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Helicobacter pylori genotypes, host factors, and gastric mucosal histopathology in peptic ulcer disease.
Tham KT, Peek RM, Atherton JC, Cover TL, Perez-Perez GI, Shyr Y, Blaser MJ
(2001) Hum Pathol 32: 264-73
MeSH Terms: African Continental Ancestry Group, Aged, Anti-Inflammatory Agents, Non-Steroidal, Antibodies, Bacterial, Biopsy, Duodenal Ulcer, Epithelium, Ethnic Groups, European Continental Ancestry Group, Gastric Mucosa, Genotype, Helicobacter Infections, Helicobacter pylori, Humans, Middle Aged, Multivariate Analysis, Peptic Ulcer, Pyloric Antrum, Smoking, Stomach, Stomach Ulcer
Show Abstract · Added March 5, 2014
From 183 patients undergoing upper gastrointestinal endoscopy, we used antral and corpus gastric biopsies for bacterial culture and histopathologic examination, blood samples to detect immunoglobulin G antibodies against Helicobacter pylori, and H pylori genomic DNA to analyze cytotoxin-associated gene A (cagA) and vacuolating cytotoxin (vacA) genotypes. As expected, among H pylori biopsy-positive patients, those with duodenal ulcer (DU) (n = 34) had significantly more severe chronic and acute inflammation (P <.001) and epithelial degeneration (P =.004) in the gastric antrum than in the gastric corpus. Each of those 3 parameters and H pylori density were significantly higher in the antrum of patients with DU than in patients with gastric ulcer (GU) or no ulcer. Colonization with vacA s1/cagA-positive strains of H pylori was associated with inflammation and epithelial degeneration in gastric mucosa and increased risk for peptic ulcer disease (PUD), whereas colonization with vacA s2m2/cagA-negative strains was associated with mild gastric histopathology and was not associated with any significant risk for PUD. The predominant H pylori strains in African Americans were vacA s1bm1/cagA-positive, whereas all genotypes were well represented in non-Hispanic-Caucasians. By multivariate analysis, H pylori colonization was significantly associated with DU (Adjusted odds ratio [AdjOR] = 3.2 [1.4-7.2]) and nonsteroidal anti-inflammatory drugs (NSAID) use was inversely associated (AdjOR = 0.3 [0.2-0.7]). NSAID use (AdjOR = 4.3 [1.02-18.5]) and African-American ethnicity (AdjOR = 10.9 [2.6-50]) were significantly associated with GU. Smoking and age were not significantly associated with either DU or GU. These data indicate that DU is associated with an antral-dominant gastritis, and H pylori genotype and NSAID use independently contribute to the pathogenesis of PUD. HUM PATHOL 32:264-273. This is a US Government work. There are no restrictions on its use.
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21 MeSH Terms
The role of CagA status in gastric and extragastric complications of Helicobacter pylori.
Perez-Perez GI, Peek RM, Legath AJ, Heine PR, Graff LB
(1999) J Physiol Pharmacol 50: 833-45
MeSH Terms: Animals, Antigens, Bacterial, Bacterial Proteins, Helicobacter Infections, Helicobacter pylori, Humans, Peptic Ulcer, Stomach Neoplasms
Show Abstract · Added March 5, 2014
Two major markers of virulence have been described in H. pylori. The first is a secreted protein (VacA) that is toxic to human cells in tissue culture. This cytotoxin causes vacuolation of epithelial cells in vitro and induces epithelial cell damage in mice. The second is a 40-Kb pathogenicity island for which the gene cagA (cytotoxin-associated gene A) is a marker. Approximately 60% of H. pylori isolates in Western countries are cagA+. The protein encoded by cagA+ has a molecular weight of 120-140 kDa and exhibits sequence heterogeneity among strains isolated from Western and Eastern countries. Although no specific function has been identified for CagA, there is increasing evidence that cagA+ strains are associated with increased intensity of gastric inflammation and increased mucosal concentration of particular cytokines including interleukin 8. Inactivation of picB (Hp 0544) or any of several other genes in the cag island ablates the enhanced IL-8 secretion of human gastric epithelial cells in tissue culture. Furthermore, persons colonized with cagA+ strains have an increased risk of developing more severe gastric diseases such as peptic ulcer and distal (non-cardia) gastric cancer than those harboring cagA- strains. We investigated the role of cagA status in both gastroduodenal and extragastroduodenal disease with H. pylori. Among the diseases limited to the antrum and body of the stomach and the duodenum, we demonstrated a correlation between CagA seropositivity and peptic ulcer disease. We also showed correlation between distal gastric cancer rated and CagA prevalence in populations in both developed and developing countries. In addition, we found that for several Asian populations, the relationship between CagA seropositivity and gastroduodenal diseases was complex. For extragastroduodenal diseases, our results confirmed previous reports that demonstrated that CagA status did not play a role in diseases such as rheumatoid arthritis and hyperemesis gravidarum. However, we found a clear negative association between the presence of a positive response to CagA and esophageal diseases. Therefore, CagA seropositivity (and thus gastric carriage) is associated with increased risks of certain diseases (involving the lower stomach and duodenum) and decreased risks of GERD and its sequelae. This apparent paradox can best be explained by differences in the interaction of cagA+ and cagA- strains with their hosts.
