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We isolated, by the subtraction cloning method, a pepsinogen C (PGC) gene fragment (the sequence between the 968th and 1179th base pairs) from a rat gastric mucosal cDNA library as a cDNA clone encoding a substance that promotes growth of the normal rat gastric mucosal cell line RGM1. Northern blot analysis revealed that PGC gene expression was enhanced not only in acetic acid-induced chronic gastric ulcers but also in indomethacin-induced gastric mucosal lesions. PGC gene expression was also increased in the Helicobacter felis-infected stomachs. Thus, the PGC gene may play a role in gastric epithelial cell growth during gastric mucosal healing.

Background: The purpose of the present study was to examine the association between interleukin-8 (IL-8) in the gastric body due to Helicobacter pylori infection and histological gastritis, as well as elucidating the effect of acid secretion inhibitors on H. pylori associated body gastritis in duodenal ulcer patients., Methods: Twenty H. pylori-negative patients, 20 H. pylori-positive patients with chronic gastritis without peptic ulceration, and 20 H. pylori-positive duodenal ulcer patients (DU) were studied. Four biopsy samples were taken, each from the greater curvature of the antrum and body of the stomach. Biopsies were histologically investigated by ELISA to determine the density of H. pylori, the degree of neutrophil infiltration and the IL-8 concentration in the mucosa., Results: In the gastric mucosa of H. pylori-negative subjects, no IL-8 and hardly any neutrophil infiltration were observed. In contrast, enhanced IL-8 production and increased neutrophil infiltration were present in those infected with H. pylori. In H. pylori-positive patients, a significant correlation was observed between the IL-8 concentration and the degree of neutrophil infiltration, but no correlation was found in the body mucosa of those with DU. Twelve of 20 DU patients demonstrated hardly any neutrophil infiltration, despite the increased mucosal IL-8 content in the body. The administration of omeprazole in DU patients markedly increased mucosal neutrophil infiltration even though it did not cause any significant change in the H. pylori density and IL-8 concentration in the body. Although the effect of omeprazole was transient, a significant increase in neutrophil infiltration continued in comparison with the status before omeprazole administration in those subsequently undergoing maintenance treatment with H2-blockers., Conclusion: In H. pylori-positive chronic gastritis, IL-8 concentration is enhanced in the mucosa of the body, and is associated with increased neutrophil infiltration. However, in DU patients, despite increases in body IL-8 concentration, neutrophil infiltration is reduced and the gastritis may be localized in the antrum.

Background: Nitric oxide has an important role in the pathophysiology of the gastric mucosa. However, to date, it is not clear if nitric oxide plays a cytoprotective or cytotoxic role in the pathogenesis of mucosal lesion., Methods: We have used the NADPH-diaphorase histochemistry that selectively stains cells containing nitric oxide synthase, the enzyme that catalyzes the production of nitric oxide on the antral gastric mucosa of children with antral gastritis., Results: In the lamina propria of the mucosa, the presence of the enzymatic activity was found in perivascular round cells and nerve fibers. In the epithelium, focal positivity to NADPH-diaphorase was found in superficial cells, mainly located in the extrusive zones. The epithelial cells in the pits and glands were negative, in the mucous layer, Helicobacter pylori were also stained by NADPH-diaphorase. A single H. pylori-infected child who was also examined after eradication of the H. pylori showed during the control examination absence of microorganisms and reduction of the NADPH-diaphorase-positive cells in the mucosa., Conclusions: Our results demonstrate that, in gastric mucosa, endogenous and exogenous structures express a NADPH-diaphorase activity.

The effect of high doses of vitamin E (Vit.E; 400 units/ day) on ornithine decarboxylase (ODC) activity and regression of small intestinal metaplasia (SIM) was studied in a 1-year double-blind intervention trial. Biochemical and morphological parameters were estimated in 14 evaluable SIM patients of 18 in the Vit.E group and in 16 of 18 intestinal metaplasia patients enrolled in control group (placebo). In the control group, there were no statistically significant changes in Vit.E content in blood plasma, ODC activity, and the rate of SIM in multiple biopsies from antrum gastric mucosa. In the Vit.E group, after 6 and 12 months of intervention, the initial content of Vit.E in blood plasma increased from 6.4 +/- 0.9 up to 17.0 +/- 1.8 and 21.2 +/- 2.3 micrograms/ml, respectively, and the initial abnormally high activity of ODC, 62.6 +/- 7.8 units, decreased by 53 and 65%, respectively. Histological analysis of multiple biopsies, taken from the gastric antrum of patients supplemented with Vit.E, revealed that in 8 of 14 patients (57%) after 6 months and in 10 of 14 patients (71%) after 12 months, no signs of SIM were observed; gastroscopic dye procedure confirmed the regression of SIM in these cases and showed the presence of only small isolated stained areas identified as SIM.

