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The ATP-dependent caseinolytic proteases (Clp) are important in resistance against environmental stresses, antibiotic treatments and host immune defences for a number of pathogenic bacteria. ClpP is the proteolytic subunit, whilst ClpA acts both as a chaperone and as an ATPase driving the degradation of damaged or mis-made proteins. The gastric pathogen Helicobacter pylori infects approximately half of the world's population and can cause gastric or duodenal ulcers, gastric malignancies and mucosa-associated lymphoid tissue lymphomas. The conditions of its in vivo environment expose the organism to host immune cells and upon treatment, antibiotics, conditions likely to cause protein damage. We generated isogenic nonpolar mutants in strain SS1 of clpP and clpA and double mutants with both genes inactivated. Such mutants showed increased sensitivity to antibacterials causing protein damage and/or oxidative stress, in addition to a reduced survival in human macrophages. In the mouse infection model the double mutant SS1 clpAP lacked all ability to colonize the murine host. This suggests that the ability to recover from protein damage is of key importance in the pathogenesis of this organism.

Fhit protein is known to play a role in the process of neoplastic transformation. It has been demonstrated that FHIT gene inactivation is manifested by a lack or very low concentration of Fhit protein in tissues collected from tumours in many organs, including head, neck, breast, lungs, stomach or large intestine. The study included a group of 80 patients with advanced gastric carcinomas. The expression of Fhit protein was assessed by means of the immunohistochemical method (avidin-biotin-streptavidin) in the sections fixed in formalin and embedded in paraffin, using rabbit polyclonal antiFhit antibody (Abcam, UK) at 1: 200. Statistical analysis did not show any correlation of the expression of Fhit protein in the main mass of tumour and in the metastasis to lymph node with gender, depth of wall invasion, histological differentiation, Lauren's classification, Bormann's classification, metastases to local lymph nodes or Helicobacter pylori infection. However, a strong statistical correlation was revealed of Fhit protein expression in the main mass of tumour with patients' age (p=0.04) and tumour location in the stomach (p=0.02). No relationship was found between Fhit expression in the main mass of tumour and survival time (p=0.26).

The eradication of Helicobacter pylori (H. pylori) with antibiotics induces complete remission in 75% of patients with gastric MALT lymphoma. We investigated the efficacy of H. pylori eradication and assessed the predictive value of BCL10 nuclear expression and t(11;18)(q21;q21) regarding resistance to H. pylori eradication in primary gastric mucosa-associated lymphoid tissue lymphoma (MALT lymphoma) patients from mainland China. Twenty-two gastric MALT cases (Stage I(E)) underwent H. pylori eradication with antibiotics, and sequential endoscopic-bioptic follow-ups were performed and assessed with regular morphologic and immunohistochemical examinations. BCL10 nuclear expression and interphase fluorescence in situ hybridization (FISH) for MALT1 and API2/MALT1 were tested. Thirteen out of the 22 cases (59.1%) achieved complete regression (CR) after the eradication of H. pylori. The longest follow-up period in the 22 patients was 68 months, with 12 patients longer than 24 months. For the 13 CR patients, the longest follow-up period after H. pylori eradication was 53 months, with 6 patients longer than 24 months. BCL10 nuclear expression was detected by immunohistochemical staining in 9 cases, including 7 (77.8%) of 9 cases who showed no response (NR) and 2 (15.4%) of 13 patients who achieved CR following eradication therapy (P < 0.05). t(11;18)(q21;q21) was evaluated by interphase FISH in 18 cases including 11 CR and 7 NR patients after H. pylori eradication. t(11;18)(q21;q21) was found in 4 (57.1%) of 7 patients who showed NR following H. pylori eradication, but one in 11 CR patients (P < 0.05). A total of 59.1% of patients with early gastric MALT lymphoma recruited in this study achieved CR after H. pylori eradication. BCL10 nuclear expression and t(11;18)(q21;q21)-positive gastric MALT lymphomas are likely to be related to a failure to respond to H. pylori eradication in Chinese patients.

