Intracellular pH alterations induced by tacrine in a rat liver biliary epithelial cell line.
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1. The effects of tacrine (THA) on intracellular pH (pH(i)) were examined in a rat liver biliary epithelial cell line (RLEC) in HEPES-buffered medium. pH(i) was recorded using the pH-sensitive fluoroprobe, carboxy-SNARF-1 (carboxy-seminaphtorhodafluor). 2. In the steady state, short-term exposures to THA resulted in alkalinization and re-acidification at 0.1 and 0.25 mM. Following a 24 h-treatment, no significant difference in pH(i) could be detected at 0.1 and 0.25 mM THA, whereas at 0.05 mM, pH(i) was slightly more acid (7.17+/-0. 02, n=16 versus 7.21+/-0.02, n=24 [control]). 3. In control and short-term treated cells, intracellular intrinsic buffering power (beta(i)) increased roughly linearly as pH(i) decreased. This dependence was not seen following long-term treatment. In all cases, beta(i) was increased by THA (by 1.6 to 3.5 fold). 4. Following an acid load (induced by 20 mM NH(4)Cl removal), pH(i) recovery in RLEC relied upon Na(+)/H(+) exchange. A short-term treatment (0.25 mM THA) did not affect total acid extrusion. In contrast, a 24 h-treatment with 0.05 mM THA reduced it (by approximately 36% at a pH(i) of 6.73) while at 0.25 mM, a large increase was detected (by approximately 109% at a pH(i) of 6.75). In Na(+)-free medium, THA (0. 25 mM) still induced an alkalinization in the steady state. Following an acid load, THA stimulated a Na(+)-independent acid efflux in a dose-dependent manner, inhibitable by alpha-cyano-4-hydroxy cinnamate (CHC, 4 mM) but not by quercetin (0. 125 mM). 6. In conclusion, this work demonstrates that THA affects pH(i) in RLEC, through a decrease in Na(+)/H(+) exchange and an increase in beta(i). Stimulation of a CHC-inhibitable, Na(+)-independent acid efflux is also detected. (+info)
Performance characteristics of magnetic resonance cholangiography in the staging of malignant hilar strictures.
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BACKGROUND: Magnetic resonance cholangiography (MRC) is currently under investigation for non-invasive biliary tract imaging. AIM: To compare MRC with endoscopic retrograde cholangiography (ERC) for pretreatment evaluation of malignant hilar obstruction. METHODS: Twenty patients (11 men, nine women; median age 74 years) referred for endoscopic palliation of a hilar obstruction were included. The cause of the hilar obstruction was a cholangiocarcinoma in 15 patients and a hilar compression in five (one hepatocarcinoma, one metastatic breast cancer, one metastatic leiomyoblastoma, two metastatic colon cancers). MRC (T2 turbo spin echo sequences; Siemens Magnetomvision 1.5 T) was performed within 12 hours before ERC, which is considered to be the ideal imaging technique. Tumour location, extension, and type according to Bismuth's classification were determined by the radiologist and endoscopist. RESULTS: MRC was of diagnostic quality in all but two patients (90%). At ERC, four patients (20%) had type I, seven (35%) had type II, seven (35%) had type III, and two (10%) had type IV strictures. MRC correctly classified 14/18 (78%) patients and underestimated tumour extension in four (22%). Successful endoscopic biliary drainage was achieved in 11/17 attempted stentings (65%), one of which was a combined procedure (endoscopic + percutaneous). One patient had a percutaneous external drain, one had a surgical bypass, and in a third a curative resection was attempted. Effective drainage was not achieved in six patients (30%). If management options had been based only on MRC, treatment choices would have been modified in a more appropriate way in 5/18 (28%) patients with satisfactory MRC. CONCLUSION: MRC should be considered for planning treatment of malignant hilar strictures. Accurate depiction of high grade strictures for which endoscopic drainage is not the option of choice can preclude unnecessary invasive imaging. (+info)
Inflammatory cytokines induce DNA damage and inhibit DNA repair in cholangiocarcinoma cells by a nitric oxide-dependent mechanism.
