Pathogenesis Of Duodenal Ulcer Research Articles

Helicobacter pylori infection in children: an overview of diagnostic methods

Children differ from adults regarding Helicobacter pylori (H. pylori) infection in many terms. H. pylori infection represents a key factor in the pathogenesis of duodenal ulcer and chronic gastritis in children. H. pylori infection causes some extraintestinal diseases as well as gastrointestinal diseases. Although, among these illnesses in children, symptoms like recurrent abdominal pain are not specific. Moreover, the role of the pathogen in the growth faltering, iron deficiency anemia, and asthma still remains controversial. A reliable method to detect H. pylori infection is a crucial issue, sand is still a matter of active debate. The tests applied for H. pylori diagnosis are grouped as either invasive or non-invasive methods. Invasive methods consist of endoscopic evaluation, the rapid urease test (RUT), histology, and bacterial culture. Non-invasive tests include the urea breath test (UBT), stool antigen test (SAT), serology, and molecular diagnostic approaches. Use of endoscopy is a pre-requisite for all invasive methods and poses difficulties in children as it is a difficult procedure and requires patient's cooperation. For this reason, the non-invasive tests have been commonly used in children, although their accuracy is not very reliable in some cases. Invasive tests may be opted to confirm the diagnosis as and when needed. This review presents the diagnostic tests used to detect H. pylori infection in children.

MPTP-induced duodenal ulcers in rat. Prevention by reuptake blockers for serotonin and norepinephrine, but not dopamine.

Abnormal activity of dopamine, serotonin, and norepinephrine may contribute to the pathophysiology of duodenal ulcers. We therefore studied the effects of neuropharmacological manipulations on 1-methly-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP)-induced duodenal ulcers. Duodenal ulcers were produced in rats by 12 subcutaneous injections of a neurotoxin, MPTP, over 4 days. At an MPTP dose of 20 mg.kg. injection, duodenal ulcers developed in 91% (43 of 47) of animals with low mortality. When neuropharmacological agents were preadministered before MPTP, the following effects on duodenal ulcers incidence were obtained. MAO-B inhibitors (pargyline [55%], deprenyl [43%]) but not MAO-A inhibitors (clorgyline [91%]) significantly decreased the frequency of duodenal ulcers suggesting that, like MPTP-induced parkinsonism, formation of a toxic metabolite, probably 1-methyl-4-phenyl-pyridinium is involved. Reuptake blockers for serotonin (fluoxetine [18%], indalpine [25%]) also decreased the frequency of duodenal ulcers. Reuptake blockers for norepinephrine (desmethylimipramine [17%], tomoxepine [31%], but not amfonelic acid [82%]) decreased the frequency of duodenal ulcers. Reuptake blockers for dopamine (benztropine [73%], amfonelic acid [82%], GBR-12909 [80%]) did not protect against duodenal ulcers. However, GBR-12909 significantly decreased the severity of those duodenal ulcers that were produced. These data suggest that abnormally low levels of synaptic transmission in serotonergic and possibly noradrenergic neurons play an important role in the pathogenesis of duodenal ulcer while the role of dopamine may be limited to modulation of ulcer severity.

Influence of prostate stem cell antigen gene polymorphisms on susceptibility to Helicobacter pylori-associated diseases: a case-control study.