Unlabelled: AIMS, BACKGROUND, AND METHODS: In Tuscany, Italy, gastric cancer mortality has been decreasing since 1950, although with relevant geographical variability across the region. In Eastern Tuscan areas close to the mountains (high risk areas), gastric cancer mortality has been and is still significantly higher than that recorded in Western coastal areas and in the city of Florence (low risk areas). High-risk areas also showed higher Helicobacter pylori seroprevalence. Aim of this paper is to study gastric cancer mortality trends in high and low-risk areas, during the period 1971-2004, using age-period-cohort models., Results: In high-risk areas, gastric cancer mortality rates declined from 61.4 per 100,000 in 1971-74 to 19.8 in 2000-2004 and in low-risk areas from 34.9 to 9.8. Mortality decline in high-risk areas was mainly attributable to a birth cohort effect, whereas in low-risk areas it was due either to a birth cohort effect or a period effect. In low- and high-risk areas, birth-cohort risks of dying decreased over subsequent generations, except for the birth cohorts born around the second world war., Conclusions: Gastric cancer mortality in areas with higher H. pylori seroprevalence in Tuscany (high-risk areas) showed a predominant decline by birth cohort, in particular for younger generations, possibly due to the decrease of the infection for improvement of living conditions.

Background: Although Helicobacter pylori infection is closely associated with gastric cancer development, follow-up studies after H. pylori eradication are still scarce., Aim: To clarify the cancer preventive effect of H. pylori eradication, with special attention to differences in effect according to histology., Methods: Patients who underwent H. pylori eradication therapy and were followed-up endoscopically for at least 1 year were analysed. The incidence of gastric cancer and factors associated with cancer development were investigated., Results: A total of 1807 patients were enrolled. Six of 1519 H. pylori eradicated and five of 288 persistent subjects developed gastric cancer. Four of the eradicated subjects developed the intestinal type and two the diffuse type, while four of the persistent subjects developed the intestinal type and one the diffuse type. Kaplan-Meier analysis indicated a significantly lower incidence in eradicated patients than in persistent patients. The incidence of intestinal type was significantly lower than in eradicated patients, while the diffuse type could not be evaluated because of the low incidence., Conclusions: Helicobacter pylori-eradicated patients had a reduced incidence of gastric cancer compared with H. pylori-persistent patients, particularly the intestinal type, suggesting that H. pylori is strongly associated with intestinal-type gastric cancer.

Background: We previously REPORTED that mice with diabetes and short-term Helicobacter felis infection had an increase in glycated hemoglobin (HbA1c). Here we report the effect of long-term infection., Materials and Methods: Six-week-old C57BL/6 mice were injected with streptozotocin to induce diabetes and started on daily insulin. Following streptozotocin injection, animals were paired according to their HbA1c values and randomized to orally receive either H. felis or culture medium alone. Weight and HbA1c were monitored monthly for 6 months., Results: Thirty animals corresponding to 15 pairs were included in the study. H. felis-infected diabetic mice developed significantly more gastritis than uninfected animals. Sixteen mice died during the observation period. As compared to uninfected animals, infected mice died more frequently (40% versus 67%, p = .14) and earlier (160 versus 61 days, p = .20); both variables combined showed that H. felis infection significantly decreased the chances of survival during the study period (p = .045). In addition, infected mice showed a trend for higher increase in their HbA1c (0.97 +/- 2.5% versus - 0.22 +/- 3.0%; p = .21) and lower weight gain (2.0 +/- 3.4 g versus 2.9 +/- 2.0 g; p = .15) than uninfected mice., Conclusion: Long-term H. felis infection had a deleterious effect in mice with streptozotocin-induced diabetes resulting in increased mortality. If the same phenomenon occurs in humans this could lead to interventions to improve the long-term outcome of patients with diabetes.

The host immune response plays a critical role in determining disease manifestations of chronic infections. Inadequate immune response may fail to control infection, although in other cases the specific immune response may be the cause of tissue damage and disease. The majority of patients with chronic infections are infected by more than one organism yet the interaction between multiple active infections is not known, nor is the impact on disease outcome clear. Using the BALB/c strain of mice, we show that Toxoplasma gondii infection in a host infected with Helicobacter felis alters the natural outcome of T. gondii infection, allowing uncontrolled tachyzoite replication and severe organ damage. Survival rates decrease from 95% in T. gondii infection alone to 50% in dual-infected mice. In addition, infection with T. gondii alters the specific H. felis immune response, converting a previously resistant host to a susceptible phenotype. Gastric mucosal IFN-gamma and IL-12 were significantly elevated and IL-10 substantially reduced in dual-infected mice. These changes were associated with severe gastric mucosal inflammation, parietal cell loss, atrophy, and metaplastic cell changes. These data demonstrate the profound interactions between the immune response to unrelated organisms, and suggest these types of interactions my impact clinical disease.