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Chronic infection and inflammation are risk factors for the development of cholangiocarcinoma, a highly malignant, generally fatal adenocarcinoma originating from biliary epithelia. However, the link between inflammation and carcinogenesis in these disorders is obscure. Because nitric oxide (NO) is generated in inflamed tissues by inducible nitric oxide synthase (iNOS) and because DNA repair proteins are potentially susceptible to NO-mediated nitrosylation, we formulated the hypothesis that inflammatory cytokines induce iNOS and sufficient NO to inhibit DNA repair enzymes leading to the development and progression of cholangiocarcinoma. iNOS and nitrotyrosine were demonstrated in 18/18 cholangiocarcinoma specimens. Furthermore, iNOS and NO generation could be induced in vitro by inflammatory cytokines (mixture of interleukin-1beta, IFN-gamma, and tumor necrosis factor alpha) in three human cholangiocarcinoma cell lines. NO-dependent DNA damage as assessed by the comet assay was demonstrated during exposure of the three cholangiocarcinoma cell lines to cytokines. Moreover, global DNA repair activity was inhibited by 70% by a NO-dependent process after exposure of cells to cytokines. Our data indicate that activation of iNOS and excess production of NO in response to inflammatory cytokines cause DNA damage and inhibit DNA repair proteins. NO inactivation of DNA repair enzymes may provide a link between inflammation and the initiation, promotion, and/or progression of cholangiocarcinoma. (+info)
Mucobilia in association with a biliary cystadenocarcinoma of the caudate duct: a rare cause of malignant biliary obstruction.
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Mucobilia is a rare condition characterized by the accumulation of abundant mucus within the intra- or extrahepatic biliary tree. A variety of hepatobiliary and pancreatic neoplasms are mucin producing and have been associated with the development of mucobilia including biliary mucinosis, biliary papillomatosis, mucin-producing cholangiocarcinoma (MPCC), or cystic neoplasms of the pancreas or biliary tree (cystadenoma or cystadenocarcinoma). We report the case of 46 year-old male with a biliary cystadenocarcinoma of the caudate lobe which resulted in chronic biliary obstruction and relapsing cholangitis. A review of the literature for both mucobilia and biliary cystadenocarcinoma is provided along with a discussion addressing the clinical presentation, diagnosis, treatment, and prognosis for this rare entity. (+info)
Response to percutaneous transhepatic portal embolization: new proposed parameters by 99mTc-GSA SPECT and their usefulness in prognostic estimation after hepatectomy.
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Accumulation of 99mTc-galactosyl human serum albumin (GSA) in the liver correlates well with the parameters of hepatic function tests. We performed 99mTC-GSA SPECT before and after percutaneous transhepatic portal embolization (PTPE) to induce compensatory hypertrophy of the remnant lobe before extensive hepatic resection and analyzed the responses of new proposed parameters in the future remnant lobe that showed hypertrophy. The aim of this study was to evaluate the usefulness of these parameters in prognostic estimation after hepatectomy. METHODS: We studied 10 patients with cholangiocarcinoma and 1 patient with metastatic liver tumor from sigmoid colon cancer. 99mTc-GSA SPECT was performed immediately before and 2 wk after PTPE. We analyzed the responses of the liver uptake ratio (LUR), functional volume (FV), and liver uptake density (LUD) in the future remnant lobe and evaluated their relationship with the prognosis after subsequent hepatic resection. RESULTS: LUR and FV increased slightly but were not associated with the prognosis after hepatic resection. LUD increased significantly after PTPE in the group showing a good outcome after hepatic resection but decreased after PTPE in the group showing a poor outcome (post-PTPE LUD, 0.064+/-0.017%/cm3 versus 0.035+/-0.006%/ cm3, P<0.05; response rate, 22.2%+/-11.9% versus -8.9%+/-17.6%, P<0.01). CONCLUSION: Responses of LUD to PTPE before hepatic resection in the future remnant lobe represent changes in asialoglycoprotein receptor activity per hepatocyte and predict responses to subsequent hepatic resection. LUD may be an important parameter for determining the outcome after hepatic resection. (+info)
Contribution of apoptosis and apoptosis-related proteins to the malformation of the primitive intrahepatic biliary system in Meckel syndrome.