Patients with duodenal ulcer have a reduced risk of developing gastric cancer compared to those without. Recently, the prostate stem cell antigen (PSCA) rs2294008 C>T polymorphism was found to be associated with different pathogenesis of duodenal ulcer and gastric cancer developments. However, whether PSCA rs2294008 C>T polymorphism is associated with severity of gastric mucosal atrophy is unclear. We examined the influence of the PSCA rs2294008 C>T polymorphism on susceptibility to H. pylori-related diseases and the relationships between PSCA polymorphism and gastric mucosal atrophy. PSCA rs2294008 C>T polymorphism was assessed in H. pylori-positive Japanese patients (n = 488) with noncardia gastric cancer (n = 193), gastric ulcer (n = 84), duodenal ulcer (n = 61), and atrophic gastritis (n = 150), as well as in H. pylori-negatives (n = 266). Frequency of PSCA rs2294008 C/C genotype in duodenal ulcer was 36.1%, which was significantly higher than those with gastric cancer (12.4%), gastric ulcer (19.0%), gastritis (10.7%), and H. pylori-negatives (19.5%) (p < .001). Compared with duodenal ulcer, having the T allele significantly increased the risk of gastric cancer (OR: 3.97, 95% CI: 2.02-7.80; p < .001), gastric ulcer (2.40, 1.13-5.10; p = .023), and gastritis (4.72, 2.26-9.86; p < .001). Mean pepsinogen (PG) I/PG II ratio in T allele carriers (2.17 ± 0.75) was significantly lower than that in C/C genotype (3.39 ± 1.27, p < .001). The PSCA rs2294008 C>T polymorphism is associated with differing susceptibilities to H. pylori-associated diseases. The PSCA rs2294008 C>T polymorphism may be acting through induction of gastric mucosal atrophy, finally leading to development of gastric ulcer and gastric cancer in PSCA rs2294008 T allele carriers, but not duodenal ulcer.

Deep-sea water containing selenium provides intestinal protection against duodenal ulcers through the upregulation of Bcl-2 and thioredoxin reductase 1.

Deep-sea water (DSW), which is rich in micronutrients and minerals and with antioxidant and anti-inflammatory qualities, may be developed as marine drugs to provide intestinal protection against duodenal ulcers. We determined several characteristics in the modified DSW. We explored duodenal pressure, oxygenation, microvascular blood flow, and changes in pH and oxidative redox potential (ORP) values within the stomach and duodenum in response to tap water (TW, hardness: 2.48 ppm), DSW600 (hardness: 600 ppm), and DSW1200 (hardness: 1200 ppm) in Wistar rats and analyzed oxidative stress and apoptosis gene expressions by cDNA and RNA microarrays in the duodenal epithelium. We compared the effects of drinking DSW, MgCl2, and selenium water on duodenal ulcers using pathologic scoring, immunohistochemical analysis, and Western blotting. Our results showed DSW has a higher pH value, lower ORP value, higher scavenging H2O2 and HOCl activity, higher Mg2+ concentrations, and micronutrients selenium compared with TW samples. Water infusion significantly increased intestinal pressure, O2 levels, and microvascular blood flow in DSW and TW groups. Microarray showed DSW600, DSW1200, selenium water upregulated antioxidant and anti-apoptotic genes and downregulated pro-apoptotic gene expression compared with the TW group. Drinking DSW600, DSW1200, and selenium water but not Mg2+ water significantly enhanced Bcl-2 and thioredoxin reductase 1 expression. Bax/Bcl-2/caspase 3/poly-(ADP-ribose)-polymerase signaling was activated during the pathogenesis of duodenal ulceration. DSW drinking reduced ulcer area as well as apoptotic signaling in acetic acid-induced duodenal ulcers. DSW, which contains selenium, provides intestinal protection against duodenal ulcers through the upregulation of Bcl-2 and thioredoxin reductase 1.

Anti-inflammatory and carbonic anhydrase restoring actions of yam powder (Dioscorea spp) contribute to the prevention of cysteamine-induced duodenal ulcer in a rat model

