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With the emergence of new, exotic diseases, it's easy to forget that the diagnosis and management of such ordinary but troublesome infections as peptic ulcer disease, prostatitis, and genital herpes have improved dramatically. So has outcome. [ABSTRACT FROM AUTHOR]

Since Helicobacter pylori burst on the gastric scene around 10 years ago, researchers have scrambled to restructure clinical thinking about treatment of peptic ulcers. The changes are rapid -- and often surprising. [ABSTRACT FROM AUTHOR]

Eradication of Helicobacter pylori with an antibiotic regimen cures most gastric and duodenal ulcers, and recurrence rates are low. You have your doubts? Consider the evidence. [ABSTRACT FROM AUTHOR]

The chemoprevention of colorectal cancer (CRC) is a realistic option given the low acceptance and cost of screening colonoscopy. NSAIDs, currently not recommended for CRC prevention, are the most promising agents. Here, we review relevant work and assess the chemopreventive potential of NSAIDs. The chemopreventive efficacy of NSAIDs is established by epidemiological and interventional studies as well as analyses of cardiovascular-prevention randomized clinical trials. The modest chemopreventive efficacy of NSAIDs is compounded by their significant toxicity that can be cumulative. Efforts to overcome these limitations include the use of drug combinations; the emphasis on the early stages of colon carcinogenesis such as aberrant crypt foci, which may require shorter periods of drug administration; and the development of several families of chemically modified NSAIDs such as derivatives of sulindac, nitro-NSAIDs and phospho-NSAIDs, with some of them appearing to have higher safety and efficacy than conventional NSAIDs and thus to be better candidate agents. The successful development of NSAIDs as chemopreventive agents will likely require a combination of the following: identification of subjects at high risk and/or those most likely to benefit from chemoprevention; optimization of the timing, dose and duration of administration of the chemopreventive agent; novel NSAID derivatives and/or combinations of agents; and agents that may prevent other diseases in addition to CRC. Ultimately, the clinical implementation of NSAIDs for the prevention of CRC will depend on a strategy that drastically shifts the currently unacceptable risk/benefit ratio in favor of chemoprevention.

Annexin A1 (ANXA1) inhibits NF-κB, a key regulator of inflammation, the common pathophysiological mechanism of inflammatory bowel diseases (IBD). MC-12, an ANXA1-based tripeptide, suppresses NF-κB activation. Here, we determined the efficacy of MC-12 in the control of IBD. Mice with colitis induced by dextran sodium sulfate (DSS) or 2,4,6-trinitro benzene sulfonic acid (TNBS) were treated with various doses of MC-12 administered intraperitoneally, orally or intrarectally. We determined colon length and the histological score of colitis, and assayed: in colon tissue the levels of TNF-α, IFN-γ, IL-1β, IL-6 and IL-10 by RT-PCR; prostaglandin E(2) (PGE(2)), cytoplasmic phospholipase A(2) (cPLA(2)) and myeloperoxidase by immunoassay; and COX-2 and NF- κB by immunohistochemistry; and in serum the levels of various cytokines by immunoassay. In both models MC-12: reversed dose-dependently colonic inflammation; inhibited by up to 47% myeloperoxidase activity; had a minimal effect on cytoplasmic phospholipase A(2); reduced significantly the induced levels of TNF-α, IFN-γ, IL-1β, IL-6 and IL-10, returning them to baseline. DSS and TNBS markedly activated NF-κB in colonic epithelial cells and MC-12 decreased this effect by 85.8% and 72.5%, respectively. MC-12 had a similar effect in cultured NCM460 normal colon epithelial cells. Finally, MC-12 suppressed the induction of COX-2 expression, the level of PGE(2) in the colon and PGE(2) metabolite in serum. In conclusion, MC-12, representing a novel class of short peptide inhibitors of NF-κB, has a strong effect against colitis in two preclinical models recapitulating features of human IBD. Its mechanism of action is complex and includes pronounced inhibition of NF-κB. MC-12 merits further development as an agent for the control of IBD.

The use of non-steroidal anti-inflammatory drugs has become ubiquitous worldwide and remains a common source of gastrointestinal morbidity. Antisecretory medications, particularly proton pump inhibitors, are effective in the treatment and prevention of NSAID-related gastrointestinal complications, including peptic ulcer disease and non-ulcer dyspepsia. A careful assessment of patients' risk factors for developing NSAID-related gastrointestinal complications should be undertaken prior to initiation of any NSAIDs. Patients who are considered at risk for developing gastrointestinal complications should receive concurrent antisecretory medical therapy to minimize the risk for GI complications.

It is well established that nonsteroidal anti-inflammatory drugs (NSAIDs) and aspirin confer significant morbidity and mortality. The widespread use of these drugs has increased the absolute numbers of cases of NSAID- or aspirin-related upper gastrointestinal complications. Emerging data indicate that antidepressants, such as selective serotonin reuptake inhibitors and tricyclic antidepressants, may also increase risk for gastrointestinal bleeding. Multiple factors have been identified that increase risk for NSAID- and aspirin-related upper gastrointestinal complications. The highest risks are related to age (>60 years) and prior complicated peptic ulcer; additional risk factors include use of multiple NSAIDs and high doses of NSAIDS. Recent studies have demonstrated enhanced healing and prevention of NSAID- and aspirin-related gastrointestinal lesions with proton pump inhibitors.