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In the developing liver, the complete or partial persistence of the primitive double-layered cylinder of biliary-type cells that surrounds the branches of portal vein and its mesenchyme gives origin to portal tracts with an increased number of bile duct structures. The term "ductal plate malformation of the liver" was coined to label the insufficient remodeling of the primitive intrahepatic biliary system. Meckel syndrome is an autosomal recessive inherited disease characterized by occipital encephalocele, postaxial polydactyly, diffuse cystic renal dysplasia, and malformation of the ductal plate of the liver. We studied 52 fetuses with Meckel syndrome from five German centers (Berlin, Freiburg, Heidelberg, Mainz, and Marburg). Analysis of apoptosis and cell proliferation (Ki-67) was performed by terminal deoxynucleotide transferase-mediated dUTP nick-end labeling (TUNEL) and immunohistochemistry in the liver of 24 normal fetuses of different gestational ages (14-38 weeks of gestation) and in 14 fetuses with Meckel syndrome (17-38 weeks of gestation). The expression of two apoptosis-related proteins, Fas (a transmembrane cell surface protein involved in the apoptosis) and Bcl-2 (an anti-apoptotic protein), was studied by immunohistochemistry in the liver of 11 normal fetuses of different gestational ages (14-40 weeks of gestation) and in 40 fetuses with Meckel syndrome (16-38 weeks of gestation). In control fetuses, apoptosis rate and cell proliferation were high in the remodeling ductal plate and moderate in the ductal plate and in remodeled bile ducts. During gestation, expression of Fas and Bcl-2 decreased and increased, respectively. The malformed ductal plates in the fetal livers with Meckel syndrome showed a marked decrease in the apoptotic rate and Fas expression and an increase in proliferative activity and Bcl-2 expression in comparison with control fetuses. Furthermore, by linear regression analysis, we found that both proliferation activity and apoptosis rate in the ductal plate malformation of fetuses with Meckel syndrome were practically constant along the gestation. These results, which represent the first systematic study of apoptosis in ductal plate malformation of the liver, indicate that 1) animals harboring the gene defect of Meckel syndrome could be a good model for the study of the abnormal development of the primitive intrahepatic biliary system, 2) a decreased cell turnover occurs in the ductal plate malformation of fetuses with Meckel syndrome, and 3) the increase of Bcl-2 expression contributes to the pathogenesis of the lack of remodeling of ductal plate of the liver in Meckel syndrome. (+info)
Partial hepatectomy and bile duct ligation in rainbow trout (Oncorhynchus mykiss): histologic, immunohistochemical and enzyme histochemical characterization of hepatic regeneration and biliary hyperplasia.
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Hepatic regeneration following partial hepatectomy (PH) and biliary hyperplasia subsequent to bile duct ligation (BDL) were characterized in rainbow trout (Oncorhynchus mykiss) by light microscopy using routine and special (immunohistochemical and enzyme histochemical) stains. Both PH and BDL involved initial hypertrophy and hyperplasia of bile preductular epithelial cells (BPDECs). BPDECs are small oval cells that form junctional complexes with hepatocytes and bile ductular cells and are commonly found in hepatic tubules of teleost liver. Proliferating BPDECs transitioned through intermediate cell types before final differentiation into large basophilic hepatocytes (following PH) or biliary epithelial cells (after BDL). Normal BPDECs and hepatocytes were both negative for cytokeratin intermediate filaments in control fish when screened with the monoclonal antibody AE1/AE3. In contrast, hyperplastic BPDECs and their progeny (intermediate cells, immature hepatocytes, ductal epithelial cells) were all strongly cytokeratin positive. Cytokeratin expression was transient in newly differentiated hepatocytes (expression decreased as hepatocytes acquired characteristics consistent with full differentiation) but was permanent in biliary epithelial cells (expression was very strong in large mature ducts). BPDECs, intermediate cells, and immature ductal cells were also strongly positive for alkaline phosphatase following BDL. Chronology of histologic events and cytokeratin and enzyme expression all support the hypothesis that BPDECs possess the capacity to differentiate into either hepatocytes or biliary epithelial cells. Thus, BPDECs may be the teleost equivalent of a bipolar hepatic stem cell in mammals. (+info)
Adult alpha1-antitrypsin deficiency.
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Three adults with alpha 1-antitrypsin deficiency are described. In two of the cases the deficiency was genetically determined (cases 1 and 2), and each demonstrated unusual features of the disease. The liver in case 1 (homozygous) showed cholangiolar hyperplasia which has been recorded only once before. Case 2 (heterozygous) had emphysema and cirrhosis, a combination not previously documented in a heterozygote, in addition to malabsorption. Case 3 represents a case of spurious alpha 1-antitrypsin deficiency with cirrhosis included to emphasize the diagnostic improtance of phenotyping in such cases. (+info)