Functionally significant polymorphisms of the MMP-9 gene are associated with peptic ulcer disease in the Caucasian population of Central Russia.

This study analyzed the association of functionally significant SNPs of matrix metalloproteinase (MMP) genes in the development of peptic ulcer disease (PUD) in Caucasians from Central Russia. Ten SNPs of the MMP-1, MMP-2, MMP-3, MMP-8, and MMP-9 genes were analyzed for association with PUD in a cohort of 798 patients with PUD (including 404 H. pylori-positive and 394 H. pylori-negative) and 347 H. pylori-negative controls using logistic regression and assuming the additive, recessive, and dominant genetic models. The variants of MMP-1, MMP-2, MMP-3, and MMP-8 did not manifest any significant associations with the diseases. Five SNPs of the MMP-9 gene demonstrated such association. Allele G of the rs17576 MMP-9 locus conferred a higher risk for PUD (ORadj = 1.31, pperm = 0.016), haplotype AACG of loci rs17576-rs3787268-rs2250889-rs17577 of the MMP-9 gene decreased risk for PUD (ORadj = 0.17, pperm = 0.003). Also, allele C of rs3918249, allele G of rs17576 and haplotype CG of rs3918249-rs17576 of the MMP-9 gene increased risk for H. pylori-positive PUD (ORadj = 1.82, pperm = 0.002; ORadj = 1.53-1.95 pperm = 0.001-0.013 and ORadj = 1.49 pperm = 0.009 respectively). The above loci and 50 linked to them possess significant regulatory effects and may affect the alternative splicing of four genes and the expression of 17 genes in various organs and tissues related to the PUD pathogenesis.

Histo-blood group carbohydrates as facilitators for infection by Helicobacter pylori.

Helicobacter pylori infect millions of people around the world. It occupies a niche in the human gastrointestinal tract characterized by high expression of a repertoire of carbohydrates. ABO and Lewis histo-blood group systems are controlled by genes coding for functional glycosyltransferases which synthesize great diversity of related fucosylated carbohydrate in different tissues, including gastrointestinal mucosa, and exocrine secretions. The structural diversity of histo-blood group carbohydrates is highly complex and depends on epistatic interactions among gene-encoding glycosyltransferases. The histo-blood group glycosyltransferases act in the glycosylation of proteins and lipids in the human gastrointestinal tract allowing the expression of a variety of potential receptors in which H. pylori can adhere. These oligosaccharide molecules are part of the gastrointestinal repertoire of carbohydrates which act as potential receptors for microorganisms, including H. pylori. This Gram-negative bacillus is one of the main causes of the gastrointestinal diseases such as chronic active gastritis, peptic ulcer, and cancer of stomach. Previous reports showed that some H. pylori strains use carbohydrates as receptors to adhere to the gastric and duodenal mucosa. Since some histo-blood group carbohydrates are highly expressed in one but not in others histo-blood group phenotypes it has pointed out that quantitative differences among them influence the susceptibility to diseases caused by H. pylori. Additionally, some experiments using animal model are helping us to understand how this bacillus explore histo-blood group carbohydrates as potential receptors, offering possibility to explore new strategies of management of infection, disease treatment, and prevention. This text highlights the importance of structural diversity of ABO and Lewis histo-blood group carbohydrates as facilitators for H. pylori infection.

Circadian time structure of circulating plasma lipid peroxides, antioxidant enzymes and other small molecules in peptic ulcers.

