Yoshihiro Kohli

Endoscopic sphincterotomy of the ampulla of Vater

Endoscopic sphincterotomy at the papilla of Vater, combining and modifying technics already established for retrograde cannulation and electrosurgical polypectomy, has been successfully performed in 2 patients with removal of stones impacted in the ampulla and proximal common bile duct. The authors caution that further investigation is in order to assure the safety and efficacy of the procedure.

Analytical studies on growth of human gastric cancer.

Doubling times of early and advanced gastric cancers were determined on serial double-contrast roentgenographs, and those of tumor metastatic to the abdominal wall from the stomach were calculated from direct measurement. Doubling times of early gastric cancer ranged from 577 to 3462 days, while advanced gastric cancer had doubling times from 69 to 305 days. Doubling times of tumors metastatic to the abdominal wall were shorter, that is, from 17.7 to 60.2 days. The difference of growth rates in these three situations may result from differences in cell loss in each case. Equally important, the peptic ulceration which accompanies early gastric cancer seemed to have a dual significance; that is, in many cases of early gastric cancer it had an important role as a factor in cell loss, but in some cases it was likely to accelerate to a deeper cancerous invasion. From the retrospective or prospective follow-up study, early gastric cancer, type IIb, was likely to show abnormal redness or discoloration on the mucosal surface, which could be more easily recognized at endoscopy with the dye-spraying method.

Full-Length Sequence Analysis of the vacA Gene from Cytotoxic and Noncytotoxic Helicobacter pylori

Some clinical isolates of Helicobacter pylori fail to express vacuolating cytotoxin, despite possessing a copy of the vacA gene on the chromosome. To gain insight into the differences between vacA from cytotoxic and noncytotoxic strains, the vacA open-reading frames from 16 cytotoxic and 22 noncytotoxic strains were sequenced. Mutations that cause truncation of VacA in 11 of 22 noncytotoxic strains were identified, including internal duplication, large deletion, 1-bp insertion, and non-sense mutations. In contrast, none of the 16 cytotoxic strains had any truncation of VacA. Four cytotoxic strains had inserted sequences downstream of vacA. Three were mini-IS605, and the other was a putative rfaJ gene that encodes lipopolysaccharide glucosyltransferase. The rfaJ gene identified in this study had a poly(C) tract, resulting in premature termination of the gene product. The phylogenetic tree based on the vacA open-reading frame indicated that two different H. pylori lineages are circulating in Japan and the West.

A proton pump inhibitor, E3810, has antibacterial activity through binding to Helicobacter pylori

Helicobacter pylori infection is causally related to atrophic gastritis, and it may also be associated with peptic ulcer and gastric carcinoma. Eradication ofH. pylori is recommended in patients with such diseases, especially in those with peptic ulcer. A new potent proton pump inhibitor, E3810, had an antibacterial effect onH. pylori, as has been reported for omeprazole and lansoprazole, two other proton pump inhibitors. The minimum inhibitory concentration of E3810 was 1.57–3.13 μg/ml, lower than that of omeprazole or lansoprazole. To clarify the mechanism of the antibacterial effect of E3810, we analyzed the characteristics of E3810 binding toH. pylori. Scatchard plot analysis of this binding showed a curvilinear profile, indicating the presence of several molecules with different affinities to E3810 onH. pylori. The binding capacity of E3810 toH. pylori was calculated to be about 2×106 sites/cell. These results suggested that E3810 has an antibacterial effect againstH. pylori and that the effect may be mediated through direct binding toH. pylori.

Helicobacter pylori-negative gastric and duodenal ulcers.

