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We investigated the side effects of interferon (IFN) on the endocrine and respiratory system in 545 cases of chronic hepatitis C. Eleven of 494 (2.2%) patients with chronic hepatitis C who were treated with natural or recombinant interferon (IFN) developed thyroid disease while on treatment. Eight patients developed hyperthyroidism and 3 patients developed hypothyroidism. All 11 patients required definitive therapy, who became euthyroid after the therapy. Two patients received nIFN alpha and one patient received rIFN alpha 2b developed diabetes mellitus. Two patients received rIFN alpha 2a and rIFN alpha 2b, respectively, developed interstitial pneumonia 12 weeks and 24 weeks later, respectively. One patient showed positive reaction for RA test and LE factor and positive LE cell, and complained of fever, arthralgia and dry cough. These phenomenon disappeared after the cessation of IFN therapy.

Stomachs with multiple submucosal glands keep our attention because of their high risk for having gastric carcinomas, but little is known about the relationship between submucosal glands and occurring cancers. So we investigated the structure of submucosal glands including location of proliferating cells. We labeled proliferating cells of three stomachs with cancerous lesions by circulating artificial blood through the isolated organs with bromodeoxyuridine (BrdU). Serial sections of submucosal glands were stained with hematoxylin eosin, periodic acid Schiff, Alcian blue, high iron diamine-Alcian blue, concanavalin A paradox, galactose oxidase Schiff as well as anti-BrdU immunohistochemically. Results showed that most of submucosal glands were composed of functionally matured cells and these cells made regular structure just like those of mucosal layer. Labeling index of BrdU of these submucosal glands were low (0.2%-0.7%). Two atypical glands were seen, and labeling index were 2.6% and 22.2% respectively. In conclusion, submucosal glands of the stomachs were thought to be made by moving proliferating cells from mucosal layer to submucosal layer. So we saw these submucosal glands paracancerous lesions rather than precancerous ones. But we couldn't deny the possibility to occur cancerous lesions from atypical glands in submucosal glands.

The effects of somatostatin analogue, SMS 201-995, on systemic and splanchnic hemodynamics and glucagon secretion were investigated in control and cirrhotic rats induced by thioacetamide administration. Hemodynamics were measured using the radioactive microsphere method. Immunoreactive glucagon (IRG) was determined in the portal vein and femoral artery and the splanchnic output (OP) of IRG was calculated. In control rats, SMS 201-995 induced a decrease of 5.6% in portal venous inflow and a 25.8% decrease in OP of IRG. In cirrhotic rats, SMS 201-995 produced a 14% decrease in portal pressure, a 13.6% decrease in portal venous inflow, and a 57.8% decrease in OP of IRG. In systemic hemodynamics no significant changes were noted following SMS 201-995 administration in the control or cirrhotic rats. The ratio of cirrhotic rats to the controls in the rate of decrease in portal venous inflow was similar to that in the percentage of decrease in OP of IRG. We conclude that SMS 201-995 is useful for the treatment of portal hypertension because of its effect of reducing portal pressure with mild changes in systemic hemodynamics. We suspect that the decrease in portal venous inflow by SMS 201-995 is mainly due to a reduction in the release of glucagon, a vasodilatory gastrointestinal hormone.

In this study SASP metabolite levels were measured in colonic mucosal specimens and plasma samples from 31 patients with ulcerative colitis (UC) under treatment with the drug. Colonic tissue specimens were obtained by endoscopically guided biopsy and plasma was isolated from peripheral blood. Measurements were performed by HPLC according to the procedure of Fischer et al. The levels of 5-ASA and SP in either of colonic tissue or plasma were significantly lower than those of Ac-5-ASA and Ac-SP, respectively. The tissue level of 5-ASA had a significant correlation to the dosage of 5-ASA. The tissue levels of 5-ASA and Ac-5-ASA were low in an active stage of UC than during a remission period and the difference observed with respect to the latter metabolite was significant. These findings suggest that acetylation of 5-ASA is inhibited in the colonic mucosa in an active stage of the disease.

To evaluate correctly the proliferative activity of tumor cells, it is necessary to clarify not only S-phase fraction but also the growth fraction of tumor tissues. We used combined BrdU and DNA polymerase alpha (pol-alpha) immunohistochemistry to gastric biopsy specimens, and analyzed the proliferation of the neoplastic lesions of various degrees of malignancy. The results were as follows: The distribution of pol-alpha positive cells were almost the same as that of BrdU positive cells, but the percentage of pol-alpha positive cells was higher than that of BrdU positive cells irrespective of the mucosal specimens. In the adenomas, both BrdU and pol-alpha positive cells distributed generally superficially in the mucosal layer. In the well differentiated adenocarcinomas, both BrdU and pol-alpha positive cells distributed diffusely in the deeper layer of the mucosa. The ratio of the number of BrdU positive cells to that of pol-alpha positive cells, which means the S-phase fraction in the growth fraction, was higher in the tumor and that higher in the well differentiated adenocarcinomas than that of the adenomas. In conclusion, the combined BrdU and pol-alpha immunohistochemistry in gastric biopsy specimens are useful to evaluate the degree of malignancy.

