We examined in NORDCAN database how the annual age group-specific incidence rates (IR) of gastric cancer (GCA), and correspondingly the GCA risk, have declined in Finland during the twentieth century, and whether this decline corresponds to a decrease in the cohort-specific prevalence rate of Helicobacter pylori (Hp) gastritis that is considered an important precancerous risk condition for GCA.

In modelling with partial least squares regression (PLSR), the logarithmically transformed IRs (ln(IR) of GCA were well explained with age and birth cohort as explanatory model variables. By considering the observed (actual) and the PLSR-modelled IRs, the IR of GCA (and the risk of GCA) has decreased gradually in Finland from 1900 onward, cohort by cohort. By prediction of the future with PLSR, the IRs of GCA will be markedly lower in all cohorts during the twenty-first century than in the twentieth century. By PLSR modelling, less than 10 GCA cases per 100,000 people are predicted to appear annually in cohorts (generations) born at the turn of the 20th and 21st centuries, even when these people will be 60-80 years old in the years 2060-2070.

The IR of GCA and GCA risk progressively declined by cohort in Finland during the whole twentieth century. This decline corresponds in extent and time window to earlier observations in the decline of the prevalence rate of Hp gastritis in the same birth cohorts and supports the hypothesis of the role of Hp gastritis as an important risk condition of GCA.

To predict how the10-year birth cohort specific prevalence rates of chronic non-atrophic (CG) and atrophic gastritis (AG), related to Helicobacter pylori (Hp) infection, will decline during the 21^st century among the native adult Finns.

The predictions are based as continuums of our earlier observations of gradual and significant declines in birth cohort specific prevalence rates of CG and AG in endoscopic biopsies from gastric antrum and corpus of 2298 adult dyspeptic outpatients or asymptomatic volunteers born 1890-1977 that were endoscopied in 1972-1997 in Finland.

We could predict that the Hp related CG and AG will gradually disappear in history among the native Finns during the 21^st century. From the 2020s onward, the CG and AG would decrease with time in prevalence rate, cohort-by-cohort, and would be more and more highlighted in the middle aged or elderly age groups only. Finally, since all birth cohorts (generations) infected with Hp have passed away by 2080, the Hp related gastrites would not appear anymore in notable counts among the native Finns. Correspondingly, gastric cancers and peptic ulcers (both duodenal and gastric), which are etiopathogenetically linked with Hp gastrites, would similarly become gradually more and more infrequent and rare disorders among native Finns during the 21^st century.

Helicobacter pylori infection, chronic gastritis (CG) and atrophic gastritis (AG) are a continuum of consecutive events in the stomach mucosa. We studied the birth cohort and age group-specific prevalence rates of 'healthy' (N) and 'diseased' stomachs with CG or AG in endoscopic biopsies in adult people born in Finland in 1890-1977.

Study series consisted of 690 and 1608 adults with a diagnostic gastroscopy in 1972-1997. All subjects were divided to 10-year age groups and birth cohorts. Based on biopsy histology, relative frequencies (prevalences) of N, CG and AG were estimated by the observed number of cases with N, CG and AG in each study category.

Prevalence rate of a histologically 'diseased' stomach (CG or AG) decreased and that of 'healthy' stomach (N) increased, cohort-by-cohort, from 1900 onward by rate 9-12% per every 10-year period in the two study subpopulations, respectively. Prevalences of CG remained unchanged over study groups when N, CG and AG were noted concurrently. By noting 'diseased' stomachs only, the prevalence rate of AG increased, and that of CG decreased with age, at rate 9-13% per every 10 years of calendar age.

Over 70-year period from 1900 onward, the prevalence rate of 'diseased' stomach (CG or AG) decreased and that of 'healthy' (N) stomach increased in birth cohorts over 50%, by rate about 10% over every 10-year period of time. In birth cohorts, CG progressed to AG with aging of the subjects at a rate of about 10% over every 10 years of calendar age.