Nitric oxide-releasing aspirin (NO-ASA) is emerging as a potentially important chemopreventive agent against colon cancer. We examined in HT-29 human colon adenocarcinoma cells the effect of NO-ASA on the inducible form of nitric oxide synthase (NOS2), an enzyme implicated in colon carcinogenesis. NO-ASA inhibited in a time- and concentration-dependent manner the expression of NOS2 up to 70% compared to control (IC50 for this effect = 46 microM). NO-ASA also decreased the corresponding steady-state mRNA levels and this reduction preceded the reduction of protein levels by at least 6 h. NO-ASA also reduced the enzymatic activity of NOS2, as determined by a direct enzyme assay (maximal reduction = 80%) and by determining the accumulation of NO in the culture medium (IC50 for this effect = 36 microM). These effects of NO-ASA on NOS2 were paralleled by inhibition in cell growth (IC50 = 8.5 microM). These findings indicate that NO-ASA profoundly inhibits both the expression and enzymatic activity of NOS2 and suggest that these effects may represent an important mechanism for the colon cancer chemopreventive effect of NO-ASA.

Helicobacter pylori infection remains a ubiquitous infection, especially in populations with poor socioeconomic conditions. Severe clinical outcomes of chronic infection include peptic ulcer disease and gastric cancer. Consensus meetings have developed guidelines for diagnosis, treatment, and management of H. pylori infection and related disorders in various populations. Clear benefits are obtained for H. pylori eradication in peptic ulcer disease and gastric mucosa-associated lymphoid tissue lymphoma. Most authorities agree that first-degree relatives of gastric cancer patients should undergo testing for H. pylori infection. H. pylori eradication in dyspepsia remains controversial. Global investigations continue to identify specific host and bacterial factors that are responsible for H. pylori-related inflammatory processes and development of clinical disease. Effective eradication regimens have been identified. The proton pump inhibitor (PPI)-based triple therapies are considered first-line therapy because of high patient compliance and good eradication rates. "Quadruple therapy" with bismuth-metronidazole-tetracycline plus a PPI is another first-line therapy with a similar eradication rate. This therapy is preferred in patients with penicillin allergy or prior exposure to clarithromycin. Rescue regimens are being developed because of rising antimicrobial resistance to metronidazole and clarithromycin in H. pylori strains. Emerging rescue combination therapies include furazolidone, rifabutin, and quinolones. These combination regimens are still preliminary and should be reserved for patients who have failed first-line therapies. Vaccine development remains elusive.

Background: Increasingly, primary care (PC) physicians will be the first to encounter patients with hepatitis C virus (HCV) infection., Aim: To determine opinions and practices of PC residents regarding HCV., Methods: We administered a one-page questionnaire to 180 PC residents at five U.S. training programs., Results: Respondents were distributed equally across postgraduate year, 83% were U.S. graduates, and 44% had seen >11 (HCV) patients in the past year. Residents tested for HCV in persons with: increased transaminases (83%), history of blood transfusion (46%), multiple tattoos (57%), +ANCA (16%), and alcohol abuse (31%). Sixteen percent of respondents tested all patients. Forty-one percent would vaccinate HCV patients for hepatitis A and 65% for hepatitis B while only 19% and 78% knew the respective vaccination schedules. Although no vaccine is available, 66% recommended vaccination for HCV. Only 37% and 29%, respectively, reported HCV genotype 1 as most common and most resistant to treatment. Fifty-three percent recommend liver biopsy before treating HCV. Only 52% reported alpha-interferon (IFN) with ribavirin as initial treatment for HCV while 28% recommend ribavirin or lamivudine alone or combinations of IFN and lamivudine or amantadine. As contraindications to treatment, 33% reported AIDS with PCP infection, 19% coronary artery disease, and 19% suicidal ideation. Sixty-nine percent felt that there was insufficient information on HCV., Conclusions: Many PC residents lack adequate knowledge of recommended guidelines for the management of HCV. Many test for HCV in inappropriate situations, are unclear regarding available vaccines and their administration, and are uncertain about current treatment. Education of PC residents on guidelines for detection and management of HCV must be improved.

Clinical and basic mechanisms of interaction between Helicobacter pylori and its host have been the subject of numerous publications in the past year. Two additional proton pump inhibitors (PPIs), esomeprazole and rabeprazole, have shown effectiveness in H. pylori eradication when combined with amoxicillin and clarithromycin, and esomeprazole has demonstrated its effectiveness with only one daily dose. Other important recent developments worldwide include evidence-based treatment guidelines established at a European consensus meeting, improved accuracy in the urea breath test and the stool antigen test, new recommendations for second-line therapy, and a greater understanding of antimicrobial resistance in treatment failure. In addition, new studies have confirmed that H. pylori infection and use of nonsteroidal anti-inflammatory drugs or aspirin are the major causes of peptic ulcer disease and ulcer bleeding. This paper reviews the results of these studies and their implications for future research.

Background: Relatives of gastric cancer patients have an increased risk of gastric cancer, possibly related to genetically-related strains of Helicobacter pylori or a common environment., Methods: The pattern of gastritis and H. pylori from gastric cancer patients and their first-degree relatives were compared using detailed DNA fingerprints and vacA, cagA, and iceA genotyping., Results: Sixteen index cases from Korea, the US, or Colombia and their 38 first-degree relatives (brothers, sisters, sons and daughters) were studied. No definite, or consistent, relationship between the pattern of gastritis and the relatedness of the H. pylori strain was observed (i.e. relatives could have an identical or a totally different pattern of gastritis regardless if they were infected with identical or highly similar organisms). For example, three elderly siblings of an index case with atrophic pangastritis had identical H. pylori isolates and environments in childhood and yet two had antral predominant nonatrophic gastritis, which is typically associated with duodenal ulcer instead of gastric cancer., Conclusions: The results of this study are not consistent with the hypothesis that specific virulence factors or similar H. pylori strains correlate with a specific histologic pattern or outcome even among those sharing the same environment in childhood.