The role of sialic acid for the adhesion of Helicobacter pylori to gastric mucosa cells and/or to the mucin layer is still under debate. Several but not all H. pylori strains express a sialic acid-binding adhesin, specific for terminal alpha-2,3-sialic acid residues. Recently, the production of sialidase by H. pylori was reported [Dwarakanath, A.D. et al. (1995) FEMS Immunol. Med. Microbiol. 12,213 216]. We analysed several strains isolated from gastric biopsies cultivated both in liquid media and on agar plates for sialidase. Activity of this enzyme was first assayed using the fluorigenic substrate 4-methylumbelliferyl-alpha-D-N-acetylneuraminic acid. Since the fluorimetric assay can give false-positive results caused by non-specific interactions with umbelliferyl-tagged substances, we used also the more sensitive and specific assay with sialyl-[3H]lactitol as a substrate. No evidence for sialidase activity of H. pylori strains, cultivated under both inducible and non-inducible conditions, was obtained.

The two subunits of the gastric H/K ATPase, namely the catalytic alpha-subunit and the glycoprotein beta-subunit, are the major targets of parietal cell autoantibodies associated with human and murine autoimmune gastritis. The murine disease induced by neonatal thymectomy is T cell-mediated. We have previously shown that transgenic expression of the H/K ATPase beta-subunit gene in the thymus prevented the development of autoimmune gastritis induced by thymectomy. However, little is known of the contribution of the H/K ATPase alpha-subunit in disease development. Here, we show that (1) in contrast to the gastric H/K ATPase beta-subunit, the alpha-subunit gene is expressed in normal BALB/c thymus. (2) transgenic expression of the gastric H/K ATPase alpha-subunit gene in the thymus failed to prevent the development of autoimmune gastritis and (3) normal BALB/c and transgenic mice expressing the alpha-subunit in the thymus develop autoimmune gastritis following immunisation with purified murine gastric H/K ATPase, whereas transgenic mice expressing the beta-subunit in the thymus do not. We propose that the expression of the H/K ATPase alpha-subunit in the normal thymus may account for the predominant role of the beta-subunit in the development of autoimmune gastritis induced either by thymectomy or by immunisation with the ATPase.

Serum cholinesterase /ChE/ investigation in children with gastroduodenitis or peptic ulcer disease indicate its low activity, specially in children with peptic ulcer disease. These investigation can be index of parasympathetic tonus in digestive tract disease.

Reactive oxygen metabolites have been implicated in gastric mucosal injuries. Superoxide dismutase, a scavenger of superoxide radical, is a key enzyme in gastric mucosal protection against several damaging factors. This study was aimed at investigating the relationship of superoxide dismutase activity to Helicobacter pylori-induced antral gastritis in children. Two groups of 11 children each, one positive and the other negative for Helicobacter pylori, were studied. Biopsies from the antrum and corpus were obtained for evaluation of Helicobacter pylori by CLOtest and histology as well as for superoxide dismutase activity (cytochrome c method). Erythrocytic and serum superoxide dismutase levels were determined as well. Superoxide dismutase activity was significantly higher only in the antrum of children with Helicobacter pylori-induced antral gastritis. There was no significant difference in superoxide dismutase activity in the corpus, erythrocytes, or serum of both groups. These findings may suggest a pathogenic relationship between the presence of Helicobacter pylori and oxygen radicals in inducing antral mucosal injury.

Background: Rapid ureas tests (RUTs) provide a simple, sensitive method of detecting Helicobacter pylori infection., Objectives: Our aim, therefore, was to determine whether the yield of detecting H. pylori infection by RUT varied depending on the site of gastric biopsy., Materials and Methods: Gastric biopsies were obtained from 50 patients for RUT by use of hpfast (GI Supply, Camp Hill, PA). Biopsies were taken from the prepyloric greater curve antrum, from the gastric angle, and from the greater curve in mid-corpus. One biopsy specimen was placed in the RUT gel, and the biopsy from the adjacent mucosa was placed in formalin for subsequent histological evaluation by using the Genta stain. RUTs were examined and scored at intervals of 5, 10, 15, 30, and 45 minutes and after 1, 2, 4, and 24 hours., Results: Fifty patients were entered in the rest (150 RUTs), 32 having H. pylori infection. There were no false-positive RUTs (specificity, 100%). The gastric angle site was positive in 100%. The prepyloric site was positive in 87%, and the corpus site was positive in 84.4% (p < .052 for angle or prepyloric antrum versus corpus). The most common pattern was for all to be positive (74%). The median time to positivity was similar with angle and prepyloric sites (37.5 and 60 minutes, respectively, p = not significant) and shorter than the corpus biopsy (180 minutes); (p < .05 for angle or prepyloric antrum versus corpus)., Conclusion: The maximum probability for detecting H. pylori infection using a RUT is to obtain a biopsy from the gastric angle. To prevent missing a positive result when intestinal metaplasia is present, we recommend that (at a minimum) biopsies be taken from both the angle and the corpus.