Since its' introduction by Warren and Marshall 27 years ago, Helicobacter pylori (HP) has become the linchpin in our understanding of important gastric conditions including gastritis, intestinal metaplasia (IM), gastric/duodenal ulcers (GU/DU), Mucosal Associated Lymphoid Tumour (MALToma) and gastric cancer. Initially named Campylobacter pyloridis, it was re-named HP when biochemical and genetic characterization of the organism showed that it was not a member of the Campylobacter genus. The finding in 1983 was seminal. It is now recognized that HP is the most common chronic human bacterial infection and it is the most common cause of gastritis. It is strongly implicated in the development of peptic ulcer disease and gastric neoplasms. In the years since its' discovery, much headway has been made in the understanding of this ubiquitous organism that had remained elusive, with much work focused on eradication, in part driven by pharmaceutical research and development. Standard triple therapy emerged to eradicate HP. However, with the emergence of HP resistance, newer regimes have been put forth that include quadruple therapy, sequential therapy and a dizzying array of other combinations bent on eradicating HP. Much less is known about the natural history of HP, the different faces of HP internationally, HP eradication and its effect on gastritis, IM, GU/DU and gastric cancer. This review will address the changing face of HP in 2011.

To describe and explore the natural history of Helicobacter pylori infection and chronic gastritis in terms of gastric mucosal atrophy and ulcer development over time in a population-based cohort.

A population-based cohort of 314 volunteers was re-screened (median follow-up interval of 8.4 years) with gastroduodenoscopy with biopsy, assessment of H. pylori status, analysis of pepsinogens, and monitoring of a nonsteroidal anti-inflammatory drug (NSAID) use and alcohol and smoking habits.

The incidence of duodenal or prepyloric ulcer was 0.45 per 100 person years and was associated with weekly NSAID use (odds ratios, OR 27.8), weekly alcohol consumption (OR 19.4) and smoking (OR 31.0), but not with H. pylori status. De novo infection with H. pylori was not observed, and the infection had disappeared in 11 of 113 subjects. Among subjects with chronic gastritis, the incidence of atrophy of the corpus mucosa was 1.4 per 100 person years. Atrophy development was related to age (OR 1.23) and to the severity of chronic inflammation in the corpus mucosa at baseline (OR 8.98). Substituting atrophy for subnormal S-pepsinogen I/S-pepsingen II gave similar results.

In this cohort, the minimum incidence of ulcer was 0.45 per 100 person years. Smoking, alcohol, and NSAIDs, but not H. pylori infection were significant risk factors. The incidence of atrophy of the corpus mucosa was 1.4 per 100 person years with a positive relation to age and to the degree of chronic inflammation at baseline. Atrophy was stationary in advanced stages.

It is known that patients infected with H pylori can spontaneously become free from infection, and that the reverse change can occur. The time-scale of these conversions is expressed as percentages per year. Since they have been investigated in terms of serology, the changes are called sero-reversion and sero-conversion respectively. Using serological evidence to investigate these phenomena is open to the criticisms that positive serology can be present in the absence of all other evidence of infection, and that a time-lag of 6-12 mo or longer can occur between eradication of the infection and sero-reversion. Investigations using direct evidence of current infection are sparse. The few that exist suggest that some individuals can seroconvert or sero-revert within six to twelve weeks. If these findings are confirmed, it means that some patients have an ability that is variable in time to resist, or spontaneously recover from, H pylori infection. Evidence suggests that the deciding factor of susceptibility is the level of gastric secretion of acid.

Chronic atrophic gastritis (CAG) is a well-established precursor of intestinal gastric cancer, but epidemiologic data about its occurrence are sparse. We provide an overview on studies that examined the prevalence of CAG in different parts of the world. Articles containing data about the prevalence of chronic atrophic gastritis in unselected population samples and published until November 2005 were identified by searching the MEDLINE database. Furthermore, the references in the identified publications were screened for additional suitable studies. Studies comprising at least 50 subjects were included. Forty-one studies providing data on the prevalence of CAG in unselected population samples could be identified. CAG was determined by gastroscopy in 15 studies and by pepsinogen serum levels in 26 studies. Although results are difficult to compare due to the various definitions of CAG used, a strong increase with age, the lack of major gender differences, and strong variations between populations and population groups (in particular, relatively high rates in certain Asian populations) could be observed quite consistently. We conclude that CAG is relatively common among older adults in different parts of the world, but large variations exist. Large-scale international comparative studies with standardized methodology to determine CAG are needed to provide a coherent picture of the epidemiology of CAG in various populations. Noninvasive measurements of CAG by pepsinogen levels may be particularly suited for that purpose.

