D. Y. Graham

Treatment of helicobacter pylori reduces the rate of rebleeding in peptic ulcer disease

BACKGROUNDnWe evaluated whether therapy designed to eradicate Helicobacter pylori infection resulted in a reduction in rebleeding in patients with peptic ulcer disease. Patients presenting because of major upper gastrointestinal hemorrhage from peptic ulcer and whose ulcers healed in a study in which they were randomized to receive ranitidine alone or triple therapy plus ranitidine were followed up regularly with endoscopy. No maintenance anti-ulcer therapy was given after ulcer healing.nnnMETHODSnPatients received ranitidine, 300 mg, or ranitidine plus triple therapy. Triple therapy consisted of tetracycline, 2 g; metronidazole, 750 mg; and bismuth subsalicylate, 5 or 8 tablets (151 mg bismuth per tablet), and was administered for the first 2 weeks of treatment; ranitidine therapy was continued until the ulcer had healed or 16 weeks had elapsed. After ulcer healing, no maintenance antiulcer therapy was given. Development of ulcer recurrence with or without recurrent upper gastrointestinal bleeding was evaluated.nnnRESULTSnThirty-one patients with major upper gastrointestinal bleeding from peptic ulcer were studied; 17 received triple therapy and 14 ranitidine alone. Major rebleeding occurred significantly (p = 0.031) more often in those in the ranitidine group (28.6%), compared with none (0%) in the triple therapy group.nnnCONCLUSIONnEradication of H. pylori infection reduces the rate of ulcer recurrence and rebleeding in complicated ulcer disease.

Mycobacterium avium subsp. paratuberculosis as one cause of Crohn’s disease

A number of theories regarding the aetiology of Crohn’s disease have been proposed. Diet, infections, other unidentified environmental factors and immune disregulation, all working under the influence of a genetic predisposition, have been viewed with suspicion. Many now believe that Crohn’s disease is a syndrome caused by several aetiologies. The two leading theories are the infectious and autoimmune theories. The leading infectious candidate is Mycobacterium avium subspecies paratuberculosis (Mycobacterium paratuberculosis), the causative agent of Johne’s disease, an inflammatory bowel disease in a variety of mammals including cattle, sheep, deer, bison, monkeys and chimpanzees. The evidence to support M. paratuberculosis infection as a cause of Crohn’s disease is mounting rapidly. Technical advances have allowed the identification and/or isolation of M. paratuberculosis from a significantly higher proportion of Crohn’s disease tissues than from controls. These methodologies include: (i) improved culture techniques; (ii) development of M. paratuberculosis‐specific polymerase chain reaction assays; (iii) development of a novel in situ hybridization method; (iv) efficacy of macrolide and anti‐mycobacterial drug therapies; and (v) discovery of Crohn’s disease‐specific seroreactivity against two specific M. paratuberculosis recombinant antigens. The causal role for M. paratuberculosis in Crohn’s disease and correlation of infection with specific stratification(s) of the disorder need to be investigated. The data implicating Crohn’s as an autoimmune disorder may be viewed in a manner that supports the mycobacterial theory. The mycobacterial theory and the autoimmune theory are complementary; the first deals with the aetiology of the disorder, the second deals with its pathogenesis. Combined therapies directed against a mycobacterial aetiology and inflammation may be the optimal treatment of the disease.

Challenge model for Helicobacter pylori infection in human volunteers

Background: A reliable challenge model is needed to evaluate Helicobacter pylori vaccine candidates. Methods: A cag pathogenicity island negative, OipA positive, multiple antibiotic susceptible strain of H pylori obtained from an individual with mild gastritis (Baylor strain 100) was used to challenge volunteers. Volunteers received 40 mg of famotidine at bedtime and 104–1010 cfu of H pylori in beef broth the next morning. Infection was confirmed by 13C urea breath test (13C-UBT), culture, and histology. Eradication therapy was given four or 12 weeks post challenge and eradication was confirmed by at least two separate UBTs, as well as culture and histology. Results: Twenty subjects (nine women and 11 men; aged 23–33 years) received a H pylori challenge. Eighteen (90%) became infected. Mild to moderate dyspeptic symptoms occurred, peaked between days 9 and 12, and resolved. Vomitus from one subject contained >103 viable/ml H pylori. By two weeks post challenge gastric histology showed typical chronic H pylori gastritis with intense acute and chronic inflammation. The density of H pylori (as assessed by cfu/biopsy) was similarly independent of the challenge dose. A minimal infectious dose was not found. Gastric mucosal interleukin 8 levels increased more than 20-fold by two weeks after the challenge. Conclusion: Challenge reliably resulted in H pylori infection. Infection was associated with typical H pylori gastritis with intense polymorphonuclear cell infiltration and interleukin 8 induction in gastric mucosa, despite absence of the cag pathogenicity island. Experimental H pylori infection is one of the viable approaches to evaluate vaccine candidates.