Background: We evaluated the relationship between Helicobacter pylori and various factors associated with gastric cancer in two areas in Japan with different risks for mortality due to gastric cancer., Methods: A total of 250 sera from Niigata and 209 from Okinawa were used. H. pylori antibody and CagA antibody were measured by antigen-specific ELISAs. Serum gastrin and pepsinogen levels were determined by RIA., Results: Although there was no significant difference in H. pylori prevalence among the persons in Niigata (50%) and Okinawa (42%), CagA prevalence in these populations was significantly different, at 41% and 26%, respectively (OR = 1.98, 95%CI: 1.33-2.95, P < 0.01). Serum gastrin levels in Niigata were significantly lower than those in Okinawa in H. pylori-negative persons (P < 0.01). The serum pepsinogen I/II ratio in Niigata was significantly lower than that in Okinawa in H. pylori positive persons (P < 0.01), whereas there was no significant difference in H. pylori-negative persons. Among those positive for H. pylori, serum pepsinogen I/II ratio in Niigata was significantly lower than that in Okinawa in CagA-negative persons (P < 0.01), whereas no significant difference was observed in CagA-positive persons., Conclusions: These results suggest that the difference in the mortality ratio of gastric cancer between Niigata and Okinawa is mainly associated with the difference between areas in the prevalence of cagA-positive strains rather than that of H. pylori itself.

Aim: To analyze the clinicopathologic characteristics of surgically resected gastric lymphoma patients., Methods: We retrospectively analyzed 57 surgically resected gastric lymphoma patients, dividing them into 2 subgroups: Low grade MALToma (the LG group), High grade MALToma and Diffuse large B cell lymphoma (the HG group)., Results: The numbers of patients were: 20 in the LG group, 37 in the HG group. The diagnostic rate of gastroscopy was 34.8% at primary diagnosis and 50% including differential diagnoses. The positive rates of H pylori were similar between the 2 groups (68% vs 77%). Multiple lesions were found in 19.3%. The proportion of mucosal and submucosal lesions was 80.0%(16/20) in the LG group, and 24.3%(9/37) in the HG group (P<0.001). Lymph node invasion rates were 10.5%(2/19) in the LG group and 44.1%(15/34) in the HG group (P=0.031). The numbers of recurred patients were none in the LG group, and 8 in the HG group. By univariant analysis, group (P=0.024) and TNM stage (stage I, II vs stages III, IV, P=0.002) were found to be the significant risk factors. There was a tendency of higher recurrence rate in the subtotal gastrectomy group than in the total gastrectomy group (P=0.05)., Conclusion: The HG groups had a more advanced stage and a higher recurrence rate than the LG group. Although there was no difference between subtotal and total gastrectomies, more careful assessments of multiplicities and radical resections with lymph node dissections seem to be needed because of multiplicity and LN invasion even in LG group.

Medical ethics are not absolute; they change according to social attitudes, technological advances and alterations in the doctor/patient relationship. The discovery of Helicobacter pylori highlighted entrenched attitudes in academia and the pharmaceutical industry that were not always appropriate. The explosion of research that followed was ethically controlled by local research ethics committees and the system of peer review and editorial responsibility. Now that effective treatments are available, the control arm in trials of new therapy should be either placebo (giving the option of effective treatment later) or a first-line treatment; mono and dual therapy should not be employed because of the risk of inducing bacterial resistance. Ethical issues that still remain include whether always to test patients for H pylori at endoscopy and what information should be given when they test positive. The most important issue is the approach of the medical profession to the high death rate carried by H pylori infection. Peptic ulcer and gastric cancer together account for a large number of deaths worldwide, and the medical profession and public health services have not yet grappled with this problem, neither advocating universal testing and treatment nor funding or research to determine whether this approach would be effective.

Introduction: Complications of gastroduodenal ulcers such as bleeding and perforation have been afflicted with a mortality of up to 40 % in the past. Altered ulcer manifestation by improvement of medical treatment as well as advances in surgical techniques and intensive care medicine might currently have improved the outcome of these severely ill patients., Patients and Methods: A retrospective analysis of 73 patients with emergency operation for bleeding or perforated gastric (n = 50) and duodenal ulcer (n = 23) between 10/1994 and 7/2001 was performed., Results: The median age was 58 years (17-90 years) with 30 % of patients exceeding the age of 70 years. Eighty-one percent of patients had perforation, 19 % had bleeding. Factors predisposing for gastroduodenal ulcers were present in 88 %. Five percent of gastric perforations were due to gastric malignancies. Diagnosis of perforation was made in 88 % by conventional X-rays, in 12 % of perforations no free abdominal gas was detectable. A local surgical procedure (excision of ulcer and sutures/pyloroplasty) was performed in 64/73 patients (88 %), partial gastroduodenal resection was necessary in 9 patients (12 %). Histologic examination for helicobacter pylori was positive in 30/39 specimens (77 %). In-hospital mortality was 14 %, both for patients with bleeding and perforated ulcers. Surgical complications were 12 %., Discussion: Altered ulcer manifestation, minimized surgical therapy and improved intensive care medicine led to a recent reduction in postoperative mortality of patients suffering from perforated or bleeding gastroduodenal ulcer. A further reduction of this still high mortality might be expected by improvement of surgical training and/or restriction of therapy to a limited number of surgeons.

