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1.  Serum Helicobacter pylori CagA antibody titer was a useful marker for advanced inflammation in the stomach in Japan 
Journal of gastroenterology and hepatology  2014;29(1):10.1111/jgh.12359.
Background and aim
Subjects infected with H. pylori containing cagA do not always induce serum CagA antibody. Our previous meta-analysis showed that serum CagA seropositivity was associated with gastric cancer even in East Asian countries. However, it remains unclear why serum CagA positive status is associated with gastric cancer. In this study, we aimed to examine the relationship between anti CagA antibody titer and the levels of pepsinogen, and histological score.
Eighty-eight H. pylori positive Japanese patients with gastritis were included. Serum CagA antibody titer, pepsinogen (PG) I and PG II were evaluated by enzyme-linked immunosorbent assay. Histological scores were evaluated according to Update Sydney System. CagA expression was examined by immunoblot.
Seroprevalence of CagA antibody was found in 75.0%. Interestingly, serum CagA antibody titer was significantly correlated with PG I and PG II levels (P = 0.003 and 0.004, respectively). Serum CagA antibody titer was also significantly correlated with mucosal inflammation in the corpus (P = 0.04). On the other hand, bacterial density was not related with CagA antibody titer. CagA expression level of the strains was irrespective of the status of PG and serum CagA antibody.
Subjects with higher serum CagA antibody titer can be considered as high risk population for the development of gastric cancer from the point of strong gastric inflammatory response even in Japan. Host recognition rather than bacterial colonization might be associated with the difference of serum CagA antibody titer.
PMCID: PMC3870047  PMID: 24033876
Helicobacter pylori; CagA; serum antibody; pepsinogen
2.  Seroprevalence of Helicobacter pylori infection and gastric mucosal atrophy in Bhutan, a country with a high prevalence of gastric cancer 
Journal of Medical Microbiology  2013;62(Pt 10):1571-1578.
Gastric cancer is the second leading cause of cancer-related mortality in the world. Recently, serum Helicobacter pylori antibodies and pepsinogen (PG) have been used for gastric cancer screening. The incidence of gastric cancer in Bhutan is reported to be quite high compared with that in neighbouring countries. In this study, 381 subjects from three areas of Bhutan were assessed for gastric mucosal atrophy and serological parameters. Anti-H. pylori IgG, PG I, PG II and cytotoxin-associated gene A (CagA) antibodies were measured using ELISA. Subjects were classified into four groups according to H. pylori and PG seropositivity: Group A (H. pylori-negative/PG-negative), Group B (H. pylori-positive/PG-negative), Group C (H. pylori-positive/PG-positive) and Group D (H. pylori-negative/PG-positive). The prevalence of H. pylori in the 381 subjects was 71.1 % (271/381), with high infection rates found in rural areas. The PG I/II ratio was significantly inversely correlated with the atrophy score in the antrum and the corpus (P<0.001). Multivariate analysis showed that the PG status was significantly associated with the presence of atrophy in the corpus. The prevalence of the PG-positive status was significantly higher among H. pylori-positive subjects than among H. pylori-negative subjects (P<0.001). Based on the ABC method, Group B was the most dominant, followed by Group A, Group C and Group D. The high incidence of gastric cancer in Bhutan can be attributed to the high prevalence of H. pylori infection and gastric mucosal atrophy.
PMCID: PMC3799224  PMID: 23831768
3.  Analysis of Clinical Isolates of Helicobacter pylori in Pakistan Reveals High Degrees of Pathogenicity and High Frequencies of Antibiotic Resistance 
Helicobacter  2014;19(5):387-399.
Antibiotic resistance in Helicobacter pylori contributes to failure in eradicating the infection and is most often due to point and missense mutations in a few key genes.
The antibiotic susceptibility profiles of H. pylori isolates from 46 Pakistani patients were determined by Etest. Resistance and pathogenicity genes were amplified, and sequences were analyzed to determine the presence of mutations.
A high percentage of isolates (73.9%) were resistant to metronidazole (MTZ), with considerable resistance to clarithromycin (CLR; 47.8%) and amoxicillin (AML; 54.3%) also observed. Relatively few isolates were resistant to tetracycline (TET; 4.3%) or to ciprofloxacin (CIP; 13%). However, most isolates (n = 43) exhibited resistance to one or more antibiotics. MTZ-resistant isolates contained missense mutations in oxygen-independent NADPH nitroreductase (RdxA; 8 mutations found) and NADH flavin oxidoreductase (FrxA; 4 mutations found). In the 23S rRNA gene, responsible for CLR resistance, a new point mutation (A2181G) and 4 previously reported mutations were identified. Pathogenicity genes cagA, dupA, and vacA s1a/m1 were detected frequently in isolates which were also found to be resistant to MTZ, CLR, and AML. A high percentage of CagA and VacA seropositivity was also observed in these patients. Phylogenetic analysis of partial sequences showed uniform distribution of the 3′ region of cagA throughout the tree.
