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The characteristics of gastric polyps in patients with Peutz-Jeghers (PJ) syndrome (PJS) have not been fully investigated. The objective of this study was to reveal the endoscopic and pathologic findings of gastric polyps in patients with PJS. We reviewed 11 patients with PJS treated at 6 institutions, and summarized the endo-scopic and pathologic features of their gastric polyps. The polyps were mainly classified into 2 types: (i) soli-tary or sporadic polyps > 5 mm, reddish in color with a sessile or semi-pedunculated morphology (n = 9); and (ii) multiple sessile polyps ≤ 5 mm with the same color tone as the peripheral mucosa (n = 9). Patients who underwent endoscopic mucosal resection for polyps > 5 mm were diagnosed with PJ polyps (n = 2), whereas those who underwent biopsy were diagnosed with hyperplastic polyps. Polyps ≤ 5 mm were pathologically diagnosed as fundic gland polyps or hyperplastic polyps. This study revealed that patients with PJS present with 2 types of polyps in the stomach. Endoscopic mucosal resection of polyps > 5 mm seems necessary for the pathologic diagnosis of PJ polyps., Competing Interests: No potential conflict of interest relevant to this article was reported.

Antithrombotic therapy is a major risk factor for delayed bleeding after endoscopic submucosal dissection (ESD) for gastric neoplasia. A potassium-competitive acid blocker, vonoprazan, is expected to prevent delayed bleeding better than conventional proton pomp inhibitors (PPIs), but the evidence is controversial. We sought to clarify the efficacy of vonoprazan for prevention of delayed bleeding after gastric ESD in patients under antithrombotic therapy. We prospectively registered 50 patients who underwent gastric ESD while receiving antithrombotic therapy and vonoprazan in our institution between October 2017 and September 2018. The incidence of delayed bleeding was compared with that in a historical control group of 116 patients treated with conventional PPI. We also evaluated risk factors associated with delayed bleeding. Delayed bleeding was observed in 8 of 50 patients (16.0%), which was not dissimilar from the incidence in the historical control group (12.1%) (p=0.49). In the univariate analysis, age (> 70 years) (p=0.034), multiple antithrombotic drug use (p<0.01), procedure time (> 200 min) (p=0.038) and tumor size (> 40 mm) (p<0.01) were associated with delayed bleeding after gastric ESD, but vonoprazan was not (p=0.49). Vonoprazan may not be more effective than conventional PPIs in preventing delayed bleeding after gastric ESD in patients receiving antithrombotic therapy., Competing Interests: No potential conflict of interest relevant to this article was reported.

Upper gastrointestinal bleeding is a major adverse event of non-steroidal anti-inflammatory drugs (NSAIDs), and co-administration of proton pump inhibitors and H2 receptor antagonists has been established as a means of preventing such an effect. However, the incidence of bleeding associated with NSAID-induced ulcers under conditions where such strong anti-acid agents are used for prevention has yet to be clarified. We aimed to determine the annual incidence of serious upper gastrointestinal ulcer bleeding among Japanese patients in whom NSAIDs were used in our hospital. Before commencing the study, we recommended to all the physicians in our hospital the best method for caring for NSAID users, focusing on the concomitant use of proton pump inhibitors or H2 receptor antagonists. We conducted a cohort study involving 17,270 patients for whom NSAIDs had been newly prescribed. Bleeding from gastric ulcers was observed in 8 of the 17,270 patients using NSAIDs (0.05%). The pooled incidence rate for bleeding was calculated as 2.65 (95% confidence interval, 2.56-2.74) and 1.29 (1.27-1.31) per 1,000 patient years for low-dose aspirin and non-aspirin NSAID users, respectively. None of the bleeding ulcer patients required blood transfusion or were in serious condition. In conclusion, gastric ulcer bleeding occurred in low-dose aspirin or non-aspirin NSAID users, but its incidence was low and outcomes were not serious when adequate preventive measures were taken.