Background: Detection of Helicobacter pylori infection in clinical routine is based either on the direct visualization of the bacterium in gastric biopsies by histology or microbiology or on the demonstration of urease activity in gastric biopsies and by the labelled-urea breath test (UBT). Omeprazole has a strong inhibitory effect on H. pylori urease activity in vitro, but its effect in vivo and thus its influence on urease-based diagnostic procedures has not been investigated systematically., Aim: To investigate whether omeprazole is able to inhibit H. pylori urease activity in vivo and, if so, at which doses., Patients: Eighteen patients with H. pylori associated chronic gastritis were studied., Methods: H pylori diagnosis was based on histology, rapid urease test and culture from antral biopsies. Following a positive H. pylori diagnosis patients received omeprazole 20mg (n = 6), 40mg (n = 6) and 80mg (n = 6) once daily for 5 days and 13C-UBT was performed on day 1, 3 and 5, 30min after each omeprazole administration. The 13C-UBT was performed with 200ml 0.1 N citric acid as test drink and 75mg 13C-urea. Breath samples were collected before and 30 min after 13C-urea administration., Results: A significant inhibition of urease activity was observed only under high dose omeprazole administration (80 mg/day), and the 13C-UBT turned negative in three (50%) of these patients after 5 days therapy., Conclusion: Short-term omeprazole administration reduces H. pylori urease activity only at doses as high as 80 mg/day. A direct inhibition of enzyme activity as well as a reduction in the number of viable H. pylori bacteria may be responsible for this omeprazole-mediated reduction in urease activity. Urease-based diagnostic procedures for H. pylori are not suitable for patients under omeprazole therapy depending on the dose and duration of therapy.

Of two hundred Ethiopian patients with dyspepsia, multiple biopsies were taken from the antrum of the stomach. Helicobacter pylori was cultured from 85% of duodenal ulcer and in 75% of chronic antral gastritis patients. The overall Helicobacter pylori positivity was 70%. The sensitivity, specificity, positive and negative predictive values of the tests as compared to culture were as follows, respectively: direct urease test 100%/87%/95%/100%, direct gram stain 60%/98%/99%/51%, histological gram stain 66%/97%/98%/56%, Giemsa stain 100%/97%/99%/100% and Gimenez stain 100%/87%/95%/100%. It is concluded that gram staining of direct tissue smear or histology is an insensitive method in the diagnosis of Helicobacter pylori. All the other tests, are shown to be valid. Urease test is an excellent test for provision of presumptive diagnosis of Helicobacter pylori while awaiting confirmation either by culture of histology.

Investigations designed to study gastric mucosa (GM) in patients with chronic primary gastroduodenitis with the aid of electron microscopy showed the abnormal changes in the cellular, subcellular membranes and capillaries to be of the same type as they are in peptic ulcer (PU) though poorly manifest. Changes in GM under chronic atrophic gastroduodenitis (ChGD) suggested involutive changes while in chronic secondary gastroduodenitis (ChSGD) it was generally not different from the mucosa ultrastructure in healthy subjects except for changes in surface epithelium. Based on the histoenzymologic studies it has been ascertained that in ChPGD there occurs a rise in lysosomal enzymes similar to that encountered in PU, reflecting the intensity of catabolic processes, decrease in the activity of enzymes of the capillary wall and mitochondria respiratory chain against the background of compensatory enhancement of the activity of the glycolytic enzyme lactate dehydrogenase. In ChAGD the activity of all the enzymes was low, while in ChSGD it did not differ significantly from that in healthy subjects.

Human type A chronic gastritis or autoimmune gastritis (AIG) is associated with gastric H,K-ATPase-specific autoantibodies (HKAb). The pathogenic role of the HKAb and the triggering autoantigen(s) are unknown. In a mouse model, neonatal thymectomy (nTx) induces AIG, which is likely T cell mediated, although HKAb are always present. Our aim is to study the role of the H,K-ATPase in the initiation of AIG. The direct involvement of the H,K-ATPase in the onset of AIG is suggested by the following findings. AIG appears at the age of 1 month in susceptible BALB.D2 mice, i.e. the time at which H,K-ATPase expression reaches adult levels. A new HKAb assay system based on immunoprecipitation of native H,K-ATPase expressed in Xenopus oocytes has revealed that the early lesion is already associated with low titers of HKAb. Injection of gastric membranes, rich in H,K-ATPase, into neonatal BALB.D2 mice without adjuvant induces a persisting AIG. This new model for AIG will provide the means to identify which H,K-ATPase subunit triggers AIG.