We have identified H. pylori isolates in Pakistan which harbor pathogenicity genes and worrying antibiotic resistance profiles as a result of having acquired multiple point and missense mutations. H. pylori eradication regimens should therefore be reevaluated in this setting.
PMCID: PMC4162849  PMID: 24827414
23S rRNA gene; antibiotic resistance; cagA; clarithromycin resistance; Helicobacter pylori infection; metronidazole resistance
4.  CagA-dependent downregulation of B7-H2 expression on gastric mucosa and inhibition of Th17 responses during Helicobacter pylori infection 
Gastric epithelial cells (GECs) are the primary target for Helicobacter pylori (H. pylori) infection and may act as antigen presenting cells (APC) regulating local T cell responses. We previously reported that H. pylori infection of GECs induces the expression of the T cell co-inhibitory molecule B7-H1 on GECs. This process contributes to the hyporesponsiveness of CD4+ effector T cells and accumulation of T regulatory cells. In the studies presented herein we investigated the impact of H. pylori cytotoxin CagA on the modulation of the expression of the T cell co-stimulator B7-H2 by GEC. B7-H2 is involved in promoting Th17 type responses. H. pylori infection downregulates B7-H2 expression by GECs in a CagA dependent manner. IFNγ, which is increased in the H. pylori infected gastric mucosa, synergizes with H. pylori in downregulating B7-H2 expression by GECs. CagA-mediated modulation of B7-H2 on GEC involves p70 S6 kinase phosphorylation. The CagA-dependent B7-H2 downregulation in GEC correlates with a decrease in Th17 type responses in vitro and in vivo. Further, CagA-dependent modulation of Th17 responses inversely correlated with the H. pylori colonization levels in vivo. Our data suggest that CagA contributes to the ability of H. pylori to evade Th17 mediated clearance by modulating expression of B7-H2 and, thus, to the establishment of the H. pylori chronic infection.
PMCID: PMC3801271  PMID: 23997227
5.  Extremely low Helicobacter pylori prevalence in North Sulawesi, Indonesia and identification of a Maori-tribe type strain: a cross sectional study 
Gut Pathogens  2014;6(1):42.
Sulawesi in Indonesia has a unique geographical profile with assumed separation from Sundaland. Studies of Helicobacter pylori in this region are rare due to the region’s rural location and lack of endoscopy equipment. Indirect methods are, therefore, the most appropriate for measuring H. pylori infection in these areas; with the disposable gastric brush test, we can obtain gastric juice as well as small gastric tissue samples for H. pylori culture. We investigated the prevalence of H. pylori infection and evaluated human migration patterns in the remote areas of North Sulawesi.
We recruited a total of 251 consecutive adult volunteers and 131 elementary school children. H. pylori infection was determined by urine antibody test. A gastric brush test was used to culture H. pylori. We used next-generation and polymerase chain reaction based sequencing to determine virulence factors and multi-locus sequence typing (MLST).
The overall H. pylori prevalence was only 14.3% for adults and 3.8% for children, and 13.6% and 16.7% in Minahasanese and Mongondownese participants, respectively. We isolated a single H. pylori strain, termed -Manado-1. Manado-1 was East Asian type cagA (ABD type), vacA s1c-m1b, iceA1 positive/iceA2 negative, jhp0562-positive/β-(1,3) galT-negative, oipA “on”, and dupA-negative. Phylogenetic analyses showed the strain to be hspMaori type, a major type observed in native Taiwanese and Maori tribes.
Our data support that very low H. pylori infection prevalence in Indonesia. Identification of hspMaori type H. pylori in North Sulawesi may support the hypothesis that North Sulawesi people migrated from north.
PMCID: PMC4189669  PMID: 25299127
Helicobacter pylori; Maori; Indonesia
6.  Helicobacter pylori from Gastric Cancer and Duodenal Ulcer Show Same Phylogeographic Origin in the Andean Region in Colombia 
PLoS ONE  2014;9(8):e105392.