Continuing attempts have been made to classify pathogenic strains within bacterial populations based on DNA fingerprints and to identify virulence factors in H. pylori. We studied 287 H. pylori isolates from patients with duodenal ulcer or gastric cancer from three different geographic regions. DNA fingerprints were generated using REP-PCR and analyzed by cluster analysis. The status of three candidate virulence factors-vacA polymorphism, cagA and iceA,-were examined by PCR amplification. Cluster analysis of the REP-PCR fingerprints showed clustering by geographic region but not by disease presentation. cagA was detected in 91.3% of the isolates. Differences in vacA subtypes were observed among the three geographic regions. There was no association between iceA subtypes and clinical outcome. We conclude that geographic differences among the H. pylori strains exist in single gene allelic variants as well as in the conserved noncoding regions such as REP sequences throughout the entire bacterial genome. We did not detect any association between disease presentation and H. pylori genotypes using either DNA fingerprinting or candidate single gene virulence factors.

The actual distribution of Helicobacter pylori infection and its related diseases in various Asian countries is controversial. Only limited information is available regarding this issue. We discuss the etiological role of H. pylori in gastric cancer through the Asian experience. Seroprevalence of H. pylori infection in asymptomatic subjects and the annual incidence rate of gastric cancer per 100,000 in various Asian countries are summarized from literature reviews and World Health Organization statistics, respectively. There is a large intercountry variation in incidence of gastric cancer and H. pylori seroprevalence among Asian countries. There is a strong link between H. pylori infection and gastric cancer in many countries, such as Japan. By contrast, the prevalence of H. pylori infection is high in some countries, including India and Bangladesh, but low gastric cancer rates have been reported. These disparate observations represent the Asian enigma. Factors that may influence the etiology of gastric cancer include the genetic diversity of the infecting H. pylori strains and differences in the host genetic background in various ethnic groups, including gastric acid secretion and genetic polymorphisms in proinflammatory cytokines. These factors, in addition to environmental factors, such as personal hygiene and dietary habits, reflect the multifactorial etiology of gastric cancer.

Helicobacter pylori is a common bacterium infecting about half the world's population. It is causally linked with a diverse spectrum of gastrointestinal clinical disorders including peptic ulcer disease, gastric cancer, and gastric MALT lymphoma. The principal reservoir is the human stomach, and transmission probably occurs by person-to-person passage. Prevalence rates are generally much higher in developing countries compared to developed countries, although there are subgroups within many regions with higher H. pylori prevalence than in the general population. The prevalence of H. pylori varies by geographical location, ethnic background, socioeconomic conditions, and age. Recent studies suggest decreasing prevalence in developed countries or those with rapidly improving socioeconomic conditions. Comparative studies of the two fully sequenced H. pylori genomes are providing understanding of its large genetic diversity and bacterial virulence factors. The discovery of the type IV secretion system in H. pylori and its role in translocation of the CagA protein from the bacterial cell into the host epithelial cell provides insight into how host-bacterial interaction may lead to host disease. Cytokine promoter polymorphisms are determinants important in host gastric acid secretion status. Understanding the changing trends in H. pylori epidemiology, details of its transmission pathways, and the bacterial and host determinants leading to gastroduodenal disease remain the challenges in this area. Global epidemiological studies, advances in technology, and medical interventions have converged to help clarify the mechanisms of interaction between this ubiquitous micro-organism and its host that result in its diverse clinical manifestations.

Helicobacter pylori infection is the world's most common chronic infection in humans and is the cause of most gastritis cases. This infection is accepted as the etiology of the majority of peptic ulcers. It has been implicated as a significant contributing factor in the development of gastric malignancy--both gastric MALT lymphoma and gastric adenocarcinoma. Both endoscopic and non-endoscopic tests are available for accurate diagnosis of the infection. Several multi-drug regimens are useful for effective eradication of the infection. Strategies have been developed for managing patients with gastric MALT lymphoma. Criteria to identify populations with increased risk for gastric malignancy are being developed. H. pylori induces gastritis; it is also involved in both apoptosis and cellular proliferation. The role of H. pylori infection in the pathogenesis of premalignant lesions, altered gastric acid secretion, and significant clinical presentations is the subject of numerous studies worldwide.

Peptic ulcer disease is a common gastrointestinal disease whose management and treatment has changed dramatically over the last 25 years. Treatment of peptic ulcer disease has evolved from dietary modifications and antacids to gastric acid suppression with H2-receptor antagonists and proton pump inhibitors to eradication of Helicobactor pylori infection. Treatment of patients infected with H pylori using antibiotics has changed the natural history of peptic ulcer disease. As a result of H pylori treatment and other unknown factors ulcer disease is declining and complications from ulcer disease have diminished significantly.

Objectives: Whether gastric infection with Helicobacter pylori increases the risk of gastric mucosal injury during long term/low dose aspirin therapy is unknown. We examined whether H. pylori infection enhances upper GI mucosal damage, assessed endoscopically, in volunteers given low dose aspirin. We studied 61 healthy men and women, 29 with and 32 without active H. pylori infection., Methods: We treated volunteers for 45 days with a placebo or aspirin (either 81 mg every day or 325 mg every 3 days). Gastroduodenal mucosal damage was then assessed by endoscopy, as was gastric histology and ex vivo gastric mucosal prostaglandin E2 and F2alpha synthesis rates., Results: Erosive disease from low dose aspirin (erosions and/or ulcers) occurred in 50% of H. pylori-infected volunteers and in 16% of their noninfected counterparts (p = 0.02). Aspirin caused a significantly higher average mucosal injury score in the gastric antrum in H. pylori-infected participants than in noninfected subjects (p = 0.03), and two H. pylori-infected subjects developed antral gastric ulcers. Subjects with H. pylori gastritis treated with the placebo had nearly 50% higher gastric mucosal prostaglandin (E2 plus F2alpha) synthesis rates than their noninfected counterparts (108 +/- 6 ng/g/min versus 75 +/- 6 ng/g/min, p < 0.001). Aspirin reduced mucosal prostaglandin synthesis to similar levels in infected and noninfected participants., Conclusions: Long term/low dose aspirin therapy led to more gastric mucosal damage when H. pylori gastritis was present than when it was absent, despite similar degrees of gastric mucosal prostaglandin depletion.