Mucosal biopsy specimens from patients with Helicobacter pylori infection in gastric antrum contain an increased amount of myeloperoxidase. This study was performed to elucidate the interaction of H pylori sonicate protein(s) and neutrophils concerning myeloperoxidase release. Neutrophil degranulation with myeloperoxidase release was examined in a direct stimulating assay. Priming activity of H pylori was examined after preincubating neutrophils in sonicate, either crude or modified by heat treatment, pronase inactivation and dialysis, and stimulating with N-formyl-methionyl-leucyl-phenylalanine (fMLP) or serum opzonised zymosan (OZ). It was found that H pylori sonicate protein(s) stimulates neutrophil degranulation with myeloperoxidase release in a concentration dependent way. The activity was distinct from fMLP and capable of priming the subsequent fMLP and OZ response. Experiments with the modified bacterial sonicate suggest the activity is caused by a protein, but the findings show that non-protein molecules, for example, lipopolysaccarides were also part of the H pylori sonicate priming activity. The increased mucosal myeloperoxidase in H pylori associated disease can be a direct consequence of bacteria derived stimulation of inflammatory neutrophils.

The organism frequently colonizing the stomach of patients suffering from chronic active gastritis and peptic ulcer disease--Helicobacter pylori--possesses marked alcohol dehydrogenase (ADH) activity. Consequently, Helicobacter infection may contribute to the capacity of the stomach to metabolize ethanol and lead to increased acetaldehyde production. To study this hypothesis, we first determined ADH activity in a variety of H. pylori strains originally isolated from human gastric mucosal biopsies. ADH activity was also measured in endoscopic gastric mucosal specimens obtained from H. pylori-positive and -negative patients. Furthermore, we used a mouse model of Helicobacter infection to determine whether infected animals exhibit more gastric ethanol metabolism than noninfected controls. Most of the 32 H. pylori strains studied possessed clear ADH activity and produced acetaldehyde. In humans, gastric ADH activity of corpus mucosa did not differ between H. pylori-positive and -negative subjects, whereas in antral biopsies ADH activity was significantly lower in infected patients. In mice, gastric ADH activity was similar or even lower in infected animals than in controls, depending on the duration of infection, despite the fact that the infectious agent used--Helicobacter felis--showed ADH activity in vitro. In accordance with this, Helicobacter infection tended to decrease rather than increase gastric ethanol metabolism in mice. In humans, it remains to be established whether the observed decrease in antral ADH activity associated with H. pylori infection can lead to reduced gastric first-pass metabolism of ethanol.

Background/aims: H+,K(+)-adenosine triphosphatase (H+,K(+)-ATPase) of parietal cells is an organ-specific enzyme recognized by autoantibodies found in human and murine autoimmune gastritis (AIG). Murine AIG can be induced in BALB/c mice by thymectomy 3 days after birth and is a T cell-mediated disease. This study examined the specificity of T cells that cause AIG and the role of H+,K(+)-ATPase in this disease., Methods: From an AIG mouse, a gastritogenic T-cell clone (II-6) was established, and its reactivity to synthetic peptides of H+,K(+)-ATPase was tested., Results: II-6 cells are CD4+, V beta 14+, and interferon gamma producers. Adoptive transfer of II-6 cells to syngeneic nude mice resulted in AIG without the production of autoantibodies to parietal cells. The II-6 cells were responsive not only to murine but also to human and porcine parietal cells. Their proliferation was also induced by amino acids 891-905 (alpha 891) and 892-906 (alpha 892) of the alpha subunit of porcine and human H+,K(+)-ATPase, respectively., Conclusions: The T-cell response to a single epitope of H+,K(+)-ATPase, the amino acid sequence of which is conserved among at least three mammals tested, is sufficient to cause AIG. Autoantibodies to parietal cells are not detected in these AIG mice.

Sex and age differences in gastric alcohol dehydrogenase activity in relation to abnormalities of gastric histology and Helicobacter pylori infection were determined in 63 patients (32 men and 31 women) undergoing upper endoscopy for gastrointestinal symptoms. No sex difference was found in gastric alcohol dehydrogenase activity. Males older than 50 years had lower enzyme activity than younger males. Patients with H. pylori and/or moderate to severe chronic and acute inflammation and epithelial mucin depletion had lower alcohol dehydrogenase activity in the antrum, but not in the fundus. H. pylori was found more frequently in the older male patients. Antral alcohol dehydrogenase was most decreased in older patients of both sexes with H. pylori infection. In conclusion, H. pylori infection and/or chronic active gastritis are important causes of low gastric alcohol dehydrogenase activity.