Endoscopic biliary manometry was performed to evaluate the motor activity of the sphincter of Oddi (SO) in 28 patients, 13 with juxtapapillary duodenal diverticula (8 with biliopancreatic disease) and 15 without diverticula (10 with biliopancreatic disease). So pressure and the rate of irregular wave pattern of phasic contraction in patients with diverticula were significantly higher than those in patients without diverticula. Especially all the patients with both diverticula and biliary stones had motor disorders of the SO. The patients with diverticula were also divided into three groups by endoscopic findings for the location of diverticular; The papilla of Vater was located close to diverticula (within about 4 cm) in group A, on the edge of diverticula in group B, in the diverticula in group C. Diverticula could have more direct effect on the motor activity of the SO in group C. Those results suggest juxtapapillary diverticula have close relationship with the motor activity of the SO and biliopancreatic disease, especially in cases which the papilla of Vater located in the diverticula. We conclude that the motor disorders of the SO might be responsible for biliopancreatic disease in patients with juxtapapillary diverticula.

Endoscopic manometry using microtransducer was applied to evaluate the motor activity of the sphincter of Oddi (SO) and common bile duct (CBD) in patients with biliary tract stones and in controls. CBD pressure, SO pressure and the incidence of irregular phasic wave pattern (IRPWP) were relatively higher in patients with biliary tract stones than those in controls. There was no significant difference in CBD and SO pressure between patients with dilated CBD and patients with non-dilated CBD, however the incidence of IRPWP was significant higher in patients with dilated CBD than that in patients with non-dilated CBD. SO pressure and the incidence of IRPWP were significant higher in patients with papillitis than those in patients without it. Patients with valvular orifice of the papilla of Vater showed high incidence of IRPWP, and in such cases it was suggested that SO had different motor functions for CBD and pancreatic duct because these ducts were seen opening onto the papilla separately according to the findings of pancreatocholangiogram. We concluded that endoscopic manometry of CBD and the SO was useful to evaluate the motor activity of SO and provided a basis for the assessment of the motor function mechanism of SO. Our results indicated the motor activity of SO had close relationship with biliary tract stones, CBD dilatation and endoscopic findings of the papilla of Vater.

We have evaluated the problem of autoantibodies such as antinuclear antibodies (ANA), smooth muscle antibody (SMA) and antibodies to thyroid microsomal (TMA) and to thyroglobulin (TGA) related to interferon therapy in 27 patients with chronic hepatitis B. Anti-interferon antibody was also studied by Western blot method. Eight patients had ANA and 2 had SMA during interferon therapy. However, 6 of the 8 patients were ANA positive and one of the 2 was SMA positive prior to interferon treatment. No patients developed TMA, TGA or anti-interferon antibody. Eight (29.6%) of the 27 patients had clearance of both DNA polymerase and HBeAg and persistent normalization in alanine aminotransferase levels with interferon therapy. Seven of the 8 responders developed none of the autoantibodies related to interferon therapy. These results suggest that the presence of ANA or SMA during treatment may affect the therapeutic response to interferon.

The 2'-5' oligoadenylate synthetase (2-5 AS) activity of peripheral blood mononuclear cells and serum was measured in 23 patients with chronic non-A, non-B hepatitis during interferon therapy, 16 of whom were found to have antibody to hepatitis C virus (anti-HCV). Patients received a daily dose of either 1 million, 3 million or 6 million units of human interferon-alpha or -beta for 4 to 6 weeks. Before treatment, the 2-5 AS activity was not significantly different from that in normal control subjects or patients with chronic hepatitis B. However, during treatment the 2-5 AS activity increased 2- to 41-fold from the initial level. Alanine aminotransferase (ALT) levels normalized promptly after the start of treatment in 15 (65.2%) of the 23 patients, but remained elevated in the remaining 8 (34.8%). Six (40%) of the 15 patients showed consistently normal ALT levels for 6 to 30 months after the end of treatment. There was no significant difference between the responders and non-responders in the pattern of change of 2-5 AS activity, but pretreatment activity levels in peripheral blood mononuclear cells were significantly higher (P less than 0.001) in the patients whose ALT levels did not normalize during treatment. The frequency of patients with a positive anti-HCV was significantly higher (P less than 0.05) in the group in which ALT levels normalized. Therefore, these findings suggest that the pretreatment 2-5 AS activity and the detection of anti-HCV may be useful parameters for predicting the response to interferon therapy.