Objectives: Recent surveys of physician practice have suggested the existence of excessive, inappropriate use of the fecal occult blood test (FOBT). We studied the implementation of this test in hospitalized patients., Methods: We performed a retrospective chart review of 1000 randomly selected patients who had been discharged from the Medicine service at four teaching hospitals. Patient demographics, clinical presentation, presence or absence of overt GI bleeding, and use of medications that might affect the FOBT were recorded. Reviewers assessed whether patients who had FOBT would have been candidates for colon resection if asymptomatic colon cancer had been found., Results: Digital rectal examination was documented in 44.8% of patients; the findings were recorded in only 9%. A total of 421 patients had FOBT on admission, usually on stool obtained at digital rectal examination. Of the patients with a positive FOBT, 17% had active GI bleeding. Only 41.1% of patients with a positive FOBT were referred to the gastroenterology service. In 70.5% of patients, FOBT could be considered inappropriate because of factors such as age, active GI bleeding, or use of aspirin or other nonsteroidal anti-inflammatory drugs., Conclusions: The FOBT, which is validated only for colorectal cancer screening, is often performed inappropriately in patients admitted to the hospital. This test should be restricted in hospital practice. It would be preferable to identify patients who are appropriate candidates for colorectal cancer screening at the time of hospital discharge and to advise them about the appropriate performance of the FOBT at home.

Discussion continues on the role of Helicobacter pylori. The following debate provides a venue to examine 2 sides of this complicated issue. Dr. Vakil presents evidence that the eradication of H pylori will improve patients' health, while Dr. Go introduces evidence that suggests the presence of H pylori can be beneficial in particular cases. These clinicians also discuss the issue of whether to test and treat for H pylori and the role of H pylori in patients with gastroesophageal reflux disease.

Bacterial and host response factors play significant roles in the pathogenicity of H. pylori-related disease manifestations. The complete DNA sequences for two H. pylori strain genomes have been published. The differences in the sequences between these two unrelated strains may enable clinicians to identify rapidly other conserved and potentially virulent genes and products. Whether these two DNA sequences are sufficient representation of the H. pylori genetic heterogeneity is unknown. The host immune response and the cascade of events that occurs with H. pylori infection are being clarified rapidly. Understanding the role of this gastric bacterium in apoptosis and cellular proliferation would enable clinicians to understand its relationship to ulcerogenesis and gastric malignancy. Piecing together many observations related to H. pylori would result in understanding the interaction of H. pylori factors and host responses that lead to the variety of disease manifestations associated with this chronic infection. The development of animal models with H. pylori and other Helicobacter species has set the stage in which in vitro observations can be tested in the in vivo model.

Objective: Despite recently published national guidelines, many physicians have only limited knowledge about Helicobacter pylori infection. We conducted this study to assess internal medicine residents' knowledge about H. pylori., Methods: Two hundred and nineteen residents in seven accredited internal medicine training programs completed a self-administered questionnaire on personal demographics and practices related to testing for-and treating-H. pylori infection., Results: Noon conferences (82%), ward teaching (66%), journals (70%), and sponsored symposia (27%) were their major sources of H. pylori-related information. Forty-eight percent had used office-based tests for the infection. Testing for (and treatment of) Helicobacter pylori infection was recommended by 97% (97%) for newly diagnosed duodenal ulcer, but by only 61% (63%) for a past history of duodenal ulcer. Many recommended testing in unproven conditions and might not have offered treatment to an infected patient. A proton pump inhibitor-based triple-drug regimen was the treatment of first choice of 55%; 20% recommended proton pump inhibitor-based dual regimens. Sixty-six percent and 80%, respectively, underestimated the rates of resistance to clarithromycin and metronidazole. In the absence of gastrointestinal symptoms, 22% would have ordered Helicobacter pylori testing but only 33% of these would undergo treatment if positive., Conclusions: Internal medicine residents usually test for Helicobacter pylori infection in appropriate conditions, but may not always treat the infection when the result is positive. Most use efficacious treatment regimens although many have inaccurate knowledge of resistance rates, which may adversely influence prescribing. Education should focus on practical issues surrounding Helicobacter pylori testing and treatment such as those contained in the American College of Gastroenterology's 1998 practice guidelines.

The discovery of Helicobacter pylori and its relationship to upper gastrointestinal tract diseases has emphasized the significance of infectious pathogens in clinical disease. Severe manifestations of H. pylori-associated diseases include gastric adenocarcinoma and the recently described gastric mucosa-associated lymphoid tissue (MALT) lymphoma. Ongoing worldwide investigations of the interactions of H. pylori and the host response are rapidly clarifying the role of this bacterium in multiple gastrointestinal diseases. This review will address diagnosis, management, and follow-up of the patient presenting with gastric MALT lymphoma, including a discussion of the issues related to premalignant lesions associated with gastric adenocarcinoma. Prospective trials and long-term follow-up studies are in progress and will guide appropriate management of these diseases.

Combination antimicrobial therapies for the effective eradication of Helicobacter pylori infection have been identified and are commercially available. Ongoing studies to improve eradication rates are based on modification of currently approved treatments. Management of H. pylori infection now focuses on which patients should be treated and, by extension, which should be tested, because all patients should have a positive test result for H. pylori before starting antimicrobial therapy. Peptic ulcer disease was believed to be caused by acid abnormalities until about two decades ago, when H. pylori was successfully cultured; the clinical records of an early proponent of an infectious cause of peptic ulcer disease were recently discovered. The role of H. pylori infection in gastroesophageal disease and in ulcer disease associated with nonsteroidal anti-inflammatory drugs have become intensely investigated topics. Consensus conferences among pediatric physicians are establishing practice guidelines for H. pylori management in children and adolescents.