BACKGROUND: The circadian rhythm, as part of a broad time structure (chronome) of lipid peroxides and antioxidant defense mechanisms may relate to prevention, efficacy and management of preventive and curative chronotherapy. METHODS: Fifty newly diagnosed patients with peptic ulcers, 30-45 years of age, and 60 age-matched clinically healthy volunteers were synchronized for one week with diurnal activity from about 06:00 to about 22:00 and nocturnal rest. Breakfast was served around 08:30, lunch around 13:30 and dinner around 20:30. Drugs known to affect the free-radical systems were not taken. Blood samples were collected at 6-hour intervals for 24h under standardized, presumably 24-hour synchronized conditions. Plasma lipid peroxides, in the form of malondialdehyde (MDA), blood superoxide dismutase (SOD), glutathione peroxide (GPx), glutathione reductase (GR), catalase (CAT) activities, and serum total protein, albumin, ascorbic acid, total serum cholesterol, and HDL-cholesterol concentrations were determined. RESULTS: By population-mean cosinor analysis, a marked circadian variation was demonstrated for all variables in healthy subjects and in ulcer patients (p<0.001). As compared to controls, patients had a lower MESOR of MDA, SOD, GPx, GR, ascorbic acid, and HDL-C. They also had smaller circadian amplitude of SOD, CAT, GPx, GR, ascorbic acid, T-C, and HDL-C, but larger circadian amplitude of MDA and albumin. As compared to healthy subjects, the circadian acrophase of ulcer patients occurred later for MDA and GR and earlier for GPx. CONCLUSION: Mapping circadian rhythms, important chronome components that include trends with age and extra-circadian components characterizing antioxidants and pro-oxidants, is needed for exploring their putative role as markers in the treatment and management of peptic ulcers.

[THE EFFECTIVENESS OF ERADICATION IN PATIENTS WITH PEPTIC ULCER DISEASE ASSOCIATED WITH HELICOBACTER PYLORI, DEPENDING ON THE GENOTYPE OF THE DRUGMETABOLISM OF PROTON PUMP INHIBITORS].

One of the most likely causes of the lack of effectiveness of eradication therapy of peptic ulcer associated with Helicobacter pylori, is a feature of omeprazole metabolism by cytochrome CYP2C19. The paper work presents evidence that the rate of reduction of the clinical picture and the likelihood of scarring ulcers and eradication rates higher in patients slow metabolizers of omeprazole.

[HIGH FREQUENCY OF CYP2C19 ULTRARAPID METABOLIZERS IN RUSSIAN PATIENTS WITH PEPTIC ULCER].

INTRODUCTION: The main enzyme responsible for metabolism of proton pump inhibitors (PPI) is cytochrome P-4502C19 (CYP2C19). Among all CYP2C19 polymorphisms ulrarapid CYP2C19*17 allele plays an important role in clinical practice as in CYP2C19*17 allele carriers acid suppression achieved with PPI including eradication regimens may be insufficient. THE AIM OF THE STUDY: To find the frequency of CYP2C19 ultrarapid metabolizers in Russian patients with peptic ulcer METHODS: We retrospectively reviewed the results of pharmacogenetic tests of 971 Russian patients with endoscopically and histologically proven ulcers, 428 male (44%) and 543 female (56%). The mean age was 44.6 ± 11.9 years (range 15-88 years). DNA was extracted from EDTA whole blood samples (10 mL). The polymorphisms CYP2C19 *2, *3 *17 were evaluated using real-time polymerase chain reaction (RT-PCR). RESULTS: We found that among 971 peptic ulcer patients ultrarapid metabolizers (CYP2C19*1/*17, CYP2C19*17/*17) were the most frequent genotype--39.75%. Extensive metabolizers with CYP2C19*1/*1 genotype were less frequent--32.65%. Frequency of poor and intermediate metabolizers was found to be 1.5% and 25.85% respectively. We were the first to investigate CYP2C19*17 allele frequency in Russian patients with peptic ulcer which was found to be 27.4%. CONCLUSION: High frequency of CYP2C19 ultrarapid metabolizers in Russian patients with peptic ulcer may be associated with insufficient response to proton pump inhibitors.

Synergistic effect of the combination of gallic acid and famotidine in protection of rat gastric mucosa.