It remains controversial whether gastric atrophy is reversible after Helicobacter pylori eradication therapy.

To clarify whether gastric atrophy improves after H. pylori eradication therapy using a histologic approach.

Subjects were 87 H. pylori infection-cured patients (treatment group) and 29 continuously H. pylori-infected patients (control group). The subjects in the treatment and control groups were followed for 10-49 months (mean, 22 months) and 11-50 months (mean, 22 months), respectively. Biopsy specimens were obtained from the greater curvature of the antrum and corpus at the beginning and end of the observation period; histologic analyses of these specimens were performed for detection of activity, inflammation, atrophy, and intestinal metaplasia. Results were scored without any clinical information according to the Sydney system.

In the treatment group, the histologic score for atrophy was improved in the corpus but not in the antrum. Intestinal metaplasia was not improved in either the antrum or the corpus. There were no significant differences during the follow-up in gastric atrophy and intestinal metaplasia in the control group.

Gastric atrophy was improved in the corpus approximately 2 years after H. pylori eradication therapy.

Adherence may be an important virulence factor for Helicobacter pylori. Current methods available for quantitation of adherence are time consuming and liable to observer error. A new direct technique for fluorescent labelling of bacteria has been developed to quantitate adherence of H. pylori to epithelial cells by fluorescence activated cell sorting (FACS). Type strains of H. pylori, H. mustelae, H. cinaedi and H. fennelliae were grown microaerobically in broth culture for 24 h and fluorescently labelled by incubation with carboxyfluorescein diacetate succinimidyl ester (CFDA-SE) at 37 degrees C. After washing to remove excess CFDA-SE, bacteria were co-incubated (ratio 10:1) with gastric epithelial cells at 37 degrees C for up to 24 h. After washing to remove non-adherent bacteria, epithelial cells were detached with EDTA (2 mM) and fixed with formaldehyde for flow cytometry. Adherence was quantitated both in terms of the proportion of cells with adherent H. pylori and as the mean number of adherent bacteria per cell. All H. pylori strains adhered to gastric-type epithelial cells. The proportion of cells with bound bacteria varied from 40-99% and the number of bacteria per cell from 1-50, both of which correlated with microscopy (r = 0.6, and r = 0.8 respectively, n = 35). Time course studies demonstrated saturation of binding by H. pylori within 90 min. For H. mustelae, H. cinaedi and H. fennelliae the proportion of cells with bound bacteria varied from 5-15% and the mean number of bacteria per cell was < 4. Binding of H. pylori to epithelial cells could be partly blocked by pre-incubation with polyclonal anti-sera or using oligosaccharides against potential binding epitopes of gastric mucus. Fluorescent labelling of H. pylori with CFDA-SE in combination with flow cytometry provides a quick, specific, and sensitive method to quantitate in vitro the adherence of H. pylori.

In 1985, gastric cancer was the second most common cause of cancer death in the world. The rapid decline in gastric cancer rates over the last few decades has been attributed to a decline in the prevalence of environmental risk factors for gastric cancer and/or an increase in the prevalence of protective factors. One such risk factor could be the bacterium Helicobacter pylori. Epidemiological studies have shown that areas with high gastric cancer rates often have a correspondingly high prevalence of H. pylori and prospective studies have shown that subjects with serological evidence of H. pylori infection were significantly more likely to go on to develop gastric cancer than those who did not. Helicobacter pylori itself does not appear to be either genotoxic or mutagenic. Infection is, however, associated with increased cell turnover, a chronic immune response accompanied by increased levels of reactive oxygen metabolites and a reduction in gastric levels of ascorbic acid, all conditions that could favour the development of cancer. Nonetheless, the majority of those who are infected with H. pylori do not go on to develop gastric cancer and other factors, such as the strain of the infecting organism or consumption of dietary antioxidants including vitamin C, could also affect the risk of cancer. Finally, it has been estimated that more than one third, and possibly as many as 90% of gastric cancers might be attributable to infection with H. pylori. Prevention and treatment of infection are, therefore, possible approaches to reducing gastric cancer rates. It is, however, unclear what, if any, effect eradication of the infection would have on an individual's risk of gastric cancer and, to date, anti-Helicobacter therapy has only been shown to be of potential benefit in the treatment of low grade gastric MALT lymphomas.

