Tetsuo Arakawa

Cigarette Smoking and Alcohol Consumption Associated with Gastro-Oesophageal Reflux Disease in Japanese Men

Background: Associations between lifestyle factors and gastro-oesophageal reflux disease (GORD) have been conflicting. We aimed to examine these associations in Japanese men. Methods: We performed a cross-sectional study of Japanese male workers who visit a clinic for a routine health check-up and asked them to fill out a self-report questionnaire. Logistic regression was used to calculate odds ratios (OR) with 95% confidence intervals (CI) for GORD, defined as heartburn and/or acid regurgitation at least twice weekly. Results: Of the 4095 eligible subjects, 276 (6.7%) were diagnosed as having GORD. Current smoking was significantly associated with GORD compared with non-smoking (OR r = r 1.35, 95% CI, 1.01-1.82). Moderate drinking (16-37 r mL/day) and heavy drinking ( S 38 r mL/day) were also associated with GORD, while age and body mass index were not. After adjustment for age, daily alcohol consumption and body mass index, an increase in number of pack-years of cigarette smoking was significantly associated with an increased OR of GORD ( P for trend r = r 0.034), and the OR for persons whose number of pack-years of cigarette smoking was more than 20.1 was 1.45 (CI 1.04-2.04) compared with non-smokers. Conclusion: Cigarette smoking and alcohol consumption are associated with an increased odds ratio for GORD in Japanese men.BACKGROUNDnAssociations between lifestyle factors and gastro-oesophageal reflux disease (GORD) have been conflicting. We aimed to examine these associations in Japanese men.nnnMETHODSnWe performed a cross-sectional study of Japanese male workers who visit a clinic for a routine health check-up and asked them to fill out a self-report questionnaire. Logistic regression was used to calculate odds ratios (OR) with 95% confidence intervals (CI) for GORD, defined as heartburn and/or acid regurgitation at least twice weekly.nnnRESULTSnOf the 4095 eligible subjects, 276 (6.7%) were diagnosed as having GORD. Current smoking was significantly associated with CORD compared with non-smoking (OR = 1.35, 95% CI, 1.01-1.82). Moderate drinking (16-37 mL/day) and heavy drinking (> or = 38 mL/day) were also associated with GORD, while age and body mass index were not. After adjustment for age, daily alcohol consumption and body mass index, an increase in number of pack-years of cigarette smoking was significantly associated with an increased OR of GORD (P for trend = 0.034), and the OR for persons whose number of pack-years of cigarette smoking was more than 20.1 was 1.45 (CI 1.04-2.04) compared with non-smokers.nnnCONCLUSIONnCigarette smoking and alcohol consumption are associated with an increased odds ratio for GORD in Japanese men.

Dominant-negative mutant of c-Jun gene transfer: a novel therapeutic strategy for colorectal cancer

Activator protein-1 (AP-1), a transcription factor, is activated through many oncogenic signals. However, its biological role in colorectal cancer has not been fully elucidated. To investigate the role of AP-1 in colorectal cancer, we constructed an adenovirus-expressing TAM67, a dominant-negative mutant of c-Jun lacking the transactivation domain of wild c-Jun (DN-c-Jun), to inhibit endogenous AP-1. AP-1 DNA-binding activity was increased in colon cancer cells (HT-29 cells) by serum stimulation, followed by an increase in both [3H]thymidine incorporation and cell number. Transfection of Ad-DN-c-Jun to HT-29 cells significantly inhibited serum-induced cell proliferation in vitro. As shown by flow cytometric analysis, DN-c-Jun significantly inhibited entrance into S phase after serum stimulation, thereby leading to G1 arrest. In vivo transfection of Ad-DN-c-Jun into xenografted HT-29 cell tumors in nude mice significantly decreased tumor volume on day 21 after treatment. A change was associated with decrease in Ki-67 labeling index. These observations together showed that AP-1 is a critical modulator for proliferation and cell cycle of HT-29 cells. We obtained the first evidence that DN-c-Jun gene transfer exerted a significant antitumor effect on colon cancer both in vitro and in vivo. DN-c-Jun gene transfer may be a new candidate for treatment of colorectal cancer.