BACKGROUND: Antioxidant supplements with existing drugs may confer better therapeutic efficacy in oxidative stress related diseases. The purpose of the present work was to characterize the interaction and investigate the protective effect of H2 blocker famotidine and gallic acid in combination against experimentally induced peptic ulcer. METHODS: Preventive effect of gallic acid and famotidine in different combinations was investigated against aspirin plus pyloric ligation induced ulcer in rat. Ulcer index, gastric juice volume, pH, other biochemical parameters of gastric juice and antioxidant activity using stomach tissue were estimated. RESULTS: Pretreatment with gallic acid and famotidine in combinations for 7 days, protected the gastric mucosa significantly (p<0.05, 0.01), which was evidenced by decrease in ulcer index, gastric juice volume, free and total acidity, total protein, pepsin and DNA content, and increase in pH, carbohydrates concentration in gastric juice. Combination treatment increases levels of superoxide dismutase, catalase, reduced glutathione, glutathione reductase and glucose-6-phosphate dehydrogenase, and decreases lipid peroxidation, myloperoxidase in stomach tissue. Along with higher dose combination, lower dose combinations like gallic acid (50mg/kg) plus famotidine (10mg/kg) also offered better antiulcer activity than their individual effect. Histopathological studies confirmed their antiulcer activity. CONCLUSION: Combination treatments confer synergistic protective effect against peptic ulcer in rats, which was related to the gastroprotective, antisecratory and antioxidant activity of combination treatment. Results proved that use of gallic acid with existing antiulcer drug will be more useful in the prevention/management of peptic ulcer.

Cryptogenic multifocal ulcerating stenosing enteritis associated with homozygous deletion mutations in cytosolic phospholipase A2-α.

OBJECTIVE: Cryptogenic multifocal ulcerating stenosing enteritis (CMUSE) is an extremely rare, but devastating, disease of unknown aetiology. We investigated the genetic basis of this autosomal recessive condition in a pair of affected siblings who have 40-year histories of catastrophic gastrointestinal and extraintestinal disease. DESIGN: Genome-wide single-nucleotide polymorphism homozygosity mapping in the two affected family members combined with whole-exome sequencing of one affected sibling. This was followed by confirmatory Sanger sequencing of the likely disease-causing sequence variant and functional studies in affected and unaffected family members. RESULTS: Insertion/deletion variation analysis revealed the presence of a homozygous 4 bp deletion (g.155574_77delGTAA) in the PLA2G4A gene, located in the splice donor site directly after exon 17 (the penultimate exon) of the gene in both affected siblings. This introduces a frameshift of 10 amino acids before a premature stop codon (p.V707fsX10), which is predicted to result in the loss of 43 amino acids (residues 707-749) at the C-terminus of cytosolic phospholipase A2-α (cPLA(2)α). cPLA(2)α protein expression was undetectable in the gut of both siblings, with platelet aggregation and thromboxane A(2) production, as functional assays for cPLA(2)α activity, grossly impaired. CONCLUSIONS: We have identified mutations in PLA2G4A as a cause of CMUSE in two affected siblings. Further studies are needed to determine if mutations in this gene are also responsible for disease of a similar phenotype in other cases.

Clinical features of gastroduodenal injury associated with long-term low-dose aspirin therapy.

Low-dose aspirin (LDA) is clinically used for the prevention of cardiovascular and cerebrovascular events with the advent of an aging society. On the other hand, a very low dose of aspirin (10 mg daily) decreases the gastric mucosal prostaglandin levels and causes significant gastric mucosal damage. The incidence of LDA-induced gastrointestinal mucosal injury and bleeding has increased. It has been noticed that the incidence of LDA-induced gastrointestinal hemorrhage has increased more than that of non-aspirin non-steroidal anti-inflammatory drug (NSAID)-induced lesions. The pathogenesis related to inhibition of cyclooxygenase (COX)-1 includes reduced mucosal flow, reduced mucus and bicarbonate secretion, and impaired platelet aggregation. The pathogenesis related to inhibition of COX-2 involves reduced angiogenesis and increased leukocyte adherence. The pathogenic mechanisms related to direct epithelial damage are acid back diffusion and impaired platelet aggregation. The factors associated with an increased risk of upper gastrointestinal (GI) complications in subjects taking LDA are aspirin dose, history of ulcer or upper GI bleeding, age > 70 years, concomitant use of non-aspirin NSAIDs including COX-2-selective NSAIDs, and Helicobacter pylori (H. pylori) infection. Moreover, no significant differences have been found between ulcer and non-ulcer groups in the frequency and severity of symptoms such as nausea, acid regurgitation, heartburn, and bloating. It has been shown that the ratios of ulcers located in the body, fundus and cardia are significantly higher in bleeding patients than the ratio of gastroduodenal ulcers in patients taking LDA. Proton pump inhibitors reduce the risk of developing gastric and duodenal ulcers. In contrast to NSAID-induced gastrointestinal ulcers, a well-tolerated histamine H2-receptor antagonist is reportedly effective in prevention of LDA-induced gastrointestinal ulcers. The eradication of H. pylori is equivalent to treatment with omeprazole in preventing recurrent bleeding. Continuous aspirin therapy for patients with gastrointestinal bleeding may increase the risk of recurrent bleeding but potentially reduces the mortality rates, as stopping aspirin therapy is associated with higher mortality rates. It is very important to prevent LDA-induced gastroduodenal ulcer complications including bleeding, and every effort should be exercised to prevent the bleeding complications.