Gastric cancer is the second most common cause of cancer death in the world. Helicobacter pylori infection is now a well-accepted cause of this malignancy; in some parts of the world, up to eighty percent of all gastric cancers are at least in part caused by H. pylori infection. H. pylori infection typically starts in childhood as an inflammatory process in the stomach. The changes in the gastric microenvironment facilitate gastric cancer over time. Among infected individuals, genotype of H. pylori, coincident environmental exposures, and genetic factors of host seem to play roles in determining who will get gastric cancer and who will not. Unfortunately, it remains unknown whether treatment of H. pylori prevents gastric cancer. Thus, screening for H. pylori to prevent cancer is not yet widely recommended. Some consensus groups, however, have recommended screening for and treating H. pylori infection in individuals with family histories of gastric malignancy. In high-risk countries, screening programs for early gastric cancer itself may improve therapeutic outcome for this highly lethal disease.

Advancing knowledge of the existence of Helicobacter pylori and its association with gastrointestinal tract malignancy, and previous research showing higher-than-expected gastrointestinal tract malignancy in institutionalized adults with intellectual disability (ID) prompted a review of all deaths as a result of cancer in the Stoke Park group of hospitals for people with ID between 1946 and 1996. A 50-year, retrospective case note analysis of all deaths from cancer in an institution for people with ID was undertaken. Death from stomach cancer accounted for up to 48% of all cancer deaths. A further 25 residents had died of perforated stomach ulcers. The higher proportion of deaths specifically caused by stomach cancer in a population with ID has not been noted previously. It is postulated that the high levels of H. pylori infection found in institutionalized populations may be instrumental in this higher mortality rate and that the closure of the institutions without evaluation of H. pylori status transfers the problem unresolved to the community. Existing guidelines for the screening and eradication of H. pylori developed for the general population are inadequate when applied to people with ID, and therefore, the value of population screening and mass eradication programmes is explored.

Over the 14 years since Helicobacter pylori came to the attention of the medical community, we have reached the position that the organism is generally believed to be a serious pathogen. It causes a chronic infection with complications that include gastric and duodenal ulcer, gastric mucosa-associated lymphoid tissue lymphoma and gastric cancer. It is therefore an important cause of morbidity and mortality. We still do not have a perfect treatment for the infection, but enormous strides have been made since its discovery and acceptable treatments are now available. The best of these are the acid pump inhibitor- and ranitidine bismuth citrate-based triple therapies that provide 85-95% eradication in most studies. Better treatments and vaccination programmes may become available now that the Helicobacter genome has been decoded, raising the possibility of 'designer' antibiotics and vaccines. In the meantime, the current key questions are: How can our current therapies be improved? Who should be treated? What, if any, are the potential risks of widespread H. pylori eradication? And how is the organism transmitted? Without doubt, many of these questions will be addressed in the succeeding years. The papers presented in these proceedings represent an up-to-date analysis (much of it based on new data) by recognized experts. The views expressed are often provocative, but are backed by scientific data.

Objective: Knowledge about the influence of H. pylori-related disease on life expectancy might affect physician behavior in dealing with such disease. The aim of this study was to assess how life expectancy is influenced by H. pylori infection and peptic ulcer disease., Methods: The declining exponential approximation of life expectancy was used to model the effects of H. pylori and various peptic ulcer disease conditions on life expectancy. Deaths from peptic ulcer and gastric cancer were determined from the Vital Statistics of the United States. H. pylori prevalence rates were derived from the existing literature., Results: Cure of active peptic ulcer increases life expectancy by 2.3 yr in persons aged 40-44 yr and 121 days in persons aged 70-74 yr. More substantial impact occurs in complicated ulcer, with increases in life expectancy ranging between 26.1 and 6.3 yr. Primary prevention of H. pylori could increase life expectancy by 190 days in those aged 40-44 yr and 26 days in 70-74-yr-old subjects., Conclusion: The benefit of ulcer cure or H. pylori prevention diminishes as age advances. Cure of ulcers in young patients or in those who have sustained complications results in an appreciable increase in life expectancy. Successful primary prevention of H. pylori in selected populations could substantially increase life expectancy.

