Hepatocyte growth factor promotes liver regeneration and protein synthesis after hepatectomy in cirrhotic rats.

BACKGROUND/AIMS: Hepatocyte growth factor, a potent mitogen for hepatocytes has been reported to be a hepatrophic factor in normal livers. In this study, the effect of exogenous hepatocyte growth factor on liver regeneration in cirrhotic rats was investigated, in vitro and in vivo. METHODOLOGY: Liver cirrhosis was induced by intraperitoneal injections of an emulsion, carbon tetrachloride and olive oil, twice weekly for 10 weeks. In vitro, various amounts of exogenous hepatocyte growth factor; 0, 0.5, 1, 2.5, 5, and 10 ng/mL; were added to the hepatocytes isolated using in situ perfusion method. In vivo, partial hepatectomy (Hx), according to the procedure described by Higgins and Anderson, was performed on cirrhotic rats. Saline solution (control group) or 3 micrograms/kg of exogenous hepatocyte growth factor (HGF group) was then injected through the tail vein at intervals 12 hours after Hx. RESULTS: In vitro, DNA synthesis in hepatocytes obtained from cirrhotic livers increased following exogenous hepatocyte growth factor in dose-dependent fashion. In vivo, the labeling index of 5-bromo-2'-deoxyuridine at 24 hours after Hx was markedly increased by exogenous hepatocyte growth factor (control, 10.0 +/- 3.1%; hepatocyte growth factor, 25.8 +/- 9.8%; P < 0.01). Furthermore, serum albumin at 24 and 72 hours and a normotest at 24 hours after Hx, were significantly higher in the HGF group than in the control group. CONCLUSIONS: These results indicate that exogenous hepatocyte growth factor may promote DNA synthesis and protein synthesis during liver regeneration after Hx with cirrhosis.

A comparison of hepatocellular carcinoma associated with HBV or HCV infection.

BACKGROUND/AIMS: Close relationships between hepatocellular carcinoma (HCC) and hepatitis virus infection have been elucidated. However, clinical differences between HBV- and HCV-associated HCC remain unclear. METHODOLOGY: Four hundred and sixteen patients with HCC were examined for both HBsAg and HCV-Ab. Sixty-nine of the 416 patients (16.6%) were positive for HBsAg and negative for HCV-Ab (B-HCC), while 290 patients (69.7%) were negative for HBsAg and positive for HCV-Ab (C-HCC). Various comparisons were made between the 2 groups. RESULTS: B-HCC patients were younger in age (p < 0.0001), and had significantly better liver function than C-HCC patients. The motivation of HCC detection was different between the 2 groups (p < 0.0001), and the tumor size of B-HCC was significantly larger when comparing groups with regard to symptoms (p < 0.05). Although B-HCC demonstrated better survival in Stage I/II treated by surgery (p < 0.05), it was associated with poorer survival in Stage III/IV receiving hepatic arterial infusion chemotherapy when compared to C-HCC (p < 0.01). CONCLUSIONS: These results suggest that clinical differences between B-HCC and C-HCC may depend upon the difference of the natural course between HBV and HCV infection, and B-HCC may be more resistant to treatment than C-HCC in the advanced stage. This also illustrates the need for early tumor detection in B-HCC.

The reduced expression of e-cadherin, alpha-catenin and gamma-catenin but not beta-catenin in human lung cancer.

Cadherins are Ca2+-dependent cell-cell adhesion molecules, and are involved in the formation and maintenance of the histo-architecture. Using a combination of biochemical and immunohistochemical methods, we analyzed the expression of cadherin-catenin complexes in 37 non-small cell lung carcinomas. In 19 cases, decreased expression of E-cadherin protein was observed. In 12 of them, decreased expression of alpha-catenin protein was also observed. Thus, decreased expression of alpha-catenin was apparently preceded by decreased expression of E-cadherin. In no cases was decreased expression of beta-catenin observed. In the 12 cases in which mRNA expression was analyzed by Northern blot analysis, decreased expression of mRNAs for E-cadherin and alpha-catenin was observed in 11 and 9 cases, respectively. In cases with reduced E-cadherin and alpha-catenin expression, immunohistochemistry revealed two types of staining pattern for the proteins. In the first type, almost all the cells in a tumor were stained weakly (homogeneous pattern). In the second type, different percentages of cells were stained strongly, the rest being almost negative for the staining (heterogeneous pattern).

The expression of cadherin-catenin complex in association with the clinicopathologic features of early gastric cancer.