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8 MeSH Terms
Helicobacter pylori vacuolating cytotoxin (VacA) disorganizes the cytoskeletal architecture of gastric epithelial cells.
Pai R, Cover TL, Tarnawski AS
(1999) Biochem Biophys Res Commun 262: 245-50
MeSH Terms: Actin Cytoskeleton, Actins, Animals, Bacterial Proteins, Cell Adhesion, Cell Adhesion Molecules, Cell Line, Cell Membrane, Centrosome, Cytoskeleton, Focal Adhesion Kinase 1, Focal Adhesion Protein-Tyrosine Kinases, Gastric Mucosa, Helicobacter pylori, Intermediate Filaments, Microtubules, Peptic Ulcer, Phosphorylation, Phosphotyrosine, Protein-Tyrosine Kinases, Rats, Tubulin
Show Abstract · Added March 5, 2014
Helicobacter pylori colonization of the gastric mucosa induces peptic ulcer disease and interferes with ulcer healing. Re-epithelialization is an essential component of ulcer healing. It requires cell migration and proliferation which are dependent on the cell cytoskeleton. Most H. pylori strains produce a toxin (VacA) that induces multiple structural and functional changes in epithelial cells. In this study, we investigated the effects of VacA on the gastric epithelial cell cytoskeletal architecture. Exposure of rat gastric epithelial cells to purified VacA from H. pylori 60190 significantly inhibited actin stress fiber formation (83 +/- 5% reduction; p < 0.0001) and disorganized microtubule pattern (90 +/- 8%; p < 0.001). Furthermore, VacA treatment significantly reduced tyrosine phosphorylation of focal adhesion kinase (FAK) (by 45 +/- 6%; p < 0.002) and its expression in focal adhesions (73 +/- 8%; p < 0.0001). These findings suggest that H. pylori VacA interferes with cytoskeleton-dependent cell functions and with the transmission of signals related to cell spreading and growth.
Copyright 1999 Academic Press.
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22 MeSH Terms
Decreased prevalence of Helicobacter pylori infection in gastroesophageal reflux disease.
Varanasi RV, Fantry GT, Wilson KT
(1998) Helicobacter 3: 188-94
MeSH Terms: Adult, Aged, Aged, 80 and over, Female, Gastroesophageal Reflux, Helicobacter Infections, Helicobacter pylori, Humans, Male, Middle Aged, Peptic Ulcer, Prevalence
Show Abstract · Added March 5, 2014
BACKGROUND - An increased incidence of reflux esophagitis has been reported after eradication of H. pylori in patients with duodenal ulcer. To determine if H. pylori is associated with lower rates of esophagitis, we studied the prevalence of H. pylori infection in patients with and without reflux esophagitis and a subgroup of patients with concomitant peptic ulcer disease.