Objective: Our aim was to determine whether gastric mucosal ODC activity is altered after successful eradication of HP. Recent reports have suggested that Helicobacter pylori (HP) infection of the stomach is associated with the development of gastric cancer. Gastrointestinal cancers usually do not arise de novo; a series of mucosal changes leading to neoplastic transformation and degrees of dysplasia are believed to precede the development of cancer. These conditions are associated with increased cellular proliferation. Ornithine decarboxylase (ODC) activity is induced by factors that stimulate cellular proliferation, and has been shown to be elevated in gastrointestinal neoplasia, including gastric cancer., Methods: Gastric antral and body biopsies were obtained from 17 HP-positive patients at endoscopy, for ODC activity and histology (including Warthin Starry stain) before and 4-6 wk after successful triple therapy., Results: Patients included 12 males and five females, with a mean age of 55 yr (27-73 yr). Mean ODC activity (in pmol CO2/mg protein/h) was significantly decreased after eradication of HP, compared with pretreatment levels in antral (147 +/- 26 vs. 80 +/- 15) and body mucosa (76 +/- 21 vs. 20 +/- 5) (p < 0.05)., Conclusion: Successful eradication of HP decreases mucosal proliferative activity, as reflected by decreased ODC activity. We speculate that by decreasing mucosal proliferative activity, HP eradication may help decrease the subsequent risk of gastric cancer.

The synthetic peptides AC-Glu-Phe-Phe (NO2)-Arg-amide (peptide VP) and AC-Ile-Glu-Phe-Phe (NO2)-Arg-amide (peptide VIP) are more readily hydrolyzed by human pepsin in gastric juice of patients of gastritis than those of duodenal ulcer and normal subjects. The kinetic parameters suggest that S3 subsite of the enzyme plays a role in the elevation of enzyme activity in gastric disease.

The paper deals with a description of the biochemical properties of the isoforms of pepsinogen pepsin of gastric mucosa and blood serum in children suffering from duodenal ulcerative disease as well as in atrophic and subtrophic lesions of gastric mucosa. Atrophic gastritis was found to involve an inhibited biosynthesis of the Ist fraction of pepsinogen while ulcerative-erosive lesions of the gastro-duodenal area--an increased level of the 3rd isoform of pepsinogen.

Activity of Cu/Zn superoxide dismutase (SOD) and catalase (CAT) in gastric mucosa was examined in 12 control subjects and 48 patients with various degree of chronic gastritis. Bioptic specimens of mucosa for enzymologic assays were sampled during gastroscopic examination after overnight fasting. Compared to the control group, a significant increase of SOD activity was observed in samples from superficial gastritis and only insignificant changes in samples from atrophic gastritis, while a remarkable and significant increase in the activity of both SOD and CAT was observed in samples from gastritis after partial gastrectomy. Application of vitamin E significantly reduced activities of SOD and CAT in subjects with chronic gastritis. The authors suppose that the increase in the activities of antioxidant enzymes was caused by an increased formation of superoxide anion radical and hydrogen peroxide, both originating from phagocyting leucocytes in inflamed mucosa. The reduced activity of SOD and CAT after application of vitamin E indicates an inhibition of the formation of active oxygen species in gastric mucosa. Relation of chronic gastritis and elevated concentrations of active oxygen species to gastric carcinogenesis is discussed in the report. (Tab. 2, Fig. 1, Ref. 22.)

Gastroscopy with gastric biopsy was performed in 109 individuals aged 25-71 years. Activities of three antioxidant enzymes were assayed in biopsy specimens: Cu/Zn superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px). Patients were classified according to the endoscopic and histological findings in the following groups: normal findings (N), superficial gastritis (SG), mild (MAG) and severe (SAG) atrophic gastritis, gastritis after partial gastrectomy (PGG), hyperplastic polyp (HP), and gastric adenoma (A). Compared with the N group, increased activity of SOD was found in groups SG (+37%), PGG (+67%) and A (+35%), increased CAT activity in PGG (+40%), and increased GSH-Px activity in groups SG (+57%), SAG (+46%), PGG (+185%), HP (+50%) and A (+50%). Increased activity of antioxidant enzymes could be induced by higher concentrations of superoxide anion radicals, hydrogen peroxide and lipid peroxides, produced by phagocytic leucocytes or by polyunsaturated fatty acid in cellular membranes of gastric mucosa. The relation of reactive oxygen species to the induction of precancerous conditions and to carcinogenesis of the stomach requires further study.

A 63-year-old woman was diagnosed as autoimmune gastritis by the presence of serum antibody against alpha-subunit of gastric H+,K(+)-ATPase. The patient did not have pernicious anemia, but showed achlorhydria, marked hypergastrinemia, enterochromaffin-like cell hyperplasia and an extremely high histidine decarboxylase activity in the gastric fundic mucosa. Intragastric acidification by infusion of hydrochloric acid via a nasogastric tube induced a transient reduction of serum gastrin level and fundic mucosal histidine decarboxylase activity. A marked increase in fundic mucosal histidine decarboxylase activity as well as hypergastrinemia appears to be the pathophysiologic response to achlorhydria caused by autoimmunity against gastric H+,K(+)-ATPase.