A recent report has shown that the phylogenetic origin of Helicobacter pylori based on multi-locus sequence typing (MLST) was significantly associated with the severity of gastritis in Colombia. However, the potential relationship between phylogenetic origin and clinical outcomes was not examined in that study. If the phylogenetic origin rather than virulence factors were truly associated with clinical outcomes, identifying a population at high risk for gastric cancer in Colombia would be relatively straightforward. In this study, we examined the phylogenetic origins of strains from gastric cancer and duodenal ulcer patients living in Bogota, Colombia.
We included 35 gastric cancer patients and 31 duodenal ulcer patients, which are considered the variant outcomes. The genotypes of cagA and vacA were determined by polymerase chain reaction. The genealogy of these Colombian strains was analyzed by MLST. Bacterial population structure was analyzed using STRUCTURE software.
H. pylori strains from gastric cancer and duodenal ulcer patients were scattered in the phylogenetic tree; thus, we did not detect any difference in phylogenetic distribution between gastric cancer and duodenal ulcer strains in the hpEurope group in Colombia. Sixty-six strains, with one exception, were classified as hpEurope irrespective of the cagA and vacA genotypes, and type of disease. STRUCTURE analysis revealed that Colombian hpEurope strains have a phylogenetic connection to Spanish strains.
Our study showed that a phylogeographic origin determined by MLST was insufficient for distinguishing between gastric cancer and duodenal ulcer risk among hpEurope strains in the Andean region in Colombia. Our analysis also suggests that hpEurope strains in Colombia were primarily introduced by Spanish immigrants.
PMCID: PMC4133377  PMID: 25121764
7.  Identification of the Genes That Contribute to Lactate Utilization in Helicobacter pylori 
PLoS ONE  2014;9(7):e103506.
Helicobacter pylori are Gram-negative, spiral-shaped microaerophilic bacteria etiologically related to gastric cancer. Lactate utilization has been implicated although no corresponding genes have been identified in the H. pylori genome. Here, we report that gene products of hp0137–0139 (lldEFG), hp0140–0141 (lctP), and hp1222 (dld) contribute to D- and L-lactate utilization in H. pylori. The three-gene unit hp0137–0139 in H. pylori 26695 encodes L-lactate dehydrogenase (LDH) that catalyzes the conversion of lactate to pyruvate in an NAD-dependent manner. Isogenic mutants of these genes were unable to grow on L-lactate-dependent medium. The hp1222 gene product functions as an NAD-independent D-LDH and also contributes to the oxidation of L-lactate; the isogenic mutant of this gene failed to grow on D-lactate-dependent medium. The parallel genes hp0140–0141 encode two nearly identical lactate permeases (LctP) that promote uptake of both D- and L-lactate. Interestingly an alternate route must also exist for lactate transport as the knockout of genes did not completely prevent growth on D- or L-lactate. Gene expression levels of hp0137–0139 and hp1222 were not enhanced by lactate as the carbon source. Expression of hp0140–0141 was slightly suppressed in the presence of L-lactate but not D-lactate. This study identified the genes contributing to the lactate utilization and demonstrated the ability of H. pylori to utilize both D- and L-lactate.
PMCID: PMC4117512  PMID: 25078575
8.  Proteomic Helicobacter pylori biomarkers discriminating between duodenal ulcer and gastric cancer 
Protein patterns of 129 Helicobacter pylori strains isolated from Korean and Colombian patients suffering from duodenal ulcer or gastric cancer were analyzed by the high-throughput methodology SELDI-TOF-MS. Eighteen statistically significant candidate biomarkers discriminating between the two clinical outcomes were selected by using the Mann–Whitney test. Three biomarker proteins were purified and identified as a neutrophil-activating protein NapA (HU HPAG1_0821), a RNA-binding protein (HPAG1_0813), and a DNA-binding histone-like protein HU, respectively (jhp0228). These novel biomarkers can be used for development of diagnostic assays predicting the evolution to gastric cancer in H. pylori-infected patients.
PMCID: PMC4088323  PMID: 19328750
Helicobacter pylori; SELDI-TOF-MS; Biomarker; Gastric cancer; Duodenal ulcer
9.  The significance of virulence factors in Helicobacter pylori 
Journal of digestive diseases  2013;14(7):341-349.