Chronic Helicobacter pylori infection is associated with mucosal inflammation. The aim of the present study was to assess human neutrophil and monocyte activation induced by H. pylori strains with different virulence genotypes. Bacterial sonicates from 12 strains were used to induce phagocyte up-regulation of adherence molecule CD11b, assessed by fluorescence flow cytometry, and oxidative burst responses, assessed by chemiluminescence. A dose-dependent induction of the expression of CD11b was observed with sonicate from all H. pylori strains on both neutrophils and monocytes. Strains negative for cagA and picB genes had the same inducing activity of upregulation of CD11b as strains positive for these genes. A vacA-S2 type strain had the same activity as vacA-S1 type strains. The induction of toxic oxygen radicals by H. pylori-activated neutrophils gave higher median values for the cagA-positive strains than for the cagA-negative strains. For the monocyte chemiluminescence response, cagA-negative strains gave higher median values compared to cagA-positive strains. We conclude that upregulation of the neutrophil and monocyte adherence molecule CD11b induced by H. pylori sonicates is not associated with the presence of cagA, picB or mosaic pattern of vacA, and that cagA, picB-negative strains and vacA-S2 strains retain their inflammatory capacity.

Chronic Helicobacter pylori infection is associated with mucosal inflammation. The aim of the present study was to assess human neutrophil and monocyte activation by H. pylori strains obtained from patients with different clinical presentations. Bacterial sonicates from 12 strains were used to stimulate phagocyte upregulation of CD11b/CD18 adherence molecules assessed by fluorescence flow cytometry and oxidative burst responses assessed by chemiluminescence. A dose-dependent activation of CD11b/CD18 adherence molecules was observed with all strains on both neutrophils and monocytes. The activities were similar for strains from patients with duodenal ulceration and for strains from asymptomatic volunteers irrespective of histopathologic grades of the biopsy specimens from the antral mucosa. The neutrophil chemiluminescence response correlated with histopathologic severity. We conclude that upregulation of neutrophil and monocyte adherence molecules by H. pylori sonicates is not associated with clinical presentation of the infection.

Objective: Whether Helicobacter pylori infection and use of nonsteroidal antiinflammatory drugs (NSAIDs) are independent risk factors for ulcerogenesis remains unclear. We undertook this study to evaluate H. pylori isolates from gastric ulcer patients to determine whether the genotype of the infecting isolate could be correlated with the use or nonuse of NSAIDs., Methods: Fifty-two patients presenting with gastric ulcer and infected with H. pylori were included; 26 patients were taking NSAIDs or aspirin (ASA) regularly at the time of ulcer diagnosis. Polymerase chain reaction (PCR) was employed to assess the presence and mosaicism of the following H. pylori genes: cagA, vacA, iceA, and picB., Results: We found no statistical differences in the presence of these genes in H. pylori isolates from gastric ulcer patients taking or not taking prescription NSAIDs or ASA. A 297-bp fragment of the cagA gene was detected in 96% of the isolates from the NSAID and ASA users and 100% from the non-NSAID users (p = 1.0). A larger and more variable region of the cagA gene was detected more frequently among the isolates from non-NSAID users than those from NSAID users (p = 0.05). Ninety-two percent of the isolates were identified as vacA genotype s1. The dominant vacA subtype was s1b, 76.9% and 65.4% in isolates from non-NSAID-taking or NSAID-taking patients, respectively (p = 0.4). iceA1 genotype was not correlated with gastric ulcer as this allele was only detected in 17.3% of all isolates., Conclusions: No significant differences in the presence of the candidate virulence genes vacA, cagA, picB, or iceA were detected in isolates from gastric ulcer patients taking prescription NSAIDs or ASA, compared with those not taking these drugs, indicating that single gene presence does not allow discrimination of isolates that may be important in NSAID-induced ulcerogenesis. A variable region of the cagA gene was more frequently detected in isolates from patients not taking NSAIDs or ASA, suggesting that this gene may be modified by NSAID- or ASA-related factors or that certain strains may be selected for in patients taking these medications.

An algorithmic approach to evaluation of dyspepsia or abdominal discomfort begins with differentiation between peptic ulcer disease and gastroesophageal reflux disease as well as recognition of alarm signs and symptoms for gastric cancer, which are indications for early endoscopy. In the absence of alarm symptoms, most patients should undergo noninvasive testing for H pylori infection with a serologic, urea breath, or stool antigen test. Factors to consider in selection of appropriate testing include reliability, specificity, sensitivity, cost, and local access and expertise. As a general rule, physicians should choose a test that has the best accuracy for the level of testing expertise available. The basic principle underlying testing for H pylori is that patients should not undergo testing unless the physician is willing to treat on the basis of a positive test result. In patients who receive treatment, confirmation of cure is important for preventing further morbidity and reducing risk of transmission of infection.

Peptic ulcer disease associated with H pylori infection is curable. The important factors in selecting therapy are efficacy of eradication, prevention of resistance, avoidance or minimization of adverse effects, patient compliance, and cost. The most effective regimens include a bismuth preparation or antisecretory drug (proton pump inhibitor or H2 receptor antagonist) plus two antibiotics administered for 14 days. Dual-drug therapies are not recommended. Triple-drug regimens are more likely to eradicate H pylori and less likely to generate resistant strains among surviving organisms. In general, cure of the infection should be confirmed 4 weeks after completion of the treatment. Antibiotic resistance is an important consideration in choosing therapy, and patients should be taught the importance of compliance. When treatment fails, antibiotic combinations should not be repeated. Considerations for anti-H pylori treatment in a managed care environment mirror those for good medical practice in general, with special attention to stringent cost-control or outcomes-driven measures.

