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Background: Bacterial meningitis (BM) causes apoptotic damage to the hippocampus and homocysteine (Hcy) accumulation to neurotoxic levels in the cerebrospinal fluid of children. The Hcy pathway controls bioavailability of methyl, and its homeostasis can be modulated by vitamin B 12 , a cofactor of the methionine synthase enzyme. Herein, the neuroprotective potential and the underlying mode of action of vitamin B 12 adjuvant therapy were assessed in an infant rat model of BM., Methods: Eleven-day old rats were intracysternally infected with Streptococcus pneumoniae serotype 3, or saline, treated with B 12 or placebo, and, 24 h after infection, their hippocampi were analyzed for apoptosis in the dentate gyrus, sulfur amino acids content, global DNA methylation, transcription, and proximal promoter methylation of candidate genes. Differences between groups were compared using 2-way ANOVA followed by Bonferroni post hoc test. Correlations were tested with Spearman's test., Results: B 12 attenuated BM-induced hippocampal apoptosis in a Hcy-dependent manner (r = 0.80, P < 0.05). BM caused global DNA hypomethylation; however, B 12 restored this parameter. Accordingly, B 12 increased the methylation capacity of hippocampal cells from infected animals, as inferred from the ratio S-adenosylmethionine (SAM):S-adenosylhomocysteine (SAH) in infected animals. BM upregulated selected pro-inflammatory genes, and this effect was counteracted by B 12 , which also increased methylation of CpGs at the promoter of Ccl3 of infected animals., Conclusion: Hcy is likely to play a central role in hippocampal damage in the infant rat model of BM, and B 12 shows an anti-inflammatory and neuroprotective action through methyl-dependent epigenetic mechanisms.

Background: Although, outer membrane protein OipA of Helicobacter pylori has been associated with gastric mucosal damage and gastroduodenal diseases, studies evaluating gastric cancer patients are scarce. We investigated whether the functional oipA "on" status was associated with gastric cancer in the North-eastern Brazil, region with high prevalence of gastric cancer., Methods: We included samples from 95 H. pylori positive subjects (23 patients with gastritis, 24 with gastric cancer, 32 first-degree relatives of gastric cancer patients and 16 children). oipA was assayed by polymerase chain reaction (PCR) and DNA sequencing. cagA and vacA status were evaluated by PCR., Results: Overall 81.1% of the H. pylori strains had functional oipA. In adults, the oipA "on" status (OR = 9.20; 95%CI = 1.45-58.48, P = 0.02) and increasing age (OR = 1.08; 95%CI = 1.03-1.14; P = 0.003) were independently associated with gastric cancer in a logistic model. The oipA "on" status (OR = 14.75; 95%CI: 2.53-86.13, P = 0.003) was also associated with first-degree relatives of gastric cancer patients when compared with gastritis. The frequency of oipA "on" status did not differ between children and adults (P = 0.87). The oipA "on" status was significantly correlated with the presence of cagA and vacA s1 m1., Conclusion: oipA "on" status was independently associated with gastric cancer and first-degree relatives of gastric cancer patients in North-eastern Brazil.