In 68 subjects the activities of Cu/Zn-superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-Px) were investigated in gastric mucosa. The patients were classified according to the histological finding into following groups: 12 with normal finding (N), 16 with superficial gastritis (SG), 13 with mild atrophic gastritis (MAG), 19 with severe atrophic gastritis (SAG) and 8 with gastritis after partial gastrectomy (PGG). The comparison of groups SG, MAG, SAG and PGG with the group N revealed the following changes: in SG increased SOD and GSH-Px, in MAG and SAG no significant changes, and in PGG increase in SOD, CAT and GSH-Px were observed. It was supposed that increased enzymatic activities were caused by higher concentration of active oxygen species produced by phagocytizing leukocytes in inflamed gastric mucosa. Administration of vitamin E resulted in significant reduction of SOD and CAT activities, on the other hand GSH-Px activity significantly increased. The explanation of this effect of vitamin E requires further studies. A prolonged interaction of active oxygen species with chemical carcinogens (N-nitroso- or diazonium compounds, PAH) can exhibit a significant promoting effect on the development of intestinal type of gastric cancer from its precancerous conditions, above all after partial gastrectomy.

The presence of ammonium in gastric contents was described in 1852; urease activity in the stomach was identified 70 years later. The discovery of gastric urease resulted in intense research activity to discover its origin, function, and relation to the gastric levels of ammonium and urea. Interest in urease waned in the 1960s as most pertinent questions appeared to have been addressed and there was strong evidence that gastric urease was not a property of the stomach but was of microbial origin. Identification of Helicobacter pylori as the source of urease in the stomach in the last decade has resulted in a rebirth of interest in gastric urease and its products. There is little actual evidence to support a role for toxicity of ammonia in relation to H. pylori and the bulk of the evidence suggests that the products of urease activity are not toxic and may even be beneficial. The purpose of this review is to examine the older literature and to examine new findings in the perspective of what is already known and to suggest areas remaining to be examined. We ask, 'What is old, what is new, and what needs to be done?'

Autoimmune gastritis develops spontaneously in approximately 60% of BALB/c mice thymectomized neonatally. Histologically and clinically it is similar to the atrophic gastritis associated with pernicious anaemia in humans. Here we identified antigenic protein relating to the pathogenesis of autoimmune gastritis in these mice. All sera from 32 thymectomized mice with gastritis contained autoantibodies to the vesicular fraction prepared from rat gastric parietal cells. Immunoblot analysis revealed all of these to react with a 94-kD protein corresponding in molecular mass with the H+/K(+)-ATPase alpha subunit. Some sera were also reactive with 65-85-kD and/or 60-kD proteins, whose sizes correspond to the H+/K(+)-ATPase beta subunit and intrinsic factor, respectively. The finding that immuno-adsorption with these sera resulted in reduction of H+/K(+)-ATPase activity in the vesicular fraction, supported a conclusion of H+/K(+)-ATPase alpha and/or beta subunits as the antigenic proteins. After immunization of normal syngeneic mice with various doses of gastric parietal cells or their vesicular fraction, all sera from animals demonstrating atrophic gastric mucosa with lymphocyte infiltration reacted with the H+/K(+)-ATPase alpha subunit. No antibodies to other proteins were induced even in mice immunized with higher doses of antigen. We therefore conclude that H+/K(+)-ATPase alpha subunit is important as the target antigen in pathogenesis of autoimmune gastritis in neonatally thymectomized mice, probably due to a high affinity for the MHC molecule.

The aim of this study was to investigate the precise origin of the acid pre-duodenal lipase during human development and to evaluate its possible changes, at the tissue level, in children with gastritis or pancreatic insufficiency. Human gastric lipase appears around the 11th week of gestation and increases slowly during pre- and postnatal development. It is localized in the fundus of the stomach without any lingual localization. Human gastric lipase reaches its adult level in the third month of life, and does not vary in relation to pancreatic insufficiency. It is only rarely impaired during gastritis.

Concentrations of 5-, 12-, 15-HETE versus myeloperoxidase activity in the periulcerous area were investigated in 40 peptic ulcer patients. A control group consisted of 20 healthy subjects. In ulcer patients the activity of lipoxygenase pathway of metabolism of arachidonic acid and myeloperoxidase was enhanced. This is likely to promote chronic inflammation of the mucosa in the periulcerous area, this inflammation being an important prognostic factor for ulcerogenesis.

