Flumequine enhances the in vivo mutagenicity of MeIQx in the mouse liver.

The combined effects of various carcinogens found in food products are a concern for human health. In the present study, the effects of flumequine (FL) on the in vivo mutagenicity of 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) in the liver were investigated. Additionally, we attempted to clarify the underlying mechanisms through comprehensive gene analysis using a cDNA microarray. Male gpt delta mice were fed a diet of 0.03 % MeIQx, 0.4 % FL, or 0.03 % MeIQx + 0.4 % FL for 13 weeks. The effects of cotreatment with phenobarbital (PB) were also examined. Treatment with MeIQx alone increased gpt and Spi(-) mutant frequencies, and cotreatment with FL, but not with PB, further exacerbated these effects, despite the lack of in vivo genotoxicity in mice treated with FL alone. FL caused an increase in Cyp1a2 mRNA levels and a decrease in Ugt1b1 mRNA levels, suggesting that the enhancing effects of FL may be due in part to modification of MeIQx metabolism by FL. Moreover, FL induced an increase in hepatocyte proliferation accompanied by hepatocellular injury. Increases in the mRNA levels of genes encoding cytokines derived from Kupffer cells, such as Il1b and Tnf, and cell cycle-related genes, such as Ccnd1 and Ccne1, suggested that FL treatment increases compensatory cell proliferation. Thus, the present study clearly demonstrated the combined effects of 2 different types of carcinogens known as contaminants in foods.

The effects of long-term exposure to ozokerite mainly consisting of an aliphatic series of hydrocarbons using F344 rats.

Combined chronic toxicity and carcinogenicity studies of ozokerite (OZK), a natural wax substance used as a food additive for a gum base, were performed in male and female F344 rats. Dietary concentrations of 0%, 0.05%, 0.1% and 0.2% OZK were applied in a 52-week chronic toxicity study and 0%, 0.1% and 0.2% in a 104-week carcinogenicity study. In the chronic toxicity study, treatment with OZK caused a xenobiotic reaction against absorbed OZK, including formation of histiocytosis and granulomas with crystalline material in many organs in all of the treated males and females. Particularly in the liver, granulomatous inflammation was accompanied by hepatocellular vacuolation and changes in the serum biochemical parameters indicative of hepatic disorder. The number and area of glutathione S-transferase placental form (GST-P) positive foci were increased in all of the treated groups of both sexes, suggesting the proliferative effect of OZK. In the carcinogenicity study, the incidence of hepatocellular adenoma and the total tumor incidence in the liver of all of the treated males were significantly increased compared with the controls. In conclusion, long-term exposure to OZK caused systemic chronic inflammation due to a foreign body response. OZK was weakly carcinogenic in the liver of male F344 rats.

RUNX3 expression correlates with chief cell differentiation in human gastric cancers.

RUNX3 is a novel tumor suppressor in gastric carcinogenesis and an important factor for differentiation of chief cells in the normal gastric fundic mucosa. In this study, we confirmed RUNX3 immunolocalization in the fundic gland (bottom part) but minimum in surface mucous cell epithelium (top part) in the isolated gland from fundic mucosa. We also analyzed RUNX3 expression by immunohistochemistry in 102 gastric cancers and made a histological assessment of the expression of differentiation markers to evaluate interrelations. Among them, 45 and 57 cases were judged to be RUNX3 positive and negative, respectively, and 33 and 69 cases were pepsinogen I positive and negative, with no link to histological types. RUNX3 expression was significantly associated with that of pepsinogen I (P<0.001), but not mucins, including MUC5AC and MUC6, or the parietal or intestinal phenotypes. In conclusion, the present study showed, for the first time to our knowledge, a relation between RUNX3 and pepsinogen I expression in human gastric cancers. RUNX3 is strongly associated with chief cell phenotypic expression in human gastric cancers, as well as in normal gastric mucosa, and could be considered to play an important role in maintaining the chief cell phenotype.

Synergistic upregulation of inducible nitric oxide synthase and cyclooxygenase-2 in gastric mucosa of Mongolian gerbils by a high-salt diet and Helicobacter pylori infection.