We have previously developed an enzyme-linked immunosorbent assay (ELISA) to measure stool decay-accelerating factor (DAF) and found that stool DAF concentrations were significantly elevated in patients with colorectal cancer, suggesting that the measurement of stool DAF may be valuable for the detection of colorectal cancer. In order to refine the assay for the measurement of stool DAF, we investigated 1) effects of centrifugation of stool samples, 2) effects of detergents, and 3) adequate combination of various anti-DAF monoclonal antibodies for the ELISA system using only monoclonal antibodies. We found that high-speed centrifugation could be omitted and that only the removal of large undigested food residues by centrifugation of short duration in a low-speed benchtop microcentrifuge sufficed to adequately prepare the stool samples. Addition of 2 detergents, octyl beta-glucoside and sodium deoxycholate, known to solubilize glycosyl-phosphatidylinositol-anchored proteins such as DAF, did not influence stool DAF values. By using 2 mouse anti-DAF monoclonal antibodies (clone 4F11 and 1C6), we were able to achieve a stable ELISA for the measurement of stool DAF using a uniform source of antibodies. The results should allow us to consistently apply the DAF assay for routine use in the detection of colorectal cancer.

We developed a monoclonal antibody (MoAb) (clone 5E8) against an antigen on the bile canalicular membrane of rat hepatocyte. By immunoblotting, MoAb 5E8 detected a band of 110 kD. In this study, we used the phage display technique to identify the target antigen recognized by MoAb 5E8. We screened a random phage display library expressing 12-mer peptide sequences and identified a peptide sequence, FHFNPYTGHPLT, as an epitope. We compared this peptide sequence with those of dipeptidyl peptidase IV (DPP IV, E.C.3.4.14.5) and Cell-CAM105, which proteins were located by a database search based on the information of tissue localization and approximate molecular weight of the MoAb 5E8 antigen, and sequence similarity with a region in DPP IV (amino acids 225-233) but not with Cell-CAM105 was found. In addition, we immunohistochemically stained various tissues (liver, small intestine, and kidney) of Japanese Fischer 344 rats, known to be deficient for DPP IV, with MoAb 5E8 and showed that the expression of MoAb 5E8 antigen was negligible or weak. In contrast, tissues sampled from the same organs of Sprague-Dawley rats, known to express DPP IV, were positively stained. These findings suggest that the antigen recognized by MoAb 5E8 is DDPIV and its major epitope is located in amino acids at positions 225-233.

Anti-idiotype antibodies (Ab2) play an important role in the homeostasis of immune responses and are related to the development and the disease activity of certain autoimmune diseases. The asialoglycoprotein receptor (ASGPR) is considered one of the target antigens in the pathogenesis of autoimmune chronic active hepatitis (AIH). We previously developed a mouse monoclonal antibody (clone 8D7) which recognizes rat and human ASGPR. In this study, to help investigate the anti-ASGPR antibody-anti-idiotype antibody network in patients with AIH, we developed a syngeneic mouse monoclonal Ab2 to the 8D7 anti-ASGPR antibody (Ab1). One clone, designated as 3C8, tested positive for specific reactivity to 8D7-Ab1 and did not bind to other irrelevant immunoglobulins. By competitive inhibition assays, the binding of 8D7-Ab1 to liver membrane extracts, i.e., the crude antigen preparation, was inhibited by 3C8-Ab2 in a dose-dependent manner, and the binding of 8D7-Ab1 to 3C8-Ab2 was inhibited by the liver membrane extracts. In the immunohistochemical analysis, 3C8-Ab2 blocked the specific staining of sinusoidal margins of rat hepatocytes by 8D7-Ab1. These results suggest that 3C8 anti-idiotype antibody recognizes the specific idiotypic determinants within the antigen-binding site of 8D7-Ab1.

