Infection with the bacterium Helicobacter pylori is associated epidemiologically with development of gastric cancer. To better understand the role of H. pylori in carcinogenesis, we examined the effects of H. pylori on cell cycle-related events in the AGS gastric cancer cell line. During coculture, wild-type, toxigenic, cagA-positive H. pylori induced both apoptosis and inhibition of cell cycle progression at G1-S in AGS cells. These effects were most apparent in AGS cells synchronized by serum-deprivation and then stimulated to progress through the cell cycle by refeeding. An isogenic cagA-negative mutant H. pylori, produced similar effects. In contrast to changes induced by 5-fluorouracil, the inhibition of cell cycle progression from G1 to S caused by H. pylori was not accompanied by sustained changes in p53 or p21cip1, but was associated with reduced expression of p27kip1 and inhibition of transcriptional activation of the serum-response element of c-fos. Our results indicate that H. pylori inhibits cell cycle progression at G1-S and induces apoptosis, associated with reduced expression of p27kip1 in AGS gastric cancer cells. In vivo, similar effects as a result of H. pylori infection may lead to potentially deleterious compensatory hyperproliferation by nonneoplastic gastric epithelial cells.
Rates of antimicrobial-resistance among H. pylori strains are increasing worldwide, resulting in declining eradication rates with current therapies, especially those containing clarithromycin or levofloxacin. To improve H. pylori management, a paradigm shift is needed, from the empiric approaches formerly employed, to regimen selection based upon knowledge of local and patient-level antimicrobial susceptibility data. We review the mechanisms of H. pylori antimicrobial resistance and the available worldwide pattern of resistance to key antimicrobials used in H. pylori therapy. The practicalities and challenges of measuring susceptibility in clinical practice is discussed, including not only conventional culture-based techniques but also novel sequencing-based methods performed on gastric tissue and stool samples. Though clinical trials of "tailored" (susceptibility-based) treatments have yet to show the clear superiority of tailored over empiric regimen selection, the ability to measure and modify treatment based upon antimicrobial susceptibility testing is likely to become more frequent in clinical practice and should lead to improved H. pylori management in the near future.
It has been well-established that inappropriate and excessive laboratory testing presents a credible threat to patient safety and imposes unnecessary added costs to the healthcare system. This case report details our experience at the Providence VA Medical Center with a seemingly benign test with significant potential for misuse—the serology-based antibody screen for H. pylori infection. Although GI professional society guidelines--as early as 1998--have advocated use of urea breath testing or stool antigen testing as the standard of care for diagnosing active H. pylori infection, the antibody test remains in widespread use despite poor performance characteristics in lower prevalence populations, such as in much of the United States. In the past few years, in an attempt to minimize morbidity associated with treating false-positive patients, the antibody test has been discontinued from testing 'menus' of the major diagnostic labs and is increasingly no longer reimbursed by insurers. In light of this and since our facility still continued to offer the antibody test, a quality improvement initiative was undertaken to characterize our current H. pylori testing practices and use that data to effect change--ideally in eliminating the test from our roster. In our study of 551 patients who presented for H. pylori testing over a 5 year period, we found that nearly 70% were initially diagnosed with the incorrect (antibody) test, and of those seropositive patients ultimately treated with antibiotics, approximately 80% were essentially mismanaged in that they received no other confirmatory testing before therapy was initiated. We furthermore noted that inappropriate ordering of antibody testing was concentrated in the primary care setting, likely by providers not familiar with current guidelines or the unfavorable performance characteristics of the antibody test in our low-prevalence, Veteran population. Sharing these data with our Laboratory Utilization Committee directly led to discontinuation of the antibody test at our facility.
Helicobacter pylori increases gastrin release in duodenal ulcer patients. This may be through disruption or changes in the mucus layer affecting the access of luminal stimulants to gastrin releasing cells. The effect of suppressing H pylori on gastrin release stimulated by a non-luminal stimulus, gastrin releasing peptide (GRP), was examined. Eleven patients with active duodenal ulcer disease and colonised with H pylori received an intravenous infusion of GRP (2.9 pmol/kg/minute for 30 minutes) and the plasma gastrin response was measured. Basal and peak pentagastrin stimulated acid output were also determined. Patients were treated with tripotassium dicitratobismuthate (De-Nol) and metronidazole to suppress H pylori and the tests were repeated. Suppression of H pylori decreased plasma gastrin concentrations during GRP infusion, but acid output was not affected. Chromatographic analysis of the forms of gastrin in plasma showed a significant fall in gastrin 17, the predominant form found in the gastric antrum. Gastrin 34 did not fall significantly. This study shows that suppression of H pylori decreases the hypergastrinaemia caused by the nonluminal stimulant, GRP, mainly via decreasing gastrin 17.
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