Increased acid output, accompanied with a defective defense system, is considered a fundamental pathogenesis of duodenal ulcer (DU). However, relapse of DU occurs despite proton pump inhibitors and H2 receptor antagonists, hence imposing the enforcement of the defense system. Dried powder of the yam tuber (Dioscorea spp) has been used in traditional folk medicine as a nutritional fortification. We hypothesized that dried-yam powder would prevent DU through improvement of anti-inflammatory actions and carbonic anhydrase (CA) activity. Therefore, we investigated the preventive effects of dried-yam powder against the cysteamine-induced DU and elucidated the underlying mechanisms. Duodenal ulcers were induced in Sprague-Dawley rats by intragastric administration of 500 mg/kg cysteamine-HCl. The dried-yam powder was used as a pretreatment before the cysteamine-HCl. The number and size of DU were measured. The expressions of inflammation mediators were checked in duodenal tissues, and the expressions of CAs and malondialdehyde levels were also examined. Cysteamine provoked perforated DU, whereas dried-yam powder significantly prevented DU as much as pantoprazole and significantly reduced the incidence of perforation. The messenger RNA expressions of cyclooxygenase-2 and inducible nitric oxide synthase were remarkably decreased in the yam group compared with the cysteamine group, and the serum levels of proinflammatory cytokines including interleukin-1β, interleukin-6, and tumor necrosis factor were significantly attenuated in the yam group. Cysteamine significantly decreased the expression of CAs, whereas yam treatment significantly preserved the expressions of CA IX, XII, and XIV. In conclusion, dried-yam powder exerts a significant protective effect against cysteamine-induced DU by lowering the activity of inflammatory cytokines and free radicals and restoring the activity of CAs, except in CA IV.

Abstract 2549: A genome-wide association study identifies PSCA as a susceptibility locus for gastric cancer and duodenal ulcer in the Japanese population.

Abstract Through a genome-wide association analysis using a total of 7,035 duodenal ulcer cases and 25,323 controls of Japanese populations, we identified two susceptibility loci at the Prostate stem cell antigen (PSCA) on 8q24 and at the ABO blood group (ABO) on 9q34. A C-allele of rs2294008 at PSCA increased the risk of duodenal ulcer (odds ratio (OR) of 1.84 with P value of 3.92 x 10-33) in a recessive model, while it decreased the risk of gastric cancer (OR of 0.79 with P value of 6.79 x 10-12) as reported previously. A T-allele of SNP rs2294008 created the upstream translational initiation codon and affects the protein localization from cytoplasm to cell surface. SNP rs505922 on ABO also associated with duodenal ulcer in a recessive model (OR of 1.32 with P value of 1.15 x 10-10). Our finding implies the crucial roles of genetic variations on the pathogenesis of duodenal ulcer. Citation Format: Chizu Tanikawa, Koichi Matsuda, Yusuke Nakamura. A genome-wide association study identifies PSCA as a susceptibility locus for gastric cancer and duodenal ulcer in the Japanese population. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2549. doi:10.1158/1538-7445.AM2013-2549

Cyclooxygenase (COX)-1 and COX-2 Both Play an Important Role in the Protection of the Duodenal Mucosa in Cats

Although nonsteroidal anti-inflammatory drugs often cause ulcers in the duodenum in humans, the role of cyclooxygenase (COX) isoforms in the pathogenesis of duodenal ulcers has not been fully elucidated. We examined in cats the 1) ulcerogenic effects of selective COX-1 (SC-560, ketorolac) and COX-2 (celecoxib, meloxicam) inhibitors on the gastrointestinal mucosa, 2) effect of feeding and cimetidine on the expression of COX isoforms and prostaglandin E(2) (PGE(2)) level in the duodenum, and 3) localization of COX isoforms in the duodenum. COX inhibitors were administered after the morning meal in cats once daily for 3 days. Gastrointestinal lesions were examined on day 4. Localization and expression of COX isoforms (by immunohistochemistry, Western blot) and PGE(2) level (by enzyme immunoassay) were examined. Results were as follows. First, selective COX-1 or COX-2 inhibitors alone produced marked ulcers in the duodenum but did not cause obvious lesions in the small intestine. Coadministration of SC-560 and celecoxib produced marked lesions in the small intestine. Second, feeding increased both the expression of COX isoforms and PGE(2) level in the duodenum, and the effects were markedly inhibited by pretreatment with cimetidine. Third, COX-1 was localized in goblet and Brunner's gland cells, Meissner's and Auerbach's plexus, smooth muscle cells, and arterioles; and COX-2 was observed in capillaries, venules, and basal granulated cells. The expression of COX isoforms in the duodenum is up-regulated by feeding, and inhibition of either COX-1 or COX-2 causes ulcers in the duodenum, suggesting that both isoforms play an important role in the protection of the duodenal mucosa.