Abstract: It is unclear whether Helicobacter pylori infection is essential to the development of peptic ulcers. In this study, we examined the rates of H. pylori-negativity among patients with peptic ulcers. We also attempted to clarify the characteristics of H. pylori-negative peptic ulcers to throw light on the pathogenesis of peptic ulcers. The study included 215 consecutive patients with gastric ulcers (GUs) and 120 consecutive patients with duodenal ulcers (DUs). After routine endoscopic examination and phenol red dye endoscopy, forceps biopsies were performed for culture, histology, and the rapid urease test. A patient was considered H. pylori-negative when the serum anti-H. pylori IgG and the three tests on biopsied specimens were all negative. H. pylori-negative rates were 3.2% in the patients with GUs and 1.7% in the patients with DUs. Lack of atrophy of the gastric mucosa was significantly more common in the H. pylori-negative patients with GUs. A history of ulcer disease was less common and antral ulcers were more common in H. pylori-negative GU patients, but not significantly so. As the urea breath test had not been performed, the possibility of a false-negative result cannot be completely ruled out, but we believe that the H. pylori-negative rate in our study is more reliable than these rates in previous reports, because we visualized H. pylori distribution by phenol red dye endoscopy to avoid false-negative results in biopsies, and we used both biopsy and serum anti-H. pylori IgG findings to establish an H. pylori-negative diagnosis. Since H. pylori-negative peptic ulcers certainly exist, H. pylori infection is thought not to be essential to the development of peptic ulcers. There were few differences between the characteristics of H. pylori-negative and H. pylori-positive peptic ulcers in our study. A large-scale study is required to clarify the characteristics of H. pylori-negative peptic ulcers.

Endoscopic Diagnosis of Intestinal Metaplasia in Canada and Japan

We carried out comparative studies on chronic atrophic gastritis with accompanying intestinal metaplasia using the methylene blue dye spraying, endoscopic technique on 167 Japanese and 77 Canadian outpatients free of gross stomach disease. In both population samples (Kyoto, Japan and St. Johns, Newfoundland) with increasing subject age, the fundic-pyloric (F-P) border shifted cephalad indicating atrophy of the fundic mucosal glands. Japanese subjects, however, showed greater variation in location of the F-P border. The reduction in fundic gland area with aging was followed by intestinal metaplasia, the incidence and severity of which was greater in Japanese than in Canadian outpatients. From these data we conclude that a difference in the gastric mucosa in these two countries may be related to the pathogenesis of gastric cancer.

Significance of ammonia produced by Helicobacter pylori

Objective To clarify the effect of ammonia produced by Helicobacter pylori, which has strong urease activity, on the blood ammonia level. Design (1) The quantification of ammonia production by live H. pylori in vitro. (2) The measurement of venous and portal ammonia levels following the instillation of H. pylori into the stomachs of normal or cirrhotic rats. Methods (1) The urease reaction was carried out at 37C with bacteria suspended in phosphate-buffered saline and 400 mmol/l urea solution in acetate buffer, pH 5.0. (2) Bacterial suspensions with or without urea solution were instilled into the stomachs of male normal Wistar rats or into rats in which cirrhosis had been induced by injection of carbon tetrachloride; venous and portal ammonia levels were then measured. Results (1) Ammonia production by 105 CFU/ml of live H. pylori was about 5.88–11.76 mmol/l (0.01–0.02%) at 37C over 120 min. (2) In the normal rats, when 107CFU/ml of H. pylori was instilled into the stomach, the venous ammonia level reached about 120 xmol/l after 120min, and about 210 mUmol/l in the cirrhotic rats. Conclusions These data suggest that the ammonia produced by H. pylori may play a role in the pathogenesis of hyperammonemia if this organism is widely distributed and is present in large numbers in the stomach, particularly in the presence of hepatic cirrhosis.