Antiulcer and antioxidant activities of a new steroid from Morus alba.

AIMS: Morus alba is a plant that is well known for its medicinal properties. In Asian countries, it is traditionally used for anti-inflammatory, hypoglycemic, hypolipidemic and antioxidant applications. The aim of this study was to evaluate the antiulcer and antioxidant activity of a new steroid from M. alba. MAIN METHODS: Column chromatography was employed to isolate different compounds from M. alba. The molecular structures of the compounds were characterized via IR, UV, (1)H NMR, (13)C NMR and mass spectroscopic methods. A newly isolated compound was tested for antiulcer activity in pylorus-ligation- and ethanol-induced ulcer models and biochemically estimated for SOD, CAT, GR, GPx, GSH and LPO levels. KEY FINDINGS: Five new compounds were isolated; one of these was a new steroid named albosteroid. This new compound exhibits significant (P<0.05, P<0.01 and P<0.001) antiulcer activity in pylorus-ligation- and ethanol-induced ulcer models. Furthermore, this compound showed significant dose-dependent reversal of ethanol-diminished activity in antioxidant enzymes, such as SOD, CAT, GPx and GSH, and reduced the ethanol-elevated levels of GR and LPO. SIGNIFICANCE: The present study clearly demonstrates the anti-ulcer and antioxidant potential of compound 1, which was supported by macroscopic and histopathological studies of stomach wall tissues of differently treated groups of rats.

Association between gastric mucosal glutathione-S-transferase activity, glutathione-S-transferase gene polymorphisms and Helicobacter pylori infection in gastric cancer.

AIM: Helicobacter pylori infection, though common, leads to gastric cancer (GC) in less than 1% individuals, suggesting the role of host factors. We previously reported the role of glutathione-S-transferase (GST) polymorphisms, the gene encoding a carcinogen-detoxifying enzyme, in GC. This study was aimed to evaluate GST enzyme activity, GST polymorphism, glutathione (GSH) levels and H. pylori in patients with GC. METHODS: GST and GSH levels were estimated in gastric biopsies of 52 patients with GC, 37 functional dyspepsia (FD) and 39 peptic ulcer (PU), and correlated with H. pylori (ELISA) infection and GST polymorphisms. GST polymorphisms were separately analyzed in relationship to H. pylori in 82 GC, 72 FD, 53 PU and 89 healthy controls (HC). RESULTS: GST activity was lower in patients with GC in comparison to PU (p = 0.03), but GSH levels were comparable. GSTT1 null genotype (GSTT1*0) and simultaneous deletion of both GSTT1 and GSTM1 genes was associated with lower enzyme activity (p = 0.02 and 0.01, respectively). GST and GSH levels in H. pylori positive and negative patients with GC, FD and PU were comparable. Presence of H. pylori infection along with GSTT1*0 (p = 0.006) and GSTM1*0 (p = 0.05) was associated with lower enzyme activity. GSTT1*0 was associated with higher odds ratio (OR) of GC in presence of H. pylori (GC vs. HC: p = 0.02, OR 2.6 [95% CI = 1-6] vs. p = 0.7, 1.3 [0.4-5.0]; GC vs. PU: p = 0.04, OR 3 [95% CI = 1-9] vs. not applicable (OR could not be computed as frequency of GSTT1*0 in H. pylori negative patients with PU was zero)]. CONCLUSIONS: GC is associated with reduced GST activity. Odds ratio of GC associated with GSTT1*0 is enhanced in presence of H. pylori probably due to combined effect of both on enzyme activity.