In autoimmune chronic active hepatitis (AIH) and primary biliary cirrhosis (PBC), various autoantibodies including anti-asialoglycoprotein receptor (ASGPR) antibodies have been found in patients' sera. We have previously developed a mouse monoclonal antibody against rat and human ASGPR. In this study, we developed a capture enzyme-linked immunosorbent assay (ELISA) for detection of anti-ASGPR antibodies using this monoclonal antibody and investigated the occurrence of anti-ASGPR antibodies in the sera of patients with various liver diseases. Serum samples were obtained from 123 patients with various liver diseases, including 21 patients with AIH and 40 patients with PBC. In this capture ELISA, the target antigen in the crude rat liver membrane extracts was captured on the ELISA wells by the ASGPR-specific mouse monoclonal antibody. Thus, the cumbersome process of antigen purification was rendered unnecessary. Using this capture ELISA, we detected the anti-ASGPR antibody in 67% of the patients with AIH, in 100% of the patients with PBC, and in 57% of the patients with acute hepatitis type A. However, the anti-ASGPR antibody was rarely detected in patients with other liver diseases such as primary sclerosing cholangitis and obstructive jaundice. Our findings suggest that this capture ELISA would be useful for the detection of anti-ASGPR antibodies in autoimmune liver diseases.

UDP-galactosyltransferase (UDP-Gal-T) is a key enzyme in the synthesis of mucus glycoprotein which plays an important role in gastric mucosal defensive mechanisms. Analysis of gastric UDP-Gal-T activity should clarify the mechanisms of the action of antiulcer drugs regarding gastric defensive factors. Here, we examined UDP-Gal-T activity in rat gastric mucosa treated with the antiulcer drugs geranylgeranylacetone (GGA) and cetraxate hydrochloride (CET). The effects of coadministration of indomethacin and exogenous administration of prostaglandins (PGs) were also studied. GGA and CET significantly increased UDP-Gal-T activity, and coadministration of indomethacin inhibited the increase of enzyme activity. UDP-Gal-T activity level with GGA was significantly higher than the control level, even in the presence of indomethacin. With CET, however, this was not the case. Among PGs, PGE1 significantly increased enzyme activity. Concomitant administration of PGE1 and GGA or CET increased UDP-Gal-T activity even with indomethacin to the levels achieved when these antiulcer drugs were administered without indomethacin. Our findings suggest that GGA and CET exert antiulcer effects by increasing mucus glycoprotein synthesis and that endogenous PG synthesis may be involved in this process. However, mechanisms not mediated by endogenous PGs may also exist in the stimulatory action of GGA on UDP-Gal-T activity.

To characterize primary sclerosing cholangitis (PSC) in Japanese patients and its association with inflammatory bowel disease (IBD), 155 reported cases of PSC, including 6 cases of our own, were reviewed. The prevalence of IBD was less in Japanese PSC patients than in Western patients (23% versus 62-100%). Japanese PSC patients with IBD were younger (mean age, 33.1 versus 51.8 years) and were more often women (51% versus 36%) than those without IBD. Seventy-four percent of PSC patients with IBD had extensive colonic lesions, and 89% of those developed IBD simultaneously, with or prior to PSC. There were 3 cases of neutrophilic cholangitis among the PSC patients with IBD but none in those without IBD. Based on these observations, we speculate that there may be subtypes of PSC which differ pathophysiologically.

To clarify the immunological function of 'M' (microfold or membranous) cells in the large intestine, we examined the expression of intercellular adhesion molecule-1 (ICAM-1) and HLA-class II antigens immunohistochemically in M cells and follicle-associated epithelia (FAE) covering isolated lymphoid follicles of the human colon in comparison with their expression in Peyer's patches of the small intestine. In Peyer's patches of the small intestine, ICAM-1 was not expressed on the epithelial cells covering the lymphoid follicles, but their cell surfaces were stained positively for HLA-DR. In contrast, colonic M cells expressed ICAM-1 on their cell surfaces but were negative for HLA class II antigens. By immunoelectron microscopy, ICAM-1 was seen to be distributed on the surface of microfolds, on the membranes of apical vesicles and on part of the basolateral plasma membranes of M cells, but was not expressed on adjacent FAE. These findings imply that the M cells in the colon and in Peyer's patches have different immunological roles. In addition, identification of ICAM-1 expression on the colonic M cells should help elucidate the pathogenesis of some inflammatory colonic diseases which appear to start in the lymphoid follicles of the colonic mucosa.