Although impaired expression of E-cadherin (E-cad) is frequently observed in tumors with aggressive histopathologic characteristics, the correlation between alpha-catenin (alpha-cat) expression and the clinicopathologic features of early gastric cancer have not been fully examined. In this study, we evaluated the expression of E-cad and alpha-cat by early gastric carcinomas, and examined the relationships between this expression and various clinicopathologic characteristics. A total of 69 specimens obtained from surgery were studied by immunohistochemistry. Reduced expression of E-cad and alpha-cat were found in 53.6% and 65.2% of the tumors, respectively, and a significant correlation was observed between the decreased expression of E-cad or alpha-cat and tumor histology, the quantity of stroma, and the infiltration pattern of the tumor. The reduced expression of alpha-cat correlated more strongly with these features than E-cadherin expression. Furthermore, alpha-cat expression was also related to the lymph node metastasis of tumors. The expression of E-cad or alpha-cat in the primary tumor was consistent with the expression of tumor cells that invaded the lymphatic vessels, but discordant with staining in the metastasized lymph nodes. In some cases, as the tumor invaded deeper, the expression of E-cad or alpha-cat changed from preserved to reduced. Our observations suggest that the reduced expression of E-cad or alpha-cat may be involved in the initial steps leading to the invasion and metastasis of early gastric cancer.

E-cadherin but not N-cadherin expression is correlated with the intracellular distribution of catenins in human hepatocellular carcinomas.

Cadherins are Ca2+-dependent cell-cell adhesion molecules, and are involved in the formation and maintenance of the histo-architecture. Using a combination of biochemical and immunohistochemical methods, we analyzed the expression of the cadherin-catenin complex in 34 human hepatocellular carcinomas. Unexpectedly, we found the expression of N (neural)-cadherin in normal hepatocytes and all hepatocellular carcinomas examined. In 18 cases, the decreased expression of E (epithelial)-cadherin was observed. Among them, the decreased expression of alpha-catenin and gamma-catenin (plakoglobin) was also observed in 9 and 6 cases, respectively. Thus the decreased expression of alpha-catenin and gamma-catenin was apparently preceded by the decreased expression of E-cadherin. The decreased expression of beta-catenin was not observed in any of the cases analyzed. beta-Catenin was found to accumulate in the cytoplasm of hepatocellular carcinomas with the decreased expression of E-cadherin, despite the presence of N-cadherin at the cell-cell contacts. These results suggest a pivotal role of E-cadherin in the intracellular distribution of catenins in hepatocellular carcinomas.

Response of patients with cirrhosis who have undergone partial hepatectomy to treatment aimed at achieving supranormal oxygen delivery and consumption.

BACKGROUND: This study was undertaken to evaluate the response to therapy aimed at achieving supranormal cardiac and oxygen transport variables (cardiac index > than 4.5 L/min/m2, oxygen delivery > 600 ml/min/m2, and oxygen consumption > 170 ml/min/m2) in patients with cirrhosis who have undergone partial hepatectomy and to assess the relationship between those parameters and outcome. METHODS: Thirty-four consecutive patients underwent elective hepatectomy for hepatocellular carcinoma. The postoperative outcomes and hemodynamic and oxygen transport values in 16 patients (group S) who maintained supranormal values were compared with those in 18 patients (group N) treated to maintain normal hemodynamic values. Patients in group S received volume expansion and then, if necessary, dobutamine (3 to 15 micrograms/kg/min) to increase cardiac index, oxygen delivery, and oxygen comsumption simultaneously during the first 12 hours. RESULTS: The hemodynamic targets were reached by 56% of patients in group S during the first 12 hours and 31% during the next 12 hours. Postoperative blood lactate levels at 12 and 24 hours were lower in group S than in group N, and total bilirubin concentrations, hepatic venous oxygen saturation, and arterial ketone body ratio, useful markers of postoperative liver function, also showed more favorable changes in group S than in group N. Postoperative morbidity and mortality rates were not significantly different in the two groups, but the incidence of hyperbilirubinemia and liver failure was much lower in group S than in group N. CONCLUSIONS: These results suggest that fluid therapy aimed at achieving a supranormal pattern by 12 hours after hepatectomy improved the systemic oxygen demand-supply dynamics and hepatic hemodynamics, decreasing the incidence of postoperative hyperbilirubinemia and liver failure in patients with liver cirrhosis.

Hepatic hemodynamics in a patient with nodular regenerative hyperplasia.