[Modeling damage of the mucous membrane of the gastrointestinal tract in rats].

We studied the effect of NSAIDs on the stomach lining and intestines. Animals received the selective and nonselective NSAIDs. Revision of the abdominal cavity was performed after 24 hours and 14 days. In the mucosa was determined by the levels of prostaglandins and measured the index of damage. Lowering the synthesis of PG in the mucosa of the gastrointestinal tract contributes to the formation damage. After 24 hours when receiving non-selective COX inhibitors and selective inhibitors of COX-2 revealed the presence of mucous membrane lesions that are smaller than in groups of animals treated with selective NSAIDs. After 14 days of reception remains a low level of GHGs in the group of animals treated with nonselective NSAIDs. Visually mucosal damage are insignificant, but in the submucosal layer preserved microcirculatory blood flow disturbances.

Enteric glia promote intestinal mucosal healing via activation of focal adhesion kinase and release of proEGF.

Wound healing of the gastrointestinal mucosa is essential for the maintenance of gut homeostasis and integrity. Enteric glial cells play a major role in regulating intestinal barrier function, but their role in mucosal barrier repair remains unknown. The impact of conditional ablation of enteric glia on dextran sodium sulfate (DSS)-induced mucosal damage and on healing of diclofenac-induced mucosal ulcerations was evaluated in vivo in GFAP-HSVtk transgenic mice. A mechanically induced model of intestinal wound healing was developed to study glial-induced epithelial restitution. Glial-epithelial signaling mechanisms were analyzed by using pharmacological inhibitors, neutralizing antibodies, and genetically engineered intestinal epithelial cells. Enteric glial cells were shown to be abundant in the gut mucosa, where they associate closely with intestinal epithelial cells as a distinct cell population from myofibroblasts. Conditional ablation of enteric glia worsened mucosal damage after DSS treatment and significantly delayed mucosal wound healing following diclofenac-induced small intestinal enteropathy in transgenic mice. Enteric glial cells enhanced epithelial restitution and cell spreading in vitro. These enhanced repair processes were reproduced by use of glial-conditioned media, and soluble proEGF was identified as a secreted glial mediator leading to consecutive activation of epidermal growth factor receptor and focal adhesion kinase signaling pathways in intestinal epithelial cells. Our study shows that enteric glia represent a functionally important cellular component of the intestinal epithelial barrier microenvironment and that the disruption of this cellular network attenuates the mucosal healing process.

[The role of E2 and F2alpha prostaglandins in development of erosive-ulcerative lesions of the gastroduodenal region].

THE PURPOSE OF THE STUDY: To study role of E2 and F2alpha prostaglandins in development of erosive-ulcerative lesions of gastrointestinal tract. MATERIALS AND METHODS: were examined patients with mucosal erosive-ulcerative and inflammatory lesions of gastrointestinal tract, as well as patients with osteoarthritis who received selective and non selective NSAIDs. Determination of E2 and F2alpha endogenous PG group was investigated with help of immunefuoration method with help of R&D Systems, Inc. Control group was 15 healthy patients. RESULTS: in presented work you can find that there is relationship between degree of reduction of PG level and severity of gastrointestinal mucosal lesion area. The lowest values of PGE2 and PG F2alpha observed in patients with gastric ulcer disease, especially during exacerbation. Patients with low PG synthesis in body increases likelihood of gastropathy as to reception of non-selective COX inhibitors, and at receiving selective COX-2 inhibitors.

[Substituted 1,5,6,7-tetrahydro-4H-benzimidazol-4-ones as inhibitors of urease].

A comparative kinetic study of the inhibition of urea hydrolysis by 9 substituted 1,5,6,7-tetrahydro-4H-benzimidazol-4-ones (BI I-IX) has been carried out. The inhibition had reversibl competitive character; the inhibition constants K(i), varied from 29 up to 754 microM in dependence of the structure of BI I-IX. Three BI I-III, having the K(i) values from 29 to 82 microM, may be used as the potential therapeutic agents for gastroenterology for treatment of stomach and duodenal ulcers.

