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To evaluate the efficacy of lafutidine (20mg) , famotidine (40mg) and placebo in patients with mild reflux esophagitis (Grades A and B according to the Los Angeles classification) , a double-blind, multicenter, randomized clinical trial was performed for the first time in Japanese patients. In addition to each physician's evaluation, efficacy was evaluated by judging panels using images submitted by each physician. The healing rate after 8 weeks for lafutidine, famotidine and placebo were 67.7%, 56.6% and 41.2%, respectively. Lafutidine was significantly more effective than placebo (p=0.002, according to the judging panels) . Based on the evaluation of endoscopic images by the judging panels, 91 (27.1%) of 336 images submitted by each physician were judged to not be mucosal breaks. Judging panels are considered one of the ways to resolve the problem of the need to unify the criteria.

The details on prevalence of heartburn and reflux esophagitis have not been clarified, since no large-scale survey has been conducted to date. Accordingly, we conducted the nationwide survey regarding prevalence of heartburn and reflux esophagitis by asking new outpatients and patients with the first endoscopy to be performed who visited the medical institutions participating in this survey to fill out the questionnaire and undergo endoscopy. The result showed that heartburn was reported from 1,994 patients (42.2%) out of 4,723, and reflux esophagitis classified as grade A-D was reported from 602 patients (16.7%) out of 3,608. Meanwhile, fat intake, sweet food and anti-inflammatory analgesics were proven to be causes of heart-burn. Furthermore, frequency of heartburn and severity of reflux esophagitis were slightly correlated, although those were not necessarily obviously related.

We examined whether 13C-urea breath test with powdered 13C-Urea is affected with urease activity in the oral cavity and oropharynx in H. pylori negative cases. We also examined whether the degree of gargling affects the results of 13C-UBT. The results demonstrated that the urease activity not only in the oral cavity, but in the oropharynx may influence the UBT value. Therefore, it is possible that the UBT value may be affected with relic urease activity in the oropharynx if only the oral cavity is gargled. In conclusion, Gargling of the oropharynx in addition to the oral cavity is important to obtain true negative diagnosis with 13C-UBT in patients without Helicobacter pylori infection.

We attempted to evaluate the relationship between the expression of IL-8 and RANTES and the dynamics of their target cells in human gastric mucosa of H. pylori associated gastritis, including their changes after H. pylori eradication. We performed the measurement of the mucosal level of IL-8 and RANTES protein by ELISA and immunohistochemistry. The neutrophil infiltration into the gastric mucosa was identified by the histological examination based on the Updated Sydney system and the measurement of MPO activity. The memory T lymphocyte and eosinophil were indicated by immunohistochemistry of CD45RO that is one of surface markers indicating memory T lymphocytes and MBP that is contained in the granules of eosinophils. H. pylori positive gastric mucosa demonstrated a remarkable increase in neutrophils. CD45RO positive cells and eosinophils, compared to H. pylori negative gastric mucosa. Gastric mucosal level of IL-8 and RANTES protein and MPO activity was significantly higher in H. pylori positive cases than that in H. pylori negative controls after H. pylori eradication, both of the level of IL-8 protein and MPO activity reduced at the same levels as negative controls. However, RANTES expression, CD45RO positive T lymphocytes and eosinophils remained in H. pylori eradicated gastric mucosa at the significantly high level, compared with H. pylori negative cases. Therefore, it seems possible that IL-8 might enhance the inflammation by facilitating the neutrophil infiltration into H. pylori infected gastric mucosa and that RANTES might play an important role in the specific immune response against H. pylori and the maintenance of the immune memory after H. pylori eradication.

In this study, we performed immunohistochemical studies using p53 and Ki-67 immunostaining in 48 depressed type adenomas, and compared with protruded type adenomas (n = 28) and depressed type well differentiated mucosal gastric cancers (mcancer: n = 46). Focal and diffuse p53 staining patterns were not noticed in depressed type adenomas and in protruded type adenomas, but were noticed in mcancers (focal: 4.3%, diffuse: 41.3%). Ki-67 positive cells were noticed in surface epithelium in 24.4% of depressed type adenomas, in 21.4% of protruded type adenomas and in 87.0% of mcancers. Ki-67 positive rate in foveolar epithelium (superior, middle, inferior) were noticed in (31.1%, 12.9%, 6.1%) of depressed type adenomas, in (33.4%, 15.4%, 6.9%) of protruded type adenomas and in (33.4%, 31.4%, 20.4%) of mcancers. These results suggest that from the point of immunohistochemistry, depressed type adenomas were similar to protruded type adenomas, but were different from mcancers.

