicenter randomized controlled trial included 219 cirrhotic patients admitted for endoscopy‐proven acute variceal bleeding and randomized to receive repeated injections of terlipressin during 6 days (n = 105) or emergency sclerotherapy (n = 114). Success was defined as obtaining control of bleeding (24‐hour bleeding‐free period during the first 48 hours) and lack of early rebleeding (any further bleeding from initial control to 5 days later) and survival during the study. Both groups were similar at inclusion. Failure rate for terlipressin was 33% and 32% for sclerotherapy (not significant (NS)). Early rebleeding was responsible for 43% and 44% of failures, respectively. This high efficacy was observed in both Child‐Pugh class A + B and Child‐Pugh class C patients. Both treatments were similar regarding transfusion requirements, in‐hospital stay, and 6‐week mortality (26 vs. 19 patients). Side effects appeared in 20% of patients receiving terlipressin and in 30% of those on sclerotherapy (P = .06); being serious in 4% and 7%, respectively (NS). In conclusion, terlipressin and sclerotherapy are equally highly effective therapies achieving the initial control of variceal bleeding and preventing early rebleeding. Both treatments are safe, but terlipressin is better tolerated. Therefore, terlipressin may represent a first‐line treatment in acute variceal bleeding until the administration of elective therapy, especially in hospitals where a skilled endoscopist is not available 24 hours a day.
TNF‐related apoptosis‐inducing ligand (TRAIL) selectively induces apoptosis in various transformed cell lines but not in almost‐normal tissues. It is regulated by 2 death receptors, TRAIL receptor 1 (TRAIL‐R1) and TRAIL‐R2, and 2 decoy receptors, TRAIL‐R3 and TRAIL‐R4. We investigated the expression of TRAIL‐R– and TRAIL‐induced apoptosis in human hepatocellular carcinomas (HCCs). TRAIL‐R1, ‐R2, and ‐R4 were expressed in 6 HCC cell lines examined, but TRAIL‐R3 was expressed in only 2 of the 6 cell lines. In addition, immunohistochemical results revealed a high and prevalent expression of TRAIL‐R1 and ‐R2 in human HCC tissues. Despite the expression of TRAIL‐R1 and ‐R2, all 6 HCC cell lines showed resistance to TRAIL‐induced apoptosis with no relation to nuclear factor κ B (NF‐κB) levels induced by TRAIL. TRAIL‐induced death signal was inhibited with both decreased caspase‐8 and caspase‐3 activity. However, TRAIL induced significant apoptosis in the presence of a subtoxic level of actinomycin D, indicating that the TRAIL‐induced apoptotic pathway is in place in these cell lines. In addition, we found that treatment with conventional chemotherapeutic agents, doxorubicin and camptothecin, dramatically augmented TRAIL‐induced cytotoxicity in most of the HCC cell lines. Actinomycin D and camptothecin almost completely suppressed NF‐κB induction by TRAIL, whereas doxorubicin had little effect. These results indicate that TRAIL, in combination with chemotherapeutic agents, may have therapeutic potential in the treatment of human HCC.
doi: 10.1053/jhep.2000.16470pmid: 10960440
Interferon gamma (IFN‐γ) plays an important role in host defense mechanism and participates in the progression of chronic liver disease. IFN‐γ exerts its pleiotrophic effects by transcriptional regulation of expression of numerous genes, such as major histocompatibility complex (MHC) class I and Fas, through interaction with IFN‐γ receptor (IFN‐γ‐R). Although hepatocytes in normal liver express weak or no IFN‐γ‐R, those in acute and chronic liver disease up‐regulate its expression. A study using IFN‐γ‐R α‐chain knock‐out mice revealed the actions of IFN‐γ on tumor cells as an extrinsic tumor‐suppressor mechanism. However, it is unclear whether or how hepatocellular carcinoma (HCC) blocks the signal transduction of IFN‐γ to evade host immune surveillance. We examined the expression of IFN‐γ‐R and IFN‐γ–inducible genes in 44 cases with HCC using real‐time reverse‐transcriptase polymerase chain reaction (RT‐PCR) and immunohistochemistry. In noncancerous liver tissues (n = 38), IFN‐γ‐R expression on the cell surface was up‐regulated in 27 cases. In IFN‐γ‐R–negative cases (n = 15), tumor size was larger (P = .032), serum α‐fetoprotein (AFP) level was higher (P = .001), intrahepatic and extrahepatic metastasis was more common (P = .044 and .013, respectively), and Ki‐67 labeling index (LI) was higher (P = .041), compared with IFN‐γ‐R–positive cases. Accordingly, the evasion mechanism may play an important role in progression, especially metastasis, in HCC. The significant correlation between the status of IFN‐γ‐R and the expression of Fas and MHC implies that the loss of IFN‐γ‐R might contribute to the mechanism of escape from host immune rejection in HCC.