Cytotoxin and urease activities of Helicobacter pylori isolates from Japanese patients with atrophic gastritis or duodenal ulcer

The vacuolating cytotoxin and urease secreted by Helicobacter pylori are thought to be virulent factors. Because vacuolation is potentiated by the presence of ammonium ion, which is produced by urease in vitro, it is of interest to examine whether cytotoxin and urease work reciprocally in the development of atrophic gastritis or duodenal ulcer. In the present study, patients (all H. pyloripositive) were divided into four groups: mild atrophic gastritis (group 1; nine patients), severe atrophic gastritis (group 2; 36 patients), duodenal ulcer with mild atrophic gastritis (group 3; 19 patients) and duodenal ulcer with severe atrophic gastritis (group 4; 12 patients). Cytotoxin production and urease activity of H. pylori isolated from these patients were analysed. Cytotoxin production was observed in four of nine (44.4%), 28 of 36 (77.8%), 11 of 19 (57.9%) and eight of 12 (66.7%) isolates from groups 1, 2, 3 and 4, respectively. Cytotoxin‐producing H. pylori isolates were found significantly more in patients with severe atrophy than in patients with mild atrophy (P= 0.048). The mean of relative activity of cytotoxin in H. pylori isolate was 1. 6. ± 2. 3, 7. 9. ± 7. 4, 5. 8. ± 6. 0 and 9. 0 ± 9. 1 in groups 1, 2, 3 and 4, respectively. Helicobacter pylori isolates from severe atrophy or duodenal ulcer patients in groups 2 or 4 possessed significantly higher activity than those from non‐ulcer patients in group 1 (P= 0.017 and 0.030, respectively). The mean of urease activity was 8. 6 ± 4. 6, 10. 0 ± 5. 9, 10. 0 ± 8. 5 and 11. 2 ± 7. 7 IU/mg in groups 1, 2, 3 and 4, respectively. These differences indicated no statistical significance. In each H. pylori isolate, the production of cytotoxin and urease were independent, which indicated that there was no reciprocal effect between them in vivo. Thus, cytotoxin‐producing H. pylori isolates were more prevalent in patients with severe atrophic gastritis and the cytotoxin activities of H. pylori isolates from the patients with severe atrophic gastritis or duodenal ulcer were much higher than those from the patients with mild atrophic gastritis, which suggested that vacuolating cytotoxin may be a disease‐inducing factor.

Bile Reflux due to Disturbed Gastric Movement Is a Cause of Spontaneous Gastric Ulcer in W/Wv Mice

Abstractc-Kit is a receptor tyrosine kinase, and it isencoded by the mouse W locus. Mutant W/Wvmice develop spontaneous gastric antral ulcers. The aimof the present study was to investigate the pathogenesis of these gastric ulcers and to examine theeffects of two antiulcer drugs; a proton pump inhibitor(2{[4-(3-methoxypropoxy)-3-methylpyridine-2-yl]methyl-sulfinyl}-1H-benzimidazole sodium salt, rabeprazole) and a mucosal protective drug(geranylgeranylacetone, GGA), on the gastric ulcers. Theinhibition of the gastric acid secretion by rabeprazole(30 mg/kg body weight, subcutaneous injection once a dayfor six weeks) significantly increased the gastriculcer formation compared to the controls. In contrast,the GGA treatment (100 mg/kg body weight, oraladministration for six weeks) significantly inhibited the ulcer formation. Bile reflux was seen inthese mutant mice, and they showed no cyclic intensecontractions in the gastric antrum. These resultssuggest that bile reflux due to the disturbance ofgastric antral movement is a cause of the spontaneousgastric ulcers in W/Wv mice.

Earlier diagnosis of gastric infiltrating carcinoma (scirrhous cancer).

We approached the early diagnosis of gastric infiltrating carcinoma, scirrhous cancer, by a retrospective study of 19 patients, together with a prospective study of a single patient, by reexamination and follow-up of gastric roentgenographs and endoscopic films. This study suggests that an early feature of this type of gastric cancer might be IIc- or III + IIc-like depression in the body of the stomach, probably in the fundic region of the stomach. A shallow depression or a slight stiffness of the gastric wall may be one of the earliest roentgenographic or endoscopic findings helpful in early detection of this disease.