AIMS: The intake of salt and salty food is known as a risk factor for gastric cancer. We have previously demonstrated that a high-salt diet dose-dependently enhances Helicobacter pylori (H. pylori)-associated gastritis and stomach carcinogenesis in Mongolian gerbils. In this study, we focused on the influence of excessive salt intake on the expression of inflammatory mediators involved in progression of H. pylori-induced chronic gastritis. METHODS AND RESULTS: A total of 45 stomach samples from Mongolian gerbils were evaluated by immunohistochemistry. The animals were infected with H. pylori and fed basal (0.32%) or a high-salt (10%) diet, and sacrificed after 40 weeks. Proliferative activity and expression of cyclooxygenase-2 (COX-2) in gastric mucosa were significantly increased in H. pylori-infected gerbils. The additional high-salt diet significantly up-regulated the expression of inducible nitric oxide synthase (iNOS) and COX-2 in H. pylori-infected groups (P<0.01 and P<0.05, respectively), while no significant effects were noted in non-infected animals. There was significant synergistic interaction between H. pylori infection and 10% NaCl diet on the expression of iNOS (P<0.05) and also a tendency for enhanced COX-2 expression (P=0.0599). CONCLUSIONS: The present results suggest that a high-salt diet works synergistically with H. pylori infection to enhance iNOS and COX-2 expression in the gastric mucosa of Mongolian gerbils, and support the hypothesis that excessive salt intake may be associated with progression of H. pylori-induced gastritis.

A mechanism for mercury oxidation in coat-derived exhausts.

This paper evaluates an elementary reaction mechanism for Hg0 oxidation in coal-derived exhausts consisting of a previously formulated homogeneous mechanism with 102 steps and a new three-step heterogeneous mechanism for unburned carbon (UBC) particles. Model predictions were evaluated with the extents of Hg oxidation monitored in the exhausts from a pilot-scale coal flame fired with five different coals. Exhaust conditions in the tests were very similar to those in full-scale systems. The predictions were quantitatively consistent with the reported coal-quality impacts over the full range of residence times. The role of Cl atoms in the homogeneous mechanism is hereby supplanted with carbon sites that have been chlorinated by HCl. The large storage capacity of carbon for Cl provided a source of Cl for Hg oxidation over a broad temperature range, so initiation was not problematic. Super-equilibrium levels of Cl atoms were not required, so Hg was predicted to oxidize in systems with realistic quench rates. Whereas many fundamental aspects of the heterogeneous chemistry remain uncertain, the information needed to characterize Hg oxidation in coal-derived exhausts is now evident: complete gas compositions (CO, hydrocarbons, H2O, O2 NOx, SOx), UBC properties (size, total surface area), and the ash partitioning throughout the exhaust system are required.

[Effectiveness of DeVIC chemotherapy for recurrent primary central nervous system lymphoma].

Six cases with recurrent or refractory primary central nervous system lymphoma were treated with a new chemotherapeutic regimen "DeVIC (dexamethasone, VP16, ifosfamide, carboplatin)". Five recurrent cases had a remission period for an average of 18 months after initial treatment, but relapse occurred. One refractory case had no response after initial treatment. Then these 6 cases were treated with 1-3 courses of DeVIC chemotherapy at intervals of 4 weeks. Two cases achieved complete remission, and 3 cases attained partial remission (response rate was 83%). One case showed no response after 1 course of DeVIC chemotherapy. However, in all cases re-relapse occurred 1-5 months after remission, and only 1 case is still alive. DeVIC chemotherapy produced a high response rate for recurrent central nervous system lymphoma, but re-relapse occurred after only a few months. The establishment of maintenance chemotherapy is required.

[A long-term histological prognosis after IFN therapy for chronic hepatitis C].

In 72 chronic hepatitis C patients treated with IFN, liver biopsies were performed before and after IFN treatment, and histological changes were examined. In complete responders, the grading score improved significantly since 6-mo after IFN treatment, and the staging score improved significantly since 12-mo after IFN treatment. In long-term responders underwent a following liver biopsy 4-5 yr after IFN treatments; 5 had normal liver histology. In partial responders, both the grading and staging score did not improve significantly. But, in the cases who had sustained normalization of ALT levels after IFN treatment, both the grading and staging score improved after treatment. In non-responders, both the grading and staging score did not improve significantly.

[Interferon treatment for chronic hepatitis C--assessment of 3 regimens in patients received more than 500MU interferon treatment and their effect predictive factors for interferon treatment using multivariate analysis with the logistic regression model].

Chronic hepatitis C patients (n = 115) were treated with interferon (IFN). Total dose employed was more than 500 MU. The response rate was assessed among the three treatment groups: 2W continuous+TIW, 4W continuous+TIW, 8W continuous+TIW. The IFN treatment effect predictive factors were also assessed. Complete response (CR) rate, CR with serum HCV-RNA disappearance rate, responders' histology activity index score changes between before and after treatment, and responders' hepatocytes HCV-RNA disappearance rate did not differ among the three treatment regimens. CR to IFN treatment was dependent on serum HCV-RNA and HCV serotype. Patients of low serum HCV-RNA and serotype II were responsive to IFN treatment.