Helicobacter pylori (H. pylori) infection is linked to various gastroduodenal diseases; however, only a small fraction of these patients develop associated diseases. Despite the high prevalence of H. pylori infection in Africa and South Asia, the incidence of gastric cancer in these areas is much lower than those in other countries. The incidence of gastric cancer tends to decrease from north to south in East Asia. Such geographic differences in the pathology can be explained, at least in part, by the presence of different types of H. pylori virulence factors in addition to the host and environmental factors. Virulence factors of H. pylori, such as cagA, vacA, dupA, iceA, oipA and babA, have been demonstrated to be predictors of severe clinical outcomes. Interestingly, meta-analysis showed that CagA seropositivity was associated with gastric cancer compared with gastritis even in East Asian countries where almost of the strains possessing cagA. Meta-analysis also confirmed the significance of vacA, dupA and iceA. However, there remains the possibility that additional important pathogenic genes can be existed because H. pylori consists of approximately 1 600 genes. Despite advances in our understanding of the development of H. pylori-related diseases, further work is required to clarify the roles of H. pylori virulence factors.
PMCID: PMC3721066  PMID: 23452293
Helicobacter pylori; virulence factors; stomach neoplasms
10.  Systematic Analysis of Phosphotyrosine Antibodies Recognizing Single Phosphorylated EPIYA-Motifs in CagA of Western-Type Helicobacter pylori Strains 
PLoS ONE  2014;9(5):e96488.
The clinical outcome of Helicobacter pylori infections is determined by multiple host-pathogen interactions that may develop to chronic gastritis, and sometimes peptic ulcers or gastric cancer. Highly virulent strains encode a type IV secretion system (T4SS) that delivers the effector protein CagA into gastric epithelial cells. Translocated CagA undergoes tyrosine phosphorylation at EPIYA-sequence motifs, called A, B and C in Western-type strains, by members of the oncogenic Src and Abl host kinases. Phosphorylated EPIYA-motifs mediate interactions of CagA with host signaling factors – in particular various SH2-domain containing human proteins – thereby hijacking multiple downstream signaling cascades. Observations of tyrosine-phosphorylated CagA are mainly based on the use of commercial phosphotyrosine antibodies, which originally were selected to detect phosphotyrosines in mammalian proteins. Systematic studies of phosphorylated EPIYA-motif detection by the different antibodies would be very useful, but are not yet available. To address this issue, we synthesized phospho- and non-phosphopeptides representing each predominant Western CagA EPIYA-motif, and determined the recognition patterns of seven different phosphotyrosine antibodies in Western blots, and also performed infection studies with diverse representative Western H. pylori strains. Our results show that a total of 9–11 amino acids containing the phosphorylated EPIYA-motifs are necessary and sufficient for specific detection by these antibodies, but revealed great variability in sequence recognition. Three of the antibodies recognized phosphorylated EPIYA-motifs A, B and C similarly well; whereas preferential binding to phosphorylated motif A and motifs A and C was found with two and one antibodies, respectively, and the seventh anti-phosphotyrosine antibody did not recognize any phosphorylated EPIYA-motif. Controls showed that none of the antibodies recognized the corresponding non-phospho CagA peptides, and that all of them recognized phosphotyrosines in mammalian proteins. These data are valuable in judicious application of commercial anti-phosphotyrosine antibodies and in characterization of CagA phosphorylation during infection and disease development.
PMCID: PMC4011759  PMID: 24800748
11.  Complete Genome Sequences of Eight Helicobacter pylori Strains with Different Virulence Factor Genotypes and Methylation Profiles, Isolated from Patients with Diverse Gastrointestinal Diseases on Okinawa Island, Japan, Determined Using PacBio Single-Molecule Real-Time Technology 
Genome Announcements  2014;2(2):e00286-14.
We report the complete genome sequences of eight Helicobacter pylori strains isolated from patients with gastrointestinal diseases in Okinawa, Japan. Whole-genome sequencing and DNA methylation detection were performed using the PacBio platform. De novo assembly determined a single, complete contig for each strain. Furthermore, methylation analysis identified virulence factor genotype-dependent motifs.
PMCID: PMC3990747  PMID: 24744331
12.  Detection of genotypic clarithromycin-resistant Helicobacter pylori by string tests 
AIM: To evaluate the utility of the string test to detect genotypic clarithromycin-resistant Helicobacter pylori (H. pylori) by polymerase chain reaction (PCR)-restriction fragment length polymorphism.
METHODS: Patients undergoing endoscopic examinations were enrolled in the present study. String tests were done on the next day of endoscopy. Segments of 23S rRNA were amplified from DNA obtained from string tests. PCR-restriction fragment length polymorphism was accomplished by restriction enzymes BbsI and BsaI recognizing the mutation site A to G at 2143 or at 2142 of 23S rRNA domain V, respectively.