The medical records of 16 consecutive patients with Crohn's disease surgically treated in our department from 1978 to 1993 were retrospectively reviewed. The indication for surgery was obstructive symptoms due to Crohn's strictures that were unresponsive to conservative therapy. The types of operations performed were classified into five categories. Nine patients (56.3%) had small bowel resection only, 4 (25.0%) underwent an ileocolonic resection, 1 (6.3%) had a total colectomy, 1 (6.3%) had Mile's operation and 1 (6.3%) had subtotal gastrectomy with gastrojejunostomy and antral mucosectomy. Of these 16 patients, 13 (81.3%) had resection with a single anastomosis and strictureplasty was concomitantly performed in only 2 cases (12.5%). Crohn's disease recurred in 3 patients (18.8%), 1 of whom required a second operation.

We studied the distribution of class 1 and class 2 major histocompatibility complex (MHC) antigens on bile duct epithelial cells in liver from patients with primary biliary cirrhosis (PBC) by an immunohistochemical method using monoclonal antibodies to HLA-ABC products and HLA-D subregion products (HLA-DR, -DP, -DQ). By light microscopy, the expression of MHC class 1 antigens (HLA-ABC antigens) was enhanced in PBC compared with controls. While negligible staining of MHC class 2 antigens was detected on the bile duct in controls, de novo expression of MHC class 2 antigens, as well as the coexpression of HLA-DR, HLA-DQ, and HLA-DP antigens on the bile duct epithelial cells, was observed in PBC. By electron microscopy, HLA-ABC and HLA-DR antigens were present preferentially along the basolateral domain of the cell surface of the bile duct epithelial cells and on the membrane of the endoplasmic reticulum in the cytoplasm, suggesting that these MHC antigens are synthesized by the bile duct epithelial cells in PBC. The distribution of these MHC antigens on the basolateral surface of the bile duct epithelial cells, where they are easily accessible to immunocytes, supports the idea that MHC-restricted cytotoxic T lymphocytes are involved in the bile duct injury in PBC.

To clarify the events related to complement-mediated immune responses in human colorectal cancers, we immunohistochemically examined the distribution of decay-accelerating factor (DAF), CD59/homologous restriction factor 20 (HRF20), membrane cofactor protein (MCP) and terminal complement complex (TCC) in human colorectal adenomas and cancers, and then compared the findings with their distribution in normal colonic mucosa. In the normal mucosa, TCC was not present on epithelial cells. Whereas DAF and CD59/HRF20 were present only occasionally on the apical surfaces of normal epithelial cells, MCP was diffusely distributed on the basolateral surfaces of most epithelial cells of the colon. These findings suggest that MCP has a primary role in the regulation of complement activation on these cells. In adenoma cells, the expression of both DAF and CD59/HRF20 was enhanced. In cancer cells, the expression of CD59/HRF20 and MCP was diminished, whereas DAF expression was markedly enhanced. Since DAF was frequently stained in the lumen of the cancer glands, it was suggested that DAF was released into the colonic lumen in patients with colorectal cancer.

To identify diffuse mucosal changes which may precede the development of colorectal cancer and a possible indicator for detecting high-risk populations, we immunohistochemically studied cell-cycle events in crypts of normal-appearing rectal mucosa of patients with colorectal adenoma and cancer using an in vitro labeling method with bromodeoxyuridine (BrdU). Biopsy specimens of endoscopically normal-appearing rectal mucosa were obtained during colonoscopy from 20 patients with colorectal adenocarcinoma, 20 with adenoma, and 15 without apparent colorectal diseases. The specimens were incubated with BrdU in vitro, and labeled S-phase cells were identified immunohistochemically using a monoclonal antibody to BrdU. Modification of the BrdU-labeling pattern in the normal appearing rectal mucosa, such as the presence of BrdU-labeled cells at the mucosal surface or in the upper one-fifth of the crypt column, was observed in 15 of the 20 patients with adenocarcinoma, 17 of the 20 patients with adenoma and 6 of the 15 controls. This upward shift in the frequency of proliferating cells in the crypt was significantly higher in the patients with colorectal adenoma and cancer than in the controls, and may be used to identify subjects at high risk for colorectal cancer.