Background: Because to date there is no available study on STAT3 polymorphism and gastric cancer in Western populations and taking into account that Helicobacter pylori CagA EPIYA-C segment deregulates SHP-2/ERK-JAK/STAT3 pathways, we evaluated whether the two variables are independently associated with gastric cancer., Methods: We included 1048 subjects: H. pylori-positive patients with gastric carcinoma (n = 232) and with gastritis (n = 275) and 541 blood donors. Data were analyzed using logistic regression model., Results: The rs744166 polymorphic G allele (p = 0.01; OR = 1.76; 95 % CI = 1.44-2.70), and CagA-positive (OR = 12.80; 95 % CI = 5.58-19.86) status were independently associated with gastric cancer in comparison with blood donors. The rs744166 polymorphism (p = 0.001; OR = 1.64; 95 % CI = 1.16-2.31) and infection with H. pylori CagA-positive strains possessing higher number of EPIYA-C segments (p = 0.001; OR = 2.28; 95 % CI = 1.41-3.68) were independently associated with gastric cancer in comparison with gastritis. The association was stronger when host and bacterium genotypes were combined (p < 0.001; OR = 3.01; 95 % CI = 2.29-3.98). When stimulated with LPS (lipopolysaccharide) or Pam3Cys, peripheral mononuclear cells of healthy carriers of the rs744166 GG and AG genotypes expressed higher levels of STAT3 mRNA than those carrying AA genotype (p = 0.04 for both). The nuclear expression of phosphorylated p-STAT3 protein was significantly higher in the antral gastric tissue of carriers of rs744166 GG genotype than in carriers of AG and AA genotypes., Conclusions: Our study provides evidence that STAT3 rs744166 G allele and infection with CagA-positive H. pylori with higher number of EPIYA-C segments are independent risk factors for gastric cancer. The odds ratio of having gastric cancer was greater when bacterium and host high risk genotypes were combined.

Background: To evaluate the prevalence of more virulent H. pylori genotypes in relatives of gastric cancer patients and in patients without family histories of gastric cancer., Methods: We evaluated prospectively the prevalence of the infection by more virulent H. pylori strains in 60 relatives of gastric cancer patients comparing the results with those obtained from 49 patients without family histories of gastric cancer. H. pylori status was determined by the urease test, histology and presence of H. pylori ureA. The cytotoxin associated gene (cagA), the cagA-EPIYA and vacuolating cytotoxin gene (vacA) were typed by PCR and the cagA EPIYA typing was confirmed by sequencing., Results: The gastric cancer relatives were significant and independently more frequently colonized by H. pylori strains with higher numbers of CagA-EPIYA-C segments (OR = 4.23, 95%CI = 1.53-11.69) and with the most virulent s1m1 vacA genotype (OR = 2.80, 95%CI = 1.04-7.51). Higher numbers of EPIYA-C segments were associated with increased gastric corpus inflammation, foveolar hyperplasia and atrophy. Infection by s1m1 vacA genotype was associated with increased antral and corpus gastritis., Conclusions: We demonstrated that relatives of gastric cancer patients are more frequently colonized by the most virulent H. pylori cagA and vacA genotypes, which may contribute to increase the risk of gastric cancer.

Background: Helicobacter pylori infection is one of the most common infections worldwide and is associated with gastric cancer and peptic ulcer. Bacterial virulence factors such as CagA have been shown to increase the risk of both diseases. Studies have suggested a causal role for CagA EPIYA polymorphisms in gastric carcinogenesis, and it has been shown to be geographically diverse. We studied associations between H. pylori CagA EPIYA patterns and gastric cancer and duodenal ulcer, in an ethnically admixed Western population from Brazil. CagA EPIYA was determined by PCR and confirmed by sequencing. A total of 436 patients were included, being 188 with gastric cancer, 112 with duodenal ulcer and 136 with gastritis., Results: The number of EPIYA C segments was significantly associated with the increased risk of gastric carcinoma (OR=3.08, 95% CI=1.74 to 5.45, p<10-3) even after adjustment for age and gender. Higher number of EPIYA C segments was also associated with gastric atrophy (p=0.04) and intestinal metaplasia (p=0.007). Furthermore, patients infected by cagA strains possessing more than one EPIYA C segment showed decreased serum levels of pepsinogen I in comparison with those infected by strains containing one or less EPIYA C repeat. Otherwise, the number of EPIYA C segments did not associate with duodenal ulcer., Conclusions: Our results demonstrate that infection with H. pylori strains harbouring more than one CagA EPIYA C motif was clearly associated with gastric cancer, but not with duodenal ulcer.Higher number of EPIYA C segments was also associated with gastric precancerous lesions as demonstrated by histological gastric atrophic and metaplastic changes and decreased serum levels of pepsinogen I., (© 2011 Batista et al; licensee BioMed Central Ltd.)