A genome-wide association study identifies two susceptibility loci for duodenal ulcer in the Japanese population

Through a genome-wide association analysis with a total of 7,035 individuals with duodenal ulcer and 25,323 controls from Japan, we identified two susceptibility loci at the PSCA gene (encoding prostate stem cell antigen) at 8q24 and at the ABO blood group locus at 9q34. The C allele of rs2294008 at PSCA was associated with increased risk of duodenal ulcer (odds ratio (OR) = 1.84; P = 3.92 × 10(-33)) in a recessive model but was associated with decreased risk of gastric cancer (OR = 0.79; P = 6.79 × 10(-12)), as reported previously. The T allele of rs2294008 encodes a translation initiation codon upstream of the reported site and changes protein localization from the cytoplasm to the cell surface. rs505922 at ABO was also associated with duodenal ulcer in a recessive model (OR = 1.32; P = 1.15 × 10(-10)). Our findings demonstrate a role for genetic variants in the pathogenesis of duodenal ulcer.

Noise-induced duodenal lesions: A light and electron microscopy study of the lesions of the rat duodenal mucosa exposed to low frequency noise

Non-auditory effects of noise, including digestive disorders have long being reported. Low frequency noise (LFN) is considered to be responsible to most of non-auditory effects of noise and is widely spread in modern societies. Only a few studies were designed to evaluate these noise-induced digestive alterations. The pathogenesis of duodenal ulcers and erosions is complex and noise may be an environmental co-factor. The aim of the present study was to investigate the morphological injury of LFN-exposed duodenal mucosa. Five groups of Wistar rats were exposed to continuous LFN, during increasing periods, since 1 to 13 weeks. A control group was kept in silence. Duodenal specimens were studied using light microscopy (LM), scanning electron microscopy (SEM) and transmission electron microscopy (TEM). We disclosed several changes in LFN-exposed rats: on LM, mucosa showed superficial erosions of the epithelial layer, degeneration, picnosis and cell death, with no inflammation. On SEM, epithelium presented displacement of cells and unequal distribution of microvilli, with coalescence and fusion. On TEM, microvilli were irregularly distributed, damaged and fragmented. The terminal web was destroyed. Morphological alterations occurred early, after just 1 week of LFN-exposure, persisted with longer noise exposition and did not suffer any evolution. Changes were similar among all LFN-exposed groups. LFN-exposed duodenal mucosa develops destruction of microvilli and terminal web, leading to cellular death and development of superficial erosions. These lesions of cytoskeleton structures could explain why cells with actinic and tubulinic structures like cilia and microvilli present severe destruction after LFN-exposure. These erosions are similar to those seen in dyspeptic patients.

Overexpression of cyclin‐dependent kinase (CDK) inhibitors p21 and p27 is a common mechanism of experimental duodenal ulcer and ulcerative colitis

Recently we demonstrated that increased expression of cyclin‐dependent kinase inhibitors p21 and p27 is an early event in duodenal ulceration (DU) induced by cysteamine or mepirizole and in indomethacin‐caused gastric erosions. We hypothesized that overexpression of p21, p27 and p16 may be involved in the mechanisms of mucosal damage in both DU and ulcerative colitis (UC). To compare the effect of chemically‐induced injury in duodenal and colonic mucosa, Sprague‐Dawley rats were treated with cysteamine (85 mg/100 g, intragastrically) or with 6% iodoacetamide (0.1 ml, intracolonically). Animals were euthanized at 0.5, 2, 6, 12, 24 hr after treatment. Mucosal scrapings of proximal duodenum and distal colon were used for RNA isolation; p16, p21 and p27 were detected by Real‐time polymerase chain reaction. The results demonstrated that cysteamine enhanced duodenal p21 and p27 mRNA expression at 2 hr by 2.9‐ and 4.6‐fold, respectively. In colonic mucosa iodoacetamide increased p21 by 4.2‐fold and p27 expression by 1.5‐fold. Expression of p16 changed in neither DU nor UC.Conclusions1) Expressions of p21 and p27 were significantly increased in rat duodenal and colonic mucosa in the early stages of DU and UC formation. 2) Thus, both p21 and p27 but not p16 seem to be a common mechanism involved in the pathogenesis of DU and UC.(This study was supported by Dept of Veterans Affairs, Medical Research Service Merit Reviews)