METHODS - Patients who underwent esophagogastroduodenoscopy and had diagnostic testing for H. pylori over a 30-month period were studied. H. pylori infection was determined by rapid urease testing, gastric histopathology, or serology. Reflux esophagitis was determined by endoscopic and/or histologic criteria.
RESULTS - Of 514 patients, 39.5% had H. pylori infection and 22.2% had reflux esophagitis. The prevalence of H. pylori infection in patients with reflux esophagitis was 30.7%, compared with 42.0% in patients without esophagitis (p = 0.039). The odds ratio for esophagitis risk with H. pylori infection was 0.61 (95% CI, 0.39-0.95). Neither patient age nor gender affected H. pylori prevalence. In patients with duodenal ulcer, H. pylori was present in 36.4% of patients with esophagitis and in 69.2% of patients without esophagitis (p = 0.018). The odds ratio for esophagitis with H. pylori infection in these patients was 0.25 (95% CI, 0.09-0.73).
CONCLUSIONS - Our study demonstrates that H. pylori infection is significantly less prevalent in patients with reflux esophagitis and may protect against its development. In duodenal ulcer patients, this effect was more dramatic. Further study is required to confirm these findings and elucidate mechanisms underlying possible beneficial effects of H. pylori.
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12 MeSH Terms
No association between calcium channel blocker use and confirmed bleeding peptic ulcer disease.
Smalley WE, Ray WA, Daugherty JR, Griffin MR
(1998) Am J Epidemiol 148: 350-4
MeSH Terms: Adrenergic beta-Antagonists, Aged, Aged, 80 and over, Calcium Channel Blockers, Cohort Studies, Female, Hospitalization, Humans, Male, Medicaid, Peptic Ulcer, Tennessee, United States
Show Abstract · Added March 5, 2014
Calcium channel antagonists are commonly used drugs that have recently been reported to be associated with an increased incidence of gastrointestinal hemorrhage. We performed a retrospective cohort study among 105,824 enrollees of the Tennessee Medicaid program 65 years of age or older between 1984 and 1986. Exposure to calcium channel blockers and other medications was determined from pharmacy files. Hospitalization for bleeding peptic ulcers was identified by hospital claims and verified by a review of the medical record. Univariate estimates of relative risk for current users of calcium channel blockers and beta-blocker users were 1.8 (95% confidence interval (CI) 1.2-2.7) and 1.1 (95% CI 0.7-1.6) (reference group was nonuse of either). After adjustment for potential confounders, the relative risks for bleeding peptic ulcer among current users of calcium channel blockers and beta blockers were 1.1 (95% CI 0.7-1.7) and 1.0 (95% CI 0.7-1.6), respectively, when compared with those who used neither drug. In this population, after controlling for important confounders, there was no increased risk for hospitalization with bleeding peptic ulcer among users of calcium channel blockers.
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13 MeSH Terms
The m2 form of the Helicobacter pylori cytotoxin has cell type-specific vacuolating activity.
Pagliaccia C, de Bernard M, Lupetti P, Ji X, Burroni D, Cover TL, Papini E, Rappuoli R, Telford JL, Reyrat JM
(1998) Proc Natl Acad Sci U S A 95: 10212-7
MeSH Terms: Alleles, Bacterial Proteins, Bacterial Toxins, Base Sequence, Cytotoxins, DNA Primers, DNA, Bacterial, Genes, Bacterial, HeLa Cells, Helicobacter pylori, Humans, Peptic Ulcer, Polymerase Chain Reaction, Stomach Neoplasms, Transfection, Vacuoles, Virulence
Show Abstract · Added March 5, 2014
The Helicobacter pylori toxin VacA causes vacuolar degeneration in mammalian cell lines in vitro and plays a key role in peptic ulcer disease. Two alleles, m1 and m2, of the mid-region of the vacA gene have been described, and the m2 cytotoxin always has been described as inactive in the in vitro HeLa cell assay. However, the m2 allele is associated with peptic ulcer and is prevalent in populations in which peptic ulcer and gastric cancer have high incidence. In this paper, we show that, despite the absence of toxicity on HeLa cells, the m2 cytotoxin is able to induce vacuolization in primary gastric cells and in other cell lines such as RK-13. The absence of Hela cell activity is due to an inability to interact with the cell surface, suggesting a receptor-mediated interaction. This result is consistent with the observation that the m2 allele is found in a population that has a high prevalence of peptic ulcer disease and gastric cancer. VacA is the first bacterial toxin described for which the same active subunit can be delivered by different receptor binding domains.