RESULTS: One hundred and thirty-four patients with H. pylori infection underwent string tests. To compare phenotypic resistance, 43 isolates were successfully cultured in 79 patients in whom 23S rRNA was successfully amplified. Of five patients with clarithromycin-resistant H. pylori, 23S rRNA of H. pylori isolates from four patients could be digested by BsaI. In 38 susceptible isolates, 23S rRNA of H. pylori isolates from 36 patients could not be digested by either BsaI or BbsI. The sensitivity and specificity of the string test to detect genotypic clarithromycin resistance were 66.7% and 97.3%, respectively. Positive and negative predictive values were 80% and 94.7%, respectively.
CONCLUSION: String test with molecular analysis is a less invasive method to detect genotypic resistance before treatment. Further large-scale investigations are necessary to confirm our results.
PMCID: PMC3964405  PMID: 24695835
Helicobacter pylori; String test; Clarithromycin resistance; Polymerase chain reaction-restriction fragment length polymorphism
13.  The incidence of primary antibiotic resistance of Helicobacter pylori in Vietnam 
To determine the susceptibility of Helicobacter pylori strains isolated from a Vietnamese population to 5 antibiotics.
The incidence of antibiotic resistance in H. pylori infection is increasing worldwide and has become a leading cause for failure of treatment. Antibiotic susceptibility testing is very important to provide optimal regimens in a clinical setting.
We isolated 103 H. pylori strains from the gastric mucosa of H. pylori-infected patients from 2 areas in Vietnam (Ho Chi Minh and Hanoi) in 2008. Epsilometer test was used to determine the minimum inhibitory concentrations of amoxicillin (AMX), clarithromycin (CLR), metronidazole (MNZ), levofloxacin (LVFX), and tetracycline (TC).
Among the 103 strains, the resistance rates were 0% (AMX), 33% (CLR), 69.9% (MNZ), 18.4% (LVFX), and 5.8% (TC). The resistant strains showed a high-level of resistance (≥256 μg/mL) to CLR, 23.5% (8/34), and MNZ, 29.1% (21/72). The resistance rate for CLR was significantly higher in Ho Chi Minh than in Hanoi (49% vs. 18.5%, P = 0.001). Resistance to both CLR and MNZ was most commonly observed (24.3%). Two strains (1.9%) were resistant to 4 of the 5 antibiotics. No significant association was observed between antibiotic resistance rates and age, gender, or clinical outcomes of the patients.
High incidence of resistance to CLR and MNZ suggests that standard triple therapies may not be useful as first-line treatment in Vietnam. Alternative strategies such as bismuth-based quadruple therapies or sequential therapy may be more effective in Vietnam.
PMCID: PMC3556356  PMID: 23090037
Helicobacter pylori; drug resistance; Vietnam
14.  Intact long-type dupA as a marker for gastroduodenal diseases in Okinawan subpopulation, Japan 
Helicobacter  2012;18(1):66-72.
Helicobacter pylori dupA can be divided into two types according to the presence or absence of the mutation. In addition, full-sequenced data revealed that dupA has two types with different lengths depend on the presence of approximately 600 bp in the putative 5' region (presence; long-type and absence; short-type), which has not been taken into account in previous studies.
A total of 319 strains isolated from Okinawa, the south islands of Japan, were included. The status of dupA and cagA was determined by polymerase chain reaction. The presence of mutations in long-type dupA was determined by DNA sequencing.
The prevalence of long-type dupA was 26.3% (84/319). Sequence analysis showed that there were only 6 cases (7.1%) with point mutations lead to stop codon among 84 long-type dupA strains studied. Interestingly, intact long-type dupA without frameshift mutation, but not short-type dupA was significantly associated with gastric ulcer and gastric cancer than gastritis (P = 0.001 and P = 0.019, respectively). After adjustment by age, gender and cagA, the presence of intact long-type dupA was significantly associated with gastric ulcer and gastric cancer compared with gastritis (odds ratio [OR] = 3.35, 95% confidence interval [CI] = 1.55–7.24 and OR = 4.14, 95% CI = 1.23–13.94, respectively).
Intact long-type dupA is a real virulence marker for severe outcomes in Okinawa, Japan. The previous information gained from PCR-based methods without taking long-type dupA into account must be interpreted with caution.
PMCID: PMC3545078  PMID: 23067336
Helicobacter pylori; intact long-type dupA; gastric ulcer; duodenal ulcer; gastric cancer
15.  Helicobacter pylori cagA 12-bp insertion can be a marker for duodenal ulcer in Okinawa, Japan 
Helicobacter pylori cagA can be classified into mainly two types (East-Asian-type and Western-type cagA) according to the repeat regions located in the 3′ region. Recent studies showed that the Western-type cagA in strains from Okinawa, Japan formed a different cluster (J-Western-type cagA subtype). We also reported that J-Western-type cagA possess a 12-bp insertion located in the 5′ region of cagA sequence.