Molecular mechanisms in therapy of acid-related diseases.

Inhibition of gastric acid secretion is the mainstay of the treatment of gastroesophageal reflux disease and peptic ulceration; therapies to inhibit acid are among the best-selling drugs worldwide. Highly effective agents targeting the histamine H2 receptor were first identified in the 1970s. These were followed by the development of irreversible inhibitors of the parietal cell hydrogen-potassium ATPase (the proton pump inhibitors) that inhibit acid secretion much more effectively. Reviewed here are the chemistry, biological targets and pharmacology of these drugs, with reference to their current and evolving clinical utilities. Future directions in the development of acid inhibitory drugs include modifications of current agents and the emergence of a novel class of agents, the acid pump antagonists.

Association of myeloperoxidase -463 G/A polymorphism with clinical outcome of Helicobacter pylori infection in Iranian patients with gastrointestinal diseases.

BACKGROUND: Polymorphisms in the immune related genes are important in the clinical outcome of Helicobacter pylori infection. Myeloperoxidase -463 G/A polymorphism has been shown to reduce enzyme expression and activity. OBJECTIVE: the aim of the present study is to investigate the association of myeloperoxidase G-463A polymorphism with clinical outcome of Helicobacter pylori infection. METHODS: two hundred and eighty five patients with positive culture of Helicobacter pylori from their gastric biopsies are included in this study. Human leukocyte DNA was extracted using salting out method and myeloperoxidase G-463A polymorphism was investigated by PCR-RFLP. All clinicopathological data were collected from individual records. RESULTS: When the patients were categorized according to the high (GG) and low + intermediate (AG+AA) genotypes of myeloperoxidase producers, there was a significant association between myeloperoxidase G-463A genotypes and clinical outcome of Helicobacter pylori infection (p=0.006). In search for combined effect of cagA status and myeloperoxidase genotypes on clinical presentations, only in cagA- Helicobacter pylori infected patients a significant association between myeloperoxidase genotypes and clinical outcome was found (p=0.0001). Also this association was found only in patients infected with vacA s1m1 genotype (p=0.008). CONCLUSIONS: Our findings suggest that the myeloperoxidase G-463A polymorphism is a host genetic factor which determines the clinical outcome of Helicobacter pylori infection. Moreover, the combination of host and bacterial genetics could provide a better understanding of clinical outcome after infection with Helicobacter pylori.

Association between genetic polymorphisms in the cyclooxygenase-1 gene promoter and peptic ulcers in Japan.

Cyclooxygenase-1 (COX-1) has been regarded as a constitutively expressed enzyme that generates prostaglandins for gastrointestinal integrity. We attempted to clarify the association between potentially functional polymorphisms (T-1676C and A-842G/C50T) in the COX-1 gene promoter and gastroduodenal disorders in a Japanese population. The study was performed with 480 stocked DNAs from subjects (gastric ulcers in 93 subjects and duodenal ulcers in 44) with no evidence of gastric malignancy. We employed the PCR-SSCP method to detect gene polymorphisms. The severity of histological chronic gastritis in antral biopsy specimens was classified according to the updated Sydney system. The T-1676C polymorphism was not associated with either gastric mucosal atrophy or infiltration of inflammatory cells into gastric mucosa. In non-NSAID (non-steroidal anti-inflammatory drug) users, male gender and Helicobacter pylori (HP) infection were significantly associated with both gastric and duodenal ulcers, whereas the -1676T allele carrier was significantly associated with only gastric ulcers (OR, 2.86; 95% CI, 1.29-6.34). In NSAID users, the number of -1676T alleles was significantly associated with developing gastroduodenal ulcers (OR, 5.80; 95% CI, 1.59-21.1), whereas male gender and HP infection were not. The -842T/ C50T polymorphism was not detected in any of the 480 Japanese subjects. In conclusion, a carrier of the -1676T allele in the COX-1 gene promoter, as well as HP infection and male gender, seem to be significant risk factors for developing gastric ulcers, and the number of -1676T alleles was also a significant risk factor for the NSAID-induced ulcer, whereas the frequency of the A-842G polymorphism was thought to be very rare in the Japanese population.