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17 MeSH Terms
Helicobacter pylori upregulates expression of epidermal growth factor-related peptides, but inhibits their proliferative effect in MKN 28 gastric mucosal cells.
Romano M, Ricci V, Di Popolo A, Sommi P, Del Vecchio Blanco C, Bruni CB, Ventura U, Cover TL, Blaser MJ, Coffey RJ, Zarrilli R
(1998) J Clin Invest 101: 1604-13
MeSH Terms: Adenocarcinoma, Amphiregulin, Cell Division, Cell Line, EGF Family of Proteins, Epidermal Growth Factor, ErbB Receptors, Gastric Mucosa, Gastritis, Glycoproteins, Growth Substances, Helicobacter Infections, Helicobacter pylori, Heparin, Heparin-binding EGF-like Growth Factor, Humans, Intercellular Signaling Peptides and Proteins, Peptic Ulcer, RNA, Messenger, Recombinant Proteins, Stomach Neoplasms, Transforming Growth Factor alpha, Up-Regulation, Virulence
Show Abstract · Added March 5, 2014
Acute exposure to Helicobacter pylori causes cell damage and impairs the processes of cell migration and proliferation in cultured gastric mucosal cells in vitro. EGF-related growth factors play a major role in protecting gastric mucosa against injury, and are involved in the process of gastric mucosal healing. We therefore studied the acute effect of H. pylori on expression of EGF-related growth factors and the proliferative response to these factors in gastric mucosal cells (MKN 28) derived from gastric adenocarcinoma. Exposure of MKN 28 cells to H. pylori suspensions or broth culture filtrates upregulated mRNA expression of amphiregulin (AR) and heparin-binding EGF-like growth factor (HB-EGF), but not TGFalpha. This effect was specifically related to H. pylori since it was not observed with E. coli, and was independent of VacA, CagA, PicA, PicB, or ammonia. Moreover, H. pylori broth culture filtrates stimulated extracellular release of AR and HB-EGF protein by MKN 28 cells. AR and HB-EGF dose-dependently and significantly stimulated proliferation of MKN 28 cells in the absence of H. pylori filtrate, but had no effect in the presence of H. pylori broth culture filtrates. Inhibition of AR- or HB-EGF- induced stimulation of cell growth was not mediated by downregulation of the EGF receptor since EGF receptor protein levels, EGF binding affinity, number of specific binding sites for EGF, or HB-EGF- or AR-dependent tyrosine phosphorylation of the EGF receptor were not significantly altered by incubation with H. pylori broth culture filtrates. Increased expression of AR and HB-EGF were mediated by an H. pylori factor > 12 kD in size, whereas antiproliferative effects were mediated by both VacA and a factor < 12 kD in size. We conclude that H. pylori increases mucosal generation of EGF-related peptides, but in this acute experimental model, this event is not able to counteract the inhibitory effect of H. pylori on cell growth. The inhibitory effect of H. pylori on the reparative events mediated by EGF-related growth factors might play a role in the pathogenesis of H. pylori-induced gastroduodenal injury.
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24 MeSH Terms
Density of Helicobacter pylori infection in vivo as assessed by quantitative culture and histology.