Comparison of gastrointestinal symptoms and psychological factors of functional dyspepsia to peptic ulcer or panic disorder patients

Abstract.Symptoms of functional dyspepsia (FD) may look like those of peptic ulcers or panic disorders. But, there is no comparative data between the symptoms of peptic ulcers or panic disorders.Methods:To evaluate general symptoms, we used the previously validated questionnaires: 1. the Gastrointestinal Symptom Rating Scale (GSRS), 2. the Self-Rating Depression Scale (SDS), 3. the State-Trait Anxiety Inventory (STAI), and 4. the Coping Inventory for Stressful Situations (CISS). Ninety-six patients with FD (ulcer-like, dysmotility-like, and nonspecific: 28.1 %, 41.7 %, and 30.2 %) diagnosed according to the Rome II criteria, 24 peptic ulcer patients, 21 panic disorders, and 50 healthy controls were enrolled in this study.Results:Total GSRS score of FD was higher than controls (12.8 ± 1.2 vs. 5.9 ± 0.7), and similar to peptic ulcers. Ratio over than a cut-off SDS score of FD was higher than controls (28 % vs. 11 %), although it was lower than panic disorders (65 %). Ratios over than cut-off scores of state- and trait-anxiety of FD were higher than controls (74 % and 62 % vs. 50 % and 36 %) and tended to be higher than peptic ulcers. Positive ratio of state-anxiety scores of FD was similar to panic disorders. As these scores increased, morbidity rate of FD (FD/FD+control) increased (P for trend <0.01). Among CISS scores, task-oriented coping scores of FD tended to be low compared to controls, but emotion-oriented coping scores of FD and controls were significantly lower than panic disorders.Conclusion:Severity of gastrointestinal symptoms but not anxiety of FD was similar to peptic ulcers. Psychological scales of FD were also similar to panic disorders except for the emotion–oriented coping. These findings suggested that the complicated pathogenesis of FD was similar to but not completely consistent with peptic ulcers or panic disorders.

Increased expression of transforming growth factor-alpha and epidermal growth factor receptors in rat chronic reflux esophagitis

Background and Aim:u2002 Transforming growth factor‐alpha (TGF‐α), which binds to epidermal growth factor receptors (EGF‐R), stimulates esophageal epithelial cell proliferation, enabling rapid repair after mucosal injury. The aim of the present study was to examine epithelial proliferation and dynamics of TGF‐α and EGF‐R gene and protein expression in rat chronic acid reflux esophagitis.

COX-2 is essential for EGF induction of cell proliferation in gastric RGM1 cells.

Growth factors upregulate cyclooxygenase-2 (COX-2) expression and extracellular signal-regulated kinase (ERK) activity, yet little is known regarding the interaction between COX-2 and ERK in terms of mitogenic signal transduction pathways in gastric epithelial cells. Therefore, we examined the role of COX-2 in EGF-induced proliferation of gastric epithelial RGM1 cells. EGF treatment significantly induced ERK activity (peaked at 30 min) and significantly increased COX-2 protein (peaked at 6 hr), production of prostaglandin E2 (PGE2), and cell proliferation. MEK inhibitor (PD98059) decreased ERK activity and cell proliferation induced by EGF. The selective COX-2 inhibitor (NS-398) significantly reduced EGF-induced cell proliferation. Exogenous PGE2 partly reversed the NS-398-induced inhibitory action on cell proliferation, clearly indicating the importance of PGE2 in mitogenic pathway. The induction of COX-2 protein by EGF was completely blocked by preincubation with MEK inhibitor. These results suggest that the ERK–COX-2 pathway is critical for EGF-induced proliferation of gastric epithelial cells.

Roles of cyclooxygenase 2 and microsomal prostaglandin E synthase 1 in rat acid reflux oesophagitis