H pylori infection is so common as to seem ubiquitous in many areas of the world. Transmission is believed to be primarily person to person. The pathogen invariably damages the gastric mucosa, resulting in both structural and functional abnormalities. It causes histologic gastritis and is critical in the pathogenesis of the gastritis-associated diseases, namely, gastric ulcer, duodenal ulcer, gastric adenocarcinoma, and primary gastric lymphoma. Elimination of the infection results in healing of gastritis and cure of peptic ulcer disease.

Objective: Few studies have examined the genetic relationships of Helicobacter pylori strains affecting family members. Our aim was to do so., Methods: We characterized H. pylori isolates obtained from members of a single family presenting with various gastroduodenal diseases to examine H. pylori bacterial genetic similarity. Endoscopic evaluation with gastric mapping was performed on each individual to establish clinical and histological disease. Genomic DNA extracted from each H. pylori isolate was used to generate DNA fingerprints for each strain by REP-PCR. vacA genotypes and cagA presence were established by PCR., Results: Gastrointestinal diseases among the five members of this family included gastric adenocarcinoma in a 52-yr-old man (index patient), gastric MALT-lymphoma in the 73-yr-old mother; intestinal metaplasia (IV) and atrophic gastritis in the 48-yr-old brother; intestinal metaplasia (I-III) in the 47-yr-old brother, and a duodenal ulcer scar in the 42-yr-old sister. REP-PCR DNA fingerprints of H. pylori isolates from the index patient, his mother, and both of his brothers were identical or highly similar. By contrast, the H. pylori DNA fingerprint from the sister was markedly different from the H. pylori DNA fingerprints from the other family members. All isolates had the genotype cagA-positive and vacA slb/ml mosaic genotype., Conclusions: The DNA fingerprints of H. pylori strains obtained from members of this family with malignancy or premalignant histological disease were identical or highly similar and markedly different from the H. pylori DNA fingerprint from the sibling with duodenal ulcer disease. All H. pylori isolates within the family possessed genetic markers of enhanced virulence (presence of the cagA gene and vacA sl/ml mosaicism). In addition to host genetics and environmental factors, these findings suggest that infection with genetically similar H. pylori strains is a significant factor in determining the clinical outcome of an infection with H. pylori.

Overwhelming evidence implicates Helicobacter pylori as a significant causative factor in many gastroduodenal diseases. Effective multidrug antimicrobial regimens are available for cure of the infection, so investigative efforts are focusing on cost-effectiveness and treatment outcome in various populations. Potential associations between H. pylori and nongastric disorders are being examined. Recognition that infection is largely acquired during childhood has emphasized the need to study pediatric issues. Posttreatment studies confirm the importance of the bacterium in pathogenesis and relapse of peptic ulcer disease. Antimicrobial resistance has a negative impact on cure of the infection and healing of gastroduodenal lesions. Methodology to evaluate H. pylori antimicrobial susceptibility has been standardized by the National Committee for Clinical Laboratory Standards, and minimum inhibitory concentration breakpoints to standardize resistance assays are being established. Surveillance of H. pylori antimicrobial resistance is underway in a Centers for Disease Control and Prevention multisite project in the United States.

In each of six gastric cancer patients, repetitive extragenic palindromic PCR DNA fingerprints of 18 single colonies of Helicobacter pylori from the gastric antrum, corpus, and cardia were identical and matched that of the parental isolate. In three additional gastric cancer patients, 17 of 18 single-colony DNA fingerprints were identical to each other and to the DNA fingerprint of the corresponding parental isolate.

The galE gene product, UDP-galactose 4-epimerase, mediates the incorporation of galactose in extracellular polysaccharide materials such as the O-side chain of lipopolysaccharide (LPS). The O-side chain in H. pylori LPS has been shown to cross-react with Lewis x and/or y blood group antigens, suggesting its potential involvement in H. pylori-linked autoimmune disease. To study its role in H. pylori LPS biosynthesis, the galE gene was cloned, sequenced, and a galE-knockout H. pylori strain was constructed. The H. pylori galE gene encoded a protein of 344 amino acids with a molecular weight of 39K. The LPS profile from the galE-knockout H. pylori strain showed a lower molecular weight than that of the parental strain, indicating the involvement of the galE gene in LPS biosynthesis of H. pylori.

The vacA genotypes s1,m1 and s1,m2 were detected in 44 and 30% of Helicobacter pylori isolates, respectively, from patients with gastric mucosa-associated lymphoid tissue lymphoma, compared to 26 and 56% of isolates, respectively, from individuals with gastritis. The vacA s1 genotype was significantly associated with, but not predictive of, the presence of vacuolating cytotoxin activity.

We previously identified four potential putative gastroduodenal disease fragments by using the interspersed repetitive extragenic palindromic DNA sequence based PCR (REP-PCR) technique. We investigated these fragments with regard to their disease specificity. The putative disease-specific REP-PCR fragments were cloned, mapped by restriction enzymes, cross-hybridized, and confirmed by Southern hybridization. The four fragments were also used as probes against REP-PCR amplicons from H. pylori isolates obtained from gastritis (N = 20), duodenal ulcer (N = 30), and gastric cancer patients (N = 30). Three of these fragments (1.4- and 0.76-kb for gastritis; 1.35 kb for duodenal ulcer) were amplified without any discrimination between any disease-specific H. pylori isolates. However, amplification following hybridization with the fourth 0.81-kb fragment was observed only from gastritis (60%) and duodenal ulcer (52%) but with none (0%) of gastric cancer patients. Nucleotide sequence analysis of the 0.81-kb fragment revealed that it was an open reading frame of the hypothetical protein HP0373 matched to the position of 380,966 to 383,068 nucleotides of the H. pylori complete genome sequence. Hence, the REP-PCR sequence was not a extragenic palindromic DNA sequence. The hypothetical protein was also present in all the tested isolates. The REP-PCR fingerprinting technique is useful to differentiate disease-specific H. pylori strains based on the interspersed repetitive extragenic palindromic DNA sequences; however, it may not be useful to identify disease-specific virulence determinant(s) without being confirmed by DNA sequence analysis and functional studies.