Serological markers of gastritis, like pepsinogen A, pepsinogen C, gastrin, and Helicobacter pylori antibodies, can be used to explore the state of the gastric mucosa in populations with contrasting cancer risks. A decreasing pepsinogen A:C ratio and an increasing serum gastrin are known to reflect an increasing severity of atrophic corpus gastritis, which is a precursor of gastric cancer. In 723 subjects (without gastroduodenal surgery) from Japanese (n = 225) and Dutch (n = 498) working populations, which had a similar composition of age (mean 48 years), sex (male to female ratio 6:1), and type of occupation, fasting serum samples were analysed for IgG antibodies to H pylori, pepsinogen A, pepsinogen C, and gastrin in the same laboratory. H pylori infection was significantly more prevalent in the Japanese than in the Dutch (74.7% and 31.3%); as was a very low pepsinogen A, indicative of severe mucosal atrophy (4.4% and 1.6%). Among subjects with and without severe mucosal atrophy the H pylori seropositivity rate was similar. Between the Japanese and the Dutch there were significant differences in mean gastrin (31.8 and 13.4 pmol/l) and pepsinogen A:C ratio (1.7 and 2.9). These intercountry differences were as great for H pylori negative subjects (gastrin: 23.7 and 10.3 pmol/l, pepsinogen A:C ratio: 2.4 and 3.2) as for H pylori positive subjects (gastrin: 34.6 and 20.1 pmol/l, pepsinogen A:C ratio: 1.5 and 2.5). The intercountry difference in gastrin nearly disappeared after stratification into categories of pepsinogen A:C ratio. In conclusion, the intercountry differences in pepsinogen A:C ratio and gastrin reflect a higher prevalence of mild and severe mucosal atrophy of the corpus in the Japanese than in the Dutch, both among H pylori positive and negative subjects. Thus, these findings suggest that in the Japanese the development of atrophic gastritis is in part unrelated to H pylori.

Helicobacter pylori seems to be the commonest cause of chronic gastritis, but the natural course of H. pylori-associated gastritis is largely obscure.

We present a histologic follow-up of 39 patients with H. pylori-positive gastritis. Gastroscopies with stepwise biopsies were performed in all the patients at an interval of 10 years.

Of the patients 87% (34/39) had a persistent infection and showed a significant decrease in the grades of antral gastritis, eosinophilic granulocytes, corpus eosinophilic granulocytes, and foveolar hyperplasia and a significant increase in the grade of corpus neutrophilic granulocytes. The quantities of H. pylori as estimated histologically did not change significantly during the follow-up period in patients with a persistent infection. In the five other patients (13%) the H. pylori infection had apparently disappeared spontaneously, and this was accompanied by decreases in the amount of inflammatory cells in the gastric mucosa.

H. pylori infection in the gastric mucosa is chronic and may be associated with both regressive and progressive histologic changes. Spontaneous healing of H. pylori infection is possible and is associated with partial resolution of the inflammatory changes in the gastric mucosa.

The course of gastric ulcer disease and its relations to certain indicators of inflammation and Helicobacter pylori in the gastric mucosa were examined in a 10-year follow-up.

Thirty-three patients with gastric ulcer were examined endoscopically with biopsies in 1981-82 and invited for re-examination in 1991-92. Twenty-one of them were able to comply with the invitation. A gastroscopy with biopsies was performed on each of these, and the results were compared with those of age- and sex-matched control patients with non-ulcer H. pylori-positive gastritis.

All the patients were H. pylori-positive at the first examination and had a persistent infection at the second examination, if they had not undergone a gastric resection. Thirteen patients had a non-operated stomach at the second examination. The grades of gastritis and intestinal metaplasia in the antrum at the second examination were significantly higher in the ulcer patients than in the controls (p = 0.009 and p = 0.04, respectively). Eosinophilic granulocytes in both the antral and the corpus mucosa had decreased significantly in the controls (p = 0.002 and p = 0.04, respectively) but not in the ulcer patients.