Genetic susceptibility to nonsteroidal anti-inflammatory drug-related gastroduodenal bleeding: role of cytochrome P450 2C9 polymorphisms.

BACKGROUND AND AIMS: Several nonsteroidal anti-inflammatory drugs (NSAIDs) are metabolized by the cytochrome P450 2C9 (CYP2C9). Two common variants of the CYP2C9 gene (CYP2C9*2 and *3) were reported to significantly affect the activity of the CYP2C9 enzyme. The aim of this study was to evaluate the impact of CYP2C9 polymorphisms on the risk of gastroduodenal bleeding in acute NSAID users. METHODS: This case-control study included 26 patients with endoscopically documented NSAID-related gastroduodenal bleeding lesions and 52 age-, sex- and NSAID use-matched controls with no lesions at endoscopy. Both cases and controls were Helicobacter pylori negative and acute users of an NSAID or cycloxygenase-2 inhibitor that undergoes CYP2C9 metabolism (ie, celecoxib, diclofenac, ibuprofen, naproxen, or piroxicam). Two marker single nucleotide polymorphisms in the CYP2C9 gene, identifying the CYP2C9 *2 and *3 allele, were evaluated in all subjects. RESULTS: Setting the CYP2C9*1/*1 wild type as reference, significantly higher frequencies of CYP2C9*1/*3 (34.6% vs 5.8%; P < .001; odds ratio [OR], 12.9; 95% confidence interval [CI], 2.917-57.922) and CYP2C9*1/*2 (26.9% vs 15.4%; P = .036; OR, 3.8; 95% CI, 1.090-13.190) were identified in bleeding versus control patients, whereas no differences between bleeding and controls were observed in the distribution of CYP2C9*2/*3 heterozygotes. Considering allele carriers, the presence of CYP2C9*3 allele was associated with a significant high risk of bleeding (adjusted OR, 7.3; 95% CI, 2.058-26.004). CONCLUSIONS: CYP2C9 genotyping may identify subgroups of persons who potentially are at increased risk of gastroduodenal bleeding when treated with NSAIDs metabolized by CYP2C9. Further studies that evaluate the effectiveness of a strategy using CYP2C9 genotyping in NSAID users are needed before genotyping is introduced into clinical practice.

Clinical significance of telomerase activity in peritoneal lavage fluid from patients with gastric cancer and its relationship with cellular proliferation.

AIM: To evaluate the efficacy of telomerase activity assay and peritoneal lavage cytology (PLC) examination in peritoneal lavage fluid for the prediction of peritoneal metastasis in gastric cancer patients, and to explore the relationship between telomerase activity and proliferating cell nuclear antigen expression. METHODS: Telomeric repeated amplification protocol (TRAP)-enzyme-linked immunosorbent assay (ELISA) was performed to measure the telomerase activity in 60 patients with gastric cancer and 50 with peptic ulcer. PLC analysis of the 60 patients with gastric cancer was used for comparison. The proliferating cell nuclear antigen (PCNA) in gastric carcinoma was immunohistochemically examined. RESULTS: The telomerase activity and PLC positive rate in peritoneal lavage fluid from patients with gastric cancer was 41.7% (25/60), and 25.0% (15/60), respectively. The positive rate of telomerase activity was significantly higher than that of PLC in the group of pT(4) (15/16 vs 9/16, P < 0.05), P(1-3) (13/13 vs 9/13, P < 0.05) and diffuse type (22/42 vs 13/42, P < 0.05). The patients with positive telomerase activity, peritoneal metastasis, and serosal invasion had significantly higher levels of average PCNA proliferation index (PI), (55.00 +/- 6.59 vs 27.43 +/- 7.72, 57.26 +/- 10.18 vs 29.15 +/- 8.31, and 49.82 +/- 6.74 vs 24.65 +/- 7.33, respectively, P < 0.05). CONCLUSION: The TRAP assay for telomerase activity is a useful adjunct for cytologic method in the diagnosis of peritoneal micrometastasis and well related to higher proliferating activity of gastric cancer. The results of this study also suggest a promising future therapeutic strategy for treating peritoneal dissemination based on telomerase inhibition.