Good survival rates have been reported for resected early gastric adenocarcinoma (EGC) in patients found via screening procedures. However, the prevalence of Helicobacter pylori in EGC in unscreened populations is unclear. The major purpose of this investigation was to analyze the clinical experience and incidence of H. pylori in unscreened patients presenting with EGC at Charity Hospital over a 34-year period. From 1963 through 1997, the tumor registry at Charity Hospital compiled data on 2497 patients evaluated for gastric carcinoma. Of these patients, 26 (1%) had lesions that were confined to the mucosa or submucosa, i.e., T1N0M0 (American Joint Commission on Cancer classification). Pathology specimens and medical records were retrieved for confirmation of diagnosis and retrospective analysis for H. pylori. H. pylori was analyzed by Steiner staining and immunohistochemistry using a polyclonal antibody. EGC was detected in 12 men and 14 women with a mean age of 62 years. Upper gastrointestinal X-ray studies were performed on 19 of the 26 patients and failed to conclusively demonstrate a lesion in any case. Endoscopy was performed on 22 patients, and preoperative biopsies were positive in 95 per cent of these. Operative procedures included 2 local excisions and 22 subtotal and 2 total gastrectomies. No extended nodal dissections were performed. Microscopic evaluation revealed lesions limited to the mucosa in 63 per cent of cases and involving the submucosa in 37 per cent of the cases. Of the 14 patients evaluable of H. pylori, 79 per cent were positive for the bacterium. The status of 2 patients is unknown, and only 1 patient died of the original gastric cancer, for a disease-free survival of 96 per cent. The 5-year and 10-year overall survival rates were calculated to be 50 per cent and 21 per cent, respectively, when all causes of death were taken into consideration. Median follow-up of the survivors was 64 months. Resection of early gastric carcinoma in unscreened patients without extended lymphadenectomy yielded excellent results. H. pylori was present in 79 per cent of cases. These data suggest an association between H. pylori and EGC. Whether H. pylori infection is an etiologic factor in gastric cancer remains an area of active research.

Objective: To determine whether there is an independent association between Helicobacter pylori infection of the stomach and ischaemic heart disease., Design: Prospective study with measurement of IgG antibody titres specific to H pylori on stored serum samples from 648 men who died from ischaemic heart disease and 1296 age matched controls who did not (nested case-control design)., Subjects: 21,520 professional men aged 35-64 who attended the British United Provident Association (BUPA) medical centre in London between 1975 and 1982 for routine medical examination., Main Outcome Measure: Death from ischaemic heart disease., Results: The odds of death from ischaemic heart disease in men with H pylori infection relative to that in men without infection was 1.06 (95% confidence interval 0.86 to 1.31). In a separate group of 206 people attending the centre, plasma fibrinogen was virtually the same in those who were positive for H pylori (2.62 g/l) and those who were negative (2.64 g/l)., Conclusions: A study that by its size and design minimised both random error and socioeconomic bias found no relation between H pylori infection and ischaemic heart disease. The validity of the study was shown by its confirmation of the recognised association between H pylori infection and stomach cancer (odds ratio 4.0 (1.9 to 8.2); P < 0.001). Eradication of H pylori infection may greatly reduce the incidence of stomach cancer, one of the most common causes of death from cancer worldwide, but it cannot be expected to have any effect in preventing ischaemic heart disease.

The preoperative seropositivity of Helicobacter pylori was determined in 128 patients who had undergone gastrectomy for primary gastric adenocarcinoma during the past 5 years. The overall seroprevalence of H. pylori was 64 per cent. Gastric cancers positive for H. pylori were associated with tumours located in the lower third of the stomach which were of localized type (Borrmann I and II) (P < 0.05), but not with age, sex, blood type, tumour size, invasion depth, lymph node metastases, histological type, DNA ploidy or type of surgery. The cumulative 5-year survival curves after surgical resection were significantly better in patients who were positive for H. pylori. Multivariate analysis revealed that seropositivity for H. pylori was not an independent prognostic factor. Pathological tumour node metastasis staging was the only prognostic indicator. Better prognosis for those with H. pylori-seropositive gastric cancer may be attributed to the more advanced stage of H. pylori-seronegative gastric cancers. The potential role of H. pylori in gastric cancer carcinogenesis and its biological significance warrant further investigation.