The results suggest that the course of ulcer-associated H. pylori-positive gastritis is different from that of non-ulcer-associated H. pylori-positive gastritis and that abnormal eosinophilic infiltration persists in patients with gastric ulcer.

Helicobacter pylori is associated with B-type gastritis, duodenal ulcer disease, and possibly gastric carcinoma. The object of this study was to assess the effect of eradication of H. pylori infection on gastric epithelial cell proliferation.

Gastric epithelial cell proliferation was assessed in 22 H. pylori-positive duodenal ulcer patients before and 6 weeks after 'triple therapy' with bismuth, tetracycline and metronidazole. Cell proliferation was studied either by immunostaining for the proliferating cell nuclear antigen (PCNA) or by a microdissection technique.

Eradication was successful in 10 of the 22 H. pylori-positive patients. Treatment with 'triple therapy' resulted in a significant fall in the rate of gastric epithelial cell proliferation; this effect was seen in both the gastric body and antrum. There was a significant correlation between the number of PCNA-labelled cells and the histological grade of activity (neutrophil inflammation) (r = 0.49, P = 0.02); the same correlation was found for the number of mitoses per gland (r = 0.5, P = 0.02). There was no significant difference in the treatment effect for eradicated or non-eradicated patients or either the body or antrum. Six patients, who had at least one antral biopsy that showed evidence of focal intestinal metaplasia, had a higher rate of cell proliferation.

The reduction in epithelial cell proliferation in the body and antrum after triple therapy is independent of successful eradication of H. pylori, and it may be due to an anti-inflammatory effect of triple therapy.

We studied the capacity of glutaraldehyde-fixed Helicobacter pylori to stimulate natural killer (NK) cell activity. Bacteria were incubated overnight with peripheral blood lymphocytes enriched for large granular lymphocytes (LGL), the mediators of non-major histocompatibility complex-restricted cellular cytotoxicity. Then, the cytolytic activity of LGL was tested against various tumor target cells. We observed that efficient cytolytic activity was generated against resistant and nonresistant tumor target cell lines. Nine local clinical isolates of H. pylori and the reference strain NCTC 11637 were tested, and they all were equally effective in inducing NK cell activity. However, flagellin antigen, glycine extract, urease, and lipopolysaccharide prepared from H. pylori NCTC 11637 all failed to induce significant NK cell activity. The supernatants which were collected after coincubation of bacteria with LGL contained a factor(s) which could activate resting LGL into efficient cytolytic activity. The supernatants were also analyzed for interferon (IFN) activity. We observed that high titers of IFN were produced and that IFN activity was neutralized with anti-gamma interferon (IFN-gamma) antiserum, but not with anti-IFN-alpha antiserum. Thus, contact of lymphocytes with H. pylori leads to efficient stimulation of NK cell activity and the production of IFN-gamma.

To determine the association between infection with Helicobacter pylori and dyspepsia.

Cross sectional study of dyspeptic subjects and age and sex matched controls identified by a questionnaire survey of all inhabitants aged 20-69. (Endoscopy, histological examination, and microbiological examinations of biopsies from the gastric mucosa were performed blind.)

Population based survey in Sørreisa, Norway.

All 782 dyspeptic subjects (excluding those with a previous history of peptic ulcer, gall stones or kidney stones, and coronary heart disease) and controls were offered an endoscopy, of whom 309 dyspeptic subjects and 310 controls attended.

Prevalences of endoscopic and histological diagnoses and of cultures positive for H pylori.

A high prevalence of positive cultures, increasing with age, was found in both dyspeptic subjects (48%) and non-dyspeptic controls (36%) (p = 0.004). Positive cultures in both dyspeptic subjects and controls were strongly associated with histological gastritis (70%, 95% confidence interval 65.5 to 85.3; 60%, 52.7 to 67.7, respectively) and peptic ulcer (92%, 61.5 to 99.8; 64.1, 9.4 to 99.2, respectively). Only 3% of subjects with a histologically non-inflamed gastric mucosa had this infection (dyspeptic subjects 2%, 0.2 to 7.0; controls 4%; 1.2 to 8.8).

The relation between dyspeptic symptoms and H pylori is dubious; H pylori seems to have a pathogenetic role in gastritis and may be a contributing factor but not a cause of peptic ulcer.