S1773 Identification of microRNA Expressed in Duodenal and Gastric Mucosa, and Modulation By the Duodenal Ulcerogen Cysteamine

MicroRNAs (miRNAs) are non-coding small RNAs, which are found to regulate gene expression in many tissues/organs in various physiologic processes. Cysteamine induces duodenal and rarely gastric ulcers in patients receiving cysteamine for cystinosis or hepatic damage and animal models. The rat model has been widely used to study the pathogenesis and healing of duodenal ulcers. In this study, we have performed miRNA microarray to complement our previous DNA microarray analysis of gene expression in rat duodenal mucosa to identify gene expression changes specifically associated with duodenal ulceration. Goals: To identify molecular pathways leading to duodenal ulcer formation induced by duodenal ulcerogens like cysteamine. Methods and Results: Groups of unfasted Sprague-Dawley female rats (180200g) were given cysteamine-HCl (25mg/100g, once) by gavage. Rats were euthanized by CO2 inhalation 2 hr after cysteamine administration. Proximal duodenal and gastric mucosa was scraped. Total RNA including the miRNA fraction was extracted from mucosal samples and further processed for Exiqon miRCURY microarray (289 rat miRNAs). Real-time PCR was performed to confirm some candidate miRNAs. Eight miRNAs were found to have 4fold or higher difference in expression level between duodenal and gastric mucosa. Among them,miR-215 was reported to be upregulated in Barrett's esophagus and is likely a duodenal/ small intestinal specific miRNA. Cysteamine changed the expression level of 20 miRNAs in duodenal mucosa by over 2-fold; two of these by more than 4-fold. Eleven of them are unpublished novel miRNAs. miR-542-5p was increased more than 8-fold by cysteamine. In silico analysis shows its target genes include insulin-like growth factor 2 receptor, paired-like homeodomain transcription factor 3, RCE1 homolog and hypothetical protein LOC152485. Conclusions: 1) We have identified a group of miRNAs differentially expressed in duodenal and gastric mucosa. 2) Cysteamine modulates the expression of several miRNAs which may control wound healing, tissue repair and angiogenesis. 3) Thus, miRNA analysis provides a new way to study gene expression changes in the pathogenesis of duodenal ulceration.

Duodenal Ulcer-related Antigens from Helicobacter pylori: Immunoproteome and Protein Microarray Approaches

Helicobacter pylori is an important risk factor of duodenal ulcer (DU). Although many virulence factors of H. pylori have been identified, few have been reported to show an association with the pathogenesis of DU. The aims of this study were to identify H. pylori antigens showing a high seropositivity in DU and to develop a platform for rapid and easy diagnosis for DU. Because DU and gastric cancer (GC) are considered clinical divergent gastroduodenal diseases, we compared two-dimensional immunoblots of an acid-glycine extract of an H. pylori strain from a patient with DU probed with serum samples from 10 patients with DU and 10 with GC to identify DU-related antigens. Of the 11 proteins that were strongly recognized by serum IgG from DU patients, translation elongation factor EF-G (FusA), catalase (KatA), and urease alpha subunit (UreA) were identified as DU-related antigens, showing a higher seropositivity in DU samples (n = 124) than in GC samples (n = 95) (FusA, 70.2 versus 45.3%; KatA, 50.8 versus 41.1%; UreA, 44.4 versus 27.4%). In addition, we found that the use of multiple antigens improved the discrimination between patients with DU and those with GC as the odds ratios increased from 1.82 (95% confidence interval (CI), 0.79-4.21; p = 0.1607) for seropositivity for FusA, KatA, or UreA alone to 4.95 (95% CI, 2.05-12.0; p = 0.0004) for two of the three antigens and to 5.71 (95% CI, 1.86-17.6; p = 0.0024) for all three antigens. Moreover a protein array containing the three DU-related antigens was developed to test the idea of using multiple biomarkers in diagnosis. We conclude that FusA, KatA, and UreA are DU-related antigens of H. pylori, and the combination of these on a protein array provided a rapid and convenient method for detecting serum antibody patterns of DU patients.