We measured hepatitis C virus antibody titers in 13 patients with chronic hepatitis C to determine whether titration of hepatitis C virus antibody was useful or not, to predict and evaluate the efficacy of interferon (IFN) treatment. During administration of IFN, hepatitis C virus titers declined in all patients. Antibody titers performed before treatment as well as just at the end of treatment did not correlate with change of the alanine aminotransferase levels during administration of IFN. Antibody titers declined continuously after treatment in 5 patients with normal alanine amino-transferase levels for over 6 months after discontinuation of IFN. Antibody titers rose again in 6 patients whose alanine aminotransferase levels fluctuated after treatment. An exceptional pattern of change occurred in 2 patients whose antibody titers declined continuously although their alanine aminotransferase levels fluctuated after treatment. Repeated titration of hepatitis C virus antibody appears to be useful for evaluating the long-term efficacy of IFN treatment.

Mucus glycoprotein is one of the major components of gastric mucus which plays an important role in mucosal defensive mechanisms as a mucus-bicarbonate barrier. Analysis of the mucus glycoprotein synthesis is a useful tool for evaluating gastric mucosal defensive factors. UDP-galactosyltransferase (UDP-Gal-T) is one of the regulating enzymes for the synthesis of the mucus glycoprotein. In the present paper, we studied assay methods for UDP-Gal-T activity in rat gastric mucosa using radiolabeled UDP-galactose and two different kinds of acceptor proteins, namely ovomucoid and asialomucin, and analyzed effects of antisecretory agents on the UDP-Gal-T activity. We used crude supernatants of homogenized scrapings of the fundic part of rat stomach as an enzyme preparation and determined optimal conditions. In each acceptor, Mn2+ and the non-ionic detergent Triton X-100 were required for the enzyme activity. With each acceptor molecule, the type of glycosidic linkages of galactose was beta-type linkage. With asialomucin as an acceptor, UDP-Gal-T activities of rat gastric mucosa decreased after intraperitoneal administration of antisecretory agents, while change of the enzyme activity was not observed with ovomucoid as an acceptor.

The immunologic mechanisms mediated by anticolon antibodies have been suggested for the injury of colonic mucosa in ulcerative colitis (UC). For the understanding of pathogenetic relevance of the anticolon antibody in UC, we examined the class and the subclass of the anticolon antibody reactive to rat colonic epithelial cells in sera from 10 patients with UC immunohistochemically by an indirect immunoperoxidase method. We also examined the distribution of the antigen recognized by the anticolon antibody by immunoelectron microscopy. The antibody reactive to the rat colonic epithelial cell was detected in 2 of the 10 patients, and the class and subclass of the antibody was mainly IgG2. The antigen recognized by the anticolon antibody was located on the apical membrane of the colonic epithelial cells and mucous substances of the goblet cells. These findings suggest that the anticolon antibody detected in this study is inadequate to cause the colonic mucosal injury by activating complements or mediating antibody-dependent cellular cytotoxicity. A potential pathogenetic role of the anticolon antibody in UC remains to be established.

Serum specimens from 12 patients with type A hepatitis were analyzed for immunoglobulin M-type antibody to hepatitis A virus (IgM anti-HA). A recently developed solid-phase radioimmunoassay kit for IgM anti-HA (HAVAB-M, Abbott Laboratories) and a competitive binding radioimmunoassay kit (HAVAB, Abbott Laboratories) with or without 2-mercaptoethanol treatment, as modified by Yano et al. (Acta Hepatol. Jpn. 21, 704-712, 1980) were used to obtain an M-index. All specimens obtained within 60 days of the onset of illness and specimens from 2 of 4 patients later than 60 days after the onset were positive with the HAVAB-M test. This test gave negative results to sera which were positive for anti-HA by a standard HAVAB test in the following: 3 patients with type B hepatitis; 5 with non-A, non-B hepatitis; 11 healthy adults; and 10 sera strongly positive for rheumatoid factor. The M-index for type A hepatitis in sera within 30 days of the onset (mean value of the M-index, m, = 1.52; standard deviation, SD, = 0.25) was significantly higher than that for non-A hepatitis (m = 1.05; SD = 0.15) and for healthy adults (m = 1.02; SD = 0.10). The simplicity and usefulness of the HAVAB-M test in diagnosis of acute type A hepatitis over those measuring the M-index by HAVAB tests were shown by direct comparison of the results.