We investigated the quantitative changes in colonic mucins of rats with colitis. Male Wistar rats were treated with dextran sodium sulfate (DSS) or N-ethylmaleimide (NEM) to induce colitis. Both DSS and NEM caused depletion of goblet cells, infiltration of inflammatory cells and erosion at the colonic mucosa around the anus. Though the goblet cells decreased, colonic mucins increased in the distal colon. These phenomena may explain the clinical features of human ulcerative colitis, namely the goblet cell depletion and the mucous stool. The increase of colonic mucins may be a compensatory function of the colon tissue in response to the localized decrease of mucin production.

13C-urea breath test (UBT), available for diagnosis of Helicobacter pylori (HP) in the stomach, measures the 13CO in the breath in which 13C urea is resolved in the stomach by urease derived from HP. Accordingly UBT is useful for a test of HP infection. This study is aimed at clarifying the relationship between the UBT and gastric histological findings. For this study we selected 63 patients with HP infection who showed both positive UBT and positive histological diagnosis. Briefly in the UBT procedure, the patients were given 13C-urea (100 mg dissolved 100 ml water) in a fasting state and kept in the left decubitus position for 5 minutes, and then the patients were asked to expire into testing bags before and 20 minutes after administration of the urea. Biopsy specimens were taken endscopically from the gastric antrum and the body. The specimens of all patients showed positive CLO test. HP organisms, inflammation, activity, and atrophy of the gastric specimens, were expressed in score from 0 to 3 according to the Update Sydney system. The UBT values were high correlated with the increase of HP organisms. The UBT was 11.8, 26.3, and 37/1000 in the groups with the scores of 0.1, and 2 in the number of HP organisms from the gastric body, respectively. The UBT was 19.2, 22.2, 36.1, 26.7/1000 in the groups with scores of 0, 1, 2, and 3 for the specimens from the antrum, respectively. The results show that there is a positive correlation between the UBT values and HP organisms. As a result, the UBT correlated with the activity score. Grade of gastric mucosal atrophy was expressed histologically in scores of 0,1,2, and 3. The UBT was 29.4, 19.1, 17.5, and 9.3/1000 in the groups with scores 0,1,2, and 3 in the grades of gastric atrophy from the gastric body, respectively. There was a negative correlation between the UBT values and the grade of gastric atrophy. We conclude that the UBT values which indicate the number of HP organisms can be used not only for diagnosis of HP infection but also the quantitative index of HP load.

In this study, we investigate simple breath test for detection of Helicobacter pylori (HP) infection using 13C-urea. Thirty-nine patients (30 were HP positive, 9 were HP negative) were given three different doses (50, 100 and 150 mg) of 13C-urea at fasting, and keep sitting after mouth washing with water. Breath samples were taken before and 10, 20, 30, 45, and 60 minutes after urea administration. More than 100mg of 13C-urea was necessary for correct diagnosis of HP infection, because 2 HP positive cases were not detected by 50mg 13C-urea administration. In cases with patchy distribution of HP in the stomach, it may be necessary to change the posture to distribute urea within the whole stomach. In most of HP positive cases, peak delta 13CO2 were obtained within 30 minutes, but one HP negative case showed high delta 13CO2 at 10 minutes, which was probably caused by urease activity in the mouth. So it is appropriate to take breath sample at 20 minutes after urea administration. In this study, cut-off value for a positive test can be setted between 4 to 7 delta/1000, it is necessary to investigate much more cases to set exact cut-off value.