The prevalence of 12-bp insertion in cagA in Okinawa and the United States (U.S.) was examined by DNA sequencing. We then designed the primer pair which can detect the 12-bp insertion only by polymerase chain reaction (PCR). The prevalence of strains with 12-bp insertion was examined in 336 strains isolated from Okinawa by PCR.
In case of Western-type cagA/vacA s1m2 strains, the prevalence of 12-bp insertion was significantly higher in strains isolated from Okinawa than that from the U.S. (P = 0.002). Phylogenetic tree showed that strains with 12-bp insertion formed two individual clusters within J-Western-type cagA subtype; one is from Okinawa and another is from the U.S. Our designed primer set showed high sensitivity (100%) and specificity (90.8%) in Okinawa. The 12-bp insertion was found in 23.7%, 14.3%, 4.2%, and 4.0% of strains with duodenal ulcer (DU), gastritis, gastric cancer (GC), and gastric ulcer (GU), respectively (P < 0.001 for DU vs. GU) in Okinawa.
Although the mechanisms are unknown, the presence of 12-bp insertion was associated with the presence of DU and might have a suppressive action on GU and GC.
PMCID: PMC3734362  PMID: 23190390
Helicobacter pylori; 12-bp insertion; Okinawa; cagA
16.  Complete Genome Sequences of Helicobacter pylori Clarithromycin-Resistant Strains 
Genome Announcements  2013;1(6):e00912-13.
We report the complete genome sequences of two Helicobacter pylori clarithromycin-resistant strains. Clarithromycin (CLR)-resistant strains were obtained under the exposure of H. pylori strain 26695 on agar plates with low clarithromycin concentrations. The genome data provide insights into the genomic changes of H. pylori under selection by clarithromycin in vitro.
PMCID: PMC3828311  PMID: 24233587
18.  Helicobacter pylori infection in Japan 
The prevalence of Helicobacter pylori infection is gradually decreasing in Japan. On the main island of Japan, nearly all H. pylori isolates possess cagA and vacA with strong virulence. However, less virulent H. pylori strains are frequently found in Okinawa where cases of gastric cancer are the lowest in Japan. Eradication therapy for peptic ulcer, idiopathic thrombocytopenic purpura, gastric mucosa-associated lymphoid tissue lymphoma and early gastric cancer after endoscopic resection has been approved by the Japanese national health insurance system. However, the Japanese Society for Helicobacter Research recently stated that all ‘H. pylori infection’ was considered as the indication for eradication irrespective of the background diseases. To eliminate H. pylori in Japan, the Japanese health insurance system should approve the eradication of all H. pylori infections.
PMCID: PMC3732492  PMID: 23265147
guideline; Helicobacter pylori; Japan; management; resistance; treatment
19.  Virulence factors or ancestral origin of Helicobacter pylori: which is a better predictor of gastric cancer risk? 
Gut  2011;61(3):10.1136/gutjnl-2011-300317.
PMCID: PMC3808968  PMID: 21610271
20.  Diversity of Helicobacter pylori genotypes in Iranian patients with different gastroduodenal disorders 
AIM: To investigate the diversity of Helicobacter pylori (H. pylori) genotypes and correlations with disease outcomes in an Iranian population with different gastroduodenal disorders.
METHODS: Isolates of H. pylori from patients with different gastroduodenal disorders were analyzed after culture and identification by phenotypic and genotypic methods. Genomic DNA was extracted with the QIAamp DNA mini kit (Qiagen, Germany). After DNA extraction, genotyping was done for cagA, vacA (s and m regions), iceA (iceA1, iceA2) and babA with specific primers for each allele using polymerase chain reaction (PCR). All patients’ pathologic and clinical data and their relation with known genotypes were analyzed by using SPSS version 19.0 software. χ2 test and Fisher’s exact test were used to assess relationships between categorical variables. The level of statistical significance was set at P < 0.05.