Autoantibodies in the sera of patients with pernicious anemia recognize, in addition to the alpha subunit of the gastric H+/(+)-ATPase, an abundant gastric microsomal glycoprotein of apparent Mr 60,000-90,000. Herein we have colocalized the glycoprotein and the alpha subunit of the gastric H+/K(+)-ATPase to the tubulovesicular membranes of the parietal cell by immunogold electron microscopy. Moreover, the glycoprotein and the alpha subunit were coimmunoprecipitated, and copurified by immunoaffinity chromatography, with an anti-glycoprotein monoclonal antibody. The pig glycoprotein was purified by chromatography on tomato lectin-Sepharose, and five tryptic peptides from the purified glycoprotein were partially sequenced. The complete amino acid sequence, deduced from the nucleotide sequence of overlapping cDNA clones, showed 33% similarity to the sequence of the beta subunit of the pig kidney Na+/K(+)-ATPase. We therefore propose that the 60- to 90-kDa glycoprotein autoantigen is the beta subunit of the gastric H+/K(+)-ATPase and that the alpha and beta subunits of the proton pump are major targets for autoimmunization in autoimmune gastritis.

Serum lysozyme was reevaluated in inflammatory bowel disease and other gastrointestinal disorders. A total of 109 patients were divided into six groups: ulcerative colitis (28), Crohn's disease (9), simple atrophic gastritis (16), atrophic gastritis and pernicious anemia (23), functional dyspepsia (17), and controls (16). Elevated levels of lysozyme, compared with control levels, were found not only in ulcerative colitis and Crohn's disease but also in atrophic gastritis with or without pernicious anemia and in functional dyspepsia. The elevation of lysozyme, since it results from the product of granulocytes and macrophages present in increased amounts in the mucosa of inflammatory bowel diseases, is easily explained. The cellular infiltration in atrophic gastritis may also explain the elevated lysozyme levels. The higher lysozyme levels in some patients with functional dyspepsia could possibly reflect an underlying latent inflammatory process.

Free glutamine content and phosphate-dependent glutaminase activity were studied in the biopsy specimens from the tissue of ulcer, polyps, carcinoma and the surrounding gastric mucosa of patients with precancerous diseases and carcinoma of the stomach. The glutamine content in carcinoma was not significantly different from that in the normal gastric mucosa. The glutamine level in the gastric mucosa remote from the tumour was considerably higher than normal. In case of polyposis of the stomach glutamine was present in the polyps and absent in the remote gastric mucosa. A marked glutaminase activity was revealed in the carcinoma of the stomach, but its level did not differ from the normal or in the case of precancerous diseases.

Using a method of electrophoretic separation on agar gel, the hexokinase (HK) isoenzymes were determined in biopsies from patients with gastric and esophageal cancer and nonmalignant diseases (gastric benign tumors and gastritis) as well as in biopsies from healthy people. In the malignant neoplasms studied, a significant elevation of HK-II and the appearance of additional anodal bands (HK-IIf and HK-III) have been demonstrated. As a rule, the HK isoenzyme spectrum in gastric polyps was similar to that of normal mucosa and characterized by a predominance of HK-I. Changes in the HK isoenzyme composition in gastric mucosa with intestinal metaplasia were expressed in lesser degree but had similar cancerous tendency. The HK isoenzyme analysis in biopsy samples may be used for differential diagnosis of malignant and benign tumors, and/or as definite diagnostic implication of an early sign of malignancy in the study of premalignant lesions.

The LDH isoenzyme pattern of the uninvolved mucosa of gastric cancer patients differs as regards the LDH isoenzyme pattern from that of similar tissue of patients with benign gastric disease; the former tissue is characterised by a high M/H ratio of the LDH isoenzymes (M and H sub-units). A high M/H ratio characterises antral mucosa when the latter is compared with fundic mucosa. Mucosa showing superficial and atrophic gastritis also has a higher M/H ratio, whereas the presence of intestinal metaplasia does not appear to influence the M/H ratio. These observations are consistent with the concept that the tissue from which the cancer arose may possess a pre-malignant biochemical lesion.

A metalloproteinase was extracted from a medium of cultured gastric tissues following acetic acid-induced ulcer or taurocholic acid-induced gastritis, and the enzyme was partially purified by Sephadex G-200 column chromatography. This proteinase was released in active and latent forms with apparent molecular weights of 170,000 and 210,000, respectively. Its activity was abolished by treatment with ethylenediaminetetraacetic acid or 1,10-phenanthroline, but not with phenylmethylsulfonyl fluoride or soybean trypsin inhibitor. This enzyme degraded type I gelatin and type IV collagen but did not attack type I collagen. In contrast, very little of this enzyme was released from gastric tissue following erosion caused by water-immersion stress or from normal gastric tissue. These results suggest that this metalloproteinase plays an important role in gastric lesions by breaking down the basement membrane.