Transmission of Helicobacter pylori Infection Studies in Families of Healthy Individuals

Helicobacter pylori is accepted as the commonest cause of type-B gastritis. Detailed information about the mode of transmission remains scanty. We investigated the frequency of H. pylori infection within families, defined as consisting of a husband and wife with at least one biologic child, all living in the same household. Inclusion criteria required that both the parents and the children had been born in the United States, had used no antibiotic or bismuth for the previous 2 months, had no recent major illness or surgical operation, and had no symptoms referable to the upper gastrointestinal tract. H. pylori infection was identified with a 13C-urea breath test and an enzyme-linked immunosorbent assay for anti-H. pylori IgG. Forty-one families (151 healthy individuals) were enrolled. Before the results of the H. pylori tests were known, one parent was selected as the index subject. H. pylori infection clustered; that is, 68% of spouses of H. pylori-infected index subjects were also H. pylori-infected, compared with 9% of spouses of H. pylori-negative index subjects (p less than 0.0001). The children of infected index parents were also more likely to be infected than children of uninfected index parents--40% versus 3%, respectively (p less than 0.0001)--and the results in the children were independent of whether the father or the mother was the index subject. Clustering of H. pylori infection within families suggests person-to-person transmission or common source exposure. The high frequency of H. pylori infection in spouses suggests that genetic factors are less important than living conditions for transmission of H. pylori infection.

Gastritis OLGA-staging and gastric cancer risk: a twelve-year clinico-pathological follow-up study

Aliment Pharmacol Theru200231, 1104–1111

Cure of Helicobacter pylori Infection Improves Gastric Acid Secretion in Patients with Corpus Gastritis

BACKGROUNDnFor more than 30 years it has been known that gastric acid secretion is inversely related to the extent and severity of corpal gastritis. We therefore evaluated the effect of cure of Helicobacter pylori infection on basal and pentagastrin-stimulated acid secretion.nnnMETHODSnBasal acid output (BAO) and maximal acid output (MAO) were assessed in 11 H. pylori-infected dyspeptic patients (8 women and 3 men; mean age, 28 years) before and after successful anti-H. pylori therapy.nnnRESULTSnThe gastritis index was significantly lower after therapy and was associated with an increase in both BAO and MAO after cure of the H. pylori infection (BAO from 0.3 mmol/h and MAO from 4.8 mmol/h to 19 mmol/ h). Basal and stimulated acid concentrations also increased (29.1 +/- 36.6 to 54 +/- 31 mmol/l and 72.5 +/- 46 to 120.1 +/- 30 mmol/l, respectively, for basal and stimulated acid concentrations; P < 0.05 for peak and MAO, P = 0.07 for BAO).nnnCONCLUSIONnGastric acid secretion increased into the normal range after successful treatment of H. pylori infection, suggesting that gastric function can recover to normal or almost normal after cure of H. pylori infection.

Review article: prevention of non-steroidal anti-inflammatory drug gastrointestinal complications--review and recommendations based on risk assessment.

The incidence of non‐steroidal anti‐inflammatory drug‐related ulcer complications remains high despite the availability of potent anti‐ulcer drugs and selective cyclo‐oxygenase‐2 inhibitors. Non‐steroidal anti‐inflammatory drug‐related ulcer complications can be minimized by prospective assessment of patients’ baseline risk, rational choice and use of non‐steroidal anti‐inflammatory drugs, and selective use of co‐therapy strategies with gastroprotectives. Current recommendations regarding strategies using anti‐ulcer drugs and cyclo‐oxygenase‐2 inhibitors for prevention of clinical non‐steroidal anti‐inflammatory drug upper gastrointestinal events are largely derived from studies using surrogates such as endoscopic ulcers, erosions, and symptoms in low‐ to average‐risk patients. Conclusions based on surrogate and potentially manipulatable end‐points are increasingly suspect with regard to applicability to clinical situations. This article reviews the risks associated with non‐steroidal anti‐inflammatory drugs including aspirin and includes the effect of the patients’ baseline risk, and the confounding effects of Helicobacter pylori infection. In addition, uncertainties regarding the clinical efficacy of anti‐ulcer drugs and cyclo‐oxygenase‐2 inhibitors against non‐steroidal anti‐inflammatory drug‐related ulcer complications are put into perspective. We propose management strategies based on the risk category: low risk (absence of risk factors) (least ulcerogenic non‐steroidal anti‐inflammatory drug at lowest effective dose), moderate risk (one to two risk factors) (as above, plus an antisecretory agent or misoprostol or a cyclo‐oxygenase‐2 inhibitor), high risk (multiple risk factors or patients using concomitant low‐dose aspirin, steroids, or anticoagulants) (cyclo‐oxygenase‐2 inhibitor alone with steroids, plus misoprostol with warfarin, or plus a proton pump inhibitors or misoprostol with aspirin), and very high risk (history of ulcer complications) (avoid all non‐steroidal anti‐inflammatory drugs, if possible or a cyclo‐oxygenase‐2 plus a proton pump inhibitors and/or misoprostol). The presence of H. pylori infection increases the risk of upper gastrointestinal complications in non‐steroidal anti‐inflammatory drug users by two‐ to fourfold suggesting that all patients requiring regular non‐steroidal anti‐inflammatory drug therapy be tested for H. pylori.