Time Trends of Ulcer Mortality in Europe

The aim of the present study was to follow the time trends of ulcer disease in a representative sample of European countries and assess whether the most recent behavior of peptic ulcer still fits the overall pattern governed by an underlying birth-cohort phenomenon. Mortality data from 6 countries between 1921 and 2004 were analyzed, including Denmark, France, Germany, The Netherlands, Spain, and Switzerland. The age-specific death rates of gastric and duodenal ulcers from each individual country were plotted as period-age and cohort-age contours. The data from the past 50-80 years show striking similarities among the 6 European countries. In all countries alike, the risk of dying from gastric and duodenal ulcer increased among consecutive generations born during the second half of the 19th century until shortly before the turn of the century, and then decreased in all subsequent generations. The time trends of gastric ulcer preceded those of duodenal ulcer by 10-30 years. The increase in nonsteroidal anti-inflammatory drug consumption or introduction of potent antisecretory medications have not affected the long-term downward trends of ulcer mortality. The birth-cohort pattern has continued to influence the temporal variations of peptic ulcer until most recently. The unique shape of the birth-cohort patterns of gastric and duodenal ulcers and their identical appearance in countries with different health care systems and varying political and socioeconomic histories reflect the overriding influence of Helicobacter pylori infection.

Mucosal Plug in the Etiology of Peptic Ulcer Disease

The pathogenesis of duodenal ulcer begins at a site remote from the acid-pepsin pool. It is usually located a little farther away from the pylorus but within the first part of the duodenum, known as the duodenal cap. The etiological factors involved in the infliction of a particular site with duodenal ulceration have been highlighted in a recent study [1]. The famous dictum stated by Schwartz 90 years ago was “No acid, no ulcer” [2]. This has never been disputed since, but what was never defined in that phrase was how a particular site away from the pylorus could be inflicted with acid injury and how this injury could be limited to a few millimeters within the duodenal bulb if the acid had traversed through the pyloric sphincter? These pertinent issues are dealt with in this study. In recent studies, Helicobacter pylori, by contrast, has been implicated as one of the etiological factors in the pathogenesis of peptic ulcer disease [3], but why such bacterial injury inflicts a particular site when the bacteria are present diffusely in the antrum and the duodenum is not understood. This could occur if the particular site were exclusively isolated from the rest of the duodenum and were exclusively exposed to bacterial colonization, but that is not possible. Hence, the development of an ulcer at a particular site must be governed by intrinsic factors.

IL1RN Polymorphism and cagA-Positive Helicobacter pylori Strains Increase the Risk of Duodenal Ulcer in Children

Duodenal ulcers in children are associated with Helicobacter pylori gastric infection with cagA-positive strains, but factors linked to the host are poorly known. The authors evaluated the role of proinflammatory interleukin-1 gene cluster polymorphisms in the pathogenesis of duodenal ulcer. They studied prospectively 437 children 1 to years old, 209 of whom were H. pylori positive and 228 of whom were H. pylori negative. IL1B-511-C/T, -31T/C, and IL1RN Variable number of tandem repeats were genotyped by polymerase chain reaction (PCR) restriction fragment length polymorphism, PCR with confronting two-pair primers, and PCR, respectively. cagA status was evaluated by PCR. The role of the proinflammatory cytokine genotypes in the genesis of duodenal ulcer was evaluated before and after stratification of H. pylori status on logistic regression models. In the group of children without duodenal ulcer, no association was observed between H. pylori status and proinflammatory polymorphisms. Furthermore, no association between IL1 cluster genotypes and cagA status was seen in the H. pylori-positive children. However, increasing age, male sex, and IL1RN*2 were independently associated with duodenal ulcer. After stratification, in the H. pylori-positive children, increasing age, male sex, the presence of ILRN*2 allele, and cagA-positive status were independently associated with duodenal ulcer. The risk for the development of duodenal ulcer increased when a combined association of the presence of IL1RN*2 allele and infection by a cagA-positive H. pylori strain was the variable. This study provides evidence supporting independent roles of IL1RN*2 allele and cagA-positive status in the genesis of duodenal ulcer in children.