Involvement of membrane-bound transglutaminase in the invagination of transferrin into rat reticulocyte plasma membrane.

We demonstrated the invagination of transferrin into reticulocyte plasma membrane to learn whether membrane-bound transglutaminase (TGase, a Ca(2+)-dependent enzyme) is involved in this invagination. The invagination was assessed by acid-resistance assay and antibody-inaccessibility assay. The invagination was blocked in the absence of ATP. [14C]Putrescine, a substrate for TGase, was incorporated into the membrane during the invagination. This incorporation was decreased in the absence of ATP or transferrin and was completely blocked in the presence of monodansylcadaverine or EGTA. The TGase inhibitor and EGTA also decreased the invagination. In the sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) analysis, the labeling of 43 kDa membrane protein with [14C]putrescine and the increase in aggregation of proteins were observed in a transferrin-, ATP- and Ca(2+)-dependent manner. These results provide the first evidence for modification of protein by TGase accompanying the invagination of transferrin into the membrane, and suggest that membrane-bound TGase is involved in the invagination step of endocytosis.

Serum hyaluronic acid and interleukin-6 as possible markers of carpal tunnel syndrome in chronic hemodialysis patients.

To elucidate the precise mechanism of carpal tunnel syndrome (CTS), serum hyaluronic acid (HA), interleukin-1 beta (IL-1 beta), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-alpha) were measured in 71 chronic hemodialysis patients with or without CTS and/or shoulder pain. Patients were divided into two groups: Group 1 (n = 40) was the control group, and Group 2 (n = 31) patients had carpal tunnel syndrome, shoulder pain, or both. None of the patients had liver disease, rheumatoid arthritis, other inflammatory disease, or cancer. Serum HA concentrations in Groups 1 and 2 were 106.0 +/- 77.5 and 442.6 +/- 564.7 ng/dl (mean +/- SD), respectively. The difference between the groups was significant (p < 0.01). The serum concentrations of IL-6 in Group 1 were significantly lower than in Group 2 (p < 0.05); however, there was no significant difference in serum IL-1 beta and TNF-alpha levels. The mechanisms regulating in vivo synthesis of HA was obscure; however, in vitro studies suggest that inflammatory cytokines may stimulate an increased production of HA. In this study, CTS might be associated with increased serum concentrations of HA, and HA production might be mediated by IL-6.

Ovarian metastasis in patients with colorectal carcinoma.

The records of 159 patients who underwent surgical resection of colorectal cancer were reviewed to assess the incidence of ovarian metastasis and to define the role of oophorectomy. Four of these patients presented with metachronous metastases, and one patient had synchronous ovarian involvement. The incidence of ovarian involvement was higher in younger patients. While most patients with ovarian involvement had the primary tumor located at the rectosigmoid region, a similar distribution of the primary tumor was observed in patients without ovarian metastasis. The histological type and degree of differentiation was similar regardless of whether or not ovarian metastasis was present. Of the patient without ovarian metastasis, 57% presented with nodal metastases and 3.2% with peritoneal dissemination, while all patients with ovarian metastasis had nodal and peritoneal involvement. Our results suggest that histological type and degree of differentiation of the primary tumor do not influence likelihood of ovarian metastasis. However, the exposure of the tumor to the serosal surface and the subsequent peritoneal dissemination may be an important route by which malignant tumor cells reach the ovaries. However, due to the wide lymphatic involvement in patients with ovarian metastasis, the lymphatic route may be important as well. Thus, we consider that oophorectomy should be performed in all postmenopausal women, when the ovaries are macroscopically affected, and in premenopausal patients with Astler-Coller B2 tumors or over.

[Ultrasonography in cholelithiasis].

Ultrasonography has become the first line examination in the diagnosis of cholelithiasis. As for the gallbladder, extracorporeal ultrasonography is the most useful and the safest procedure. Ultrasonic properties of gallstones even suggest the feasibility of dissolution therapy. The detectability of choledocholithiasis is, however, not satisfactory. This deficiency has been overcome by combining endoscopy with ultrasound. Endoscopic ultrasonography, as well as ERCP, is a useful tool for examining the extrahepatic bile duct and the pancrease. Recently, with the development of laparoscopic cholecystectomy, intraoperative ultrasonography during laparoscopic surgery has considerably improved with introduction of new probes and may replace most of the methods of intraoperative cholangiography in the future.