Nodular regenerative hyperplasia of the liver is an uncommon condition. Approximately 50% of these patients develop portal hypertension. Few previous reports document the site of increased resistance to blood flow within the liver in this disorder. We measured Doppler waveform patterns of the right hepatic vein by pulsed Doppler ultrasonography and portal, wedged hepatic, and free hepatic venous pressure by intravenous catheter before and after splenectomy in a 47-yr-old woman with nodular regenerative hyperplasia who presented with portal hypertension and pancytopenia. Nodular regenerative hyperplasia was histologically confirmed. Pre- and postoperative measures indicated a marked difference between wedged hepatic venous pressure and free hepatic venous pressure, whereas there was little difference between portal venous pressure and wedged hepatic venous pressure. Doppler waveform patterns of the right hepatic vein showed an unclear pulsatile flow pattern with a decreasing reversed phase. The above data suggest that portal hypertension in nodular regenerative hyperplasia is primarily sinusoidal, similar to that seen with cirrhosis.

Cloning of an alternative form of plakoglobin (gamma-catenin) lacking the fourth armadillo repeat.

Plakoglobin is a member of a protein family with a repeating amino acid motif called the armadillo repeat, and is a cytoplasmic protein found in both adherens junctions and desmosomes. Little is known about its function, but it has been shown to form distinct complexes with cadherins or desmosomal cadherins. Also, plakoglobin has been shown to form a complex with APC, a tumor suppressor gene product. We have isolated a cDNA clone encoding plakoglobin by means of the polymerase chain reaction (PCR) from a human transitional carcinoma cell line. The cDNA has the same nucleotide sequence as the previously published one [Franke et al. (1989) Proc. Natl. Acad. Sci. USA 86, 4027-4031], except that it has a deletion of 120 bp. The deleted sequence encodes the fourth armadillo repeat. Southern blot analysis of genomic DNA revealed that there is a single copy of the plakoglobin gene per haploid genome. Cloning and sequencing of a genomic DNA fragment containing the 120-bp deletion and the surrounding sequences revealed that these sequences are encoded by a single exon sequence. PCR amplification of the genomic DNA fragment of the corresponding region excluded the possible presence of the 120-bp deletion in the gene. Therefore the variant form is most likely derived through alternative splicing of precursor RNA transcripts in an exon sequence.

Prinzmetal's variant angina associated with subarachnoid hemorrhage: A case report.

Prinzmetal's variant of angina occurred in a 48-year-old man who sustained two attacks of subarachnoid hemorrhage within 10 days. The first anginal pain started at the same time that the second cerebrovascular accident developed, but subsequent anginal episodes were not accompanied by other symptoms or signs that indicated new development of subarachnoid hemorrhage. Twelve days later, when nuchal rigidity was fairly improved, the episodes of chest pain ended. A vasospasm of the large coronary arteries--probably due to the derangement of the autonomic nervous system caused by subarachnoid hemorrhage--was presumed to contribute to the occurrence of the variant angina. Based on this case and on review of the literature, we propose that coronary arterial spasm is one of several causes of the cardiac changes seen in subarachnoid hemorrhage.

Myocardial ultrastructural changes in Kugelberg-Welander syndrome.

Electron microscopical study of a biopsied specimen of myocardium from a patient with the Kugelberg-Welander syndrome revealed myocardial degeneration, including preferential loss of myosin filaments and abnormalities in the Z bands. Leptomeric fibrils were also observed in the cardiac muscle cell; there does not appear to be a previous report of the finding of such fibrils in human myocardium.

Tachycardia- and bradycardia-dependent left bundle branch block associated with first degree a-v block. A study using his bundle electrogram during carotid sinus compression.

His bundle electrographic examination was performed during carotid sinus compression as well as atrial pacing in a patient who exhibited intermittent left bundle branch block (LBBB) and first degree A-V block. LBBB was observed at the corrected RR intervals below 920 msec and above 1600 msec. The QRS complexes showed normal intraventricular conduction between these 2 values. The critical cycle lengths could not be determined when ordinary RR intervals were used. The HQ interval remained constant at 70 msec regardless of the pattern of intraventricular condution. It was demonsrated that the patient had both tachycardia- and bradycardia-dependent LBBB with first degree A-V block due to HV block. The authors believe this to be the first case of tachycardia- and bradycardia-dependent bundle branch block studied by His bundle electrography. The important role of His bundle recordings and carotid sinus compression in the diagnosis of rate dependent intraventricular conduction disturbance was stressed and possible mechanisms underlying this rare condition were discussed.