It has recently come to be thought that cases of juvenile polyposis have a natural tendency to develop adenoma and/or carcinoma. Here we present a case of juvenile polyposis coli with adenomatous change in a 21-year-old male, with a review of 34 cases of juvenile polyposis in the Japanese literature, and discuss the pathogenetic development of the polyps and their malignant potential. In this case, focal or entire adenomatous areas were found in large part of the polyps in the resected sigmoid colon and rectum, though these findings had not been recognized in 23 polypectomy specimens from the rectum 10 months prior to the operation. It was suggested that adenomatous change developed quickly in a very short time.

We measured the sequential changes in 2',5' oligoadenylate synthetase activity in 21 patients with acute viral hepatitis (5 with type A, 6 with type B, and 10 with type non-A, non-B hepatitis) by radioimmunoassay. Liver biopsies were performed during the acute phase in all patients. Among patients with acute hepatitis A and B, the 2',5' oligoadenylate synthetase levels were transiently elevated at the time of the peak alanine aminotransferase level in the patients in whom a liver biopsy showed acute hepatitis or non-specific reactive hepatitis. Of 10 patients with acute non-A, non-B hepatitis, 4 showed a similar 2',5' oligoadenylate synthetase activity pattern and liver histology to those observed in acute hepatitis A and B. In the remaining 6, the 2',5' oligoadenylate synthetase levels remained elevated for 3.5 to 6 months while the alanine aminotransferase was elevated. Liver biopsy in these patients showed chronic hepatitis. Persistent detection of raised 2',5' oligoadenylate synthetase activity levels during the acute stage of non-A, non-B hepatitis may thus be an indicator of progression of the disease.

To elucidate the cell biological significance of ras oncogene, the expression of ras-p21 was analyzed in 53 cases of liver tissues including 34 cases of hepatocellular carcinoma (HCC), by using immunohistochemical method. In result, 22 (65%) cases of 34 HCC and 34 (79%) cases of 43 liver cirrhosis were positive for p21, whereas all of chronic hepatitis and normal livers were negative. Especially, comparative study between the expression of p21 and clinicopathological background of HCC revealed that p21 was prominently expressed in well differentiated form, nodular type, small liver cancer, and the cases showing AFP levels below 400 ng/ml. From these results, it was indicated that ras oncogene might play an important role in malignant transformation of hepatocytes or differentiation of HCC.

The thickness of Brunner's glands was measured using an ocular micrometer in 297 cases of surgically resected peptic ulcer and in 120 autopsy cases (control group). The mean maximum thickness of Brunner's glands in the control group was 1.55 +/- 0.37mm (mean +/- SD) and no difference in thickness was noted for each decade of age. The mean maximum thickness of Brunner's glands in patients with gastric ulcer, duodenal ulcer and gastroduodenal ulcer was 2.34 +/- 1.06, 3.18 +/- 1.07 and 3.24 +/- 1.05mm, respectively. When an ulcer is within the duodenum, Brunner's glands near the ulcer were thicker than those contralateral to it. In patients with gastric ulcer, Brunner's glands were the thickest in the pyloric ulcer group and negative correlation was noted between the thickness of Brunner's glands and the distance to the ulcer from the pyloric ring. Since gastric acidity is supposed to be lower when an ulcer is located more proximally, these results suggest that Brunner's glands become hyperplastic not only with the presence of an ulcer in the duodenum but also by acid hypersecretion of the stomach.

The effect of intraluminal bile on the well-known feedback regulatory mechanism of exocrine pancreatic secretion exerted by intraluminal trypsin was investigated in conscious rats with pancreatic, biliary and duodenal fistulae. The stimulated pancreatic enzyme secretion caused by diversion of bile-pancreatic juice from the intestine was apparently suppressed by intraduodenal reintroduction of pancreatic juice or bile-pancreatic juice, while it was slightly suppressed by intraduodenal reintroduction of bile. Although additional reintroduction of bile did not alter the already suppressed pancreatic enzyme secretion by the presence of pancreatic juice in the intestine, diversion of bile stimulated the suppressed pancreatic enzyme secretion by intraluminal bile-pancreatic juice. Infusion of sodium taurocholate into the duodenum with diversion of bile-pancreatic juice effectively inhibited pancreatic enzyme secretion. The inhibitory effect seemed to be dependent on the concentration of taurocholate infused into the duodenum. The results suggest that bile and bile acid have an important role in the feedback regulatory mechanism of pancreatic enzyme secretion, at least partly directly inhibiting the secretion.