A recently modified method using peroxidase labeled antibodies for light and electron microscopic demonstration of hepatitis B virus (HBV) was applied to the evaluation of hepatitis B surface antigen (HBsAg) on the surface of liver cells in biopsy specimens from 24HBsAg chronic carriers. Membranous distribution of HBsAg was demonstrated in diffuse or scattered hepatocytes in all 4 asymptomatic carriers and in 3 of the 20 patients with HBsAg-positive chronic active hepatitis or liver cirrhosis. In these patients with membranous expression of HBsAg, hepatitis B e antigen, Dane particles and DNA polymerase were often detected in sera, and large amounts of hepatitis B core antigen appeared in the liver. These results suggest that membrane-bound HBsAg may be expressed by the HBV genome. The ultrastructural study of liver cells showing membranous expression disclosed dense deposits of reaction product indicative of HBsAg on the cell membrane and/or on assembled particles within the extracellular space. In some hepatocytes showing both diffuse cytoplasmic and membranous expression of HBsAg, HBsAg-positive membrane of cisternae open to the intercellular space was connected with the liver cell membrane. These findings supported the conjecture that HBV associated antigens are integrated into the liver cell membrane.

In electron microscopic observation of a liver biopsy obtained from a hepatitis B surface antigen-positive patient, noncoated core particles were occasionally seen budding into the hepatocytic cisterni and many Dane particles were found in the pericanalicular vesicles of hepatocytes. Noncoated core particles were also localized in clusters within the bleb of microvilli. There were some core particles being protruded from microvilli into the lumen of bile canaliculi by budding. These findings suggest hepatitis B virus being released from the hepatocyte to the bile canaliculi by two different modes; through vesicle by reversed phagocytosis and from the microvilli by budding.

Antibody to hepatitis B core antigen (anti-HBc) was measured by radioimmunoassay using CORAB (Abbott Laboratories) in 10 cases of chronic persistent hepatitis (CPH), 46 cases of chronic aggressive hepatitis (CAH), 33 cases of liver cirrhosis (LC) and 53 cases of hepatocellular carcinoma (HCC) in relation to hepatitis B surface antigen (HBsAg) and its antibody (anti-HBs). Ninety-eight point four percent of patients with HBsAg and 93.8% of patients with anti-HBs were positive for anti-HBc and the titers of anti-HBc in patients with HBsAg were significantly higher than those with anti-HBs. Thirty-five point five percent of patients negative for either HBsAg or anti-HBs were positive for anti-HBc. The titers of anti-HBc in patients with CPH, CAH and LC were relatively low, whereas 7 (46.8%) of the HCC patients negative for either HBsAg or anti-HBc had high titers of anti-HBc. The significance of the presence of anti-HBc alone is discussed.

In 144 cases of hepatocellular carcinoma (HCC), 166 cases of cirrhosis without HCC and 142 cases of chronic hepatitis, we examined HBsAg, anti-HBs and anti-HBc in sera and compared the following factors between hepatitis B virus marker-negative and -positive patients: age, sex, alcohol consumption, family clustering of liver diseases, and histories of blood transfusion and post-transfusion hepatitis. Results of this study demonstrated several distinct differences in clinical backgrounds between non-B (negative for HBsAg, anti-HBs and anti-HBc) and B (positive for HBsAg) patients with HCC. Non-B patients were significantly older, had a lower frequency of familial tendencies for liver diseases, and more frequently had cancers other than HCC in their families. Some of these differences were also observed between non-B and B patients with cirrhosis and chronic hepatitis. Among patients with chronic hepatitis, the non-B patients had received blood transfusion or had post-transfusion hepatitis more frequently than the B patients. However, this difference was not apparent in patients with liver cirrhosis or HCC, suggesting that progression of non-A, non-B post-transfusion hepatitis to cirrhosis and HCC may not be as frequent as progression to chronic hepatitis.