This study is aimed at a role of Helicobacter pylori (HP) infection in reflux esophagitis of the elderly. 46 patients with reflux esophagitis aged at older than 60 years are selected for this study with informed consent. 43 patients without reflux esophagitis, peptic ulcer, and gastric cancer are used as a control group. In reflux esophagitis, gastric mucosal atrophy is judged as closed type of endoscopic findings in all cases. In control, 27 of 43 patients were judged as open type. Serum pepsinogen I, II ratio is 4.73 +/- 1.28 which is higher significantly than 3.39 +/- 1.69 in control. Serological positive rate of HP antibody is 39.1% in reflux esophagitis. This rate is significantly lower than 62.7% in control. In conclusion, low frequency of chronic HP infection protects gastric mucosa from atrophy, and keeps secretion of gastric acid, resulting in reflux esophagitis of the elderly accompanied with various abnormal esophago-gastric functions.

The preoperative diagnosis of less than ss depth gallbladder cancer is difficult. Its preoperative diagnosis rate was low (27.5%), and even lower with the presence of concomitant gallstone. In the latter case, the diagnosis rate was particularly low when the stones diameter was greater than 1 cm. Gallstones are frequently associated with macromorphologically invasive type of gallbladder cancer and this may be the reason for the lower diagnostic rate. We compared preoperative diagnosis rate of ultrasonography (US), computed tomography (CT) and drip infusion cholecystography (DIC) for each invasion depth. In US, the preoperative diagnosis rate for m depth invasion was 6/16 (37.5%), pm depth was 1/13 (7.7%), and ss depth was 14/41 (34.1%). In CT, its rate for m depth was 3/11 (27.3%), pm depth was 1/10 (10.0%), and ss depth was 11/37 (29.7%). In DIC, its rate for m depth was 3/11 (27.3%), pm depth was 1/10 (10.0%), and ss was depth 1/23 (4.3%). None of the currently used imaging techniques were very accurate in diagnosing gallbladder cancer. Thus, during preoperative work up, if one discovers a gallbladder full of stones, stones of greater than 1 cm in diameter, thickened gallbladder wall, or a non visualized gallbladder with DIC, gallbladder cancer must be highly suspected.

The effects of tetragastrin on mucus glycoprotein (mucin) metabolism and mucosal protection in rat gastric mucosa were investigated. Rats were administered with various doses of tetragastrin (12, 120, or 400 micrograms/kg body weight; s.c.), followed by 50% ethanol-induced gastric injury. Tetragastrin caused a significant increase in mucin content in the corpus mucosa and prevented 50% ethanol-induced gastric mucosal damage in a dose-dependent manner. For assessment of the effects of tetragastrin on the metabolism of gastric mucin in detail, changes in mucin distribution in the three different layers of rat gastric mucosa were examined one hour after single administration of tetragastrin. A significant increase in the mucin content was noted in the mucus gel and surface mucosal layer. Mucin content in the deep mucosa corresponding mainly to the mucus neck cell mucin underwent virtually no change by this treatment. An increase in mucin in the mucus gel and surface mucosa would thus appear due to the administration of tetragastrin and may possibly be related to the protective action of the gastric mucosa against injury. The data demonstrate a possibility that gastrin may have potential for enhancing gastric mucosal protection associated with mucus secretion and/or mucus synthesis on the surface mucosa of rat gastric mucosa.

A method was established for recovering the mucus gel layer of rat gastric mucosa without damage to underlying surface epithelium. The mucus gel was solubilized by stirring the gastric mucosa in a solution of N-acetylcysteine (NAC), a mucolytic agent. Optimal mucus gel solubilization was possible by treatment with 2% NAC for 5 minutes at room temperature. Mucus glycoprotein was quantitatively extracted and measured from the mucus gel sample obtained by the NAC treatment. This treatment caused no damage to surface epithelial cells, as observed by a light microscope. Besides NAC, pronase solution was also adequate for solubilizing the mucus gel layer without any damage to the surface epithelium. However, extraction and measurement of mucus glycoprotein from the pronase-treated mucus gel sample was not possible due to contamination by high molecular hexose-containing substances which were eluted along with the mucus glycoprotein from the column of Bio-Gel A-1.5m. This NAC method was used to examine changes in mucus glycoprotein content in the mucus gel at one hour following the oral administration of 16,16-dimethyl prostaglandin E2. A significant increase in mucus glycoprotein of the gel was brought about by the prostaglandin treatment. Thus, the present method was suitable for estimating the amount of mucus secreted in to the mucus gel layer.