RESULTS: A total of 71 isolates from 177 patients with different gastroduodenal disorders were obtained. Based on analysis of the cagA gene (positive or negative), vacA s-region (s1 or s2), vacA m-region (m1 or m2), iceA allelic type (iceA1 and iceA2) and babA gene (positive or negative), twenty different genotypic combinations were recognized. The prevalence of cagA, vacA s1, vacA s2, vacA m1, vacA m2, iceA1, iceA2, iceA1+iceA2 and babA were 62%, 78.9%, 19.7%, 21.1%, 78.9%, 15.5%, 22.5%, 40.8% and 95.8%, respectively. Interestingly, evaluation of PCR results for cagA in 6 patients showed simultaneous existence of cagA variants according to their size diversities that proposed mixed infection in these patients. The most prevalent genotype in cagA-positive isolates was cagA+/vacAs1m2/iceA1+A2/babA+ and in cagA-negative isolates was cagA-/vacAs1m2/iceA-/babA+. There were no relationships between the studied genes and histopathological findings (H. pylori density, neutrophil activity, lymphoid aggregation in lamina propria and glandular atrophy). The strains which carry cagA, vacAs1/m1, iceA2 and babA genes showed significant associations with severe active chronic gastritis (P = 0.011, 0.025, 0.020 and 0.031, respectively). The vacAs1 genotype had significant correlation with the presence of the cagA gene (P = 0.013). Also, babA genotype showed associations with cagA (P = 0.024). In the combined genotypes, only cagA+/vacAs1m1/iceA2/babA+ genotype showed correlation with severe active chronic gastritis (P = 0.025).
CONCLUSION: This genotyping panel can be a useful tool for detection of virulent H. pylori isolates and can provide valuable guidance for prediction of the clinical outcomes.
PMCID: PMC3769906  PMID: 24039362
Helicobacter pylori; cagA; vacA; iceA; babA
21.  Antibiotics resistance rate of Helicobacter pylori in Bhutan 
AIM: To survey the antibiotic resistance pattern of Helicobacter pylori (H. pylori) strains isolated from Bhutanese population.
METHODS: We isolated 111 H. pylori strains from the gastric mucosa of H. pylori-infected patients in Bhutan in 2010. The Epsilometer test was used to determine the minimum inhibitory concentrations (MICs) of amoxicillin (AMX), clarithromycin (CLR), metronidazole (MNZ), levofloxacin (LVX), ciprofloxacin (CIP), and tetracycline (TET).
RESULTS: Nineteen of the isolated H. pylori strains were susceptible to all antibiotics tested. The isolated strains showed the highest rate of antibiotic resistance to MNZ (92/111, 82.9%). Among the 92 MNZ-resistant strains, 74 strains (80.4%) showed high-level resistance (MIC ≥ 256 μg/mL). Three strains were resistance to LVX (2.7%). These strains were also resistance to CIP. None of the strains showed resistance to CLR, AMX and TET.
CONCLUSION: CLR-based triple therapy is a more effective treatment approach over MNZ-based triple therapy for H. pylori infection in Bhutan.
PMCID: PMC3761104  PMID: 24023494
Helicobacter pylori; Drug resistance; Bhutan
22.  The relationship between Helicobacter pylori infection and Alzheimer’s disease in Japan 
Journal of neurology  2011;258(8):1460-1463.
Although two studies have indicated a possible link between Alzheimer’s disease (AD) and Helicobacter pylori (H. pylori) infection, these were reported from Europe, where the prevalence of H. pylori infection is not very high. In this study, the prevalence of H. pylori infection was examined in AD patients in Japan, where there is a high prevalence of H. pylori. Consecutive patients referred to the Memory and Dementia Outpatient Clinic from August 2002 to March 2009 were studied. H. pylori infection status was determined by measuring urinary levels of anti-H. pylori antibody (RAPIRUN®). Multiple stepwise logistic regression analyses were used to examine the associations of AD with the main predictor variables. Of the 917 patients who visited the clinic, 385 were diagnosed as having AD. Ninety-seven patients did not have dementia and were considered controls. On univariate analysis, average age and the proportion of males were significantly higher in AD patients than in controls. There was no difference in the prevalence of H. pylori infection between patients with AD and controls (62.0% vs. 59.7%, p = 0.67, crude odds ratio (OR), 1.10). Multiple logistic regression analysis showed that older age and male sex, but not H. pylori status, were significantly associated with AD (p < 0.001, p = 0.01, p = 0.83, respectively). The prevalence of H. pylori infection did not differ between AD patients and controls among Japanese subjects. The high prevalence of H. pylori in controls may contribute to the discrepancy with previous reports.
