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Background: Non-alcoholic fatty liver disease (NAFLD) is usually asymptomatic and lacks a specific biomarker; therefore, many individuals might remain undiagnosed even with advanced liver fibrosis. The aim of this study was to clarify the prevalence and clinical features of subjects with a high risk of advanced liver fibrosis in the general population, using the Fibrosis-4 (FIB-4) index.Methods: We retrospectively investigated 6,087 subjects without known liver disease who had participated in an annual health checkup examination. We analyzed the factors associated with high FIB-4 index (≥ 2.67) using a logistic regression analysis.Results: Among the 6,087 subjects, 76 (1.2%) had high FIB-4 index. Multivariate analysis identified hypertension (odds ratio [OR]; 9.040; 95% confidence interval [CI], 4.081-20.024; P < 0.001) and diabetes mellitus (OR = 4.251; 95% CI, 1.773-10.193; P = 0.001) as important risk factors for high FIB-4 index. The rates of hypertension and diabetes mellitus in subjects with high FIB-4 index were 78.9% and 23.7%, respectively. No significant association was observed between obesity or large waist circumference and high FIB-4 index. A history of cardiovascular disease was significantly more common in subjects with high FIB-4 index. These results were also observed in subjects with normal liver function test.Conclusions: The present study revealed that approximately 1% of the general Japanese population has a high risk of advanced liver fibrosis. Many of these patients had hypertension and/or diabetes mellitus. Our findings suggest that there are many undiagnosed patients NAFLD with risk of advanced liver fibrosis in the general population. [ABSTRACT FROM AUTHOR]

COPII vesicles are formed at specific subdomains of the ER, termed ER exit sites (ERESs). Depending on the cell type, ERESs number from a few to several hundred per cell. However, whether these ERESs are functionally and compositionally identical at the cellular level remains unclear. Our live cell-imaging analysis in Saccharomyces cerevisiae revealed that the isoforms of cargo-adaptor subunits are unequally distributed to each ERES at steady state, whereas this distribution is altered in response to UPR activation. These results suggest that in S. cerevisiae cargo loading to ERES is dynamically controlled in response to environmental changes. [ABSTRACT FROM AUTHOR]

Gastrointestinal motility is impaired in patients with diabetes mellitus (DM). Interstitial cells of Cajal (ICC) in the gastrointestinal tract play a central role in gastrointestinal motility. The present study examined whether ICC density, or expression of neuronal nitric oxide synthase (nNOS)- and substance P (SP)-containing nerves in the gastric antrum, were altered in patients with type 2 DM. Paraffin-embedded gastric specimens from 51 controls and 36 male DM patients with gastric cancer were used for immunohistochemistry. Serial sections were stained with Kit and mast cell tryptase-specific antibodies. Fresh-frozen gastric specimens from patients with gastric cancer were used for immunofluorescence. The specimens were stained with antibodies to Kit, nNOS, and SP, and levels of expression of these three markers were compared between controls and DM patients. ICC density in the inner circular muscle layer, but not in the myenteric plexus, was lower in patients with severe DM than in controls in paraffin-embedded specimens. In addition, decreased expression of nNOS and SP accompanied by reduced ICC density was observed in frozen specimens from patients with DM. These results suggest that lower gastric ICC, nNOS, and SP densities in patients with DM may be associated with the pathogenesis of diabetic gastroparesis. [ABSTRACT FROM AUTHOR]

Long-term administration of a histamine H2 receptor (H2R) antagonist (inverse agonist) induces upregulation of H2R in parietal cells, which may be relevant to the rebound hypersecretion of gastric acid that occurs after withdrawal of treatment. The mechanisms underlying this effect are unknown. We hypothesized that the H2R upregulation could be related to receptor trafficking and used H2R-green fluorescent protein (H2R-GFP) to test the hypothesis. Human H2R-GFP was generated and functionally expressed in HEK-293 cells. Binding of the H2R antagonist [³H]tiotidine was performed to quantify H2R expression, and H2R-GFP was imaged in living cells by confocal and evanescent wave microscopy. The binding affinity of [³H]tiotidine was not significantly different between H2R-GFP- and wild-type H2R-expressing HEK-293 cells, both of which had constitutive activity of adenylate cyclase. Visualization of H2R-GFP revealed that the agonist-induced H2R internalization and the antagonist-induced recycling of the internalized H2R from the recycling endosome within 2 h. Long exposure to the antagonist increased GFP fluorescence in the plasma membrane and also induced upregulation of H2R-GFP estimated by the binding assay, whereas long exposure to the agonist enhanced degradative trafficking of H2R-GFP. We examined whether the upregulation reflected an increase in receptor synthesis. Treatment with antagonist did not augment H2R mRNA, and subsequent inhibition of protein synthesis by cycloheximide had no effect on H2R upregulation. These findings suggested that upon exposure to an antagonist (inverse agonist), the equilibrium between receptor endocytosis and recycling is altered before H2R upregulation, probably via suppressing H2R degradation. [ABSTRACT FROM AUTHOR]

Hemobilia is relatively rare among hemorrhages in the digestive tract, and hemobilia caused by tumors of the biliary tract is particularly rare. We treated a 74-year-old-man with undifferentiated carcinoma of the gallbladder presenting with hemobilia. During hospitalization for neurogenic bladder at the Department of Urology, he showed progressive anemia. Since hemorrhage in the digestive tract was suspected, endoscopy of the upper gastrointestinal tract was performed, and bleeding from the papilla of Vater was observed. On ultrasound examination, findings were indicative of cholecystic cancer, and hemorrhage from the cystic duct was found on percutaneous transhepatic cholangioscopy. On perioral cholecystoscopy, however, masses of coagulated blood were found only in the gallbladder. Abnormalities such as dense staining of tumors or extravasation were not found on angiography. The patient died of hepatic failure due to rapid invasion of the liver by the tumor, associated with biliary infection and disseminated intravascular coagulation. At autopsy, a nodal tumor was found in the gallbladder, and the cavity of the gallbladder was filled with coagulated masses of blood. Direct invasion of the tumor to the liver, diaphragm, and transverse colon was found. The histopathological diagnosis was undifferentiated carcinoma (pleomorphic large-cell type). [ABSTRACT FROM AUTHOR]