Background: Mosaicism of the Helicobacter pylori vac A gene comprises two families of allelic variations of the signal sequence region (s1, s2) and of the mid-region (m1, m2). Initial studies suggested that peptic ulcer disease correlated with the s1 subtype of vac A. We compared the prevalence of various vac A genotypes of H. pylori isolates obtained from duodenal ulcer (DU) patients and subjects with simple gastritis. Those isolates with s1 type were further examined to determine whether the specific vac A s1 (s1a versus s1b) genotype enabled prediction of gastroduodenal disease., Methods: H. pylori isolates were obtained from 38 patients with endoscopically documented DU and 39 individuals with asymptomatic H. pylori gastritis from Houston, Texas. The vac A genotype of each isolate was determined by polymerase chain reaction (PCR) amplification of genomic DNA for specific regions of the vac A gene. Those isolates with s1 vac A subtype were further examined to determine whether they had s1a or s1b mosaicism., Results: There was no difference in frequency of the s1 genotype of isolates obtained from patients with duodenal ulcer or asymptomatic H. pylori gastritis in this sample (84% versus 79%, respectively; P = 0.77). The s1/m1 vac A genotype was detected in isolates from 16 duodenal ulcer patients versus 15 with H. pylori gastritis (P = 0.82). Detailed analysis of the s1 region failed to show a correlation of either s1a or s1b with duodenal ulcer. Both s1a and s1b genotypes were detected in 24 strains, and both m1 and m2 mid-gene PCR amplicons were seen in 16 strains., Conclusions: We were unable to use H. pylori vac A genotyping to predict type of gastroduodenal disease in our patient sample. This failure to confirm an association of vac A genotype and duodenal ulcer disease differs from samples from other regions. This most likely represents an example of differences in H. pylori strains infecting host populations in different geographic regions. This study confirms the importance of establishing statistical associations with isolates from widely separate geographic regions before concluding that disease-related associations exist.

CagA has been suggested as a marker for more virulent strains of Helicobacter pylori. Studies using purified proteins and an enzyme-linked immunosorbent assay (ELISA) method for serological detection of antibodies against CagA reported considerable discordance between the results of the ELISA and molecular detection of the cagA gene, with a tendency for estimation of the prevalence of cagA-positive H. Pylori to be higher by ELISA than by colony hybridization. It is not clear whether the discordance was either due to simultaneous infections with both cagA-positive and -negative strains or because of false-positive ELISA results. We correlated the presence of cagA-positive H. pylori by Polymerase chain reaction (PCR) with the presence of serum antibodies against the CagA protein from denatured H. pylori lysates. Gastric biopsies and sera were obtained from 75 patients from Korea; 25 each with gastric carcinoma, duodenal ulcer, and simple gastritis. Seventy-four of 75 isolates (98.6%) were cagA-positive by PCR and 70 sera were CagA antibody-positive by Western blotting. The cagA gene is common in H. pylori isolates from Korea regardless of the underlying disease. The presence of cagA is almost always associated with antibody to the CagA protein as determined by Western blotting. Western blotting may be the preferred method for serological detection of infection with cagA-positive H. pylori.

Helicobacter pylori infection is associated with duodenal and gastric ulcer disease, gastric cancer, and gastric mucosa-associated lymphoid tissue lymphoma. Although more than half the world's population harbors H. pylori, only a proportion will develop clinically significant disease. The specific clinical outcome of an individual can be examined as the modulation of host factors by H. pylori infection. Host acid-secretory status and sensitivity to gastrin can be modulated by H. pylori infection. Once H. pylori has established itself in the stomach, virtually everyone develops gastritis, and variations in gastritis patterns have been associated with different gastric acid responses to H. pylori infection. The patterns of gastritis are important because they seem to determine disease outcome. Blood group antigens have been implicated in studies of ulcer disease. Receptors to Lewis antigens in gastric mucosa indicate that host mucosal factors influence H. pylori attachment. Conversely, H. pylori strains express Lewis antigen-like molecules, suggesting an autoimmune component for some H. pylori-associated diseases. HLA genotypes may influence the host response to H. pylori infection, and those of H. pylori-infected individuals have been correlated with histological features. The clinical outcome of H. pylori infection is most likely a result of complex interactions among host, bacterial, and environmental factors. The mechanisms by which these diverse factors influence the pathogenesis of different clinical outcomes remain under investigation.

Genetic diversity and relationships in 74 Helicobacter pylori isolates recovered from patients assigned to distinct clinical categories were estimated by examination of allelic variation in six genes encoding metabolic housekeeping enzymes by multilocus enzyme electrophoresis. Seventy-three distinct allele profiles, representing multilocus chromosomal genotypes, were identified. All six loci were highly polymorphic, with an average of 11.2 alleles per locus. The mean genetic diversity in the sample was 0.735, a value that exceeds the level of diversity recorded in virtually all bacterial species studied by multilocus enzyme electrophoresis. A high frequency of occurrence of null alleles (lack of enzyme activity) was identified and warrants further investigation at the molecular level. Lack of linkage disequilibrium (nonrandom association (of alleles over loci) indicates that horizontal transfer and recombination of metabolic enzyme genes have contributed to the generation of chromosomal diversity in H. pylori. In this sample of isolates, there was no statistically significant association of multilocus enzyme electrophoretic types or cluster of related chromosomal types and disease category.