PMCID: PMC3742106  PMID: 21336779
Alzheimer’s disease; Helicobacter pylori; Urine test
23.  Role of renin-angiotensin system in gastric oncogenesis 
The renin-angiotensin system (RAS) plays an important role not only in homeostasis but also in carcinogenesis. Recent epidemiological studies suggest that hypertensive patients with upregulated systemic RAS functions are at a significantly increased risk for the subsequent development of cancers with poor outcomes, and moreover that RAS inhibitors reduce tumor development, progression, and metastasis. Notably, Helicobacter pylori infection, one of the major predictors of gastric carcinogenesis, generally leads to RAS component overexpression, as exemplified by that of angiotensin I, angiotensin II, angiotensin I converting enzyme and angiotensin II receptor. Gastric mucosal RAS expression gradually increases with time after H. pylori infection with respect to the severity of inflammatory cell infiltration. Gastric carcinogenic potential is therefore considered to relate to RAS component expression levels and activities. This hypothesis is supported by findings that RAS genotypic variation can lead to high component expression levels (e.g. angiotensin I converting enzyme, chymase and angiotensinogen), and thereby increase the risk of development of gastric cancer. Thus, the RAS may be potently associated with the pathogenesis of H. pylori-related gastric carcinogenesis, and RAS inhibitors may provide tools for specifically preventing this disease.
PMCID: PMC3739298  PMID: 22114933
chemoprevention; gastric cancer; Helicobacter pylori; renin-angiotensin system
24.  Antibodies Anti-Caga Cross-React with Trophoblast Cells: A Risk Factor for Pre-Eclampsia? 
Helicobacter  2012;17(6):426-434.
Previous studies reported an epidemiological association between CagA-positive H. pylori strains and pre-eclampsia. As antibodies anti-CagA cross-react with endothelial cells and trophoblast cells show an endothelial phenotypic profile, we hypothesized that anti-CagA antibodies may recognize antigens of cytotrophoblast cells, thus impairing their function.
Materials and Methods
Placenta samples were obtained from healthy women. Cytotrophoblast cells were cultured in a medium containing increasing concentration of polyclonal anti-CagA antibodies. Binding of anti-CagA antibodies to cytotrophoblast cells was evaluated by cell ELISA and immunofluorescence assay. Invasive potential of those cells was assessed by an invasion culture system and by measuring of MMP-2. Protein sequencing was performed on antigens precipitated by anti-CagA antibodies. Measurement of phosphorylated ERK expression and NF-kB DNA-binding activity in trophoblast cells incubated with anti-CagA or irrelevant antibodies was also performed.
Anti-CagA antibodies recognized β-actin of cytotrophoblast cells, showing a dose-dependent binding. Incubation of cytotrophoblast cells with increasing doses of anti-CagA antibodies significantly reduced their invasiveness and determined a significant decrease in phosphorylated ERK expression and a reduced NF-kB translocation activity.
This study shows that anti-CagA antibodies recognize β-actin of cytotrophoblast cells, reducing their invasiveness ability, possibly giving a biological explanation for the epidemiological association.
PMCID: PMC3739447  PMID: 23066738
CagA+; Helicobacter pylori; pregnancy
25.  Inverse association between Helicobacter pylori infection and allergic rhinitis in young Japanese 
Background and Aim
The prevalence of allergic disorders, including asthma, atopic dermatitis, and allergic rhinitis has been increasing, and the prevalence of Helicobacter pylori (H. pylori) infection has been decreasing. Chronic bacterial infection during childhood is reported to protect the development of allergic diseases. The aim of the present study was to identify whether H. pylori infection influences the prevalence of allergic rhinitis, which has become a serious social problem, especially in the developed countries.
We initially investigated the association between the prevalence of H. pylori and pollinosis symptoms in 97 healthy volunteers.We had investigated the association between the serum H. pylori–immunoglobulin (Ig) G antibodies and specific IgE antibodies for pollen, mites, and house dust in 211 consecutive patients.
There were 52.2% (36/69) of H. pylori-negative volunteers with allergic symptoms, which was significantly higher than H. pylori-positive volunteers (14.3%, 4/28, P <0.05). The risk of pollinosis symptoms by H. pylori infection was 0.148 (95% confidence interval): 0.046–0.475, P <0.05). The prevalence of H. pylori infection increased according to age, whereas that of specific IgE-positive patients gradually decreased. Among the IgE-positive patients, the prevalence of H. pylori-negative patients was significantly higher than H. pylori-positive patients who were younger in age (P <0.05).
H. pylori infection decreased the pollinosis effects, especially among the younger volunteers. However, the prevalence of pollinosis in patients who were 50 years or older were almost same between H. pylori-positive and H. pylori-negative patients; therefore, the recent increase of pollinosis might relate to not only H. pylori infection, but also change in social environment.
PMCID: PMC3732487  PMID: 20594251
allergic rhinitis; Helicobacter pylori; pollinosis

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