Clinical relevance of iceA and babA2 genotypes of Helicobacter pylori in a Shanghai population

To determine the distribution of the iceA and babA2 genotypes of Helicobacter pylori in patients with various gastroduodenal diseases in Shanghai, and to explore the association between genotype and the clinical outcome of infection. One hundred and forty-one strains of H. pylori were isolated from gastric biopsies of 43 patients with chronic gastritis, 47 with duodenal ulcer (DU), 30 with gastric ulcer (GU) and 21 with non-cardia gastric carcinoma. The iceA, babA2, cagA and vacA genotypes were determined by polymerase chain reaction (PCR). The iceA1, iceA2 and babA2 genotypes were detected in 74.5% (105/141), 15.6% (22/141) and 63.8% (90/141), respectively, of the H. pylori strains studied. Two H. pylori isolates (1.4%) were positive for both iceA alleles and 16 (11.3%) were negative for both. The prevalence of babA2 and its combination with cagA (cagA(+)/babA2(+)) in DU patients was significantly higher than that in GU patients (74.5%vs 50.0% for babA2, P = 0.028; 70.2%vs 46.7% for cagA(+)/babA2(+), P = 0.039). There was no significant difference in the prevalence of babA2 among the other disease groups, and no significant association of the iceA genotypes with the different clinical diseases (P > 0.05). The most predominant genotype of the H. pylori strains isolated from patients in Shanghai are iceA1(+)/babA2(+), and the babA2 genotype may play a different role in the pathogenesis of DU and GU. An association between iceA status and clinical outcome of H. pylori infection could not be confirmed in the present study.

Association of interleukin 1 gene family polymorphisms with duodenal ulcer disease.

Cytokine genes taking part in the immunological response to Helicobacter pylori infection are good candidates to study for genetic predisposition to duodenal ulcer disease (DU). Among cytokines, interleukin (IL)-1beta and its natural specific inhibitor, the interleukin-1 receptor antagonist, are cytokines that play a key role in regulating gastric acid secretion and modulating the immune response in the gastrointestinal mucosa. We aimed to investigate whether polymorphisms in the IL-1B and IL-1RN genes are involved in the susceptibility to duodenal ulcer. DNA from 131 unrelated Spanish Caucasian patients with DU and 105 ethnically matched healthy controls was typed for the IL-1B-511, IL-1B-31, and IL-1B + 3954 gene polymorphisms, and the VNTR polymorphism in intron 2 of the IL-1RN gene by polymerase chain reaction (PCR)-based methods and TaqMan assays. H. pylori status and non-steroidal anti-inflammatory drugs (NSAIDs) use was determined in all patients and controls. Logistic regression analysis identified H. pylori infection (OR: 9.74; 95%CI = 3.53-26.89) and NSAIDs use (OR: 8.82; 95%CI = 3.51-22.17) as independent risk factors for DU. In addition, the simultaneous carriage of IL-1RN*2, IL-1B-511*C, IL-1B-31*T and IL-1B + 3954*C alleles was a genetic risk factor for DU in patients with H. pylori infection (OR: 3.22; 95%CI = 1.09-9.47). No significant differences in IL-1RN and IL-1B genotypes were found when patients were categorized according to gender, age of onset, smoking habit, NSAIDs use, type of complication and positive family history. Our results provide further evidence that host genetic factors play a key role in the pathogenesis of duodenal ulcer.