Background: Although prostaglandin E2 (PGE2), cyclooxygenase 2 (COX-2), and microsomal prostaglandin E synthase 1 (mPGES-1) are known to play a role in various inflammatory events, their roles in the pathogenesis of gastro-oesophageal reflux disease are not known. Aims: We examined the dynamics of COX-1, COX-2, mPGES-1, mPGES-2, cytosolic PGES (cPGES), and PGE2 synthetic activity in rat acid reflux oesophagitis and the effects of COX-2 inhibitors on the severity of oesophagitis. Methods: Acid reflux oesophagitis was induced by ligating the transitional region between the forestomach and the glandular portion and wrapping the duodenum near the pylorus. Rats were killed on day 3 (acute phase) or day 21 (chronic phase) after induction of oesophagitis. Results: Expression of COX-2 and mPGES-1 was markedly increased in oesophagitis while modest changes in COX-1, cPGES, and mPGES-2 expression were observed. COX-2 and mPGES-1 were colocalised in epithelial cells of the basal layer, as well as inflammatory and mesenchymal cells in the lamina propria and submucosa. COX-2 inhibitors significantly reduced the severity of chronic oesophagitis but did not affect acute oesophageal lesions. COX-2 inhibitors significantly inhibited the increase in PGE2 synthesis in oesophageal lesions on both days 3 and 21. Epithelial proliferation was significantly increased in the basal layer on day 21. Inflammatory cells and epithelial cells of the basal layer exhibited reactions for EP4 in oesophagitis. Conclusion: PGE2 derived from COX-2 and mPGES-1 plays a significant role in the pathogenesis of chronic acid reflux oesophagitis, and possibly in basal hyperplasia and persistent inflammatory cell infiltration.

Prevalence of symptomatic gastro-oesophageal reflux disease in Japanese patients with peptic ulcer disease after eradication of Helicobacter pylori infection

Background :u2002The association between cure of Helicobacter pylori infection and the development of gastro‐oesophageal reflux disease is controversial.

Correlation of MAP kinases with COX‐2 induction differs between MKN45 and HT29 cells

Background :u2002Mitogen‐activated protein (MAP) kinases, including extracellular signal‐regulated kinases (ERK),c‐Jun NH2‐terminal kinases (JNK) and p38 MAP kinase (p38 MAPK) are important intermediates of the signal‐transduction pathway from the cell surface to the nucleus. Expression of cyclooxygenase (COX)‐2, associated with proliferation, apoptosis or both of gastrointestinal cancer cells, is mediated through MAP kinase families. However, the correlation between respective MAP kinase signals and COX‐2 in the proliferation of gastric and colon cancer cells has not been well elucidated.

Safety and Efficacy of S-1, a Novel Oral Fluorouracil Antitumor Drug, for a Chronic Renal Failure Patient Maintained on Hemodialysis

Objective: S-1 is a novel oral fluorouracil antitumor drug that combines three pharmacological agents: tegafur (FT), a prodrug of 5-fluorouracil (5-FU); 5-chloro-2,4-dihydroxypyridine (CDHP), an inhibitor of dihydropyrimidine dehydrogenase, and potassium oxonate (Oxo), a reducer of gastrointestinal toxicity. S-1 has safe and potent antitumor effects in patients with gastric cancer via these respective functions. However, the plasma 5-FU concentration is suspected to accumulate in patients with renal dysfunction, because 50% of the CDHP is excreted into the urine. There are no useful data on safety and efficacy of S-1 in chronic renal failure patients maintained on hemodialysis (HD). We examined the influence of HD on the pharmacokinetics (PK) of S-1 and its therapeutic efficacy in liver metastases from gastric cancer. Methods: For the HD patient, the dose of S-1 in a single-administration study was set at 50 mg/body/day (41.7% of the recommended dose of 80 mg/m2/day). S-1 was given to the patient 24 h after HD. Blood samples were obtained before administration and 2, 4, 6, 8, and 24 h thereafter and 1, 2, 4, and 72 h after the following HD session. The PK parameters (5-FU, CDHP, Oxo, and FT) were measured, and Cmax, Tmax, AUC0–24, and T1/2 were calculated. The dose of consecutive or maintained administrations was determined. Results: Both an increase in Cmax and an elongation of T1/2 for 5-FU, CDHP, and Oxo, but not for FT, occurred in this case as compared with controls. The AUC0–24 of 5-FU in this case was similar to that of controls at the standard dose. After HD, 87.8, 54.5, 77.4, and 66.2% of 5-FU, CDHP, Oxo, and FT, respectively, were eliminated. A slight accumulation of CDHP did not alter the 5-FU PK. Consecutive or maintained S-1 oral administration at the same dose showed similar effects on all PK parameters of a single-administration test. Liver metastases almost totally regressed with no adverse events 4 weeks after S-1 treatment (50 mg/body/day three times a week). Conclusion: Adjusted doses of S-1 according to the results of PK studies may provide therapeutic safety and high efficacy in liver metastases from gastric cancer, even in chronic renal failure patients maintained on HD.