Objective: Helicobacter pylori is an important factor in the development of duodenal ulcer disease and has been implicated in the pathogenesis of gastric adenocarcinoma. It has been suggested that the cagA gene is a marker for more virulent strains of H. pylori., Methods: We determined the prevalence of the cagA gene in 60 clinical isolates [34 from gastric carcinoma patients (CA), 26 from duodenal ulcer patients (DU)] from Korea, a country with a high incidence and mortality from gastric cancer. Genomic DNA was polymerase chain reaction-amplified by using two different primer sets for the cagA gene. The first cagA primer set amplifies a 297-bp product from the midregion of the cagA gene. The second primer set, which was previously established in a patient population from the Houston area (21 DU patients, 20 from individuals with asymptomatic gastritis) amplified a 1.4-kb region further downstream in the cagA gene., Results: The expected 297 bp polymerase chain reaction amplicon for cagA was identified in 59/60 (98.3%) H. pylori isolates from Korea (33/34 CA, 26/26 DU), and in 36/41 (88%) isolates from the Houston area (20/21 DU, 16/20 asymptomatic gastritis) (NS). Using the second cagA primer set, the expected 1.4-kb product was found in only 1/60 (1.7%) H. pylori isolates from Korea (1/34 CA, 0/26 DU), and in 36/41 (88%) of isolates from the Houston area (20/21 DU, 16/20 GST) (p < 0.001). Western blot analysis showed that all Korean H. pylori isolates expressed cagA., Conclusions: The high prevalence of the cagA gene in H. pylori isolates from Korean patients with gastric adenocarcinoma or duodenal ulcers indicates that the cagA gene is common in H. pylori strains, and therefore, is not reliable as a single marker for the discrimination of H. pylori strains with respect to a specific disease. Our data further suggest that allelic variations in the genome of H. pylori strains may exist and that distinct H. pylori populations may circulate in different geographic regions.

Background: Inhibition of Helicobacter pylori growth by bile suggests that it should be difficult for H. pylori to colonize the duodenum and cause duodenal ulcer. To search for a common mechanism, we investigated the relationship between H. pylori strain (duodenal ulcer vs gastritis), type of bile acid conjugate, and inhibition of H. pylori growth., Methods: H. pylori isolates from patients with duodenal ulcer and from volunteers with asymptomatic gastritis (six each) were grown in brain heart infusion broth medium containing mixtures of glycocholate, taurocholate, glycodeoxycholate, taurodeoxycholate, glycochenodeoxycholate, and taurochenodeoxycholate with and without lecithin., Results: Synthetic human bile with or without lecithin inhibited H. pylori growth in a dose-dependent manner. There was no difference in inhibition between H. pylori gastritis and duodenal ulcer isolates. Glycine and mixed glycine and taurine-conjugated bile acids inhibited H. pylori more than taurine-conjugated bile acids (e.g., 51%, 67%, and 80% compared to 21%, 39%, and 46% for 1, 2, and 4 mM mixed conjugates compared with taurine conjugates, p < 0.05, respectively., Conclusions: The ability of H. pylori to grow in the presence of taurine-conjugated bile acids and the precipitation of glycine but not taurine bile acid conjugates by acid may provide one missing link among inhibition of H. pylori by bile, acid secretion, ability of antisecretory therapy to accelerate ulcer healing, and the ability of H. pylori to colonize the duodenal bulb of ulcer patients, leading to duodenal ulcer. These data also explain the disparate results of previous investigations of the effect of bile reflux in the stomach on the presence of H. pylori.

Background: Helicobacter pylori infection presents as many different diseases, including asymptomatic gastritis, peptic ulcer disease, and gastric cancer. Although the virulence factor(s) responsible for different H. pylori-related diseases have not been identified, several candidate genes are being investigated for such an association. The polymerase chain reaction (PCR) frequently is used to assess the presence of genetic factors associated with pathogenesis of disease; the cagA gene and its product have been postulated to have a disease-specific relationship to peptic ulcer and gastric cancer because of differential expression in these diseases compared to histological gastritis alone., Materials and Methods: Genomic DNA was amplified by PCR, using synthetic oligonucleotide primers to the cagA gene to determine the prevalence of the cagA gene in 60 H. pylori isolates obtained from well-documented duodenal ulcer or asymptomatic gastritis patients (30 each). Results were confirmed by hybridization with a 1.4-Kb cagA probe., Results: The expected PCR product was obtained in 90% of isolates from duodenal ulcer patients, compared to 70% of isolates from individuals with asymptomatic gastritis. The PCR products were polymorphic in size, suggesting cagA gene sequence differences among isolates. Evaluation for the presence of the cagA gene by hybridization with a 1.4-Kb cagA probe showed a homologous product in 29 of 30 strains [96.7%; 95% confidence interval (CI) = 83-100%] from duodenal ulcer patients versus 25 of 30 strains (83.3%; 95% CI = 65-94%) obtained from individuals with asymptomatic gastritis (p = 0.19)., Conclusions: The high prevalence of the cagA gene in asymptomatic gastritis suggests that it will not prove to be a useful marker to distinguish more virulent or disease-specific H. pylori strains. The genetic heterogeneity among H. pylori strains makes PCR an unwise choice as the single method to determine prevalence of a putative virulence factor. In evaluation of the prevalence of a gene or genetic factor in a population of H. pylori, hybridization with extended probes might be important to ensure that the results are representative of the organism's genotype.

Twelve clarithromycin-resistant Helicobacter pylori isolates (100% of resistant isolates examined) from seven different patients each contained an A-->G transition mutation within a conserved loop of 23S rRNA. A-->G transition mutations at positions cognate with Escherichia coli 23S rRNA positions 2058 and 2059 were identified. Clarithromycin-susceptible H. pylori isolates from 14 different patients displayed no polymorphisms in a conserved loop within domain V of 23S rRNA. The study is the first to report mutations in H. pylori associated with resistance to an antimicrobial agent used in established peptic ulcer treatment regimens.