Screening of gene expression profiles in gastric epithelial cells induced by Helicobacter pylori using microarray analysis

H. pylori infection is a major risk factor in gastric cancer development. The availability of cDNA microarrays creates the unprecedented opportunity to examine simultaneously dynamic changes of multiple pathways affected by H. pylori infection.

Specific seroreactivity of Crohn’s disease patients against p35 and p36 antigens of M. avium subsp. paratuberculosis

Crohns disease (CD) is a chronic inflammatory bowel disease that is similar to Johnes disease in ruminants. Recent data have strengthened the association of M. avium subsp. paratuberculosis (M. paratuberculosis) with CD. To provide more evidence of an etiological association, antibody reactivities from CD patients were tested by immunoblotting against recombinant antigens that were identified previously from our M. paratuberculosis genomic library. Two clones (designated pMptb#40 (3.2-kb insert) and #48 (1.4-kb insert) expressing a 35K (p35)- and 36K(p36)-antigens showed specific reactivities with serum samples from CD patients. Serum samples from 75% of 53 CD patients, 14% of 35 normal individuals and 10% of 10 ulcerative colitis patients reacted to p35 antigen. Reactivities were also observed with serum samples from 89% of 89 CD patients, 14% of 50 normal controls and 15% of 29 ulcerative colitis patients reacted with p36 antigen. When the reactivity results from p35 and p36 were combined, the background from the controls was eliminated, i.e. only the CD patients reacted to both p35 and p36. The positive predictive value was 98% with specificity of 98% and the negative predictive value was 76% with sensitivity of 74% (39 positive out of 53). A statistical significance (p<0.0001) was observed when the results from CD serum samples reacting with either or both antigens were compared to the controls. The reactivity of anti-M. paratuberculosis (specifically against p35 and p36 antigens) antibodies in a significant proportion of CD patients would suggest a causal role for the organism in CD.

Serum CagA antibodies in asymptomatic subjects and patients with peptic ulcer: lack of correlation of IgG antibody in patients with peptic ulcer or asymptomatic Helicobacter pylori gastritis.

AIM/BACKGROUND: Several studies have suggested that Helicobacter pylori which express CagA may be more virulent than those that do not, but limited populations have been studied to date. The aim of this study was to confirm and extend the association of CagA positive H pylori strains in a different geographical area and to a large, well defined patient population. METHOD: A validated ELISA for serum IgG to CagA was used to investigate the prevalence of CagA seropositivity in 100 patients with peptic ulcer compared with 77 with H pylori infection without ulcer disease in a North American population. The extent of antral and corpus inflammation and H pylori density in relation to CagA seropositivity in 40 subjects with H pylori infection were assessed semiquanitatively. All studies were carried out in a coded and blinded manner. RESULTS: The prevalence of serum IgG CagA antibodies was higher in H pylori infected patients with ulcer (59%) compared with healthy H pylori infected volunteers (44%), but the difference was not significant. In contrast, the titre of serum IgG anti-CagA antibodies was higher among the seropositive subjects without ulcer disease, but again the difference was not significant. Comparison of histological features between asymptomatic individuals with H pylori infection in relation to CagA IgG antibody status revealed no differences in infiltration with acute inflammatory cells, H pylori density, or gastritis index. There was no relation evident between the degree of polymorphonuclear cell infiltration and the serum IgG antibody titre to CagA. Mononuclear cell infiltration in the antrum, but not the corpus, was greater in those with CagA IgG compared with those without (median score 5 v 3). CONCLUSIONS: A right association between the presence or titre of serum IgG to CagA and peptic ulcer disease, greater H pylori density or infiltration of the mucosa with acute inflammatory cells could not confirmed in a North American population. Perhaps geographical differences in the prevalence of circulating H pylori strains are responsible for the discrepant results reported.