Management of peptic ulcer disease not related to Helicobacter pylori or NSAIDs.

Helicobacter pylori (H. pylori) infection is widely accepted as the most important factor in the pathogenesis of duodenal ulcer. However, in parallel with more effective eradication of H. pylori, the prevalence of H. pylori is changing, and H. pylori-negative peptic ulcer disease appears to be increasing. When making a diagnosis of H. pylori-negative peptic ulcer disease, it is essential to avoid misclassification because of inaccurate diagnosis. In addition, secondary causes may need to be excluded with appropriate investigations. In the absence of H. pylori, nonsteroidal anti-inflammatory drug usage is the most common cause of peptic ulcer; surreptitious nonsteroidal anti-inflammatory drug usage is a cause of unexplained ulcer disease in up to 60% of patients. Hypersecretory syndromes such as Zollinger-Ellison syndrome, although rare, need to be excluded. Once all known etiological factors are excluded, there remains a group of patients with so-called "idiopathic ulcers." The interplay of etiological factors in the pathogenesis of idiopathic peptic ulcer disease is poorly defined but may include a genetic predisposition, altered acid secretion, rapid gastric emptying, defective mucosal defense mechanisms, psychological stress, and smoking. The management of idiopathic peptic ulcers is not defined; they appear to be more resistant to standard therapy, can be associated with more frequent complications, and those that relapse may require long-term maintenance therapy.

Prevalence and pathogenesis of duodenal ulcer in chronic alcoholic pancreatitis.

The prevalence of duodenal ulcer (DU) has been considered high in patients with chronic pancreatitis; however, its pathogenesis is unclear. We hypothesized that Helicobacter pylori infection plays the major pathogenetic role. One hundred seven cases (97 men, 10 women) of chronic alcoholic pancreatitis (CAP) were prospectively investigated from 1997 to 2001. One hundred thirty-seven DU patients and 59 nonulcer dyspepsia patients formed the two control groups. Pancreatic function was evaluated by determination of fecal fat excretion and fasting blood glucose concentration. Upper gastrointestinal endoscopy was performed in all patients, and gastric mucosal biopsies were taken for assessment of H. pylori infection with a modified Giemsa stain and rapid urease test. Fifteen (14%) of the 107 patients with CAP had active DU. There was a trend toward an association between the presence of diabetes mellitus and/or steatorrhea and the occurrence of DU in patients with CAP (p = 0.06). The rate of H. pylori infection was significantly higher in patients with CAP and DU than in those with only CAP (86.7% vs. 54.3%, p = 0.02) but the rate similar to that in patients with simple DU (75.2%). Trends toward higher prevalence of H. pylori infection in CAP with DU were noticed when they were compared with the nonulcer dyspepsia group (86.7% vs. 66.1%). There was no significant difference in prevalence of H. pylori between CAP patients without DU and dyspeptic patients (54.3% vs. 66.1%). These data demonstrate that the prevalence of DU in CAP is relatively high. H. pylori infection seems to play the major pathogenetic role in DU associated with CAP.

Eradication of Helicobacter pylori Restores the Inhibitory Effect of Cholecystokinin on Gastric Motility in Duodenal Ulcer Patients

Background: Increased gastric emptying and defective action of endogenous cholecystokinin (CCK), that is known to inhibit this emptying, have been implicated in the pathogenesis of duodenal ulcer (DU). The aim of this double blind study was to assess whether CCK and somatostatin participate in the impairment of gastric motility in active DU patients before and after Helicobacter pylori eradication. Methods: Tests were undertaken in 10 DU patients without or with elimination of the action of endogenous CCK using loxiglumide, a selective CCK-A receptor antagonist, before and 4 weeks after eradication of H. pylori with 1 week triple therapy that resulted in healing of all DUs tested. The gastric emptying rate after feeding was determined using the 13C-acetate breath test. Before each test, samples of gastric juice were obtained by aspiration using a nasogastric tube for determination of somatostatin using specific radioimmunoassay. Results: Prior to H. pylori