Recent animal studies suggest salivary epidermal growth factor (EGF) has a cytoprotective effect in the upper GI tract and is one of the important factors to promote the healing of experimental ulcer. The present study was undertaken to clarify the role of salivary EGF in peptic ulcer patients. Saliva samples were collected from 129 endoscopically normal subjects and 232 peptic ulcer patients. Salivary EGF concentration was measured by RIA. Salivary EGF output in normal subjects was 5.26 +/- 0.26 (ng/5 min) (mean +/- SE). Those in patients with gastric ulcer (GU), duodenal ulcer (DU) and gastroduodenal ulcer (GDU) were 10.74 +/- 0.15, 8.13 +/- 0.83 and 9.79 +/- 0.91. EGF output in GU and GDU patients were higher than that in normal subjects respectively. Tractable GU patients (healed within 3 months with regular regimen) had higher EGF output than intractable GU patients. Among tractable GU patients, those who had healing within 8 weeks had higher output. EGF output in patients with recurrent GU was lower than that in non-recurrent GU patients. In 10 GU patients, EGF output became higher in healing stage than in active stage. Salivary EGF may promote the healing and prevent the recurrence of human gastric ulcer.

Twenty-five patients with submucosal tumor of the esophagus were treated endoscopically. All patients underwent submucosography. The tumors were classified as intra-luminal or intra-mural types according to growth pattern. Twenty tumors were resected using electrocautery in single sessions. Another 5 lesions (more than 20 mm in diameter) were subjected to absolute ethanol injections in multiple sessions to necrotize the tissue, after the overlying mucosa was stripped off by electrocautery. These procedures were not accompanied with serious complications such as perforation or massive bleeding. Oozing bleeding occurred in 3 patients, which was easily stopped by topical injection of absolute ethanol with an endoscope. Esophageal stenosis did not occur. Local reccurence of a submucosal tumor was found in a patient after 14 months, and was retreated successfully. Although the wall of the esophagus is thinner than that of the stomach, endoscopic treatment for a submucosal tumor of the esophagus can be performed safely. Submucosography and endoscopic ultrasonography reveals the extent of the tumor in relation to the esophageal wall thickness. These examinations are helpful in preventing complications. Endoscopic treatment for submucosal tumors using electrocautery and topical injection of absolute ethanol were effective and safe.

In our previous reports, low dose acid secretagogues caused increase in corpus mucus glycoprotein content in rats. This increase was not due to the direct action of protons. The present study was conducted to determine whether this increase has a mucosal function or not Rats were given histamine (0.8 mg/kg) intraperitoneally or tetragastrin (12 micrograms/kg) subcutaneously. One hour following the acid secretagogues administration, the animals were given 1 ml of 30, 40 or 50% ethanol orally and then sacrificed after one hour. Gastric mucus glycoproteins were isolated from the corpus region of stomach. The following results were obtained: 1) Histamine prevented the gastric mucosal damage and the decrease of corpus mucus glycoprotein content induced by 40% ethanol ingestion. 2) Tetragastrin prevented the gastric mucosal damage induced by 30 approximately 50% ethanol ingestion and the decrease of corpus mucus glycoprotein content induced by 40 approximately 50% ethanol ingestion. Based on these results, the increase of corpus mucus glycoprotein content induced by acid secretagogues has a mucosal function. Moreover, tetragastrin strengthened the mucosal defence together with acid secretion.

The efficacy of two anti-ulcer drugs, Cimetidine and Cetraxate, on the mucus glycoproteins of gastric mucosa in the aspirin-induced gastric damage was studied in rats. Simultaneous or previous oral administration of Cimetidine or Cetraxate with aspirin reduced the diminution of the mucus glycoproteins which was occurred by aspirin administration. The recovery of the content of mucus glycoprotein in drug dosed rats occurred within 3 h after aspirin dosing and was nearly 90% of control at 5 h in all cases. Single administration of Cetraxate or Cimetidine produced an increase in the mucus glycoprotein content greater than that of the untreated control. Although a macroscopical method for the measurement of gastric damage was applied to this work, neither erosions nor linear ulcers were observed in all cases except the single administration of aspirin. The biochemical method used should be able to assess the efficacy of drugs on the mucosal lesion which cannot be expressed as the ulcer index.