Using an immunoperoxidase technique the distribution of secretory component, IgA, and lysozyme has been investigated in normal, inflamed, dysplastic, and carcinomatous gastric mucosa. Apart from pyloric glands which contain lysozyme, normal gastric mucosa stains negatively for all three antigens. In gastric mucosa neck cells appear to adapt by synthesising secretory component and lysozyme and transporting IgA. Intense staining for the three antigens is seen in dysplastic gastric epithelium and in well-differentiated intestinal type carcinomas. With progressive de-differentiation the tumours lose the ability to synthesise secretory component and lysozyme. Carcinomas of the diffuse type stain positively for secretory component and lysozyme and individual cells appear to take up IgA even in the absence of surrounding IgA containing plasma cells. These functional properties are retained in lymph node metastases. It is suggested that secretory component synthesising malignant cells might take up circulating dimeric IgA and that this could be a reflection of an important physiological mechanism.

Peptidases, phosphatases, glycosidases, non-specific esterases, succinate dehydrogenase, cholinesterases, and carbohydrate components were studied in bioptic material of the normal and diseased human stomach using well established older, modified older, and new qualitative histochemical methods. For the first time, an enzyme pattern is reported for all regions of the human mucosa. Local and regional enzyme histochemical differences existed between the cardiac, fundic, body, and pyloric mucosa. Differences were absent, however, in the same region, and no differences were found between the anterior and posterior wall and the large and small curvature of the stomach. In cases of histologically less severe gastritis as a rule, enzyme histochemical changes were not found. They were numerous, however, in biopsies of patients with severe gastritis; only amino-peptidases A and M were unchanged. Dipeptidyl peptidase IV was absent; gamma-glutamyl transpeptidase exhibited individual differences. Alkaline phosphatase occurred in the pericapillary stroma and adenosine phosphates were not hydrolysed in atrophic glandular epithelia. Activity increases of lysosomal dipeptidyl peptidase I and beta-D-glucuronidase were typical for inflammatory infiltration processes of the gastric mucosa. Severe atrophy was accompanied by an activity decrease of glandular non-specific esterases, dipeptidyl peptidase II, and beta-N-acetyl-D-glucosaminidase and an activity decrease of the stromal peptidases and glycosidases. Enzyme activity was absent in the gastric glands proper in cases of total atrophy. An increase in macrophage number was primarily linked with an increase in acid phosphatase activity. Alkaline phosphatase, aminopeptidase M and gamma-glutamyl transpeptidase activities were enhanced in malignant neoplasms. High activities of all peptidases and alkaline phosphatase were found in the brush border of surface epithelial cells in cases of intestinal metaplasia. Except for dipeptidyl peptidase I and II, the enzyme pattern corresponds to that of small intestinal enterocytes. Compared with histological routine procedures for gastric diagnosis and assessment of the course enzyme histochemical methods deliver additional information; practically, however, the enzyme histochemical analysis of gastric biopsies are only useful in special cases.

By using an original method of electrophoresis separation, the normal relative values of each one of the LDH isoenzymes in the gastric body and antral mucosa were determined. It has been shown in gastric tumors that there is a significance rise in the relative values of "type M" isoenzymes (iso-LDH-4-5). With intestinal metaplasia as well as gastritis, a significant elevation of the relative value of iso-LDH-5 has been demonstrated in the antral mucosa. In 6 benign gastric polyps we found a similar disturbance. This would confirm the known precancerous condition of these lesions. In the normal mucosa of subtotal gastrectomy specimens, 19 patients with antral cancer had 2 types of LDH isoenzyme patterns: one normal and the other with an increase in the relative proportion of "type M" isoenzymes. These LDH isoenzyme pattern shifts in the gastric mucosa could be an early sign of malignancy prior to the morphologic changes.

The activity of the DNA excision repair enzyme uracil-DNA glycosylase was measured in peripheral blood mononuclear cells and in bone marrow aspiration samples obtained from patients with pernicious anemia (PA) or other types of megaloblastic anemia (one case of tapeworm anemia and three cases of myelodysplastic syndromes). In addition, the expression of uracil-DNA glycosylase was investigated in biopsies from the antrum and body of the stomach obtained from nine PA patients, from five patients having atrophic gastritis (AG) not associated with PA, and from six control patients having transient upper abdominal complaints without AG. Our results revealed that there was a considerable interindividual variation in gastric uracil-DNA glycosylase activity. No clear correlation between the enzyme level and the level of gastric atrophy was noted, although AG is generally regarded as a risk factor of gastric cancer. Furthermore, uracil-DNA glycosylase activities in peripheral blood mononuclear cells and in bone marrow cells in PA and in myelodysplastic syndromes were similar to the activities observed previously in non-hematological patients and healthy persons. Transient uracil incorporation into DNA may have a role in the cellular abnormalities associated with megaloblastic hematopoiesis. The present findings demonstrated that the enzymatic activity required for rapid removal of uracil from DNA is also expressed in the megaloblastic state.