Titres of antibody to Helicobacter pylori are known to fall with eradication of bacteria. To find out what degree of fall would reliably indicate eradication, 144 patients with Helicobacter pylori infection were given antimicrobial therapy for 2 weeks and then followed up at 6 weeks, 6 months, and 12 months with serological tests, bacterial cultures, and histological studies of gastric specimens. 6 weeks after treatment IgG titres had fallen by 20-30% irrespective of the success of bacterial eradication. In the 121 bacteria-negative patients the decrease continued. 6 and 12 months after treatment the titre was 50% or less of pretreatment value in 97% of these patients. In the 23 patients who remained infected, the initial drop of IgG titres, if any, was followed by unchanged or slightly rising titres. IgA and IgM titres, initially raised in 64% and 4% of the patients, respectively, showed similar trends. The high sensitivity (97%) of the IgG antibody tests and a consistent fall within 6 months after eradication of H pylori infection made IgG the most useful immunoglobulin class for follow-up of antimicrobial therapy in individual patients. IgA antibodies were valuable in the 2% patients who had raised titres in this immunoglobulin class only. The few patients (5.5%) who had raised IgM titres also had high IgG titres. Serological tests thus are a cheap and reliable means of monitoring success of eradication of H pylori.

In a healthy population pepsinogen A and pepsinogen C increase with advancing age. As pepsinogen A and C are raised in chronic superficial gastritis which is caused by H pylori infection, we investigated whether H pylori is responsible for the age related increase of pepsinogen A and C. In H pylori positive blood transfusion donors serum pepsinogen A (mean (SD) 73 (35) micrograms/ml v 52 (19) micrograms/ml, p much less than 0.01) and C (mean (SD) 24 (13) micrograms/ml v 10 (7) micrograms/ml, p much less than 0.01) concentrations were significantly higher than in H pylori negative blood transfusion donors, while the serum pepsinogen A:C ratio mean (SD) 3.5 (1.4) v 6.2 (3.4), p much less than 0.01) was significantly decreased because of a relative greater increase in serum pepsinogen C in H pylori positive blood transfusion donors. Analysis of variance showed that pepsinogen A and C concentrations differed significantly in the different age groups (p much less than 0.01) when we considered all blood transfusion donors and H pylori positive blood transfusion donors, the mean pepsinogen levels being highest in the older age categories. In H pylori negative blood transfusion donors no such age related difference in pepsinogen A and C could be shown. In H pylori positive blood transfusion donors a weak positive but significant correlation between pepsinogen A and C and age could be shown (r = 0.30; p = 0.01 and r = 0.31; p = 0.01 respectively). In H pylori negative blood transfusion donors no correlation between serum pepsinogens and age was found. We conclude that the age related increase in serum pepsinogen A and C described in healthy control populations is caused by an increasing prevalence of H pylori infection. Serum pepsinogen A and C concentrations in patients should therefore be related to the presence or absence of H pylori infection.

To study the prevalence and course of chronic gastritis (CG), 142 adult subjects collected at random from an Estonian urban area were endoscopically and bioptically examined at a six-year interval. The histology of the antral and corpus mucosae was evaluated by grading gastritis without ("superficial gastritis"; SG) and with atrophy ("atrophic gastritis"; AG) into mild, moderate and severe categories. A total of 135 (95%) and 139 (98%) subjects showed CG in the 1st and 2nd examinations, respectively. The CG healed in one subjects (0.7%), and in 5 out of 7 subjects with normal stomach in the 1st examination the CG started during the follow-up. No change in the severity of CG was seen in 24% of subjects with gastritis in the 1st examination. The main trend of CG was a slow, "one-step progression" in severity of inflammation and appearance of atrophy and intestinal metaplasia. Inflammation progressed significantly, especially in the young age groups and in the antrum in particular. The prevalence of AG increased linearly with age in corpus (mean annual risk 1.25%). Parietal cell antibodies (PCA) were found in 2 subjects in the 1st examination, and a further 2 subjects developed these antibodies later. Three of four PCA-positive subjects belonged to a subgroup of 8 elderly subjects who had corpus AG at both examinations and who also showed normal or normalizing mucosa in the antrum. It is concluded that CG is a slowly progressive disease advancing with time and, once started, rarely healing spontaneously.