Atherton JC, Tham KT, Peek RM, Cover TL, Blaser MJ
(1996) J Infect Dis 174: 552-6
MeSH Terms: Antigens, Bacterial, Bacterial Proteins, Biopsy, Gastritis, Helicobacter Infections, Helicobacter pylori, Humans, Nucleic Acid Hybridization, Peptic Ulcer, Polymerase Chain Reaction, Prospective Studies, Stomach, Virulence
Show Abstract · Added March 5, 2014
Helicobacter pylori density was assessed by quantitative culture and histologic examination of gastric biopsy specimens from 29 H. pylori-infected dyspeptic patients. Density was correlated with cagA and vacA genotypes (assessed by polymerase chain reaction and colony hybridization), gastric inflammation and epithelial injury (assessed histologically), and peptic ulceration. Quantitative culture was more reproducible than histology, and antral density was more reproducible than corpus density. Mean antral density of cagA+/vacA sl strains was 4-fold higher than that of cagA-/vacA s2 strains (1.9 X 10(6) vs. 4.5 x 10(5) cfu/g, P = .02). Antral density was associated with mucosal neutrophilic and lymphocytic infiltration (P < .01) and with epithelial injury (P < .05). Mean antral bacteria] density was 5-fold higher in duodenal ulcer patients than in others (P = .005). In conclusion, H. pylori density in vivo is easily quantified and is associated with bacterial virulence determinants, gastric inflammation, and duodenal ulceration, suggesting a central role in pathogenesis.
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13 MeSH Terms
Pattern of non-steroidal anti-inflammatory drug use in Australia 1990-1994. A report from the Drug Utilization Sub-Committee of the Pharmaceutical Benefits Advisory Committee.
McManus P, Primrose JG, Henry DA, Birkett DJ, Lindner J, Day RO
(1996) Med J Aust 164: 589-92
MeSH Terms: Adult, Anti-Inflammatory Agents, Non-Steroidal, Australia, Drug Utilization, Female, Gastrointestinal Diseases, Humans, Male, Middle Aged, Osteoarthritis, Peptic Ulcer
Show Abstract · Added August 29, 2013
OBJECTIVE - To determine the pattern of use of non-steroidal anti-inflammatory drugs (NSAIDs) in the Australian community, 1990-1994.
DESIGN - Data from the national drug utilisation database were expressed in defined daily doses per 1000 population per day (DDDs/1000 population per day). Temporal trends were assessed and comparisons were made with NSAID use in other countries. Epidemiological data were used to estimate the likely impact of changing NSAID use on peptic ulcer hospitalisation rates.
SETTING - Australian community (excluding hospitals).
MAIN OUTCOME MEASURES - Estimated consumption of prescription NSAIDs, expressed in DDDs/1000 population per day.
RESULTS - NSAID use in the Australian community fell from 50.1 DDDs/1000 population per day in 1990 to 34.6 DDDs/1000 population per day in 1994 (down 31%). From this reduced exposure we estimated that the number of admissions for NSAID-related upper gastrointestinal complications will have fallen by about 400 per year. Market research data for this period show a lower percentage use of NSAIDs for osteoarthritis and a decrease in the proportion of use in age groups over 50 years.
CONCLUSIONS - The level of use of non-steroidal anti-inflammatory drugs in Australia has been high in comparison with other countries, but in recent years has fallen markedly. This fall occurred in conjunction with regulatory interventions, educational campaigns and increased concern in the medical and lay press regarding the risks associated with the use of NSAIDs.
1 Communities
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11 MeSH Terms
Reserpine reconsidered: no association with serious peptic ulcer disease.
Shorr RI, Ray WA, Daugherty JR, Griffin MR
(1993) J Gen Intern Med 8: 510-2
MeSH Terms: Aged, Case-Control Studies, Confounding Factors, Epidemiologic, Female, Humans, Male, Peptic Ulcer, Reserpine
Show Abstract · Added March 5, 2014
A history of peptic ulcer disease is frequently cited as a contraindication to the use of reserpine. However, the risk of ulcer disease associated with the use of reserpine at current therapeutic doses is unknown. To address this question, the authors conducted a nested case-control study of the association between reserpine use and hospitalizations for peptic ulcer disease in elderly Tennessee Medicaid enrollees. When compared with that of nonusers of reserpine, the relative risk of hospitalization for peptic ulcer disease was 0.8 (95% CI, 0.6-1.0) among current users and 0.8 (95% CI, 0.5-1.3) among former users. The authors' data provide evidence that reserpine is not associated with ulcer disease in elderly persons and suggest that a history of ulcer disease need not be a contraindication to the use of this drug.
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8 MeSH Terms